case study of patient hm

Henry Gustav Molaison: The Curious Case of Patient H.M. 

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Henry Gustav Molaison, known as Patient H.M., is a landmark case study in psychology. After a surgery to alleviate severe epilepsy, which removed large portions of his hippocampus , he was left with anterograde amnesia , unable to form new explicit memories , thus offering crucial insights into the role of the hippocampus in memory formation.

• Henry Gustav Molaison (often referred to as H.M.) is a famous case of anterograde and retrograde amnesia in psychology.
• H. M. underwent brain surgery to remove his hippocampus and amygdala to control his seizures. As a result of his surgery, H.M.’s seizures decreased, but he could no longer form new memories or remember the prior 11 years of his life.
• He lost his ability to form many types of new memories (anterograde amnesia), such as new facts or faces, and the surgery also caused retrograde amnesia as he was able to recall childhood events but lost the ability to recall experiences a few years before his surgery.
• The case of H.M. and his life-long participation in studies gave researchers valuable insight into how memory functions and is organized in the brain. He is considered one of the most studied medical and psychological history cases.

Who is H.M.?

Henry Gustav Molaison, or “H.M” as he is commonly referred to by psychology and neuroscience textbooks, lost his memory on an operating table in 1953.

For years before his neurosurgery, H.M. suffered from epileptic seizures believed to be caused by a bicycle accident that occurred in his childhood. The seizures started out as minor at age ten, but they developed in severity when H.M. was a teenager.

Continuing to worsen in severity throughout his young adulthood, H.M. was eventually too disabled to work. Throughout this period, treatments continued to turn out unsuccessful, and epilepsy proved a major handicap and strain on H.M.’s quality of life.

And so, at age 27, H.M. agreed to undergo a radical surgery that would involve removing a part of his brain called the hippocampus — the region believed to be the source of his epileptic seizures (Squire, 2009).

For epilepsy patients, brain resection surgery refers to removing small portions of brain tissue responsible for causing seizures. Although resection is still a surgical procedure used today to treat epilepsy, the use of lasers and detailed brain scans help ensure valuable brain regions are not impacted.

In 1953, H.M.’s neurosurgeon did not have these tools, nor was he or the rest of the scientific or medical community fully aware of the true function of the hippocampus and its specific role in memory. In one regard, the surgery was successful, as H.M. did, in fact, experience fewer seizures.

However, family and doctors soon noticed he also suffered from severe amnesia, which persisted well past when he should have recovered. In addition to struggling to remember the years leading up to his surgery, H.M. also had gaps in his memory of the 11 years prior.

Furthermore, he lacked the ability to form new memories — causing him to perpetually live an existence of moment-to-moment forgetfulness for decades to come.

In one famous quote, he famously and somberly described his state as “like waking from a dream…. every day is alone in itself” (Squire et al., 2009).

H.M. soon became a major case study of interest for psychologists and neuroscientists who studied his memory deficits and cognitive abilities to better understand the hippocampus and its function.

When H.M. died on December 2, 2008, at the age of 82, he left behind a lifelong legacy of scientific contribution.

Surgical Procedure

Neurosurgeon William Beecher Scoville performed H.M.’s surgery in Hartford, Connecticut, in August 1953 when H.M. was 27 years old.

During the procedure, Scoville removed parts of H.M.’s temporal lobe which refers to the portion of the brain that sits behind both ears and is associated with auditory and memory processing.

More specifically, the surgery involved what was called a “partial medial temporal lobe resection” (Scoville & Milner, 1957). In this resection, Scoville removed 8 cm of brain tissue from the hippocampus — a seahorse-shaped structure located deep in the temporal lobe .

Bilateral resection of the anterior temporal lobe in patient HM.

Further research conducted after this removal showed Scoville also probably destroyed the brain structures known as the “uncus” (theorized to play a role in the sense of smell and forming new memories) and the “amygdala” (theorized to play a crucial role in controlling our emotional responses such as fear and sadness).

As previously mentioned, the removal surgery partially reduced H.M.’s seizures; however, he also lost the ability to form new memories.

At the time, Scoville’s experimental procedure had previously only been performed on patients with psychosis, so H.M. was the first epileptic patient and showed no sign of mental illness. In the original case study of H.M., which is discussed in further detail below, nine of Scoville’s patients from this experimental surgery were described.

However, because these patients had disorders such as schizophrenia, their symptoms were not removed after surgery.

In this regard, H.M. was the only patient with “clean” amnesia along with no other apparent mental problems.

H.M’s Amnesia

H.M.’s apparent amnesia after waking from surgery presented in multiple forms. For starters, H.M. suffered from retrograde amnesia for the 11-year period prior to his surgery.

Retrograde describes amnesia, where you can’t recall memories that were formed before the event that caused the amnesia. Important to note, current research theorizes that H.M.’s retrograde amnesia was not actually caused by the loss of his hippocampus, but rather from a combination of antiepileptic drugs and frequent seizures prior to his surgery (Shrader 2012).

In contrast, H.M.’s inability to form new memories after his operation, known as anterograde amnesia, was the result of the loss of the hippocampus.

This meant that H.M. could not learn new words, facts, or faces after his surgery, and he would even forget who he was talking to the moment he walked away.

However, H.M. could perform tasks, and he could even perform those tasks easier after practice. This important finding represented a major scientific discovery when it comes to memory and the hippocampus. The memory that H.M. was missing in his life included the recall of facts, life events, and other experiences.

This type of long-term memory is referred to as “explicit” or “ declarative ” memories and they require conscious thinking.

In contrast, H.M.’s ability to improve in tasks after practice (even if he didn’t recall that practice) showed his “implicit” or “ procedural ” memory remained intact (Scoville & Milner, 1957). This type of long-term memory is unconscious, and examples include riding a bike, brushing your teeth, or typing on a keyboard.

Most importantly, after removing his hippocampus, H.M. lost his explicit memory but not his implicit memory — establishing that implicit memory must be controlled by some other area of the brain and not the hippocampus.

After the severity of the side effects of H.M.’s operation became clear, H.M. was referred to neurosurgeon Dr. Wilder Penfield and neuropsychologist Dr. Brenda Milner of Montreal Neurological Institute (MNI) for further testing.

As discussed, H.M. was not the only patient who underwent this experimental surgery, but he was the only non-psychotic patient with such a degree of memory impairment. As a result, he became a major study and interest for Milner and the rest of the scientific community.

Since Penfield and Milner had already been conducting memory experiments on other patients at the time, they quickly realized H.M.’s “dense amnesia, intact intelligence, and precise neurosurgical lesions made him a perfect experimental subject” (Shrader 2012).

Milner continued to conduct cognitive testing on H.M. for the next fifty years, primarily at the Massachusetts Institute of Technology (MIT). Her longitudinal case study of H.M.’s amnesia quickly became a sensation and is still one of the most widely-cited psychology studies.

In publishing her work, she protected Henry’s identity by first referring to him as the patient H.M. (Shrader 2012).

In the famous “star tracing task,” Milner tested if H.M.’s procedural memory was affected by the removal of the hippocampus during surgery.

In this task, H.M. had to trace an outline of a star, but he could only trace the star based on the mirrored reflection. H.M. then repeated this task once a day over a period of multiple days.

Over the course of these multiple days, Milner observed that H.M. performed the test faster and with fewer errors after continued practice. Although each time he performed the task, he had no memory of having participated in the task before, his performance improved immensely (Shrader 2012).

As this task showed, H.M. had lost his declarative/explicit memory, but his unconscious procedural/implicit memory remained intact.

Given the damage to his hippocampus in surgery, researchers concluded from tasks such as these that the hippocampus must play a role in declarative but not procedural memory.

Therefore, procedural memory must be localized somewhere else in the brain and not in the hippocampus.

H.M’s Legacy

Milner’s and hundreds of other researchers’ work with H.M. established fundamental principles about how memory functions and is organized in the brain.

Without the contribution of H.M. in volunteering the study of his mind to science, our knowledge today regarding the separation of memory function in the brain would certainly not be as strong.

Until H.M.’s watershed surgery, it was not known that the hippocampus was essential for making memories and that if we lost this valuable part of our brain, we would be forced to live only in the moment-to-moment constraints of our short-term memory .

Once this was realized, the findings regarding H.M. were widely publicized so that this operation to remove the hippocampus would never be done again (Shrader 2012).

H.M.’s case study represents a historical time period for neuroscience in which most brain research and findings were the result of brain dissections, lesioning certain sections, and seeing how different experimental procedures impacted different patients.

Therefore, it is paramount we recognize the contribution of patients like H.M., who underwent these dangerous operations in the mid-twentieth century and then went on to allow researchers to study them for the rest of their lives.

Even after his death, H.M. donated his brain to science. Researchers then took his unique brain, froze it, and then in a 53-hour procedure, sliced it into 2,401 slices which were then individually photographed and digitized as a three-dimensional map.

Through this map, H.M.’s brain could be preserved for posterity (Wb et al., 2014). As neuroscience researcher Suzanne Corkin once said it best, “H.M. was a pleasant, engaging, docile man with a keen sense of humor, who knew he had a poor memory but accepted his fate.

There was a man behind the data. Henry often told me that he hoped that research into his condition would help others live better lives. He would have been proud to know how much his tragedy has benefitted science and medicine” (Corkin, 2014).

Corkin, S. (2014). Permanent present tense: The man with no memory and what he taught the world. Penguin Books.

Hardt, O., Einarsson, E. Ö., & Nader, K. (2010). A bridge over troubled water: Reconsolidation as a link between cognitive and neuroscientific memory research traditions. Annual Review of Psychology, 61, 141–167.

Scoville, W. B., & Milner, B. (1957). Loss of recent memory after bilateral hippocampal lesions . Journal of neurology, neurosurgery, and psychiatry, 20 (1), 11.

Shrader, J. (2012, January). HM, the man with no memory | Psychology Today. Retrieved from, https://www.psychologytoday.com/us/blog/trouble-in-mind/201201/hm-the-man-no-memory

Squire, L. R. (2009). The legacy of patient H. M. for neuroscience . Neuron, 61 , 6–9.

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Key Study: HM’s case study (Milner and Scoville, 1957)

Travis Dixon January 29, 2019 Biological Psychology , Cognitive Psychology , Key Studies

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HM’s case study is one of the most famous and important case studies in psychology, especially in cognitive psychology. It was the source of groundbreaking new knowledge on the role of the hippocampus in memory. 

Background Info

“Localization of function in the brain” means that different parts of the brain have different functions. Researchers have discovered this from over 100 years of research into the ways the brain works. One such study was Milner’s case study on Henry Molaison.

The memory problems that HM experienced after the removal of his hippocampus provided new knowledge on the role of the hippocampus in memory formation (image: wikicommons)

At the time of the first study by Milner, HM was 29 years old. He was a mechanic who had suffered from minor epileptic seizures from when he was ten years old and began suffering severe seizures as a teenager. These may have been a result of a bike accident when he was nine. His seizures were getting worse in severity, which resulted in HM being unable to work. Treatment for his epilepsy had been unsuccessful, so at the age of 27 HM (and his family) agreed to undergo a radical surgery that would remove a part of his brain called the hippocampus . Previous research suggested that this could help reduce his seizures, but the impact it had on his memory was unexpected. The Doctor performing the radical surgery believed it was justified because of the seriousness of his seizures and the failures of other methods to treat them.

Methods and Results

In one regard, the surgery was successful as it resulted in HM experiencing less seizures. However, immediately after the surgery, the hospital staff and HM’s family noticed that he was suffering from anterograde amnesia (an inability to form new memories after the time of damage to the brain):

Here are some examples of his memory loss described in the case study:

• He could remember something if he concentrated on it, but if he broke his concentration it was lost.
• After the surgery the family moved houses. They stayed on the same street, but a few blocks away. The family noticed that HM as incapable of remembering the new address, but could remember the old one perfectly well. He could also not find his way home alone.
• He could not find objects around the house, even if they never changed locations and he had used them recently. His mother had to always show him where the lawnmower was in the garage.
• He would do the same jigsaw puzzles or read the same magazines every day, without ever apparently getting bored and realising he had read them before. (HM loved to do crossword puzzles and thought they helped him to remember words).
• He once ate lunch in front of Milner but 30 minutes later was unable to say what he had eaten, or remember even eating any lunch at all.
• When interviewed almost two years after the surgery in 1955, HM gave the date as 1953 and said his age was 27. He talked constantly about events from his childhood and could not remember details of his surgery.

Later testing also showed that he had suffered some partial retrograde amnesia (an inability to recall memories from before the time of damage to the brain). For instance, he could not remember that one of his favourite uncles passed away three years prior to his surgery or any of his time spent in hospital for his surgery. He could, however, remember some unimportant events that occurred just before his admission to the hospital.

Brenda Milner studied HM for almost 50 years – but he never remembered her.

Results continued…

His memories from events prior to 1950 (three years before his surgery), however, were fine. There was also no observable difference to his personality or to his intelligence. In fact, he scored 112 points on his IQ after the surgery, compared with 104 previously. The IQ test suggested that his ability in arithmetic had apparently improved. It seemed that the only behaviour that was affected by the removal of the hippocampus was his memory. HM was described as a kind and gentle person and this did not change after his surgery.

The Star Tracing Task

In a follow up study, Milner designed a task that would test whether or not HMs procedural memory had been affected by the surgery. He was to trace an outline of a star, but he could only see the mirrored reflection. He did this once a day over a period of a few days and Milner observed that he became faster and faster. Each time he performed the task he had no memory of ever having done it before, but his performance kept improving. This is further evidence for localization of function – the hippocampus must play a role in declarative (explicit) memory but not procedural (implicit) memory.

Cognitive psychologists have categorized memories into different types. HM’s study suggests that the hippocampus is essential for explicit (conscious) and declarative memory, but not implicit (unconscious) procedural memory.

Was his memory 100% gone? Another follow-up study

Interestingly, HM showed signs of being able to remember famous people who had only become famous after his surgery, like Lee Harvey Oswald (who assassinated JFK in 1963). (Image: wikicommons)

Another fascinating follow-up study was conducted by two researchers who wanted to see if HM had learned anything about celebrities that became famous after his surgery. At first they tested his knowledge of celebrities from before his surgery, and he knew these just as well as controls. They then showed him two names at a time, one a famous name (e.g. Liza Minelli, Lee Harvey Oswald) and the other was a name randomly taken from the phonebook. He was asked to choose the famous name and he was correct on a significant number of trials (i.e. the statistics tests suggest he wasn’t just guessing). Even more incredible was that he remembered some details about these people when asked why they were famous. For example, he could remember that Lee Harvey Oswald assassinated the president. One explanation given for the memory of these facts is that there was an emotional component. E.g. He liked these people, or the assassination was so violent, that he could remember a few details. 

HM became a hugely important case study for neuro and cognitive Psychologists. He was interviewed and tested by over 100 psychologists during the 53 years after his operation. Directly after his surgery, he lived at home with his parents as he was unable to live independently. He moved to a nursing home in 1980 and stayed there until his death in 2008. HM donated his brain to science and it was sliced into 2,401 thin slices that will be scanned and published electronically.

Critical Thinking Considerations

• How does this case study demonstrate localization of function in the brain? (e.g.c reating new long-term memories; procedural memories; storing and retrieving long term memories; intelligence; personality) ( Application )
• What are the ethical considerations involved in this study? ( Analysis )
• What are the strengths and limitations of this case study? ( Evaluation )
• Why would ongoing studies of HM be important? (Think about memory, neuroplasticity and neurogenesis) ( Analysis/Synthesis/Evaluation )
• How can findings from this case study be used to support and/or challenge the Multi-store Model of Memory? ( Application / Synthesis/Evaluation )

Exam Tips This study can be used for the following topics: Localization – the role of the hippocampus in memory Techniques to study the brain – MRI has been used to find out the exact location and size of damage to HM’s brain Bio and cognitive approach research method s – case study Bio and cognitive approach ethical considerations – anonymity Emotion and cognition – the follow-up study on HM and memories of famous people could be used in an essay to support the idea that emotion affects memory Models of memory – the multi-store model : HM’s study provides evidence for the fact that our memories all aren’t formed and stored in one place but travel from store to store (because his transfer from STS to LTS was damaged – if it was all in one store this specific problem would not occur)

Milner, Brenda. Scoville, William Beecher. “Loss of Recent Memory after Bilateral Hippocampal Lesions”. The Journal of Neurology, Neurosurgery and Psychiatry. 1957; 20: 11 21. (Accessed from web.mit.edu )

The man who couldn’t remember”. nova science now. an interview with brenda corkin . 06.01.2009.       .

  Here’s a good video recreation documentary of HM’s case study…

Travis Dixon is an IB Psychology teacher, author, workshop leader, examiner and IA moderator.

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Article Contents

Influential case studies, psychosurgery and asylums, temporal lobectomy, controversy, author notes.

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Remembering H.M.: Review of “PATIENT H.M.: A Story of Memory, Madness, and Family Secrets”

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David W. Loring, Bruce Hermann, Remembering H.M.: Review of “PATIENT H.M.: A Story of Memory, Madness, and Family Secrets”, Archives of Clinical Neuropsychology , Volume 32, Issue 4, June 2017, Pages 501–505, https://doi.org/10.1093/arclin/acx041

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Although many influential case reports in neuropsychology exist ( Code, Wallesch, Joanette, & Lecours, 1996 ), there are certain patients who stand out because, based upon the historical zeitgeist in which their brain injuries occurred and the attention that those cases received, their neurobehavioral deficits and circumstances of their injury greatly altered our knowledge of brain-behavior relationships.

Among the most famous of these cases is Phineas Gage, the railroad foreman whose personality dramatically changed following frontal lobe injury in 1848 from an accidental explosion that thrust his tamping iron through his skull. Gage's survival after such a serious injury was a surprise, but Gage's contribution to clinical neuroscience was his significant personality change, aptly described by his physicians with the pithy observation, “Gage was no longer Gage” ( Macmillan, 2000 ). Although his personality changes were well documented soon after the accident, much of Gage's long-term outcome may have been exaggerated for entertainment value ( Macmillan & Lena, 2010 ). Thus, the lasting neurobehavioral effects of Gage's frontal lobe injury and how the deficits may have evolved over time remain clouded in the historical record due to the absence independent scientific characterization.

The second patient is Louis Victor Leborgne, whose expressive language disturbance from a left frontal lobe lesion was described in 1861 by the famous French neurologist Pierre Paul Broca. Monsieur Tan, as he was informally called because “tan tan” was his typical verbal output, retained his capacity to understand commands. The deficits of Monsieur Tan, supported by subsequent cases, demonstrated that language could be fractionated into different components associated with distinct brain regions, and that language was predominately a function of the left brain. Monsieur Tan's contribution, however, was in no small part due to Broca's distinguished reputation as a physician and scientist since localized language effects had been previously described by Jean-Baptiste Bouillard ( Sondhaus & Finger, 1988 ).

The third and most studied of these three cases is patient Henry Molaison (H.M.). H.M. suffered a dense and persistent anterograde amnesia following bilateral medial temporal lobectomy in 1953 to treat intractable epilepsy ( Scoville & Milner, 1957 ). His scientific fame derives from the dramatic demonstration of the critical role that the mesial temporal lobe structures play in learning and memory. Unlike Gage and Monsieur Tan, H.M.’s brain injury was iatrogenic, being an unanticipated adverse event associated with the surgical treatment of his epilepsy. Another important difference is that H.M.’s surgery injury occurred in what can broadly be considered to be the beginning of the modern era of neuroscience ( Shepherd, 2010 ). Thus, his cognitive abilities were subjected to formal characterization with extensive neuropsychological testing over five decades, providing a much richer characterization of his clinical semiology compared to Gage or Monsieur Tan.

H.M.’s amnesia framed how the neuroscience community would eventually conceptualize basic memory mechanisms, beginning with Brenda Milner's early demonstration that multiple memory systems exist such that declarative and procedural memory are readily dissociable ( Milner, 1965 ). Clinically, H.M.’s amnesia meaningfully influenced pre-operative epilepsy surgery protocols across the world. After several additional cases of post-surgical amnesia developed following unilateral temporal lobectomy, it was hypothesized that the functional reserve of the contralateral temporal lobe was insufficient to support the encoding of new memories following resection of the epileptogenic temporal lobe and mesial structures, and multiple methods for characterizing functional hippocampus status were developed ( Milner, 1975 ). What remains poorly reported in standard textbooks, however, is the historical context in which the decision to undergo epilepsy surgery was made, the blurring between experimental clinical techniques and informed consent, and the profound effects on H.M.’s quality of life.

To provide this broad historical context of H.M., Luke Dittrich has published PATIENT H.M.: A Story of Memory, Madness, and Family Secrets ( Dittrich, 2016a ). This is far from a narrative review of H.M.’s contributions to understanding memory, and it is also not a typical biography. However, as the grandson of William Beecher Scoville, MD, the neurosurgeon who performed H.M.’s operation and a prolific practitioner of psychosurgery, Dittrich provides a unique “insider” perspective and captivating description of that era's medical zeitgeist that could not be easily achieved without such a personal relationship. In fact, much of the book does not directly involve H.M.’s life story, but rather, the management of significant psychiatric disease prior to the development of neuroleptics.

Scoville's neurosurgical practice primarily involved surgery for psychiatric indications rather than epilepsy surgery. The early development of psychosurgery's goals is exemplified with a quote from the 19th century physician Dr. Gottleib Burckhardt, who resected undifferentiated brain areas, that illustrates the depersonalization of patients with psychiatric disease: “Mrs. B. has changed from a dangerous and excited demented person to a quiet demented one” (p. 79). It was in late 1935, after listening to the report of operations on two chimpanzees, that Egas Moniz oversaw the first in his series of approximately 20 frontal leucotomies/lobotomies. This series significantly influenced Walter Freeman (neurologist) and James Watts (neurosurgeon) who initially worked together performing prefrontal lobotomies. The distinct approaches to frontal lobotomy developed by Scoville and Freeman also provide a striking contrast in how to best decrease the institutional burden of psychiatric disease. Although Scoville is described as an adventurer who liked expensive sports cars, he was a meticulous neurosurgeon with painstaking preparation before and during all surgical cases. Freeman's enthusiastic efforts to expand the use of frontal lobotomy was reflected by his technique in which an ice pick, inserted through the orbital sockets to a depth of approximately 3 inches, was moved back and forth for frontal disconnection before repeating the procedure on the opposite side. As practiced by Freeman, frontal lobotomy required approximately 15 min to complete, could be performed without a surgeon or an operating room, and multiple procedures could be easily performed in a single day. “Any reasonably competent psychiatrist (could be trained) to perform the ice-pick lobotomy in an afternoon” (p. 151). One can go elsewhere for the complete story of Freeman, his activities and their aftermath, which has been covered by others including the exquisite text by Elliot Valenstein (1986) .

Dittrich's concerns regarding psychiatric therapies during this era are not limited to psychosurgery. His grandmother, Scoville's wife, experienced a breakdown sometime after their marriage, suffered a brittle psychiatric course, and was institutionalized at the Hartford Institute of Living while her husband was director of neurosurgery there and was performing lobotomies at both the Institute of Living and Hartford Hospital. A variety of harsh non-surgical but unproven psychiatric treatments were used that included: (1) Continuous hydrotherapy in which patients were submerged in a tub with only their heads protruding through a small aperture. (2) Pyrotherapy in which patients were placed in a small copper coffin appearing device that, over a repeated treatment period of days, would elevate core temperatures to 105–106 °C. (3) Electric Shock Therapy. In response to patients’ fears about these therapies, treatment names were changed. “Since these treatments produce states of unconsciousness akin to normal slumber … we are adopting the names that are more truly descriptive of these treatments—INSULIN, METRAZOL, and ELECTRIC SLEEP” (p. 73). Karl Pribram, who was head of research at the Institute of Living at that time, claimed that Scoville had performed a frontal leucotomy on his wife, although Dittrich could not independently substantiate that assertion.

A recurring theme throughout PATIENT HM is the concept embodied by the Hippocratic Oath of “ primum non nocer ” (first, do no harm) as it contrasts with “ melius anceps remedium quam nullum” (it is better to do something than nothing). The tension between these approaches lies at the foundation of modern informed consent in which risks and benefits are carefully weighed as part of the decision-making processes prior to treatment initiation or when deciding to participate in clinical research. Informed consent discussion is not restricted to psychosurgery, shock therapies, or H.M. The rationale for informed consent includes the development of surgical treatment for vesicovaginal fistula by J. Marion Sims during the mid-19th century that was conducted on his slaves prior to application to white women, to the U.S. Public Health Service Tuskegee Syphilis Experiment in the 1930s, and the history of the Doctors Trial at Nuremberg after World War II resulting in the Nuremberg Code.

Scoville was a practitioner of psychosurgery rather than epilepsy surgery, and prior to H.M.’s surgery, Scoville had performed multiple bilateral temporal lobectomies for psychiatric indications. Although he describes H.M.’s surgery as an “experimental operation,” he also states that the procedure was considered due to H.M.’s seizure frequency and severity despite adequate medical therapy, and that surgery was “carried out with the understanding and approval of the patient and his family” ( Scoville & Milner, 1957 ).

By the time of H.M.’s surgery in 1953, the first reported series of temporal lobectomies for epilepsy had been published from the Montreal Neurological Institute (MNI) ( Penfield & Flanigin, 1950 ). Dittrich describes the important contributions of Wilder Penfield in epilepsy surgery development that ranged from identification of motor and sensory homunculi to how Penfield established a multidisciplinary and state of the art institute by including neurology, electrophysiology, and neuropsychology colleagues. It was in this context that Penfield hired Brenda Milner. A brief biography of Milner's early life is presented in which she designed psychological aptitude tests at Cambridge University during World War II before moving to Montreal and enrolling at McGill University as a graduate student of Donald Hebb.

Although H.M.’s surgery was not performed at the MNI, Milner's neuropsychological testing of epilepsy surgery patients at the MNI made her arguably the most appropriate individual to characterize H.M.’s memory impairment. The first formal scientific presentation of H.M.’s amnesia was published in 1957 by Scoville and Milner although his “very grave, recent memory loss” was described in 1953 at a meeting of the Harvey Cushing Society ( Scoville, 1954 ). However, the 1957 report also contains formal testing on additional temporal lobectomies performed on “seriously ill schizophrenic patients who had failed to respond to other forms of treatment” (p. 11), two of whom also developed significant amnesia following bitemporal resection. Orbital undercutting was extended to include the medial temporal lobes in the “hope that still greater psychiatric benefit might be obtained” (p. 11). The significant psychiatric disease of these patients decreased clinical awareness of memory change without Milner's formal testing given that “the psychotic patients were for the most part too disturbed before operation for finer testing of higher mental functions to be carried out” (p. 12). Thus, the extent of the memory impairment was unknown due to the significant overlaying psychiatric disease in the non-epilepsy patients on whom Dr. Scoville had performed bitemporal resection prior to H.M.

Scoville was sufficiently enthusiastic about the procedure to travel to teach other surgeons the technique. Interesting is mention of Scoville's trip to Manteno State Hospital, an extremely large psychiatric facility located south of Chicago in Manteno, Illinois. Here faculty from the University of Illinois were performing anterior temporal lobectomies that included hippocampal resection, something not undertaken by Percival Bailey in his series in Chicago. Dittrich mentions another severely amnestic case (D.C.) as an outcome of Scoville's surgery at Mantero, a physician from Chicago with a premorbid IQ of 122. He was evaluated postoperatively with the resulting amnesia, comparable to H.M., confirmed by Brenda Milner. This case was apparently very unsettling to Scoville.

It is impossible to review PATIENT HM without consideration of outside events that occurred after its publication. The New York Times Magazine published a book excerpt on August 3, 2016, beginning with interviews with H.M. illustrating the magnitude and severity of his memory impairment, briefly discussing post-mortem brain ownership disagreements between the University of California at San Diego and Massachusetts Institute of Technology, presenting background material on the tension between research groups surrounding manuscript preparation describing an previously unknown lesion in H.M.’s frontal lobe that was detected at autopsy, and discussing how H.M.’s court-appointed guardian was identified. The excerpt concludes with interview quotations from Dr. Suzanne Corkin, who was the principal investigator of H.M.’s amnesia since 1977 following the death of Hans-Lukas Teuber. Again, in an interesting personal twist, Corkin lived across the street from the Scovilles, and was one of Dittrich's mother's best friends during their childhood and adolescence.

After The Times’ excerpt appeared, MIT and other organizations quickly issued statements disputing Dittrich's assertions and conclusions ( Eichenbaum & Kensinger, 2016 ; MIT News Office, 2016 ). The main points of contention included: (1) allegation that research records were or would be destroyed or shredded, (2) allegation that the finding of an additional lesion in left orbitofrontal cortex was suppressed, and (3) allegation that there was something inappropriate in the selection of (the conservator) as Mr. Molaison's guardian. In addition, a letter signed by over 200 scientists supporting Corkin dated August 5, 2017 was sent to The Times ( DiCarlo et al., 2016 ) asserting that Dittrich's claims were untrue.

Part of the interest in the quick response by the scientific community presumably was that Corkin died on May 24, 2016 prior to the book's publication and was unable to respond to these concerns. While Dittrich (2016b) has directly addressed each of the MIT concerns, their response has nevertheless led many of our colleagues and students to assume that Dittrich's book was incendiary, and whose entire story should not be believed.

While the interested reader will examine both sides of the argument (see Vyse, 2016 ), there is no evidence to suggest that any of Dittrich's factual allegations are wrong. Thus, there are two important points to consider when deciding if this controversy should make otherwise interested individuals pass on reading the book. First, in response to the assertion that research records were shredded, some have suggested Corkin's use of “shredding” was either colloquial or referred to material no longer considered relevant. Corkin is explicit in her description of data shredding in the audio clip of her interview that Dittrich posted ( Dittrich, 2016b ). Certainly, the presence of many files in a storage room says nothing about whether any files had been shredded, particularly since there has never apparently been a comprehensive catalog of the material established. Non-published information can still inform our understanding of H.M.’s clinical course as demonstrated by Dittrich's observation that H.M. had a significant memory impairment prior to surgery, a fact that had not been formally published. Similarly, non-significant findings or “failed experiments” also demonstrate a broader representation of functions either affected or unchanged following surgery. As Dittrich notes, Corkin was a “meticulous investigator, keeping careful notes” (p. 270), and these notes have both scientific and historical value.

H.M.’s legal guardianship merits greater discussion compared to disagreements about scientific ownership and publication disputes, however, which unfortunately are sufficiently common that university committees exist to address such conflicts. Conservatorship, however, is central to this story because it affects the informed consent for H.M.’s research participation, as well as influencing the final disposition of H.M.’s brain after autopsy. Similar to research study reporting standards, the nature of informed consent has evolved over the course of H.M.’s research participation. Consequently, the absence of any conservator or formal consent process early in H.M.’s research participation reflected generally accepted standards at that time. In 1992, an independent conservator was sought for H.M. to mitigate against unintended conflict of interest by H.M.’s investigators, reflecting greater overall awareness of the importance of informed consent.

The eventual conservator was a son of a former landlady of H.M. Dittrich provides evidence that, in contrast to formal court filings, the conservator was not a relative, and that one of H.M.’s relatives was a first cousin sharing H.M.’s last name (Frank Molaison). We will never fully know how the various points are intertwined or even if H.M.’s relatives had been contacted and were not interested in assuming the role of conservator, and part of this controversy is that Corkin's perspective on Dittrich's claims cannot be obtained. Nevertheless, Dittrich's reporting these issues are neither irrelevant nor inappropriate. Careful consideration of H.M.‘s ability to provide informed consent, and how conservatorship is established in circumstances in which research subjects cannot fully consent, will increase awareness of ambiguities that will allow future researchers to confidently ensure full and appropriate consent is obtained prior to research participation.

Most of the book presents a non-controversial narrative, however, and that was not adequately captured by The Times’ excerpt. What we found to be particularly enjoyable in this book is that it provides new details on the contours of H.M.’s life. Prior to H.M.’s death, there were few personal details known to the scientific community, so it should not be surprising that much of this book's appeal is due to its biographical content reporting a variety of details about H.M.’s past. Upon hearing of H.M.’s death, the initial knowledge of his full name was both exciting but then also associated with some sense of guilt and dismay as if suddenly becoming privy to secret information that had been inadvertently revealed. We enjoyed reading about H.M.’s confusion of The Beatles with The Rolling Stones when examining a photograph, but then accurately spelling B-E-A-T-L-E-S rather than beetles, but there are many others throughout the book such as H.M.’s thick New England accent. When asked “Who, or what, is Sue Corkin,” H.M. replied “She was a … well, a senator.” The book also describes frequent angry outbursts including physical harm to himself, which contrasts with the typical H.M. description of his being agreeable and passive, and it is interesting to speculate whether this behavior might have been related to the orbitofrontal damage identified during autopsy. These pieces of personal information help humanize H.M. rather than simply being either a research subject or clinical syndrome. A particularly poignant comment by H.M. was his statement that “every day is alone in itself. Whatever enjoyment I've had, and whatever sorrow I've had” (p. 375).

Despite the controversies that arose after publication of The Times’ excerpt, or perhaps because of them, this book provides a unique glimpse into the blurring of experimental therapy and research during the mid-20th century, motivations for finding treatments for psychiatrically intractable patients prior to the development of neuroleptics, as well as professional interactions and conflicts that may arise in collaborative research settings. Unlike Gage and Monsieur Tan, the depth of clinical research and the modern era in which he lived not only makes H.M. one of the most influential case studies in clinical neuroscience, but also provides one of the most compelling individual stories about how unanticipated surgical effects robbed H.M. of the capacity to form meaningful and lasting relationships with others due to the inability to form new memories. Though clearly not a textbook, and undeniably chatty at times, this is a volume that neuropsychologists at all levels of training and experience, and particularly those with interests in the history of medicine, will enjoy reading and remembering for a long time.

PATIENT H.M: A Story of Memory, Madness, and Family Secrets received the 2017 The PEN/E. O. Wilson Literary Science Writing Award. We thank Kimford J. Meador for his helpful comments on an earlier draft of this review.

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HM, the Man with No Memory

Henry molaison (hm) taught us about memory by losing his..

Posted January 16, 2012 | Reviewed by Jessica Schrader

Henry Molaison, known by thousands of psychology students as "HM," lost his memory on an operating table in a hospital in Hartford in August 1953. He was 27 years old and had suffered from epileptic seizures for many years.

William Beecher Scoville, a Hartford neurosurgeon , stood above an awake Henry and skilfully suctioned out the seahorse-shaped brain structure called the hippocampus that lay within each temporal lobe. Henry would have been drowsy and probably didn't notice his memory vanishing as the operation proceeded.

The operation was successful in that it significantly reduced Henry's seizures, but it left him with a dense memory loss. When Scoville realized his patient had become amnesic, he referred him to the eminent neurosurgeon Dr. Wilder Penfield and neuropsychologist Dr. Brenda Milner of Montreal Neurological Institute (MNI), who assessed him in detail. Up until then, it had not been known that the hippocampus was essential for making memories, and that if we lose both of them we will suffer a global amnesia. Once this was realized, the findings were widely publicized so that this operation to remove both hippocampi would never be done again.

Penfield and Milner had already been conducting memory experiments on other patients and they quickly realized that Henry's dense amnesia, his intact intelligence , and the precise neurosurgical lesions made him the perfect experimental subject. For 55 years, Henry participated in numerous experiments, primarily at Massachusetts Institute of Technology (MIT), where Professor Suzanne Corkin and her team of neuropsychologists assessed him.

Access to Henry was carefully restricted to less than 100 researchers (I was honored to be one of them), but the MNI and MIT studies on HM taught us much of what we know about memory. Of course, many other patients with memory impairments have since been studied, including a small number with amnesias almost as dense as Henry's, but it is to him we owe the greatest debt. His name (or initials!) has been mentioned in almost 12,000 journal articles, making him the most studied case in medical or psychological history. Henry died on December 2, 2008, at the age of 82. Until then, he was known to the world only as "HM," but on his death his name was revealed. A man with no memory is vulnerable, and his initials had been used while he lived in order to protect his identity .

Henry's memory loss was far from simple. Not only could he make no new conscious memories after his operation, he also suffered a retrograde memory loss (a loss of memories prior to brain damage) for an 11-year period before his surgery. It is not clear why this is so, although it is thought this is not because of his loss of the hippocampi on both sides of his brain. More likely it is a combination of his being on large doses of antiepileptic drugs and his frequent seizures prior to his surgery. His global amnesia for new material was the result of the loss of both hippocampi, and meant that he could not learn new words, songs or faces after his surgery, forgot who he was talking to as soon as he turned away, didn't know how old he was or if his parents were alive or dead, and never again clearly remembered an event, such as his birthday party, or who the current president of the United States was.

In contrast, he did retain the ability to learn some new motor skills, such as becoming faster at drawing a path through a picture of a maze, or learning to use a walking frame when he sprained his ankle, but this learning was at a subconscious level. He had no conscious memory that he had ever seen or done the maze test before, or used the walking frame previously.

We measure time by our memories, and thus for Henry, it was as if time stopped when he was 16 years old, 11 years before his surgery. Because his intelligence in other non-memory areas remained normal, he was an excellent experimental participant. He was also a very happy and friendly person and always a delight to be with and to assess. He never seemed to get tired of doing what most people would think of as tedious memory tests, because they were always new to him! When he was at MIT, between test sessions he would often sit doing crossword puzzles, and he could do the same ones again and again if the words were erased, as to him it was new each time.

Henry gave science the ultimate gift: his memory. Thousands of people who have suffered brain damage, whether through accident, disease or a genetic quirk, have given similar gifts to science by agreeing to participate in psychological, neuropsychological, psychiatric and medical studies and experiments, and in some cases by gifting their brains to science after their deaths. Our knowledge of brain disease and how the normal mind works would be greatly diminished if it were not for the generosity of these people and their families (who are frequently also involved in interviews, as well as transporting the "patient" back and forth to the psychology laboratory). After Henry's death, his brain was dissected into 2,000 slices and digitized as a three-dimensional brain map that could be searched by zooming in from the whole brain to individual neurons. Thus, his tragically unique brain has been preserved for posterity.

Jenni Ogden, Ph.D. , clinical neuropsychologist and author of Trouble in Mind, taught at the University of Auckland.

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• Published: 28 January 2014

Postmortem examination of patient H.M.’s brain based on histological sectioning and digital 3D reconstruction

• Jacopo Annese 1 , 2 ,
• Natalie M. Schenker-Ahmed 1 , 2 ,
• Hauke Bartsch 1 , 2 ,
• Paul Maechler 1 , 2 ,
• Colleen Sheh 1 , 2 ,
• Natasha Thomas 1   na1 ,
• Junya Kayano 1   na1 ,
• Alexander Ghatan 1   na1 ,
• Noah Bresler 1 ,
• Matthew P. Frosch 3 ,
• Ruth Klaming 1 , 2 &
• Suzanne Corkin 4  

Nature Communications volume  5 , Article number:  3122 ( 2014 ) Cite this article

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• Brain imaging

Modern scientific knowledge of how memory functions are organized in the human brain originated from the case of Henry G. Molaison (H.M.), an epileptic patient whose amnesia ensued unexpectedly following a bilateral surgical ablation of medial temporal lobe structures, including the hippocampus. The neuroanatomical extent of the 1953 operation could not be assessed definitively during H.M.’s life. Here we describe the results of a procedure designed to reconstruct a microscopic anatomical model of the whole brain and conduct detailed 3D measurements in the medial temporal lobe region. This approach, combined with cellular-level imaging of stained histological slices, demonstrates a significant amount of residual hippocampal tissue with distinctive cytoarchitecture. Our study also reveals diffuse pathology in the deep white matter and a small, circumscribed lesion in the left orbitofrontal cortex. The findings constitute new evidence that may help elucidate the consequences of H.M.’s operation in the context of the brain’s overall pathology.

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Introduction.

Henry G. Molaison, known in the medical literature as Patient H.M., began experiencing minor epileptic seizures when he was 10 years old and major seizures when he was 15. The underlying aetiology of his seizure disorder remains uncertain; a minor head injury earlier in his childhood may have been a contributing factor. The worsening seizures not only compromised his health but also disrupted his school performance and social life; as a young adult, epilepsy affected his ability to work and function independently. In 1953, because even very high doses of available anticonvulsant medications were ineffective, the 27-year-old underwent a neurosurgical procedure performed by William Beecher Scoville, with the intention of decreasing the impact of his seizures on his quality of life.

Following the surgery, in which portions of the medial temporal lobes (MTL) were resected bilaterally, H.M.’s seizure frequency was reduced, although he remained on anticonvulsant medication. There was, however, an unexpected and profound effect on his behaviour: after recovering from the operation, he was unable to recollect routine events during his hospital stay and did not recognize the staff that attended him assiduously. In spite of this obvious impairment, H.M.’s intellectual abilities and personality appeared to be unaffected 1 . His language and perceptual skills were intact; moreover, based on tests done 10 months after the operation, when the seizures had subsided, his IQ was above average 2 . His attentional and working memory capacities were normal, and he was able to hold items in mind by actively rehearsing them. He could not, however, consolidate and store this information in long-term memory. For example, he was able to carry on a conversation proficiently but several minutes later would be unable to remember having had the exchange or the person with whom he spoke. Further testing gradually revealed some forms of preserved learning and memory. Notably, he demonstrated intact motor skill learning 3 , 4 , classical conditioning 5 , perceptual learning 6 , and visuoperceptual priming 7 , although he was oblivious to the fact that he had repeatedly performed these tasks with the experimenter and had no declarative knowledge of the learning experience 8 , 9 , 10 . H.M. demonstrated this new procedural learning through performance but could not verbalize what he had learned. Researchers concluded that this nondeclarative learning relied on memory circuits separate from those in the MTL region and that it did not require conscious memory processes 10 .

H.M.’s semantic memory for the years preceding the operation was preserved, but he could not retrieve any episodic, autobiographical memories from that time. Instead, he conceptualized his memories of friends and experiences, relating only general knowledge about people and places 6 , 11 , 12 , 13 . Postoperatively, H.M. was profoundly impaired in learning new episodic and semantic information, but gradually over time he acquired a few new facts and snippets of knowledge about celebrities, likely due to repeated exposure to this information 14 , 15 . The defining deficit in H.M.’s case was an inability to form new declarative memories, a syndrome that became indelibly linked to the bilateral resection of the hippocampus and neighbouring MTL structures 16 .

H.M. made his debut into the medical literature as a case described in a seminal publication, which is one of the most cited articles in the medical literature 1 . His case acquired broad significance in the field largely because the neurological substrate of memory was unknown at the time of his operation and H.M. provided the first conclusive evidence for the involvement of the hippocampal complex. Scoville’s intraoperative impressions, however, were the only estimate of the extent of H.M.’s lesions.

Before H.M.’s surgery, Scoville published several illustrations of his surgical technique 16 , 17 ; these sketches showed how metal retractors were inserted through two trephine holes ∼ 1 inch above the orbits to lift the frontal lobes. Postoperative drawings reflected Scoville’s intent to carry out a symmetrical medial resection reaching as far as 8 cm from the midpoints of the tips of the temporal lobes 1 , 18 . This procedure would have removed the uncus, amygdala and the hippocampal complex, including the parahippocampal gyrus (based on the drawings, the ablation affected the anterior calcarine cortex, which contains the representation for the peripheral visual field) 1 . At the time of the operation it was not possible to evaluate postsurgical outcomes with neuroimaging; thus, Scoville’s drawings were only speculative.

The first modern CT scans of H.M.’s brain published in 1984 did not clearly reveal the nature and extent of tissue damage in the temporal lobes 2 ; however, a better view of H.M.’s brain was obtained in 1992 and 1993 using magnetic resonance imaging (MRI) 19 . MRI scans revealed that the lesion was symmetrical as Scoville had planned, but was less extensive than his estimate 19 . It included the medial temporal polar cortex, most of the amygdaloid complex and entorhinal cortex (EC), and about half of the rostro-caudal extent of the intraventricular segment of the hippocampal formation (dentate gyrus, hippocampus and subiculum). Portions of the ventral perirhinal cortex were spared, and the parahippocampal cortex appeared largely intact. The frontal, parietal and occipital cortices had a generally normal appearance, and neocortical atrophy was slight and consistent with H.M.’s age. The authors pointed out that any residual hippocampal tissue had been significantly deafferented by the removal of the EC and was, therefore, unlikely to have preserved function.

A higher-resolution series of MRI scans conducted when H.M. was in his mid-seventies revealed a number of age-related morphological changes: cortical thinning, atrophy of deep grey matter structures and a large volume of abnormal white matter (WM) and deep grey matter 20 . Most of these alterations appeared to be of recent origin, and were attributed to acquired medical conditions, including hypertension. The MRI scans collected in vivo lacked sufficient resolution to reveal the exact anatomical boundaries of the MTL lesions, and to characterize secondary changes.

H.M. died of respiratory failure on 2 December 2008. Direct examination of the brain, combined with postmortem imaging 21 , 22 , represented the opportunity to address the limitations of previous non-invasive MRI studies 19 , 20 and to provide a clear anatomical verification of the lesion and the pathologic state of surrounding areas.

Our goal was to create a detailed three-dimensional (3D) model of the whole brain from high-resolution anatomical images so that we could revisit, by virtual dissection, Scoville’s surgical procedure and localize the anatomical borders of the lesion in the temporal lobe. The data also supported accurate measurements of H.M.’s remaining hippocampus and assessment of the tissue at the microscopic level. Because it was critical to preserve an organized archive of images and histological slices to conduct retrospective studies, we designed the protocols and instrumentation necessary to collect and image a complete series of histological sections through the whole brain. Detailed mapping at the microscopic level and 3D measurements within the digital model of the brain showed that H.M. had retained a significant portion of the hippocampus that appears histologically intact in both hemispheres.

Dissection and tomographic imaging of the brain specimen

The ventral aspect of the brain, after the removal of the leptomeninges, clearly showed the scars of the operation on both hemispheres ( Fig. 1 ). On the surface, the right and left lesions appeared roughly symmetrical in length and in respect to anatomical landmarks; however, the full extent of the injury could only be determined upon dissection. Serial sectioning and direct tomographic imaging was performed in the coronal plane in alignment with the anterior and posterior commissures (AC-PC); these interhemispheric fibre bundles run perpendicular to the major axis of the brain and form the reference points for a widely-used standard radiologic stereotaxic system 23 . AC-PC alignment ensured that histological sections could be compared with previous scans of H.M.’s brain 19 , 20 , those of other patients 24 , 25 , 26 , 27 , and neuroimaging data from population-based studies 28 . Rigorous stereotaxic orientation also guaranteed that any interhemispheric differences in the length of the lesion or in the morphology of the spared hippocampus noted in the histological images reflected actual anatomical asymmetry rather than unconventional planes of section.

The fixed specimen was photographed after removal of the leptomeninges. Evidence of the surgical lesions in the temporal lobes is highlighted by white geometric contours (a, b). A mark produced by the oxidation of one of the surgical clips inserted by Scoville is visible on the parahippocampal gyrus of the right hemisphere (black arrow). (c) encloses a lesion in the orbitofrontal gyrus that affects the cortex and WM. Marked cerebellar atrophy is consistent with H.M.’s long-term treatment with phenytoin. Scale bar, 1 cm.

The results of our examination are based on 2,401 digital anatomical images and selected corresponding histological sections that were collected at an interval of 70 μm over the course of an uninterrupted 53-hour procedure. The series of digital images of the block’s surface was obtained using a digital camera mounted directly above the microtome stage. Volumetric reconstruction from these images was the basis for subsequent visualization and 3D measurements along arbitrary planes. The dissection of the brain was video-recorded and streamed live on the web to permit scientific scrutiny and to foster public engagement in the study 29 .

3D anatomical measurements in the MTL

Using the 3D measurement tools in AMIRA (FEI Visualization Science Group, Burlington, MA, USA) we calculated the distance in each hemisphere from the anterior tip of the temporal lobe to the posterior boundary of the surgical lesion on each side. This limit was marked by the most anterior coronal anatomical images that did not show any sign of disruption in the normal anatomy, which was confirmed in corresponding stained histological slices. The lesion followed a straight, but slightly oblique path relative to the long axis of each hemisphere; measured along this axis, its length was 54.5 mm and 44.0 mm in the left and right hemispheres, respectively. The value for the left hemisphere was consistent with earlier measurements made on H.M.’s MRI scans acquired in 1992–1993 (ref. 19 ) and 2002–2004 (ref. 20 ). The lesion in the right hemisphere as measured in our postmortem data was 7 mm shorter than in the above-mentioned reports that were based on in vivo imaging.

The borders of the surgical resection were clearly demarcated in the anatomical and histological images; the latter clearly showed that the WM underlying the excised medial temporal cortex was also damaged ( Fig. 2 ). We identified a small portion of the superior-most region of the EC in both hemispheres based on its distinctive cytoarchitecture; specifically, 0.03 cm 3 and 0.11 cm 3 for the left and right hemispheres, respectively (these values correspond approximately to 1.7% and 6.5% of the normal volume, based on published MRI estimates 30 ). Portions of the centromedial nucleus of the amygdala were also preserved ( Fig. 2h,i ).

( a , d , g , j ) Cross-sectional anatomy of patient H.M.’s MTL shown at four different levels. The values below the tissue indicate the section number and in parenthesis, the distance from the origin of the standard coordinate system 23 (positive if the level is anterior to the anterior commissure, negative if posterior). Scale bar, 1 cm. ( b , c ), ( e , f ), ( h , i ), ( k , l ): close-up images acquired from thionin-stained tissue slices; these panels illustrate histological detail for the selection boxes in a , d , g , j , respectively. Scale bar, 5 mm. ( m ) Horizontal cross-sectional view reconstructed orthogonally from the original coronal images showing the correct alignment of the anterior and posterior commissures. ( n – q ): normal anatomy and histology of the MTL at the levels shown for the brain of patient H.M. The images were derived from brain slices belonging to a neurologically normal, age-matched individual. Scale bar, 5 mm. PPo, planum polare; MTG, middle temporal gyrus; ITG, inferior temporal gyrus; ITP, inferior temporopolar cortex; PRC, perirhinal cortex; CMA, centromedial amygdala; opt, optic tract; LV, lateral ventricle; PHG, parahippocampal gyrus; Ent, entorhinal cortex; LGN, lateral geniculate nucleus; Hp, hippocampus; FuG, fusiform gyrus; fi, fimbria; SN, substantia nigra; FL, frontal lobe; Cd, caudate; Pu, putamen; I, insula; AC, anterior commissure; Cl, claustrum; TL, temporal lobe; PC, posterior commissure; Ce, cerebellum; OL, occipital lobe; OrG, orbital gyrus; Pir, pirifom cortex; Amg, amygdala. The asterisks delimit the entorhinal cortex.

The extent of the spared hippocampus measured along the horizontal axis of the brain (which in our study coincided with the AC–PC line) was 23.6 mm in the left hemisphere and 24.3 mm in the right. Our measurements included the alveus and the thin band of WM that encapsulates the posterior end of the hippocampus; the fimbria was excluded from our delineations. The discrepancy between these new values and those obtained from earlier MRI data (19 and 22 mm, respectively) is small and can be explained by differences in the quality of the image data 19 . These linear measurements, however, do not fully account for the geometry of H.M.’s spared hippocampus. The high-resolution anatomical volume that we created from microtome images allowed us to inspect the MTL from multiple angles, revealing that the posterior hippocampus was bent steeply in the dorso-medial direction ( Fig. 3 ). This curvature is a normal feature of the periventricular portion of the hippocampus in the human brain, while the most anterior portion, which is immediately posterior to the amygdala and adjacent to the EC, is aligned to the horizontal plane (or major axis) of the hemisphere.

The grey lines intersect at the origin of the origins of the standard coordinate system 23 used for the orientation of the specimen. The blue line indicates the most anterior level of the temporal lobes (the temporal poles, which are damaged are not shown in this image). The orange rectangle represents the bounding box that contains the posterior spared hippocampus (outlined in green), the widest extent of which is at a more medial level than this image shows. The black arrows identify the level at which a surgical clip was positioned on a blood vessel. The red arrows indicate the presence of lesions in the subcortical WM. AC, plane of the anterior commissure; PC, plane of the posterior commissure; AC–PC, ideal plane at the level of both the AC and PC; Ce, cerebellum; LG, lateral geniculate nucleus; Pu, putamen; TP, temporal pole; RH, right hemisphere; LH, left hemisphere. Scale bar, 1 cm.

Measuring the dorso-ventral oblique length of the posterior segment of H.M.’s hippocampus rather than along the AC–PC line produced higher values, specifically, 36.0 mm for the left hemisphere and 40.0 mm for the right. The values were greater when our calculations took curvature into account: in this case, the actual ‘geodesic’ length of the preserved hippocampus amounted to 45.4 mm in the left hemisphere and 47.2 mm in the right ( Fig. 4 ).

The orange bounding box delimits the dimensions of the structure; different segments indicate different measurements; a: anterior-to-posterior extent in the coronal plane, b (dotted): major diagonal axis, c: anatomical length. The compass cube (A: anterior, L: lateral, S: superior) also functions as scale bar: 5 mm. The insert at the bottom right shows a similarly constructed model from the brain of a neurologically normal subject (78-year-old female donor; volume of the right hippocampus=3.04 mm 3 ; total brain weight 1,278). Ce, cerebellum; FuGR, fusiform gyrus of right hemisphere; IT, inferior temporal gyrus; SN, substantia nigra; Amg, amygdala.

The fact that multiple results can be obtained based on different measuring criteria makes it necessary to establish a clear terminology to describe the anatomy of H.M.’s lesion and the remaining hippocampus in relation to previous reports. In the context of this communication, we refer to the extent of H.M.’s hippocampus and related structures as their linear span in the rostro-caudal direction. This measure can be obtained simply by multiplying the number of tomographic images by the interval between them (that is, slice thickness). The anatomical length of the hippocampus is different and depends on its 3D shape and orientation in the brain. With this distinction in mind, our findings can be more easily reconciled with previous reports that were based on low-resolution scans, where only the extent of the hippocampus was actually measured 19 .

The level of sampling and image quality afforded by the current study represents a significant advance over the first clinical MRI that was performed with H.M. 19 . At that time, the two-dimensional (2D) MRI sequences produced 4–5-mm thick slabs with a 1-mm gap between each slice and an in-plane resolution slightly better than 1 mm per voxel; a T1-weighted 3D MRI scan was also acquired and produced non-isotropic voxels (1 × 1 × 3.2 mm). In these early scans, the boundaries of the posterior hippocampus were blurred by partial volume effects (the presence of multiple tissue types or structures in single large MRI voxels).

In a more recent MRI study with H.M., Salat et al. 20 calculated the volume of tissue ascribed to the posterior hippocampus (voxel size: 1 mm × 1 mm × 1.3 mm) and obtained values of 0.65 cm 3 for the left hemisphere and 0.88 cm 3 for the right. We repeated these measurements based on manual delineations made on three orthogonal views of the digital anatomical reconstruction, and determined that 2.02 cm 3 of hippocampal tissue (including the cornu ammonis, the dentate gyrus and the subiculum) was spared in the left hemisphere and 1.96 cm 3 in the right. The comparison should be interpreted with caution in view of the fact that sufficient normative data on hippocampal volume based on our new postmortem methodology is not yet available. The labelled fields representing the posterior hippocampus in each hemisphere were used to compute triangulated surface models for visualization and shape analyses ( Fig. 4 ).

Regularly spaced tissue sections through the brain were selected at an interval of 1.26 mm; these were mounted on large-format glass slides (5 × 7 in) and stained using thionin. Nissl staining with thionin showed preservation of neuronal cell bodies in CA1, CA2, CA3, CA4 and the subiculum of the hippocampal formation, posterior to the surgical lesion ( Fig. 5 ).

( a ) Whole section. Scale bar, 1 cm. ( b , c ) Higher-magnification cross-sectional image of the dentate gyrus of the spared hippocampus. The fimbria is visible below the lateral geniculate nucleus. Scale bar, 1 mm. ( d , e ) × 20 magnification image of neurons in the CA4 region of the hippocampus (in the location of the box). Scale bar, 50 μm. PrG, precentral gyrus; PL, parietal lobe; CG, cingulate gyrus; LV, lateral ventricle; cc, corpus callosum; fx, fornix; Th, thalamus; TL, temporal lobe; LG, lateral geniculate nucleus; RN, red nucleus; SN, substantia nigra; DG, dentate gyrus; fi, fimbria.

Given that H.M. required surgery because of epilepsy and that there was partial response to the surgical intervention, it is of interest that the typical neuropathologic hallmarks associated with idiopathic temporal lobe epilepsy (granule cell dispersion in the dentate gyrus, neuronal loss from the pyramidal cell layer particularly in area CA4) were not present in the residual hippocampus.

Pathologic anatomy beyond the MTL

While the general size and cortical folding of the cerebral hemispheres appeared normal for an individual of H.M.’s age, multiple WM lesions consistent with lacunar infarctions were present. Cerebellar atrophy was also evident, likely a consequence of long-term exposure to Dilantin (phenytoin sodium), which was part of H.M.’s seizure management pre- and postoperatively 31 , 32 .

Review of the MRI scans and histological sections demonstrated a spectrum of additional lesions in the WM ( Fig. 6 ). We also discovered a small focal lesion in the left lateral orbital gyrus, which was visible on the surface ( Fig. 1 c) and involved both cortex and underlying WM ( Fig. 7 ).

( a , b ) Lesions in the deep WM were visible in postmortem T1-weighted MRI images acquired ex situ (scale bar, 1 cm) and were confirmed by myelin silver-impregnation 40 , 46 ( c ) and haematoxylin and eosin (H&E) staining ( d ). Scale bar, 5 mm.

The reconstructed anatomical volume revealed a small lesion in the lateral orbital gyrus of the left frontal lobe. This is the only lesion affecting the gross structure of the cerebral cortex outside of the MTL. ( a ) T1-weighted MRI of the fixed brain acquired ex situ before cryo-sectioning. Scale bar, 1 cm. The same lesion is shown in histological material that was stained for myelinated fibres 40 , 46 ( b ) and neuronal cell bodies ( c ). Scale bar, 1 mm.

The 3D microscopic model of H.M.’s brain contained clues that help understand the surgery performed in 1953. Scoville approached the MTL of both hemispheres through two small trephine holes ( ∼ 3.8 cm in diameter) drilled above the orbits 17 . The ablation of the tip of the temporal lobe, the uncus and the amygdala was made with a scalpel; the sharp edge of the resections is noticeable in the anatomical and histological images ( Fig. 2d–f ). The more posterior MTL tissue was removed by suction; the fact that the periventricular portion of the hippocampus escaped the ablation can be explained by tracing the trajectory of the suction tube. Based on the reconstructed volume, it is clear that Scoville reached beyond and below the posterior hippocampus as indicated by the position of the surgical clip in the sagittal view of each hemisphere ( Fig. 3 ), although the placement of the clips was also contingent on the pattern of the surface vasculature.

We could reliably identify only a very minimal amount of EC in H.M.’s brain based on cytoarchitecture. The EC (via its superficial layers) is the gateway to the hippocampus for the inflow of information from the cerebral cortex and subcortical nuclei. The hippocampus has reciprocal connections to neocortical areas that deliver the original input via the deep layers of the EC and parahippocampal gyrus, creating a loop that supports the consolidation of long-term memories. Our study confirmed that this circuit was severely compromised by the ablation.

The hippocampus and EC also connect directly (that is, monosynaptically) to specific brain regions such as the nucleus accumbens, amygdala, cingulate cortex and orbitofrontal cortex. Input to and from the hippocampus is arranged along its anatomical length (as defined in this communication) according to an anterior-to-posterior functional gradient. For example, the amygdala is connected to anterior sections of the EC and hippocampus, while the visual cortex (largely residing in the occipital, parietal, lateral and ventral temporal lobes) is functionally linked to the posterior hippocampus. This organization is also reflected in the topography of differential gene expression and specific functional activation 33 , 34 , 35 . According to these maps, and based on the gradient of connectivity within the MTL and with other brain structures, the hippocampus appears broadly subdivided into an anterior segment that supports emotion, stress and sensorimotor integration, and a posterior part dedicated to declarative memory and neocortex-supported cognition 36 , 37 . According to this model, the almost complete removal of the EC in both hemispheres, resulting in severe disconnection of the remaining hippocampus, would have made a more significant contribution to H.M.’s declarative memory impairment than the ablation of the anterior hippocampus.

The excision of the anterior hippocampus, together with the bulk of the amygdala, may explain H.M.’s dampened expression of emotions, poor motivation and lack of initiative 19 . The fact that he was impaired in reporting internal states such as pain, hunger and thirst and his apparent lack of initiative was ascribed to the almost complete removal of the amygdala, although it remains difficult to distinguish between direct injury to the amygdala and disruption of connections into and out of this complex structure 6 , 38 . The sparing of the posterior segment of the parahippocampal cortex may validate observations of H.M.’s preserved visual perception, perceptual learning and perceptual priming 6 , 39 . A detailed architectonic survey of occipital, parietal and ventral temporal areas 40 , 41 could provide new clues about the neural circuits H.M. engaged during the performance of numerous perceptual tasks.

Histological staining revealed neuronal integrity in the CA4 field of the remaining hippocampus 42 and a normal compact pattern of the granule cell layer of the dentate gyrus ( Fig. 5 ). These findings raise interesting questions regarding the functional viability of H.M.’s remaining hippocampal tissue because according to established models of hippocampal connectivity, the gap in the MTL created by the surgery would have interrupted crucial connections to and from the posterior hippocampus. Additional quantitative analyses involving unbiased stereological methods can provide information regarding neuronal size and number 43 in this region. Combined with molecular approaches such as antibody staining to assess synaptic density, patterns of gliosis, and the integrity of afferent and efferent fibres, these studies could contribute further insight on the intrinsic and long-range connectivity of the human hippocampus.

The lesion on the left frontal lobe was circumscribed to a small area within the left lateral orbital gyrus ( Fig. 1 c), and it involved the cortical ribbon as well as the underlying WM ( Fig. 7 ). Because of the removal of all leptomeninges as part of the preparation of the brain prior to sectioning, it is not possible to determine the status of the immediate subpial zone in the area of the lesion, which would have assisted in discriminating a mechanical laceration from a vascular injury. As mentioned above, Scoville performed the removal of deep MTL structures while each frontal lobe was retracted to provide access to the deeper temporal structures; thus, judging from the orientation of the ablation with respect to the position of the trephine holes, the scar in the left prefrontal cortex could plausibly have been created at the time of the surgery.

In the course of the initial fixation, when the specimen was suspended upside down, the damaged portion of the temporal lobes collapsed; this geometrical artefact of fixation, combined with the relative shrinkage of the whole specimen during histological processing, should be considered when our resultsare compared with previous MRI scans obtained in vivo . It should be noted, however, that fixation, combined with cryoprotection, produced only an estimated 5–7% reduction in volume of the whole brain and these gross changes did not affect the morphology of the spared hippocampus.

Attempts to provide structure–function correlations based on the postmortem evaluation of H.M.’s MTL require a parallel assessment of age-related neuropathologic processes that developed progressively in his brain. MRI demonstrated extensive WM T2-hyperintensities, which were not related to the surgery; these were confirmed in histological sections ( Fig. 6 ). Although H.M. suffered a minor head injury before age 10, this kind of event does not typically produce long-lasting traumatic injuries that can be subsequently detected radiologically, especially in the absence of clinical signs. Rather, the nature and distribution of observed WM pathology suggest the manifestation of microvascular disease associated with hypertension. Diagnostic neuropathologic evaluation is still required to determine the types and burden of abnormalities and disease processes that occurred independently of the surgery as a result of aging and related to other aetiologies.

The purity and severity of H.M.’s memory impairment, combined with his willingness to participate in testing, made his case study uniquely influential in the field of memory research, as reflected in the broad range of scientific publications built on the studies to which he contributed 19 . During life, H.M. was the best-known and possibly the most studied patient in modern neuroscience; the availability of a large and organized collection of slices and digital anatomical images through the whole brain provides an unprecedented opportunity for collaborative and retrospective studies to continue 22 , 44 . The archive of images will also constitute a permanent digital trace for the case that defined two generations of memory research and that will likely remain as emblematic for neuroscience in the future as it is today.

Ethics statement

The study was reviewed and approved by one of UC San Diego’s Institutional Review Boards in accordance with the requirements of the Code of Federal Regulations for the Protections of Human Subjects. The removal and preservation of H.M.’s brain at autopsy, as well as disclosure of protected health information about him, was authorized by his legally appointed representative.

Preparation of the brain

Shortly after his death, H.M’s body was transported to the Anthinoula A. Martinos Center for Biological Imaging, in Charlestown, MA, where 9 h of in situ scanning was performed 21 . Following this imaging session, an autopsy was conducted; the brain removed, weighed (the total brain weight was 1,300 g) and then fixed in standard buffered formalin (4% formaldehyde; postmortem interval of ∼ 14 h). The brain was fixed for 10 weeks at 4 °C with three changes of fixative during that time; it was suspended upside down, hung by the basilar artery. When the tissue was firm enough, the brain was immersed in fixative laying on a cushion of hydrophilic cotton. Subsequently, multiple series of MRI scans of the fixed specimen were acquired in 3T and 7T scanners 21 .

H.M.’s brain was transported to The Brain Observatory in February 2009, where fixation in formaldehyde continued for 2 more months. After this additional period of fixation, the brain was imaged in a 1.5 T General Electric (GE) Excite MRI scanner using an eight-channel transmit-receive head coil ( Figs 6a,b and 7a ). We used a T1-weighted, 3-D Inversion-Recovery Fast Gradient Echo (IR-FSPRG) sequence (image matrix: 512 × 512; Slice thickness: 1mm; FOV: 256; TE: 15; 18 excitations, or NEX. Duration of the scan: ∼ 7 hours). During the scan the brain was soaked in formaldehyde solution and contained in a watertight Plexigas chamber designed to fit inside the coil above mentioned. Following MRI, the brain was immersed in solutions of increasing concentration of sucrose; specifically, 10, 20 and 30% in 4% formaldehyde solution, phosphate-buffered to pH 7.4. Treatment with sucrose lasted ∼ 10 months: it was meant to minimize the formation of ice crystals and reduced the risk of creating cracks when the brain was frozen.

Following fixation and cryoprotection, the leptomeninges were removed and the brain was embedded in a rectangular cast of 10% gelatin. The whole-brain-gelatin block was chilled to −40 °C by immersion in recirculating isopentane (2-methylbutane) using a custom-built insulated chamber. As the brain froze, the temperature of the solvent was constantly monitored and recorded via a probe connected to a personal computer running a custom programme (Labview, National Instruments Inc. Austin, TX, USA). The brain was thoroughly frozen after ∼ 5 h, when the temperature of the block and that of the surrounding fluid reached a stable equilibrium, based on probe data. The frozen block was firmly attached to the stage of a heavy-duty sliding microtome (Polycut SM 2500; Leica Microsystems Inc., Buffalo Grove, IL) and kept frozen by an assembly of interlocking hollow cuffs that transferred heat through a continuous flow of cold ethanol; the alcohol was recirculated and maintained at −40 °C by a battery of industrial chillers.

A second apparatus was mounted to the microtome to support a digital camera and lighting system directly above the microtome stage; it was designed to acquire high-resolution images of the surface of the block (gelatin and brain) through the entire slicing procedure. These images were the basis for 3D reconstruction and currently serve as a digital catalogue representing the collection of tissue slices.

Image acquisition and volume reconstruction

Tomographic images were acquired using a digital single-lens reflex camera (Nikon D700, Nikon Inc., Melville, NY) bearing a 35-mm lens (AF NIKKOR 35 mm f/2D), which was connected to a PC workstation and controlled remotely. A pair of opposite, light-emitting diode arrays were pointed at the surface of the block at an angle of 45°, providing constant illumination during the cutting procedure. The image acquisition sequence was fully automated; exposure was triggered before each new stroke was initiated. Image files were saved directly on disk in raw (uncompressed) format measuring 4,256 × 2,832 pixels (equivalent to a resolution of 46 μm per pixel). The microtome camera assembly was designed to trigger each exposure every time the microtome stage stopped at a fixed position so that the resulting image stack was registered mechanically. Dedicated team members maintained a log detailing file acquisition and inspected every newly acquired image in real time. Later, we used the quality control report to identify image artifacts in the series so that ad hoc post-processing routines for 3D reconstruction could be applied.

A Canon XLH1A digital HD camcorder (Canon U.S.A., Inc. Lake Success, NY) was used to record the procedure and provide a live feed of a close up of the brain within the microtome assembly on the web. Two additional views, of the microtome console and a wide-angle view of the lab, were provided via Microsoft LifeCam Cinema webcams (Microsoft Inc. Redmond, WA). The video from each of the three views was converted to flash with Adobe Flash Media Live Encoder 3.1 and streamed using Adobe Flash Media Server 3.5 (Adobe Systems Incorporated, San Jose, CA, USA).

Images acquired during the cutting procedure were transferred to a Dell PowerEdge 7500 workstation running a Windows 7, 64-bit operating system with 192 GB of DDR3 dynamic random-access memory (DRAM). The digital 3D volume representing the whole brain was assembled using AMIRA. Scaling factors were derived from the in-plane resolution of the images (converted from pixels to mm) and the slicing interval (that is, section thickness). The resolution of the data set was 46 × 46 × 70μm and occupied ∼ 56 GB on disk. Access to large amounts of DRAM allowed for the efficient manipulation and inspection of the entire anatomical volume. Measurements were conducted on a volume created from images that were down-sampled to 2,550 × 2,550 pixels (voxel dimensions were x : 56.9 μm; y : 56.9 μm and z : 70 μm).

The images were cropped to the edge of the gelatin block and corrected for any changes in brightness produced by fluctuations in ambient lighting that occurred during the 3-day procedure. As the ratio between brain tissue and gelatin matrix varied considerably at different levels of the series of anatomical images, we created a mask for brain tissue only and used it to adjust levels across the series. This process produced a uniform volumetric data set that was consistent in terms of luminosity and contrast in any arbitrary plane. Close inspection of the final 3D reconstruction identified occasional shifts in alignment, most likely due to accidental mechanical shifts in the equipment. Consequently, the position of outlier images was corrected by applying 2D rigid transformations (translation and rotation). The transformation matrix was computed with a local search algorithm that used a least-squares metric to compare intensities between each pair of consecutive images.

3D measurements of the hippocampus

The delineation of hippocampal structures was performed on the 3D reconstruction created from the series of digital images acquired in the course of the slicing procedure. Three main orthogonal planes were visualized concurrently in the segmentation editor of AMIRA to ensure accuracy. In the coronal plane, the hippocampus was identified starting at the posterior-most level of the mammillary bodies and the structure withered at the level of the inferior colliculi. The delineation of the inferior medial border (that is, the border between the subiculum and parahippocampal cortex) was aided by the identification of the perforant pathway in the anatomical images and changes in cytoarchitecture in corresponding Nissl-stained sections. Sagittal views afforded a clear demarcation of the hippocampus’ posterior border ( Fig. 3 ); the alveus was included in the calculation of the volume 45 . The volume of the hippocampus in each hemisphere was calculated as the number of tissue voxels comprised in the delineations multiplied by the individual voxel dimensions in mm.

The anatomical central axis of the hippocampus was defined as a 3D curve fit with a given stiffness along a path through the field of labelled voxels. We calculated a straight-line path using principal component analysis of a binary segmentation of the region of interest. The 3D line was sampled at uniform intervals (10 voxels) to define control points. The first and last control points of the line were set to the 3D locations defined by the furthermost extent of the object along the line. To improve the location of the control points, we sectioned the object at positions halfway between each pair of control points, using a plane that was orthogonal to the curve’s tangent direction at that location, and yielding one section for each control point. For each section of the binary object, we calculated its centre of mass and moved the corresponding control point towards that location. After the adjustments of all control points, a curve-smoothing operation was executed that used the predefined stiffness constraint on the curve. The extent of smoothing controlled the stiffness attached to the curve. The sectioning, adjustment and smoothing steps were repeated until convergence was achieved. This expectation–maximization approach iteratively adjusted the location of the curve’s control points towards a solution that intersected the object uniformly and had a given stiffness. The resulting 3D curve defined the ‘geodesic’ axis of the region of interest, and it was the basis for the actual anatomical length measurement.

Authors contributions

J.A. designed the neuroanatomical study and major instrumentation. M.P.F. conducted the brain extraction at autopsy assisted by J.A. Serial sectioning and tomographic imaging of the brain specimen was performed by J.A. with the assistance of N.M.S., P.M., N.T., J.K., A.G. and N.B., H.B., N.M.S., P.M. and J.A. developed the 3D model of the brain from cross-sectional image data acquired during the dissection. H.B. developed the 3D measurement and image registration tools. J.A., P.M. and C.S produced the stained histological slides. J.A. wrote the manuscript with significant editing contributions by S.C. and M.P.F. Photographs and figures were created by J.A. and C.S. Additional background research was conducted by R.K.

Additional information

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Acknowledgements

The work was supported by grants from the National Science Foundation (NSF—SGER 0714660, J.A., Principal Investigator), the Dana Foundation (Brain and Immuno-Imaging Award, 2007-4234, J.A., Principal Investigator) and by private contributions from viewers of the web broadcast of the dissection. In the course of the study, Dr. Annese was in part supported by two research grants from the National Eye Institute, R01 EY018359–02 and ARRA R01 EY018359–02S1 (J.A., Principal Investigator) and the National Institute of Mental Health, R01MH084756 (J.A., Principal Investigator). The authors would like to thank Herbert and Sharon Lurie, M.S., for their generous contribution towards publishing the article on an open access basis. We would like to dedicate the project and this publication to H.M. He transformed his difficult experience into a lifelong contribution to scientific research on the mechanisms supporting human memory. This study also honours all the researchers who conducted studies with H.M. when he was alive, and Brenda Milner, in particular, who first demonstrated the importance of his case. The authors would like to acknowledge the critical contribution of David Malmberg in the development of the instrumentation and thank Dr. Elizabeth Murphy for editorial assistance.

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Natasha Thomas, Junya Kayano and Alexander Ghatan: These authors contributed equally to this work

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The Brain Observatory, San Diego, 92101, California, USA

Jacopo Annese, Natalie M. Schenker-Ahmed, Hauke Bartsch, Paul Maechler, Colleen Sheh, Natasha Thomas, Junya Kayano, Alexander Ghatan, Noah Bresler & Ruth Klaming

Department of Radiology, University of California San Diego, San Diego, 92093, California, USA

Jacopo Annese, Natalie M. Schenker-Ahmed, Hauke Bartsch, Paul Maechler, Colleen Sheh & Ruth Klaming

C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital and Harvard Medical School, 02114, Massachusetts, USA

Matthew P. Frosch

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Suzanne Corkin

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Annese, J., Schenker-Ahmed, N., Bartsch, H. et al. Postmortem examination of patient H.M.’s brain based on histological sectioning and digital 3D reconstruction. Nat Commun 5 , 3122 (2014). https://doi.org/10.1038/ncomms4122

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Research News

H.m.'s brain and the history of memory.

Brian Newhouse

In 1953, radical brain surgery was used on a patient with severe epilepsy. The operation on "H.M." worked, but left him with almost no long-term memory. H.M. is now in his 80s. His case has helped scientists understand much more about the brain.

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• The Brain Facts Book

Patient Zero: What We Learned from H.M.

• Published 16 May 2013
• Author Dwayne Godwin
• Source BrainFacts/SfN

Memory is our most prized human treasure. It defines our sense of self, and our ability to navigate the world. It defines our relationships with others – for good or ill – and is so important to survival that our gilled ancestors bear the secret of memory etched in their DNA. If you asked someone over 50 to name the things they most fear about getting older, losing one’s memory would be near the top of that list. There is so much worry over Alzheimer’s disease, the memory thief, that it is easy to forget that our modern understanding of memory is still quite young, less than one, very special lifespan.

Meet the Patient Zero of memory disorders, H.M.

H.M. was the pseudonym of Henry Molaison, a man who was destined to change the way we think about the brain. Permanent Present Tense: The Unforgettable Life of the Amnesic Patient H.M. is a touching, comprehensive view of his life through the eyes of a researcher who also, in a sense, became part of his family.

The prologue opens with a conversation between the author, Suzanne Corkin, and Molaison in 1992. It reads a bit like a first meeting of two strangers, but then Corkin reveals a jarring truth: this meeting was one of many similar encounters they’d had over 30 years.

By now, if you’re interested in learning and memory you probably know the basics of Henry Molaison’s story. He had epilepsy from an early age that was thought to be acquired through head trauma from a bike accident (though apparently family members also had epilepsy). His surgeon, William B. Scoville (who in a remarkable twist, was a childhood neighbor of Suzanne Corkin) removed Henry’s hippocampus and amygdala in both hemispheres of his brain, in an attempt to control his seizures.

The results of the surgery are legendary. While Henry’s seizures were controlled, he suffered a type of profound anterograde amnesia that prevented him from encoding new memories, but spared certain details of his life leading up to the surgery. Henry would have no memory of those he worked with from day to day, or of new information he might encounter. The book’s title, “Permanent Present Tense”, describes his zen-like existence within the thirty or so seconds around the present moment, which was the limit of Henry’s short term memory.

If this book were a movie or video game, it would be said to be full of “Easter eggs”. There are vignettes and bits of unexpected information that add rich historical context to the state of knowledge in Molaison’s time. These include a digression on the history of neurosurgery, including the gruesome history of lobotomies and the advances brought to the field of neurosurgery by Wilder Penfield. In many ways, H.M.’s legend is a product of a unique scientific lineage – Scoville owed much to Penfield, who in turn trained under Charles Sherrington (he who gave “synapse” to the neuroscience lexicon), and Brenda Milner, who trained under Donald Hebb (who spawned our current notion of activity-dependent plasticity, embodied by the phrase, “cells that fire together wire together”).

The book also reminds us that H.M. was not the first amnesic patient produced through neurosurgical interventions to treat intractable epilepsy, but he was by far the most studied. The book conveys a sense of wonder at the accomplishments of scientists and physicians, charting terra incognita with scalpels, electrical probes and psychological test batteries.

Corkin recounts Henry Molaison’s early life, including key events - like a childhood plane ride that Henry remembered after his surgery - with gentle but thorough prose. Some of these details come from personal conversations with Henry, while others are the result of careful reporting and research.

The book is an accessible master class in learning and memory, with details and key milestones culled from Corkin’s decades of experience as a memory researcher. The details are not so burdensome as to be esoteric, nor so simple as to be trivial. The book gives only a brief overview of the growing field of knowledge about the cellular mechanisms supporting learning and memory (which might be lost on a casual reader), but this is wisely offset by the details of functional anatomy gleaned from Henry and other patients, and a solid explanation of how we encode, store and retrieve memories.

A light, scholarly tone is maintained throughout the book, but it occasionally brushes up against the deeply personal. It’s difficult to hear Henry’s story and not wonder (or actually, worry) about how it was to live as Henry lived, trapped in the moment. Corkin is reassuring on this point:

“When we consider how much of the anxiety and pain of daily life stems from attending to our long-term memories and worrying about and planning for the future, we can appreciate why Henry lived much of his life with little stress…in the simplicity of a world bounded by thirty seconds.”[p. 75].

In other words, the very thing that might cause Henry to fret about his condition was missing. Henry’s tragedy, it seems, is in the mind of the beholder. Another interesting passage concerns Henry’s moods – which were usually happy and content, but could occasionally be sad or uneasy. This is interesting given the removal during his surgery of a major part of his emotional processing circuitry of the brain, called the amygdala.

Henry Molaison’s anterograde amnesia was practically absolute. However, something not often noted is that he would occasionally surprise those studying him by recalling something he should not be able to remember - for example, colored pictures, or details of celebrities he had heard about after his surgery. Corkin reasons that a bit of spared medial temporal lobe may explain these moments.

Henry was amnesic, but he was not without memory. Through careful behavioral testing, various types of memory function could be uncovered, including recognition memory for having seen images that could persist for months. Corkin suggests that this “memory for the familiar” may have been of some comfort as he navigated what would have otherwise been a confusing experience of reality. New technologies like computers, for example, could be incorporated into his view of the world and did not appear to be jarring to him as would be expected if his capacity for recognizing the familiar did not exist.

Another key discovery from Henry was the finding that he had retained the ability to form non-declarative memories, which took the form of improvement in motor skills. This separate memory system depended on regions of the basal ganglia and motor cortex, which were spared in Henry’s surgery. Testing could improve his performance in the motor task, but his impaired declarative memory system didn’t allow him to remember taking the tests – he could be surprised by his own improvement. Along with his simple recognition memory, motor memory helped smooth challenges Henry faced as he aged, such as learning to use a walker.

Other forms of memory in which Henry showed improvement were in picture completion, where he was able to identify a picture from fragments over a series of sessions, and priming, where previously presented words could prime recognition on presenting fragments of the words. And while Henry is best known for anterograde amnesia, and is sometimes portrayed as having intact memories of things and events before the surgery, he also possessed a partial retrograde amnesia, especially for autobiographical events that happened two years before the surgery - he had only fragmented memories from before that two year window.

Did Henry Molaison have a sense of self? While his was not a fully integrated personality, he possessed “beliefs, desires and values” and seemed capable of a full set of emotions – even without his amygdalae. His view of his own appearance did not seem to cause him distress, even though his estimate of his own age could vary widely. His impairment prevented him from formulating future plans. His basic decency shines through the narrative.

Henry died in 2008 at the age of 82. His brain was scanned postmortem, and extracted for further anatomical analysis . Coming full circle from one of his remaining childhood memories of his first ride, Corkin describes her last wistful goodbye to Henry’s brain as it was conveyed by his final plane ride back to the west coast, where his brain was sliced up into thin sections for new studies. Perhaps the most documented and studied research subject in neuroscience continues to provide vast amounts of data to further our knowledge.

Henry once remarked about his testing, of which he never seemed to become bored since he carried little from one session to the next: “It’s a funny thing – you just live and learn.” He then went on to provide a poignant turn in the familiar phrase: “I’m living, and you’re learning.”

Though he’s no longer living, we’re still learning from Henry.

Permanent Present Tense is a rare look at an amazing mind, whose study formed the basis of our modern science of memory.

Corkin, Suzanne. Permanent Present Tense: The Unforgettable Life of the Amnesic Patient, H.M. (Basic Books) May 14, 2013 | ISBN-10: 0465031595 | ISBN-13: 978-0465031597

Update 6/7/2013: NPR interview with Suzanne Corkin on H.M .

Update 1/30/2014: Report on anatomical and histological findings from Henry Molaison: Postmortem examination of patient H.M.’s brain based on histological sectioning and digital 3D reconstruction . J Annese, NM Schenker-Ahmed, H Bartsch, P Maechler, C Sheh, N Thomas, J Kayano, A Ghatan, N Bresler, MP Frosch, R Klaming & S Corkin. Nature Communications 5, Article number: 3122

Update 7/6/2016: Statement on informed consent transmitted to me by Suzanne Corkin

About the Author

Dwayne Godwin

Dwayne Godwin is a Professor of Neurobiology and Neurology at the Wake Forest University School of Medicine, where he studies epilepsy, sensory processing, withdrawal and PTSD. He coauthors a comic strip on brain topics for Scientific American Mind .

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A Book Examines the Curious Case of a Man Whose Memory Was Removed

By Seth Mnookin

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PATIENT H.M. A Story of Memory, Madness, and Family Secrets By Luke Dittrich 440 pp. Random House. $28.

On Aug. 25, 1953, a Connecticut neurosurgeon named William Beecher Scoville drilled two silver-dollar-size holes into the skull of Henry Molaison, a 27-year-old man with epilepsy so severe he had been prohibited from walking across stage to receive his high school diploma. Scoville then used a suction catheter to slurp up Molaison’s medial temporal lobes, the portion of the brain that contains both the hippocampus and the amygdala. The surgeon had no idea if the procedure would work, but Molaison was desperate for help: His seizures had become so frequent that it wasn’t clear if he would be able to hold down a job.

As it happened, Scoville’s operation did lessen Molaison’s seizures. Unfortunately, it also left him with anterograde amnesia: From that day forth, Molaison was unable to form new memories. Over the course of the next half-century, Patient H.M., as Molaison was referred to in the scientific literature, was the subject of hundreds of studies that collectively revolutionized our understanding of how memory, and the human brain, works. Before H.M., scientists thought that memories originated and resided in the brain as a whole rather than in any one discrete area. H.M. proved that to be false. Before H.M., all memories were thought of in more or less the same way. H.M.’s ability to perform dexterous tasks with increasing proficiency, despite having no recollection of having performed the tasks before, showed that learning new facts and learning to do new things happened in different places in the brain. It’s no exaggeration to say that Molaison is one of the most important patients in the history of neurology; it’s likely he was also the most studied experimental subject of all time.

The broad strokes of this story are well known. In 2008, when Molaison died and his name was finally revealed to the public, it was front-page news. Several well-received books have already been written about Molaison, including one published in 2013 by Suzanne Corkin, the M.I.T. neuroscientist who controlled all access to and oversaw all research on ­Molaison for the last 31 years of his life.

What else, you might wonder, is there to say? According to the National Magazine Award-winning journalist Luke Dittrich, plenty. Dittrich arrived at Molaison’s story with a distinctly personal perspective — he is Scoville’s grandson, and his mother was Corkin’s best friend growing up — and his work reveals a sordid saga that differs markedly from the relatively anodyne one that has become accepted wisdom. “Patient H.M.,” the overstuffed result of Dittrich’s six years of reporting, tries to be many things at once: a lyrical meditation on the nature of memory, an excavation of a disturbing and dark family history, and a damning illustration of the consequences of sacrificing ethics in the name of scientific inquiry. The end result is both spellbinding and frustrating, a paradox of a book that is simultaneously conscientious and careless, engrossing and digressive, troubling and troublesome.

This push-pull is present from the opening section, where Dittrich most obviously (and distractingly) tries to mimic in his narrative the “endless little leaps of time travel during our daily lives” caused by memory. One chapter, which starts and ends atop the George Washington Bridge in 1930 and makes a pit stop at the pyramids in Egypt, includes digressions on the start of Dittrich’s career, his love of ­Lawrence Durrell’s “Alexandria Quartet” and the record for highest high dive.

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Scoville and Milner (1957)

Last updated 22 Mar 2021

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Effect of hippocampal damage on memory.

Background information: Scoville performed experimental surgery on H.M.’s brain to stop the severe epileptic seizures he had been suffering since a fall off his bicycle many years previously. Specifically, he removed parts of HM's temporal lobes (part of his hippocampus along with it). The seizures reduced drastically but H.M. suffered from amnesia for the rest of his life. Milner, who was a PhD student of Scoville’s, followed up the surgery with cognitive testing for fifty years after the original operation. Hers is a cognitive longitudinal case study of H.M.’s anterograde (after the surgery) and partial retrograde (before the surgery) amnesia. The biological part of the H.M. study is the correlation between the brain damage and the amnesia, which was assumed in the 1950s, and not verified until later brain scans in the 1990s (see Corkin, 1997)

Aim: In 1953 Scoville performed surgery on the then 27-year-old H.M. to cure him of his epileptic seizures. [Note: this is a surgical procedure – it only became a study later when the memory damage was noted].

Method: The surgery involved what was called a partial medial temporal lobe resection. Scoville removed 8 cm of brain tissue from the anterior two thirds of the hippocampus, and believed he “probably destroyed …. the uncus and amygdala” as well (Scoville and Milner, 1957). Once the extent of the memory loss was realised, Scoville and Milner wrote about this, along with the results from this type of surgery on nine other patients, in a prominent neurosurgical journal, and Milner started her cognitive studying of H.M.

Results: H.M. lost the ability to form new memories. This is called anterograde amnesia. He could do a task, and even comment that it seemed easier than he expected, without realising that he had done it hundreds of times before. His anterograde procedural memory was totally affected. He also lost his memory for events that had happened after his surgery: he could not remember moving house, nor that he had eaten a meal thirty minutes previously. He had also suffered some retrograde amnesia of events preceding the surgery, such as the death of his uncle three years before. However, his early childhood memories remained intact. His intelligence also remained as before, at slightly above average.

Conclusion: The surgery to remove part of the hippocampus, the uncus and the amygdala resulted in total anterograde amnesia and partial retrograde amnesia.

Evaluation:

This is the assumption, based on the results with other patients as well as H.M. In the absence at that time of brain-scanning equipment, other possibilities were also present. The high doses of anti-epileptic drug he was taking before, and the lower doses after the surgery, may have resulted in some memory loss. Also, so far as we can see, no memory tests were conducted on H.M. before the surgery, and the initial memory loss was largely reported by his mother, with whom he lived.

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Patient H.M. & Neurology Research: Ethical or Not?

Although tremendous advances in research and medical ethics have been made since the mid-20th century, questions continue.

The author of a recently published book questions ethics of research involving one of the best-known neurology patients, evoking a passionate response from both the public and the research community.

The positive impact of medical research on the quality of life today is undoubted. Along with the victories, medical research had its failures, such as devastating consequences of early-day psychosurgery, but lessons from these early failures contributed to success of modern research just as much. The case of Henry Molaison, formerly known as Patient H. M., is one of such therapeutic failures that taught us so much. Breakthroughs in understanding of memory aside, an important lesson learned from this and similar cases was that of ethics. Although tremendous advances in research and medical ethics have been made since the mid-20th century, it continues to be questioned. Most recently, the issue came up in Patient H.M.: A Story of Memory, Madness, and Family Secrets , a book by Luke Dittrich. 1

Briefly, in a fragment of his book published in The New York Times Magazine , Dittrich suggests that Suzanne Corkin, PhD, a researcher who dedicated her life to studying Patient H. M., destroyed research data, opposed publication that could question the validity of her work, and violated research ethics principles. 2 The fragment and, shortly after, the book evoked a range of responses from the public, research community, and the Massachusetts Institute of Technology, where Corkin conducted her research.

The public found Corkin’s actions, as described by Dittrich, disturbing, judging by the comments on The New York Times website such as “Dr. Corkin comes across as evil!” Many were convinced by Dittrich’s story, which he, as a journalist, so skillfully tells. (I was unable to confirm whether Dittrich has any medical or research background.) In a follow-up interview to The New York Times , Dittrich shares his reasons for telling the story: “I believe Henry’s story is important … because of what his case can teach us about our sometimes ruthless pursuit of knowledge.” 3

Even if we assume for a second that Corkin indeed pursued her research interests ruthlessly, this lesson has been learned many times over, and multiple measures are now in place to minimize the risk to research participants. Thus, Dittrich’s motives for telling his version of this story are unclear to me, as is its educational value. In fact, his mention of “researchers who’d built their careers on [Henry] and who had an interest in presenting his story in a particular way” made me wonder about Dittrich’s interest in telling the story in the way he does.

Unlike the public, I was not disturbed by Corkin’s actions because I am familiar with research practices. I found her actions not only acceptable but perhaps even appropriate, and my opinion echoed that of the research community’s. 4 As I am not currently involved in research and do not represent interests of any research institution, my opinion lacks bias the public might suspect in opinions of researchers.

What I did find disturbing was the fact that the book was published shortly after Corkin’s death, when she could no longer defend her work and remediate the damage the book did to the public perception of research. I was very pleased to see the research community take on this role by sending an open letter to The New York Times . 5 As long as journalists with little knowledge of research practices feel the need to tell their stories, researchers must continue to tell theirs to help the public to form an educated, unbiased opinion. 

References:

1. Dittrich L. Patient H.M.: a Story of Memory, Madness, and Family Secrets. New York: Random House; 2016.

2. Dittrich L. A brain that could not remember. The New York Times Web site. http://www.nytimes.com/2016/08/07/magazine/the-brain-that-couldnt-remember.html?_r=1 Accessed October 16, 2016.

3. Carey B. A Brain Surgeon’s Legacy Through a Grandson’s Eyes. The New York Times Web site. http://www.nytimes.com/2016/08/09/health/brain-patient-hm-book-dittrich.html Accessed October 16, 2016.

4. Hurley D. New allegations in book about patient HM kick up controversy on medical, scientific ethics . Neurology Today. 2016;16(19):48-50.

5. International Community of Scientists. Letter to the Editor of the New York Times Magazine. The MIT Department of Brain and Cognitive Sciences Web site. https://bcs.mit.edu/news-events/news/letter-editor-new-york-times-magazine Accessed October 16, 2016.

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• Standardized OR Handoffs S...

Standardized OR Handoffs Significantly Improve Surgical Communication and Patient Safety

Shrimps can save lives in the operating room.

June 18, 2024

Key Takeaways

The introduction of a standardized handoff protocol substantially improved communication among OR staff, ensuring critical information was transferred consistently.

The enhanced communication reduced potential patient safety risks and highlighted the importance of standardized handoff tools in improving surgical outcomes.

CHICAGO — A new study showcases a successful quality improvement program that significantly enhances surgical safety. By implementing a standardized handoff protocol, known as SHRIMPS, the study demonstrates how effective communication in operating rooms (OR) can reduce the risk of errors and improve patient care. The findings are published in the Journal of the American College of Surgeons ( JACS ).

"This study is a prime example of how quality improvement initiatives can lead to better patient outcomes," said study co-author Madeline Anderson, DO, a surgery resident at the University of Kentucky. "By standardizing communication during surgical procedures, we can ensure that all team members are informed and that critical information is consistently conveyed, reducing the risk of errors."

Prompted by a frontline stakeholder’s concerns about inadequate quality surgical technician handoffs, the quality improvement (QI) team at the Lexington VA Medical Center, affiliated with the University of Kentucky hospital, developed an audit tool to evaluate handoffs across various surgical cases from May 2022 to February 2024. Initial audits revealed handoffs occurred in 82.6% of cases, but with only 34.4% of critical elements being communicated.

In response, the team, in collaboration with OR staff, developed a standardized communication checklist with the acronym “SHRIMPS” (Sharps, Sponges, Hidden or held items, Replaced items, Instruments & Implants, Medications, Procedure overview, Specimens). Although it has nothing to do with the crustacean, the team chose the SHRIMPS acronym to be a helpful mnemonic device for surgical teams. This checklist was displayed prominently in all ORs at the Lexington VA Medical Center.

Key Findings

• Before implementing SHRIMPS, handoffs occurred in 82.6% of cases, with only 34.4% of critical elements communicated.
• After implementing SHRIMPS, 100% of cases included handoffs, with 98.2% of critical elements addressed.
• The duration of handoffs averaged 69.4 seconds post-implementation, ensuring thorough communication without significantly increasing handoff time.
• Announcements of handoffs to the entire OR team increased to 97.1%, ensuring all staff were aware of personnel changes.

“Part of the success of SHRIMPS comes from the QI team engaging with both topline and frontline OR stakeholders, including surgical technicians and circulating nurses,” said Dr. Anderson. “This approach ensures the tool is more effective and garners buy-in from the people ultimately using it.”

The success of the SHRIMPS protocol highlights the significant impact quality improvement programs can have in health care – by implementing standardized handoff protocols, operating rooms can achieve better communication, fewer errors, and enhanced patient care, the authors note. The study authors advocate for the widespread adoption of such tools to ensure reliable and efficient information transfer in surgical environments.

The study is published as an article in press on the JACS website.

Citation: Stephens WS, Anderson MJ, Levy BE, et al. Surgical Intraoperative Handoff Initiative: Standardizing Operating Room Communication using SHRIMPS. Journal of the American College of Surgeons , 2024. DOI: 10.1097/XCS.0000000000001115

About the American College of Surgeons

The American College of Surgeons is a scientific and educational organization of surgeons that was founded in 1913 to raise the standards of surgical practice and improve the quality of care for all surgical patients. The College is dedicated to the ethical and competent practice of surgery. Its achievements have significantly influenced the course of scientific surgery in America and have established it as an important advocate for all surgical patients. The College has approximately 90,000 members and is the largest organization of surgeons in the world. "FACS" designates that a surgeon is a Fellow of the American College of Surgeons.

• Sheila Evans | 312-202-5386
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Each panel is based on a separate regression discontinuity plot. Each scatter dot represents a 7-day average. The lines are based on fourth-degree polynomials. Age, activities of daily living (ADL), and cognitive functioning regression discontinuity estimates are not statistically significant. Impaired cognition was defined as a Cognitive Function Scale score of 3 or 4. The Changes in Health, End-stage disease and Symptoms and Signs (CHESS) regression discontinuity estimate is 0.1 (95% CI, 0.07-0.13).

Total therapy use is summation of 3 types of therapy (physical, occupational, and speech) provided at individual or nonindividual sessions. Therapy use is grouped into 50-minute intervals. The x-axis levels show the upper bound of the interval, ie, “50” means 0-50, “100” means 51-100, and so on.

Each panel is based on a separate regression discontinuity plot. Each scatter dot represents a 7-day average. The lines are based on fourth-degree polynomials.

eAppendix. STROBE Statement—Checklist of items that should be included in reports of cohort studies

eTable 1. Sample selection flow

eTable 2. Therapy use and health outcomes following the adoption of Patient Driven Payment Model (PDPM) for all skilled nursing facility patients with a 5-day assessment

eTable 3. Estimated effect of PDPM for different types of skilled nursing facilities

eTable 4. Regression discontinuity estimate using different polynomials

eTable 5. Regression discontinuity estimates shorter time windows around PDPM

eFigure 1. Number of hip fracture admissions per day

eFigure 2. Proportion of newly admitted nursing elderly nursing home patients enrolled in FFS with hip fracture diagnosis who had a 5-day scheduled assessment and were included in our primary analysis

eFigure 3. Days between admission and 5-day schedule assessment

eFigure 4. Number of Minimum Data Set (MDS) assessments in 40 days following admission

eFigure 5. Therapy use and health outcomes before and under the Patient Driven Payment Model (PDPM) for all newly admitted skilled nursing facility patients with 5-day assessment

eFigure 6. Trajectory of Therapy use before and under the Patient Driven Payment Model (PDPM)

eFigure 7. Proportion of individuals with a discharge assessment within 40 days of admission

eFigure 8. Reported therapy use in 5-day and discharge assessment before and under Patient Driven Payment Model (PDPM)

eFigure 9. Changes in Activities of Daily Living (ADL) scores at admission and discharge before and under Patient Driven Payment Model (PDPM)

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Rahman M , White EM , McGarry BE, et al. Association Between the Patient Driven Payment Model and Therapy Utilization and Patient Outcomes in US Skilled Nursing Facilities. JAMA Health Forum. 2022;3(1):e214366. doi:10.1001/jamahealthforum.2021.4366

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Association Between the Patient Driven Payment Model and Therapy Utilization and Patient Outcomes in US Skilled Nursing Facilities

• 1 Department of Health Services, Policy & Practice, Brown University School of Public Health, Providence, Rhode Island
• 2 Department of Medicine, University of Rochester, Rochester, New York
• 3 Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts

Question   Was the Patient Driven Payment Model (PDPM), implemented in October 2019, associated with rehabilitation therapy utilization and health outcomes of patients admitted to skilled nursing facilities (SNFs)?

Findings   In this cross-sectional study of 201 084 patients admitted to an SNF after hip fracture between January 2018 and March 2020, those admitted post-PDPM received about 13% fewer therapy minutes than those admitted pre-PDPM, but the likelihood of rehospitalization and functional scores at discharge remained unchanged.

Meaning   Implementation of PDPM was associated with a reduction in the volume of therapy use without changes in subsequent hospitalization risk or discharge functional scores.

Importance   In October 2019, Medicare changed its skilled nursing facility (SNF) reimbursement model to the Patient Driven Payment Model (PDPM), which has modified financial incentives for SNFs that may relate to therapy use and health outcomes.

Objective   To assess whether implementation of the PDPM was associated with changes in therapy utilization or health outcomes.

Design, Setting, and Participants   This cross-sectional study used a regression discontinuity (RD) approach among Medicare fee-for-service postacute-care patients admitted to a Medicare-certified SNF following hip fracture between January 2018 and March 2020.

Exposures   Skilled nursing facility admission after PDPM implementation.

Main Outcomes and Measures   Main outcomes were individual and nonindividual (concurrent and group) therapy minutes per day, hospitalization within 40 days of SNF admission, SNF length of stay longer than 40 days, and discharge activities of daily living score.

Results   The study cohort included 201 084 postacute-care patients (mean [SD] age, 83.8 [8.3] years; 143 830 women [71.5%]; 185 854 White patients [92.4%]); 147 711 were admitted pre-PDPM, and 53 373 were admitted post-PDPM. A decrease in individual therapy (RD estimate: −15.9 minutes per day; 95% CI, −16.9 to −14.6) and an increase in nonindividual therapy (RD estimate: 3.6 minutes per day; 95% CI, 3.4 to 3.8) were observed. Total therapy use in the first week following admission was about 12 minutes per day (95% CI, −13.3 to −11.3) (approximately 13%) lower for residents admitted post-PDPM vs pre-PDPM. No consistent and statistically significant discontinuity in hospital readmission (0.31 percentage point increase; 95% CI, −1.46 to 2.09), SNF length of stay (2.7 percentage point decrease in likelihood of staying longer than 40 days; 95% CI, −4.83 to −0.54), or functional score at discharge (0.04 point increase in activities of daily living score; 95% CI, −0.19 to 0.26) was observed. Nonindividual therapy minutes were reduced to nearly zero in late March 2020, likely owing to COVID-19–related restrictions on communal activities in SNFs.

Conclusions and Relevance   In this cross-sectional study of SNF admission after PDPM implementation, a reduction of total therapy minutes was observed following the implementation of PDPM, even though PDPM was designed to be budget neutral. No significant changes in postacute outcomes were observed. Further study is needed to understand whether the PDPM is associated with successful discharge outcomes.

Rehabilitation services delivered in skilled nursing facilities (SNFs) are a key component of patient recovery from a hospitalization stay. Roughly 20% of hospitalized Medicare patients are discharged to an SNF for postacute care, 1 with the vast majority of these patients receiving rehabilitative physical, occupational, and/or speech therapy services. From 1998 to October 2019, Medicare per diem payments to SNFs were largely determined by the amount of therapy delivered under the Resource Utilization Group (RUG) system, creating strong financial incentives for SNFs to deliver high amounts of therapy. Between 2002 and 2015, the share of SNF days classified as intensive therapy days (at least 500 minutes of therapy over a 7-day period) increased from 29% to 82%, while the share of days in the highest “ultrahigh” case mix group (at least 720 therapy minutes over a 7-day period) increased from 49% to 57% of total days. 2 These efforts contributed to substantial growth in Medicare spending on SNF care, despite a lack of evidence supporting the clinical value of the additional therapy. 3 - 5

In an effort to alter these incentives, the Centers for Medicare & Medicaid Services (CMS) implemented the Patient Driven Payment Model (PDPM) in October 2019 to replace the RUG system. Per diem payments under the PDPM are no longer linked to therapy minutes. Instead, they are determined by patients’ clinical and functional characteristics at the time of their SNF admission. 6 Previous research has demonstrated that these altered incentives resulted in modest cuts in therapy staffing levels by SNFs during the first quarter of program implementation. 7 However, the association between the PDPM and the amount and type of therapy delivered to Medicare SNF patients is unknown. Furthermore, the association of the PDPM with key patient outcomes, such as length of SNF stay, risk of rehospitalization, and improvement in activities of daily living (ADL) score, is not known. Therefore, the purpose of this study was to examine the association of PDPM implementation with therapy use and postacute outcomes through the first 2 quarters of 2020. We focused primarily on patients admitted to an SNF following hospitalization for hip fracture to isolate the association of PDPM and therapy use separate from any changes in the types of patients SNFs may have admitted following program implementation.

This study was approved by the Brown University institutional review board, which waived the requirement for participant informed consent owing to human participant exemption category 4. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guidelines for cohort studies (eAppendix in the Supplement ).

We used the 2017 to 2020 Minimum Data Set (MDS) and Medicare Beneficiary Summary File (MBSF). Under the RUG system, assessments were completed within 5 days of admission; at days 14, 30, 60, and 90 of SNF stay and quarterly thereafter; and at discharge. Under PDPM, CMS reduced the frequency of the required MDS assessments. However, the 5-day scheduled assessment is mandatory under both payment regimens, thereby providing a common assessment point to evaluate the PDPM. The MBSF includes enrollment and clinical information on Medicare beneficiaries and monthly Medicare Advantage enrollment indicators.

Our sample consisted of fee-for-service Medicare beneficiaries 65 years and older who were admitted to an SNF between January 1, 2018, and June 30, 2020, and had a 5-day scheduled MDS assessment. Patients with a previous nursing facility stay in the 1-year period prior to the admission date were excluded. Finally, our primary analyses focused on patients with hip fracture because they are commonly discharged to SNFs for postacute care 8 - 10 with substantial therapy needs. We also examined all fee-for-service enrollees with a 5-day scheduled MDS assessment in a secondary analysis.

The main exposure was SNF admission occurring on or after October 1, 2019, when the PDPM took effect, vs admission pre-PDPM between January 1, 2017, and September 30, 2019. Specifically, we included time as a daily variable that is set to zero at October 1, 2019, and ranges between −638 and 182 owing to the cohort selection window.

One of the primary outcomes of this study was therapy use, measured as the total combined number of physical therapy, occupational therapy, and speech therapy minutes provided in the preceding 7 days, as reported on the 5-day MDS assessment. We examined individual and nonindividual (concurrent and group) therapy minutes separately as well as their total. We focused on the reported minutes on the 5-day assessment, which is mandatory under both payment systems. Because 5-day assessment can be completed from days 1 to 8, we divided the reported therapy minutes by the number of days between admission date and assessment date.

We examined 3 patient outcomes focusing on the first 40 days of nursing home stay. First, we identified hospitalizations from the SNF within 40 days of SNF admission based on the MDS discharge assessments. Although hospitalizations are typically identified using claims data, we relied on the MDS because claims data corresponding to the study period were not yet available, and about 94% of SNF hospitalization events in Medicare claims can be identified using MDS 3.0 discharge records. 11 Second, we measured length of stay as a binary indicator of stays more than 40 days using discharge date. Third, we measured the change in patients’ ADL scores at admission and discharge.

Patients’ age, sex, and race and ethnicity were determined from the MBSF. This information was originally obtained from the Master Beneficiary Record of the Social Service Administration and then supplemented by additional information from CMS. 12 The categories for race and ethnicity were Black, Hispanic, White, and other race. To capture clinical complexity at the time of SNF admission, we included the ADL score, Cognitive Function Scale score, 13 Changes in Health, End-stage disease and Symptoms and Signs (CHESS) score, 14 and a series of diagnoses and symptoms captured in the MDS.

We started by checking the balance of observations pre-PDPM and post-PDPM. We first assessed how the likelihood of having a 5-day assessment and the number of days between admission and 5-day assessment changed following PDPM implementation. We also assessed whether demographic composition and patient acuity at admission changed under PDPM.

To assess the overall changes in outcomes following the implementation of PDPM, we used a regression discontinuity (RD) approach. We first plotted measures with respect to SNF admission date to assess any discontinuity in the trend following the PDPM. We also fit RD models, estimating outcomes as a function of continuous time and its fourth-degree polynomials and an indicator of admission post-PDPM. In this specification, the coefficient of the post-PDPM indicator captures any discrete jump in trend associated with PDPM. Other variables included were age, sex, race, calendar-month dummies, day-of-the-week dummies, and SNF fixed effects. We did not include MDS-reported comorbidities and acuity measure because acuity measures might be overreported following PDPM because they are used to determine payment. The 95% CIs are based on clustered errors by SNF. There are 2 important properties of this model. First, we did not interact time with the PDPM indicator because we aimed to estimate the change in average outcomes following PDPM. Such interactions are typically included in interrupted time series models and not RD models. Second, we started our study period on January 1, 2018, which allowed us to observe individuals admitted in a given month for multiple years and incorporate month fixed effects. We chose this approach because we anticipated seasonal variation in the acuity of newly admitted SNF patients, and we wanted to isolate PDPM from the usual shift owing to the start of the fall/winter season. For similar reasons, we also included day-of-the-week fixed effects.

To assess the changes in therapy minutes, we started by comparing the distribution of therapy minutes reported in 5-day assessment pre-PDPM and post-PDPM implementation (ie, October 1, 2019, and later). For the RD in therapy minutes, we included the number of days between admission and 5-day assessment as a control variable. For the RD in discharge ADL score, we included admission ADL score as a control variable. Similarly, we plotted ADL score trajectories before and after PDPM over the first 40 days of SNF stay using all ADL reporting assessments. Analyses were performed using Stata, version 17 (StataCorp LLC).

We conducted several supplementary analyses. First, we examined therapy use including interim assessments (in addition to the 5-day assessment). Second, we examined all newly admitted SNF patients with a 5-day assessment to assess whether the results that we observed in the hip fracture sample held for the entire sample. Third, we examined whether the results varied substantially across different types of SNFs, specifically, by profit status, chain affiliation, and the share of Medicare-paid residents. Fourth, we examined how sensitive our RD estimate was depending on the degree of polynomials of time in our model (we used fourth-degree polynomials in our main specification). Finally, we estimated models using observations in 2 different time windows: January 2019 to June 2020 (9 months before and after PDPM was implemented) and April 2019 to March 2020 (6 months before and after PDPM was implemented).

We started with more than 5 million Medicare beneficiaries newly admitted to a nursing home between January 2018 and June 2020. We identified 201 084 fee-for-service Medicare beneficiaries who were admitted to an SNF with a hip fracture and had a 5-day scheduled MDS assessment (see eTable 1 in the Supplement for sample size with different inclusion criteria). Of these, 147 711 patients were admitted pre-PDPM, and 53 373 were admitted post-PDPM. Following PDPM, the number of SNF admissions per day (eFigure 1 in the Supplement ) and proportion of individuals with a 5-day assessment (eFigure 2 in the Supplement ) remained roughly constant. However, we observed a discontinuous drop in days between admission date and the date of 5-day assessment (eFigure 3 in the Supplement ) and the number of MDS assessments during the first 40 days of a nursing home stay (eFigure 4 in the Supplement ).

Table 1 shows that among patients admitted before the PDPM, the mean (SD) age was 83.8 (8.3) years, and 106 080 (71.8%) were women; 5362 (3.6%) were Black patients; 1739 (1.2%) were Hispanic patients; 136 461 (92.4%) were White patients; and 4105 (2.8%) were patients of other races (includes American Indian or Alaska Native, Asian, and Native Hawaiian or Other Pacific Islander). The demographic composition remained roughly the same after the PDPM was implemented, with mean (SD) age of 83.9 (8.3) years and 37 750 (70.7%) women; 1955 (3.7%) were Black patients; 572 (1.1%) were Hispanic patients; 49 393 (92.6%) were White patients; and 1430 (2.7%) were patients of other races. Figure 1 A shows that mean age at admission declined over the study period, but there was no trend break with PDPM implementation.

Table 1 shows that the average ADL score of admitted SNF patients was roughly the same pre-PDPM and post-PDPM. The proportion of patients admitted with moderate to severe cognitive impairment increased modestly from 21.5% pre-PDPM to 23.5% post-PDPM. The prevalence of most diagnoses increased post-PDPM, with the largest increases noted in diabetes, heart failure, stroke, dementia, chronic obstructive pulmonary disorder, and aphasia. There was also a significant increase in dyspnea prevalence from 11.2% to 17.7% of patients. The mean CHESS score increased from 0.45 to 0.64 (about 30%) post-PDPM. These patterns can also be seen in Figure 1 , which shows no trend break in ADL score (B) and proportion with moderate to severe cognitive impairment (C) but a statistically significant increase in mean CHESS score (by 0.1, which is 22% higher than the pre-PDPM mean) post-PDPM implementation (D).

Total therapy use per day in the first week following admission was about 12.3 minutes less for patients admitted under PDPM compared with patients admitted pre-PDPM ( Table 2 ). Figure 2 shows that the distribution of reported therapy minutes changed after the PDPM took effect. Pre-PDPM, we observe 2 sharp spikes, one at 501 to 550 minutes and another at 701 to 750 minutes, consistent with the 500-minute threshold for the high therapy group and the 720-minute threshold for the ultrahigh therapy group under the old RUG system, respectively. More than 55% of patients received just enough therapy to be in the ultrahigh RUG category. By contrast, under the PDPM, the distribution looks bell shaped, with a peak at 451 to 500 minutes.

As shown in Table 2 and Figure 3 A, average individual therapy minutes as reported in 5-day assessment declined from 97 minutes per patient per day pre-PDPM to 78 minutes per patient per day post-PDPM implementation (RD estimate: −15.9 minutes per day). On the other hand, nonindividual therapy minutes increased post-PDPM (RD estimate: 3.60 minutes per day). Figure 3 B shows the RD time series plot of nonindividual therapy use, which was very low during the earlier months of observation, started increasing pre-PDPM, jumped from about 1 minute per day to 4 minutes per day with PDPM implementation, and then stabilized during the next 5 months before dropping to nearly zero in March 2020, coinciding with the start of the COVID-19 pandemic.

We observed similar trends in therapy use for the overall postacute-care SNF population (eFigure 5 and eTable 2 in the Supplement ) as well as in different types of MDS assessments (eFigures 6 and 8 in the Supplement ). Additionally, we observed similar trends in different types of SNFs regardless of ownership status, chain affiliation, or the share of Medicare-paid residents (eTable 3 in the Supplement ). The RD estimates are robust to different polynomial trend specifications (eTable 4 in the Supplement ) and different time window specifications around the PDPM implementation date (eTable 5 in the Supplement ).

As shown in Table 2 , the share of individuals who were discharged directly to the hospital from the SNF within 40 days of admission was 19.7% pre-PDPM and 18.3% post-PDPM (RD estimate: 0.31% chance of discharge post-PDPM; 95% CI, −1.46 to 2.09). Figure 3 C shows that the declining trend persisted throughout the study period, and there was no trend break with PDPM implementation.

The share of individuals who remained in SNF for more than 40 days declined from 42.4% pre-PDPM to 39.9% post-PDPM. However, this was mostly owing to the declining trend that was present during the entire study period ( Figure 3 D). In this plot, we do see a drop in the share of patients with SNF length of stay greater than 40 days following PDPM. Based on the regression results in Table 2 , this drop is about 2.7 percentage points (95% CI, −4.83 to −0.54), which is statistically significant at the 5% level of significance but not at 1% level of significance. However, the variance associated with this upward trend is high and probably driven by fewer discharge assessments during the last few weeks of the study period (eFigure 7 in the Supplement ). Similarly, we did not observe consistent trends in different types of SNFs in terms of ownership status, chain affiliation, or the share of Medicare-paid residents (eTable 3 in the Supplement ). Similarly, the results based on all newly admitted nursing home patients with a 5-day assessment do not point to any robust shift in trend associated with the PDPM in the likelihood of hospitalization or the SNF length of stay lasting more than 40 days (eFigure 5 and eTable 2 in the Supplement ). There was no trend break around PDPM implementation in discharge ADL scores (RD estimate: 0.04 ADL score post-PDPM; 95% CI, −0.19 to 0.26) (eFigure 9 in the Supplement ).

We found a decrease in total therapy provided as well as a shift in the distribution of therapy minutes following implementation of the PDPM in October 2019. These changes, however, did not appear to be accompanied by consistent changes in key patient outcomes, including rehospitalization, SNF length of stay, or functional scores at time of discharge. We did observe a modest increase in the reporting of certain chronic conditions, despite the overall distribution of age and functional ability among newly admitted SNF patients with hip fracture remaining fairly consistent pre-PDPM and post-PDPM.

The PDPM was designed to be budget neutral and was intended to alter financial incentives for SNFs so that they would provide therapy based on the clinical needs of patients, rather than at levels that maximize Medicare reimbursement. Our findings suggest that the policy has worked as intended. We saw a shift in the distribution of therapy minutes from pre-PDPM, when there were clear spikes at the 500-minute and 720-minute categories, and more than half of patients received just enough therapy minutes to meet the ultrahigh RUG threshold, to post-PDPM where the distribution normalized with a peak at 451 to 500 minutes. This shift in the distribution corresponded with a sharp drop in therapy volume from about 97 minutes to 81 minutes per patient per day with the implementation of the PDPM, strongly suggesting that the shift was driven by the policy change. These conclusions are also supported by recent evidence that SNFs reduced the number of therapy staff they employ or contract with in response to the PDPM. 7

The reduction in therapy minutes we observed was primarily driven by individual, or 1-on-1, therapy sessions. Nonindividual (ie, group or concurrent) therapy use was uncommon under the RUG system, with a mean of less than 1 minute per patient per day. It did increase under the PDPM to an average of 3 minutes per day, but this was still less than the individual therapy average of about 78 minutes per day, with most patients receiving zero minutes of nonindividual therapy. We also observed a drop-off in nonindividual therapy minutes in March 2020 with the onset of the COVID-19 pandemic, which resulted in SNFs severely limiting or eliminating communal activities in order to reduce virus transmission. It will be important to follow these trends over time to determine whether SNFs increase their use of nonindividual therapy in the aftermath of the pandemic.

We limited our primary analysis to patients admitted to SNFs with hip fracture to isolate the association between PDPM and therapy use and reduce potential confounding caused by SNFs admitting a different case mix of patients pre-PDPM vs post-PDPM. Because per diem reimbursement rates are now determined based on the clinical acuity of patients at time of admission, SNFs may be incentivized to admit more medically complex patients to boost reimbursement. Patients with hip fracture are less heterogeneous than the SNF population overall and generally have high therapy needs on hospital discharge. We observed that the age and functional characteristics of newly admitted patients with hip fracture remained relatively unchanged pre-PDPM and post-PDPM; however, we did observe an increase in certain chronic conditions following PDPM implementation. The discontinuous jump in CHESS scores is consistent with an increase in coding intensity of chronic conditions to improve reimbursement. Future work to explore these questions will need to examine how well case mix measured from SNF records aligns with case mix measured from the preceding hospital stay once Medicare claims for the study period become available.

The ultimate question is whether the reduction in the therapy volume is associated with worse patient outcomes. This did not appear to be the case with regard to 3 key outcomes (rehospitalization, SNF length of stay, and functional scores at time of discharge), as no significant changes were found. This suggests that the PDPM resulted in a “right-sizing” of therapy provision in SNFs and reversed prior incentives under the RUG system to provide therapy when there was minimal clinical benefit. One caveat of our rehospitalization finding, however, is that it is not risk adjusted. We did not include acuity measures while comparing outcomes before and after PDPM because changes in coding and reported acuity (shown by higher CHESS scores) following PDPM are likely attributable to bias risk adjustment and subsequently make post-PDPM risk-adjusted hospitalization rates look lower than they would without adjustment for clinical complexity. Prior studies have shown that when payment policy changes drive changes in coding intensity, it can complicate trend analyses of risk-adjusted outcomes. 15 , 16

A few limitations of the study should be noted. First, lack of claims data reduces precision of our cohort selection and outcome definitions. Our hospitalization outcome measure is not a typical hospital readmission measure, which requires an index hospital claim. We relied on the presence of 5-day assessment, which is typically performed for postacute-care patients. Second, lack of claims data also limits our ability to understand whether an increase in MDS-reported chronic conditions reflects a true increase in patient complexity or an increase in coding intensity. Finally, the fact that CMS reduced the required frequency of MDS assessments under the PDPM compared with the RUG system prevents us from comparing therapy use and ADL score changes over the duration of the SNF stay and limits us to using the admission and discharge assessments.

In this cross-sectional study of patients admitted to an SNF after hip fracture between January 2018 and March 2020, we observed a significant reduction in therapy volume and a shift in the distribution of therapy minutes away from levels that previously resulted in maximum reimbursement under the RUG system. Despite these changes, we observed no robust differences in 3 key patient outcomes: rehospitalization, SNF length of stay, and functional scores at discharge. These findings suggest that the PDPM did have its intended effect of altering financial incentives for SNFs related to therapy provision; however, future study is needed to refine the measurement of patient outcomes and examine potential changes in case mix.

Accepted for Publication: November 2, 2021.

Published: January 7, 2022. doi:10.1001/jamahealthforum.2021.4366

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2022 Rahman M et al. JAMA Health Forum .

Corresponding Author: Momotazur Rahman, PhD, Department of Health Services, Policy & Practice, Brown University School of Public Health, 121 South Main St, S-6, Providence, RI 02912 ( [email protected] ).

Author Contributions: Drs Rahman and White and Messrs Santostefano and Shewmaker had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Rahman, White, McGarry, Resnik.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Rahman, White, Shewmaker.

Critical revision of the manuscript for important intellectual content: Rahman, White, McGarry, Santostefano, Resnik, Grabowski.

Statistical analysis: Rahman, McGarry, Santostefano, Shewmaker, Resnik.

Obtained funding: Rahman.

Administrative, technical, or material support: McGarry.

Supervision: Grabowski.

Conflict of Interest Disclosures: Drs Rahman and White and Mr Santostefano reported receiving grants from the Warren Alpert Foundation during the conduct of the study. Dr McGarry reported receiving grants from the Warren Alpert Foundation during the conduct of the study; and grants from National Institute on Aging, Agency for Healthcare Research and Quality, and Robert Wood Johnson Foundation outside the submitted work. Dr Resnik reported being a licensed physical therapist who directs the Center on Health Services Research and Training, funded by the Foundation for Physical Therapy Research, and is principal investigator of LeaRRn, a P2C resource center for rehabilitation research funded by National Center for Medical Rehabilitation Research and National Institute of Nursing Research. Dr Grabowski reported receiving grants from the Warren Alpert Foundation during the conduct of the study; and personal fees from Analysis Group, Compass Lexecon, AARP, and naviHealth outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by the Warren Alpert Foundation.

Role of the Funder/Sponsor: The Warren Alpert Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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The Cognitive Neuroscience of Human Memory Since H.M

Larry r. squire.

1 Veterans Affairs Healthcare System, San Diego, California 92161

2 Department of Psychiatry, University of California, San Diego, La Jolla, California 92093

3 Department of Neurosciences, University of California, San Diego, La Jolla, California 92093

4 Department of Psychology, University of California, San Diego, La Jolla, California 92093

John T. Wixted

Work with patient H.M., beginning in the 1950s, established key principles about the organization of memory that inspired decades of experimental work. Since H.M., the study of human memory and its disorders has continued to yield new insights and to improve understanding of the structure and organization of memory. Here we review this work with emphasis on the neuroanatomy of medial temporal lobe and diencephalic structures important for memory, multiple memory systems, visual perception, immediate memory, memory consolidation, the locus of long-term memory storage, the concepts of recollection and familiarity, and the question of how different medial temporal lobe structures may contribute differently to memory functions.

INTRODUCTION

In the earliest systematic writings about human memory, it was already appreciated that the study of memory impairment can provide valuable insights into the structure and organization of normal function ( Ribot 1881 , Winslow 1861 ). This tradition of research has continued to prove fruitful and has yielded a broad range of fundamental information about the structure and organization of memory. What is memory? Is it one thing or many? What are the concepts and categories that guide our current understanding of how memory works and that underlie the classification of its disorders? It is sometimes not appreciated that the concepts and categories used in current discussions of memory are not fixed and were not easily established. Even the question of which cognitive operations reflect memory and which depend on other faculties has a long history of empirical work and discussion.

One needs only to sample nineteenth-century writings to recognize how differently memory was viewed then and now. For example, in his classic treatment of memory disorders, Ribot (1881) considered amnesias due to neurological injury together with amnesias due to psychological trauma. And he viewed aphasia and agnosia as disorders of memory, wherein (in aphasia, for example) patients have lost their memory for words or memory for the movements needed to produce words. Today, aphasia is considered a deficit of language, and agnosia a deficit of visual perception. Memory is affected but only as part of a more fundamental defect in a specific kind of information processing.

The notion that the study of brain injury can elucidate the organization of memory was itself a matter for empirical inquiry. If brain regions were highly interconnected, and the brain’s functions distributed and integrated one with another, then damage to any one area would produce a global impairment, blurred across multiple faculties and affecting all of mental life. But the fact of the matter is different. The brain is highly specialized and modular, with different regions dedicated to specific operations. As a result, localized damage can produce strikingly specific effects, including a selective and circumscribed impairment of memory.

The idea that functions of the nervous system can be localized was already well accepted by the end of the nineteenth century. This localizationist view had its roots in the writings of Gall (1825) and was supported by the experimental work of Broca (1861) , Ferrier (1876) , Fritsch & Hitzig (1870) , and others (see Finger 1994 ). Yet, these ideas centered mainly around sensory functions, motor control, and language and did not usefully address the topic of memory. Then, in the early twentieth century, an influential program of experimental work in rodents investigated directly the localization of memory with the conclusion that memory is distributed throughout the cortex and that the contribution to memory is equivalent across regions ( Lashley 1929 ). This idea was strongly challenged ( Hebb 1949 , Hunter 1930 ) by the alternative, and more modern, interpretation that memory storage is indeed distributed but that different areas store different features of the whole. Still, as the midpoint of the twentieth century approached, memory functions, while distributed, were thought to be well integrated with perceptual and intellectual functions, and no region of the brain was believed to be disproportionately dedicated to memory. All that was about to change.

In 1957, Brenda Milner reported the profound effect on memory of bilateral medial temporal lobe resection, carried out to relieve epilepsy in a patient who became known as H.M. (1926–2008) ( Scoville & Milner 1957 , Squire 2009 ) ( Figure 1 ). Remarkably, H.M. exhibited profound forgetfulness but in the absence of any general intellectual loss or perceptual disorders. He could not form new memories (anterograde amnesia) and also could not access some memories acquired before his surgery (retrograde amnesia). His impairment extended to both verbal and non-verbal material, and it involved information acquired through all sensory modalities. These findings established the fundamental principle that memory is a distinct cerebral function, separable from other perceptual and cognitive abilities, and also identified the medial aspect of the temporal lobe as important for memory. The early descriptions of H.M. can be said to have inaugurated the modern era of memory research, and the findings from H.M. enormously influenced the direction of subsequent work.

Left column Magnetic resonance images arranged from rostral ( a ) to caudal ( c ) through the temporal lobe of patient H.M. (in 1993 at age 67) and a 66-year-old healthy male ( right ). The comparison brain illustrates the structures that appear to have been removed during H.M.’s surgery in 1953. The lesion was bilaterally symmetrical, extending caudally 5.4 cm on the left side and 5.1 cm on the right. The full caudal extent of abnormal tissue is not illustrated. The damage included medial temporal polar cortex, most of the amygdaloid complex, virtually all the entorhinal cortex, and approximately the rostral half of the hippocampal region (dentate gyrus, hippocampus, and subicular complex). The perirhinal cortex was substantially damaged except for its ventrocaudal aspect. The more posterior parahippocampal cortex (areas TF and TH, not shown here) was largely intact. Adapted from Corkin et al. (1997) with permission from the Society for Neuroscience.

ANATOMY OF MEMORY

The work with H.M. is sometimes cited incorrectly as evidence of the importance of the hippocampus for memory, but this particular point could not of course be established by a large lesion that included not only the hippocampus but also the amygdala together with the adjacent parahippocampal gyrus. Which structures within H.M.’s lesion are important for memory became understood only gradually during the 1980s following the successful development of an animal model of human amnesia in the non-human primate ( Mishkin 1978 ). Cumulative studies in the monkey ( Murray 1992 , Squire & Zola-Morgan 1991 , Zola-Morgan et al. 1994 ) considerably clarified this issue. The important structures proved to be the hippocampus and the adjacent entorhinal, perirhinal, and parahippocampal cortices, which make up much of the parahippocampal gyrus ( Figure 2 ).

( a ) Schematic view of the medial temporal lobe memory system for declarative memory, which is composed of the hippocampus and the perirhinal, entorhinal, and parahippocampal cortices. In addition to the connections shown here, there are also weak projections from the perirhinal and parahippocampal cortices to the CA1-subiculum border. ( b ) Ventral view of a human brain ( upper left ), monkey brain ( upper right ), and a lateral view of a rat brain ( lower center ). The major cortical components of the medial temporal lobe are highlighted and outlined. The hippocampus is not visible from the surface and in the human lies beneath the cortex of the medial temporal lobe. Its anterior extent lies below the posterior entorhinal ( red ) and perirhinal ( purple ) cortices, and the main body of the hippocampus lies beneath the parahippocampal cortex. In the rat, the parahippocampal cortex is termed postrhinal cortex. Abbreviations: EC, entorhinal cortex; PH, parahippocampal cortex ( dark yellow ); Por, postrhinal cortex; PR, perirhinal cortex.

One particularly instructive case of human memory impairment became available during this same time period ( Zola-Morgan et al. 1986 ). R.B. developed a moderately severe, enduring impairment following an ischemic episode in 1978. During the five years until his death, his memory deficit was well documented with formal tests. Detailed histological examination of his brain revealed a circumscribed bilateral lesion involving the entire CA1 field of the hippocampus. Note that a lesion confined to the CA1 field must substantially disrupt hippocampal function because the CA1 field is a bottleneck in the unidirectional chain of processing that begins at the dentate gyrus and ends in the subiculum and entorhinal cortex. R.B. was the first case of memory impairment following a lesion limited to the hippocampus that was supported by extensive neuropsychological testing as well as neuropathological analysis.

The findings from R.B., considered together with the much more severe impairment in H.M., made two useful points. First, damage to the hippocampus itself is sufficient to produce a clinically significant and readily detectable memory impairment. Second, additional damage to the adjacent cortical regions along the parahippocampal gyrus (as in H.M.) greatly exacerbates the memory impairment. These same conclusions about the neuroanatomy of modest and severe memory impairment were also established in the monkey ( Zola-Morgan et al. 1994 ).

Another case was subsequently described (patient G.D.) with a histologically confirmed bilateral lesion confined to the CA1 field and with a memory impairment very similar to R.B. ( Rempel-Clower et al. 1996 ). Two other patients were also of interest. L.M. and W.H. had somewhat more severe memory impairment than did R.B. and G.D., but the impairment was still moderate in comparison to H.M. ( Rempel-Clower et al. 1996 ). Histological examination revealed extensive bilateral lesions of the hippocampal region, involving all the CA fields and the dentate gyrus. There was also some cell loss in entorhinal cortex and, for W.H., cell loss in the subiculum, as well. The more severe memory impairment in these two cases, in comparison to R.B. and G.D., could be due to the additional damage within the hippocampus or to the cell loss in entorhinal cortex.

There are only a small number of cases where detailed neuropsychological testing and thorough neurohistological analysis have combined to demonstrate memory impairment after limited hippocampal damage or larger medial temporal lobe lesions (see also Victor & Agamanolis 1990 ). Yet, neuroanatomical information is essential because it lays the groundwork for classifying memory disorders, for understanding qualitative and quantitative differences between patients, and for addressing questions about how specific structures may contribute differently to memory functions. Nonetheless, in the absence of histological data, valuable information can be obtained from structural imaging. Methods for high-resolution imaging of hippocampal damage were developed some time ago ( Press et al. 1989 ), and quantitative data can now be obtained that provide reliable estimates of tissue volume ( Gold & Squire 2005 ). These estimates are based on guidelines defined histologically and use landmarks in the medial temporal lobe that are visible on MRI ( Insausti et al. 1998a , b ).

An interesting observation has emerged from calculations of hippocampal volume in memory-impaired patients, usually patients who have sustained an anoxic episode. Across a number of reports, hippocampal volume (or area in the coronal plane) is typically reduced by ~40% [41%, n = 10 ( Isaacs et al. 2003 ); 44%, n = 5 ( Shrager et al. 2008 ); 43%, n = 4 ( Squire et al. 1990 ); 45%, n = 1 ( Cipolotti et al. 2001 ); 46%, n = 1 ( Mayes et al. 2002 )]. Neurohistological data from two of these patients (L.M. and W.H.) suggest an explanation for this striking consistency. As described above, these two patients had extensive cell loss in the hippocampus as well as in the dentate gyrus. Accordingly, a reduction in hippocampal volume of 40%, as estimated by MRI, may indicate a nearly complete loss of hippocampal neurons. The tissue collapses, but it does not disappear entirely. A volume loss in the hippocampus of ~40% may represent a maximum value for some etiologies of memory impairment.

While medial temporal lobe structures have received the most attention in studies of memory and memory impairment, it is notable that damage to the diencephalic midline also impairs memory. The deficit has essentially the same features as in medial temporal lobe amnesia. The best-known cause of diencephalic amnesia is alcoholic Korsakoff’s syndrome. Here, damage to the medial dorsal thalamic nucleus (alone or perhaps in combination with damage to the mammillary nuclei) has been associated with memory impairment ( Victor et al. 1989 ). Another survey of Korsakoff’s syndrome documented damage to these two structures and, in addition, identified a role for the anterior thalamic nuclei ( Harding et al. 2000 ). Six cases that were studied both neuropsychologically and neurohistologically ( Gold & Squire 2006 , Mair et al. 1979 , Mayes et al. 1988 ) consistently identified damage in the medial thalamus (as well as in the mammillary nuclei for the five cases with Korsakoff’s syndrome). Two regions of thalamus were implicated by these cases and by two neuroimaging studies of diencephalic amnesia ( Squire et al. 1989 , von Cramon et al. 1985 ): first, the medial dorsal nucleus and the adjacent internal medullary lamina; and second, the mammillothalamic tract and its target, the anterior thalamic nuclei. Damage to either of these regions can cause memory impairment. These diencephalic nuclei and tracts are anatomically related to the medial temporal lobe. The perirhinal cortex originates projections to the medial dorsal nucleus that enter through the internal medullary lamina, and the hippocampal formation projects both to the rostrally adjacent anterior nuclei and to the mammillary nuclei. These anatomical connections likely explain why patients with medial temporal or diencephalic lesions exhibit the same core deficit.

PRINCIPLES OF ORGANIZATION SUGGESTED BY H.M.’S FINDINGS

The early descriptions of H.M suggested four principles about how memory is organized in the brain. First, despite his debilitating and pervasive memory impairment, H.M. successfully acquired a motor skill. This finding raised the possibility that memory is not a single thing. Second, because his memory impairment appeared to be well circumscribed, the structures damaged in memory-impaired patients were thought not to be involved in intellectual and perceptual functions. Third, H.M. had a considerable capacity for sustained attention, including the ability to retain information for a period of time after it was first encountered. This finding suggested that medial temporal lobe structures are not needed for immediate memory or for the rehearsal and maintenance of material in what would now be termed working memory. Fourth, H.M. appeared to have good access to facts and events from time periods remote to his surgery. This observation suggested that the medial temporal lobe cannot be the ultimate storage site for long-term memory. Permanent memory must be stored elsewhere, presumably in neocortex. In the years since H.M. was described, each of these ideas has been the topic of extensive experimental work.

During the 1960s and 1970s, when human memory impairment began to be systematically studied, there was considerable debate about whether medial temporal and diencephalic structures were concerned more with storage or with retrieval. The findings from H.M. led to the view that these structures are needed for memory storage, that is, for the establishment of new representations in long-term memory. If these structures are unable to participate in forming long-term memory, then representations established in immediate memory are presumably lost or perhaps achieve some disorganized state. Consider the case of transient amnesic episodes (transient global amnesia or the memory impairment associated with electroconvulsive therapy). Here, the events that occur during the period of anterograde amnesia are not subsequently remembered after recovery from the amnesic condition. New learning again becomes possible, but events from the amnesic episode do not return to memory. Thus, if medial temporal lobe or diencephalic structures are not functional at the time of learning, memory is not established in a usable way and does not become available at a later time. More direct investigations of this issue using single-cell recording in monkeys have reached similar conclusions ( Higuchi & Miyashita 1996 ; see Squire 2006 ). The idea is that the synaptic changes that would ordinarily represent acquired information in long-term memory either are lost altogether or fail to develop into a stable, coherent ensemble.

MULTIPLE MEMORY SYSTEMS

The memory impairment in H.M. and other patients is narrower than once thought in that not all kinds of learning and memory are affected. The first hint of this idea came when H.M. was found capable of learning a hand-eye coordination skill (mirror drawing) over a period of days, despite having no recollection of practicing the task before ( Milner 1962 ). Although this finding showed that memory was not unitary, for some time it was thought that motor skill learning was a special case and that all the rest of memory is of one piece and is impaired in amnesia. Subsequently, it was discovered that motor-skill learning is but one example of a large domain of learning and memory abilities, all of which are intact in H.M. and other patients. H.M.’s motor skill learning marked the beginning of a body of experimental work that would eventually establish the biological reality of two major forms of memory.

An early insight was that perceptual skills and cognitive skills, not just motor skills, are preserved in amnesia. Specifically, amnesic patients acquired at a normal rate the perceptual skill of reading mirror-reversed words, despite poor memory for the task itself and for the words that were read ( Cohen & Squire 1980 ). This finding was the basis for the formulation of a brain-based distinction between two major forms of memory, which afford either declarative or procedural knowledge. Declarative knowledge referred to knowledge available as conscious recollections about facts and events. Procedural knowledge referred primarily to skill-based information, where what has been learned is embedded in acquired procedures.

Subsequently, memory-impaired patients were found to exhibit intact priming effects (see Tulving & Schacter 1990 ). For example, patients (like healthy volunteers) could name pictures of objects 100 ms faster when the pictures had been presented previously than when they were presented for the first time and independently of whether patients could recognize the pictures as familiar ( Cave & Squire 1992 ).

Another important insight was the idea that the neostriatum (not the medial temporal lobe) is important for the sort of gradual, feedback-guided learning that results in habit memory ( Mishkin et al. 1984 ). Thus, memory-impaired patients learned at a normal rate when explicit memorization was not useful (for example, when the outcome of each trial was determined probabilistically and performance needed to be based on a gut feeling) ( Knowlton et al. 1996 ). Furthermore, tasks that healthy volunteers could learn rapidly by memorization (such as the concurrent learning of eight different, two-choice object discriminations) could also be learned successfully by profoundly amnesic patients, albeit very gradually (healthy volunteers required fewer than 80 trials; patients required more than 1000 trials). Although memory became robust in the patients after extended training (>90% accuracy), it differed from the memory acquired by healthy volunteers in that what was learned was outside of awareness and was rigidly organized (performance collapsed when the task format was modified) ( Bayley et al. 2005a ).

Given the wide variety of learning and memory phenomena that could be demonstrated in patients (for example, priming and habit learning), the perspective eventually shifted to a framework that accommodated multiple memory systems, not just two kinds of memory. Indeed, one could ask what the various kinds of memory that were preserved in patients had in common aside from the fact that they were not declarative. Accordingly, the term non-declarative was introduced with the idea that declarative memory refers to one kind of memory system and that nondeclarative memory is an umbrella term referring to several additional memory systems ( Squire & Zola-Morgan 1988 ). Nondeclarative memory includes skills and habits, simple forms of conditioning, emotional learning, priming, and perceptual learning, as well as phylogenetically early forms of behavioral plasticity such as habituation and sensitization.

Declarative memory is the kind of memory that is referred to when the term memory is used in everyday language. Declarative memory allows remembered material to be compared and contrasted. The stored representations are flexible, accessible to awareness, and can guide performance in a variety of contexts. Declarative memory is representational. It provides a way of modeling the external world, and it is either true or false. Nondeclarative memory is neither true nor false. It is dispositional and is expressed through performance rather than recollection. These forms of memory provide for myriad unconscious ways of responding to the world. In no small part, by virtue of the unconscious status of the nondeclarative forms of memory, they create some of the mystery of human experience. Here arise the dispositions, habits, and preferences that are inaccessible to conscious recollection but that nevertheless are shaped by past events, influence our behavior and mental life, and are an important part of who we are.

VISUAL PERCEPTION

Formal testing of patient H.M. over the years documented his good performance on intelligence tests and on other tests of perceptual function and lexical knowledge ( Kensinger et al. 2001 , Milner et al. 1968 ). He could detect the anomalous features of cartoon drawings, and he performed above the control mean on the Mooney “Closure” task, which requires participants to find a face in a chaotic black and white pattern with incomplete contour ( Milner et al. 1968 ). This perspective, that visual perception is intact after large medial temporal lobe lesions, was eventually challenged, first by work in monkeys ( Eacott et al. 1994 ) and later by studies in humans ( Lee et al. 2005a , b ). These studies proposed that the perirhinal cortex, one of the structures damaged in H.M., is important for complex visual perceptual tasks involving stimuli with substantial feature overlap. It was also proposed that the hippocampus is needed when spatial processing is required, as in visual discriminations involving scenes.

Although some subsequent studies appeared to provide additional support for this perspective ( Barense et al. 2007 , Lee & Rudebeck 2010 ), attempts to replicate some of the key early work and to find impairments with new tests were unsuccessful ( Shrager et al. 2006 ). Comprehensive reviews of this topic ( Suzuki 2009 , 2010 ) raised three important issues. First, a consideration of neuroanatomic and neurophysiological data emphasizes that the perirhinal cortex has unique characteristics that distinguish it from the laterally adjacent, unimodal visual area TE. The perirhinal cortex is a poly-modal association area with strong connections to the hippocampus and entorhinal cortex, and it is difficult to view the perirhinal cortex as a visual area and as a continuation of the ventral visual pathway ( Suzuki 2010 ).

Second, many of the studies designed to test visual perception, particularly studies in monkeys, involve a significant memory requirement. Thus, impaired associative learning or impaired long-term memory for the stimulus material could have contributed to many of the deficits reported after perirhinal lesions in monkeys. Even in studies of humans, impaired associative learning could result in deficient performance when different test stimuli need to be judged against the same two comparison stimuli on every trial ( Graham et al. 2006 ). Indeed, in a new study that explored this issue, patients with hippocampal lesions were impaired when the same comparison stimuli were used on every trial but were fully intact when the stimuli were unique to every trial ( Kim et al. 2011 ). Using fixed comparison stimuli gives an advantage to those who can remember because one can learn what to look for in the test stimuli to decide which comparison stimulus it most closely resembles.

Third, patients who exhibit impaired performance on tasks of visual perception may have significant damage to lateral temporal cortex in addition to medial temporal lobe damage. This idea merits consideration, given that two of the three patients with medial temporal lobe damage who were impaired were reported to have damage lateral to the medial lobe ( Barense et al. 2007 ; Lee et al. 2005a , b ; Lee & Rudebeck 2010 ). Also, estimates of damage in most of the patients who were impaired were based on ratings of single sections through the lateral temporal cortex, not on quantitative measures of the entire region, thus leaving large amounts of tissue unexamined.

The importance of thorough neuroanatomical measurement in neuropsychological studies of memory cannot be overstated. Many current disagreements about the facts and ideas emerging from neuropsychological research on human memory can be traced to concerns about the locus and extent of lesions. If a deficit is expected but not found, perhaps the damage is less extensive than believed. If a deficit is not expected but is found, perhaps the damage is more extensive than has been detected. There is no substitute for thorough, quantitative descriptions of damage based on magnetic resonance imaging, as well as (where possible) detailed neurohistological description of the postmortem brain.

The possible role of perirhinal cortex in certain kinds of visual perception remains a topic of discussion and will benefit from detailed analysis of the lesions in the cases under study. At the present time, the weight of evidence from experimental lesion studies in monkeys, neurophysiological studies, and human neuropsychological studies continues to support the view that medial temporal lobe structures are important for declarative memory and not for perceptual functions (see also Clark et al. 2011 ).

IMMEDIATE MEMORY AND WORKING MEMORY

The early descriptions of H.M. emphasized how capable he was at focusing his attention and at retaining information for short periods of time ( Milner et al. 1968 ). For example, he could retain a three-digit number for 15 minutes by continuous rehearsal, using what would now be termed working memory ( Baddeley 2003 ). Yet when his attention was diverted, he forgot the whole event. In one dramatic demonstration, participants heard digit strings of increasing length ( Drachman & Arbit 1966 ) ( Figure 3 a ). Each string was presented as many times as needed until it was reported back correctly. Then, a new digit string was presented that was one digit longer than the previous one. Controls made their first errors with strings of eight digits and were eventually able to repeat strings as long as 20 digits (with no more than 25 repetitions at any one string length). In contrast, H.M. exhibited a marked discontinuity in performance as the string length increased. He repeated up to six digits correctly on his first try (six was his preoperative digit span), but he never succeeded at seven digits, even though he was given 25 repetitions of the same string. The interpretation was that at short string lengths H.M. could rely on his intact immediate memory and that he failed when the material to be remembered was more than could be held in mind. That is, he failed when the material exceeded his immediate memory capacity.

Intact working memory and impaired long-term memory. ( a ) The number of trials needed to succeed at each string length for patient H.M. and controls. H.M. could not succeed at repeating back 7 digits even after 25 attempts with the same string. ( b ) The number of trials needed to learn the locations of different numbers of objects for patient G.P. and controls. G.P. could not reproduce the locations of four objects, even after 10 attempts with the same display (panel a adapted from Drachman & Arbit 1966 , with permission from the American Medical Association, and panel b adapted from Jeneson et al. 2010 ).

Time is not the key factor that determines how long information can be retained by patients like H.M. The relevant factors are immediate memory capacity and how successfully material can be maintained in working memory through rehearsal. Maintenance of information is difficult when material is difficult to rehearse (e.g., faces and designs). Moreover, working memory capacity can be quite limited, and typically only three or four simple visual objects can be maintained ( Cowan 2001 , Fukuda et al. 2010 ). With these considerations in mind, it is perhaps not surprising that impaired performance after medial temporal lobe lesions has sometimes been reported at short retention intervals, usually when the task requires learning complex material or learning the relations between items (e.g., object-location associations) ( Finke et al. 2008 , Hannula et al. 2006 , Kan et al. 2007 , Olson et al. 2006 ). In these cases, the important question is whether working memory capacity has been exceeded and performance must rely on long-term memory, or whether working memory sometimes depends on the medial temporal lobe. Methods that are independent of the particular task that is used are needed to decide this question.

One approach to this issue seems promising in cases where the retention interval is long enough (about 8 seconds) to allow a manipulation to be introduced during the interval ( Shrager et al. 2008 ). Controls (but not patients) were given either distraction or no distraction between study and test. Across experiments involving names, faces, or object-location associations, patient performance was related to how distraction affected controls. The patients were impaired when distraction had no effect on control performance, and the patients were intact when distraction disrupted control performance. These results suggested that the patients were impaired when the task depended minimally on working memory (as indicated by the ineffectiveness of distraction on control performance), and they performed well when the task depended substantially on working memory (as indicated by the disruptive effect of distraction on controls). Thus, for the kinds of material studied here, including relational information for objects and locations, working memory appears to be intact after medial temporal lobe damage.

A possible approach in cases where the retention interval is very short (1–3 seconds) is based on the early study of digit span, described above. Participants saw different numbers of objects (1 to 7) arranged on a tabletop and then immediately tried to reproduce the array on an adjacent table ( Jeneson et al. 2010 ) ( Figure 3 b ). The same study-test sequence was repeated (up to a maximum of ten times) until participants correctly placed each object within a specified distance of its original location. The finding was that performance was intact when only a few object locations needed to be remembered. However, just as was found for digit strings, there was an abrupt discontinuity in performance with larger numbers of object locations. For example, patient G.P. (who has large medial temporal lobe lesions similar to H.M.’s lesions) learned 1, 2, or 3 object locations as quickly as did controls, needing no more than one or two tries at each stage. However, when four object locations needed to be remembered, he could not succeed even in 10 attempts with the same array. These findings suggest that the maintenance of relational information (in this case, object-location associations) can proceed normally, even in patients with large medial temporal lobe lesions. An impairment is evident only when a capacity limit is reached, at which point performance must depend, at least in part, on long-term memory.

These observations support the view that patients with medial temporal lobe lesions can succeed at remembering whatever they have encountered, so long as the material to be remembered can be supported by a limited-capacity, short-term memory system (see also Jeneson et al. 2011 ). This formulation touches on a large and fundamental issue: whether there is any ability at all that depends on the hippocampus and related structures, even when a task can be managed within working memory. That is, do these structures perform any online computations for which the distinction between working memory and long-term memory is irrelevant?

This is a question of considerable current interest. It runs through discussions of perceptual functions and discussions of relational memory (as considered in this section and the preceding section). The issue is especially prominent in discussions of spatial cognition. For example, the ability to path integrate (i.e., the ability to use self-motion cues to keep track of a reference location as one moves though space) has been proposed to have a fundamental dependency on the hippocampus and entorhinal cortex. That is, these structures are proposed to carry out computations essential for path integration, regardless of the memory load or the retention interval ( Whitlock et al. 2008 ). Furthermore, the hippocampus is proposed to be necessary for constructing a spatially correct mental image of either a remembered scene or an imagined scene ( Bird et al. 2010 , Bird & Burgess 2008 ), a task that need not involve recollection at all.

In the case of path integration, humans can succeed at simple paths in the absence of hippocampus and entorhinal cortex so long as the task can be managed within 30–40 seconds (presumably supported by working memory) ( Shrager et al. 2008 ). In the case of spatial imagining, patients with severe memory impairment can describe routes around their childhood neighborhoods, including when main routes are blocked and alternative routes must be found ( Rosenbaum et al. 2000 , Teng & Squire 1999 ). Furthermore, in one study, patients with hippocampal damage successfully imagined future events and provided a normal number of spatial referents ( Squire et al. 2010 ; see Hassabis et al. 2007 for a deficit on a similar task). These demonstrations appear straightforward and would seem to raise doubts about the idea that the hippocampus performs online computations. Yet there is an alternate perspective. Specifically, it has been suggested that spatial representations can be established outside the hippocampus, and in parallel with hippocampal representations, but using somewhat different computations ( Bird & Burgess 2008 , Whitlock et al. 2008 ). By this account, some spatial tasks that are accomplished successfully after hippocampal damage are in fact being accomplished using different structures and different computations than are used by healthy individuals.

The idea is that, despite intact performance in patients, some tasks are still hippocampus-dependent and could be shown to be so if one could devise tasks that can only be done with computations unique to the hippocampus. This is an interesting perspective and one that, in principle, could be applied to any example of intact performance in patients. It will be difficult to resolve issues like these without understanding which strategies are used in any particular case and without gaining experimental control over them. In addition, tasks that can be solved by different structures and using different strategies may be associated with inconsistent deficits after hippocampal lesions. In contrast, there are some tasks that depend on the medial temporal lobe, where performance deficits are invariably pronounced, and where performance cannot be made to appear normal by recruiting other brain structures or by using different strategies. These are tasks that assess the ability to form conscious long-term memory of facts and events, and the inability to carry out this function appears to be the central deficit in H.M. and other patients with medial temporal lobe lesions.

REMOTE MEMORY AND MEMORY CONSOLIDATION

A key insight about the organization of memory came with early observations of H.M.’s capacity to remember information that he acquired before his surgery in 1953. Initially, he was described as having a loss of memory (retrograde amnesia) covering the three years immediately preceding surgery and with earlier memories “seemingly normal” ( Scoville & Milner 1957 , p. 17). About ten years later, the impression was similar as there did not appear to have been any change in H.M.’s capacity to recall remote events antedating his operation, such as incidents from his early school years, a high school attachment, or jobs he had held in his late teens and early twenties ( Milner et al. 1968 , p. 216).

The first study of this issue with formal tests asked H.M. to recognize faces of persons who had become famous in the decades 1920–1970 ( Marslen-Wilson & Teuber 1975 ). As expected, he performed poorly in the postmorbid period (the 1950s and 1960s) but did as well as or better than age-matched controls at recognizing faces from the premorbid period (the 1920s–1940s). This important finding implied that medial temporal lobe structures are not the ultimate storage sites for acquired memories. Memories that initially require the integrity of medial temporal lobe structures must be reorganized as time passes after learning so as to gradually become independent of these structures. The extent of retrograde amnesia provides an indication of how long this process takes.

Retrograde amnesia can be either temporally limited, covering a few years, or prolonged, depending on the locus and extent of the damage. Patients with damage thought to be restricted to the hippocampus had retrograde amnesia for past news events that extended only a few years into the premorbid period ( Manns et al. 2003b ). By contrast, patients with large medial temporal lobe lesions (damage to hippocampus plus parahippocampal gyrus) exhibited extended retrograde amnesia that covered several decades, albeit sparing memories acquired in early life (patients E.P. and G.P.; Bayley et al. 2006 , Bright et al. 2006 ). The possibility that some amount of more lateral damage (e.g., in the fusiform gyrus) contributed to the extended retrograde impairment in E.P. and G.P. cannot be excluded.

There has been particular interest in the status of autobiographical memories for unique events following medial temporal lobe damage, and in recent years methods have been developed to assess the detail with which such recollections can be reproduced. In the earliest formal assessments of H.M. ( Sagar et al. 1985 ), he produced well-formed autobiographical memories from age 16 and younger (his surgery occurred at age 27). However, the situation seemed to change as H.M. aged. In a later update ( Corkin 2002 ), H.M. (now 76 years old) was reported to have memories of childhood, but the memories appeared fact-like and lacked detail. It was stated that he could not reproduce a single event that was specific to time and place. In a formal study reported a few years later ( Steinvorth et al. 2005 ), he was also impaired in recollecting events from his early life. It was concluded that autobiographical memories remain dependent on the medial temporal lobe so long as the memories persist.

This conclusion about H.M. is complicated by the findings from MRI scans obtained in 2002 and 2003 ( Salat et al. 2006 ). These scans documented a number of significant changes since his first MRI scans from 1992–1993 ( Corkin et al. 1997 ) ( Figure 1 ). Specifically, the scans showed cortical thinning, subcortical atrophy, large amounts of abnormal white matter, and subcortical infarcts. All these features were thought to have developed during the past decade, and they complicate the interpretation of neuropsychological data collected during and after this period. Considering the earlier reports that he could successfully retrieve past autobiographical memories ( Milner et al. 1968 , Scoville & Milner 1957 ), it is possible that remote autobiographical memories were in fact intact during the early years after surgery but were later compromised by neurological change. It is also possible that the available memories faded with time because they could not be strengthened through rehearsal and relearning.

Other work has supported the earlier descriptions of H.M. For example, methods similar to those used to assess H.M. have also been used to evaluate autobiographical memory in other patients with hippocampal damage or larger medial temporal lobe lesions ( Bright et al. 2006 , Kirwan et al. 2008 ). These patients had intact autobiographical memory from their early lives. The following example illustrates a well-formed autobiographical memory produced by E.P. about his early life, one of 18 that he produced. In this case, he was asked for a specific recollection in response to the cue word “fire.” Like most recollections, his narrative contains both fact-based and event-specific information. Note the several repetitions in the narrative, which reflect his severe anterograde amnesia.

Dad had 31/2 acres of property in Castro Valley and the back property would just grow and would be dry and for some reason, I didn’t do it, but somehow or other the next thing we knew is that it was starting to burn. I told dad and he called the Castro Valley fire department. They came up and they got it out real quick. However it started I don’t know. He had 31/2 acres of property and he just let it grow. It would be grass or whatever. Who knows how it started, but it started to burn. Dad called the Castro Valley fire department and they came up and all the volunteers came in and they got it out in a matter of 10–15 minutes. They stamped it out. They don’t know how it started. I was 16–17, in that bracket. Dad had 31/2 acres of property. It was summer time, 1938. Those sort of things I think you remember. ( Bayley et al. 2003 , p. 139)

The same finding of intact early memories was reported in 10 patients with medial temporal lobe lesions in a study of emotional (and remote) autobiographical memories ( Buchanan et al. 2005 ), and in two other patients (M.R. and P.D.), using a simpler assessment device ( Eslinger 1998 ). In another study of four patients with medial temporal lobe damage and variable damage to anterior and posterior temporal neocortex ( Rosenbaum et al. 2008 ), one patient (S.J.) was reported to have extended retrograde amnesia for autobiographical memory. The other three patients were less impaired, performing poorly in time periods closer to the onset of their amnesia. The impairment in S.J. was attributed to hippocampal damage. Alternatively, it is difficult to rule out a substantial contribution from the damage that was identified in neocortex.

It is noteworthy that, not infrequently, patients have been described as having extensive and ungraded retrograde amnesia (i.e., unrelated to how long ago the memory was formed) (for examples, see Bright et al. 2006 , Cipolotti et al. 2001 , Noulhiane et al. 2007 , Rosenbaum et al. 2008 , Sanders & Warrington 1971 ). This pattern of impairment has sometimes been taken to mean that the hippocampus (or related structures) is required as long as a memory persists. Yet, in many cases testing did not cover early adulthood and adolescence, so it is possible that the amnesia was not as ungraded as it appeared to be. In other cases, the damage was known to extend substantially into lateral temporal neocortex (see Bright et al. 2006 and Squire & Bayley 2007 for consideration of several cases). In one report of patients with unilateral temporal lobe resections, autobiographical memory was impaired across all past time periods ( Noulhiane et al. 2007 ). In these patients, damage was recorded in the medial temporal lobe as well as in the temporal pole and in the anterior aspect of the superior, middle, and inferior temporal gyri. It is difficult to know to what extent this damage outside the medial temporal lobe might have contributed to the impairment. Significant damage to lateral temporal or frontal cortex can severely impair performance on tests of remote memory, including tests of autobiographical memory about early life [7 cases, Bright et al. (2006) ; patients H.C., P.H., and G.T., Bayley et al. (2005b) ; patient E.K., Eslinger (1998) ]. If lateral temporal cortex, for example, is a site of long-term memory storage ( Mishkin 1982 , Miyashita 1993 ), then lateral temporal damage would be expected to cause severe and extended retrograde amnesia. The difficulty is knowing in any particular case to what extent such damage is responsible for impaired remote memory.

Among several single-case studies reporting impaired memory for early-life events (see Squire & Bayley 2007 for discussion), patient V.C. has been the most carefully documented. The volume of his lateral temporal lobes was reported as normal. Yet, it is striking that V.C.’s 1/9 score on the childhood portion of the autobiographical memory interview differs sharply from the good scores (and sometimes maximum scores of 9) obtained on the same test by as many as 12 patients with MRI documentation of limited medial temporal lobe damage [ n = 8, Bayley et al. (2006) ; n = 2, Eslinger (1998) ; n = 1, Kapur & Brooks (1999) ; n = 1, Schnider et al. (1995) . With the possible exception of V.C., we are unaware of memory-impaired patients who have damage limited to the medial temporal lobe (as documented by neurohistology or thorough MRI) and who do so poorly at recollecting remote autobiographical memories ( Figure 4 ).

( a ) Participants copied the Rey-Osterrieth figure illustrated in the small box in the upper left and 10–15 min later, without forewarning, tried to reproduce it from memory. The reproduction by a representative control is shown below the target figure. The left panel also shows the reproduction by patient R.B., who had histologically identified lesions of the CA1 field of the hippocampus ( Zola-Morgan et al. 1986 ). Patient E.P., who had large medial temporal lobe lesions, did not recall copying a figure and declined to guess. The right section shows reproductions by seven patients with circumscribed damage to the hippocampus. Panels b and c show scores for the same seven patients (H) and 13 controls on the autobiographical memory interview, childhood portion ( Kopelman et al. 1989 ). These findings suggest that patients who fail to produce any of the complex figure (like E.P.) or who are deficient at producing either remote semantic memories (A, maximum score, 21) or remote autobiographical events (B, maximum score, 9) will prove to have damage beyond the hippocampus. Indeed, even E.P. with his large lesions limited mainly to the medial temporal lobes, obtained maximal scores on these two tests (21/21 and 9/9).

The finding that retrograde amnesia is temporally limited after damage to the medial temporal lobe implies a process of reorganization whereby over time memories become less dependent on medial temporal lobe structures. As time passes after learning, the role of medial temporal lobe structures diminishes and a more permanent memory gradually develops, presumably in neocortex. According to a different perspective, only fact-based memories (not autobiographical memories) make this transition ( Winocur et al. 2010 ). This view discounts the possible importance of neocortical damage in patients with impaired autobiographical remembering of remote events and attributes the impairment specifically to hippocampal damage.

Some studies in experimental animals have directly tracked neural activity and structural changes in the hippocampus and neocortex after learning. Expression patterns of c-Fos described gradually decreasing activity in the mouse hippocampus after learning and parallel increases in a number of cortical regions ( Frankland & Bontempi 2005 ). These findings and others ( Restivo et al. 2009 ) reflect the increasing importance of distributed cortical regions for the representation of memory as time passes. The idea is not that memory is literally transferred from the hippocampus to neocortex but that gradual changes in the neocortex increase the complexity, distribution, and connectivity among multiple cortical regions. The next section considers what the study of patients has contributed to understanding the organization and storage of long-term memory.

MEMORY IN THE NEOCORTEX

The view that emerged from the study of H.M. and other patients is that medial temporal lobe structures are uniquely specialized to establish and maintain declarative memories. Other structures support the initial perception and processing of an experience, and these other structures are also critical for the long-term storage of the experience. A long-standing view is that the cortical processing of a multisensory experience leaves a distributed record in the same multiple regions that initially performed the processing. For example, neurons in visual areas store the visual aspect of a multisensory experience, neurons in auditory areas store the auditory aspect of the experience, other areas store the spatial aspects, and so on. According to this view, any act of remembering consists of the coordinated reactivation of the distributed neocortical regions that were engaged at the time of encoding ( Damasio 1989 , De Renzi 1982 , Mishkin 1982 , Squire 1987 ). When a memory is first formed, this reactivation depends on the hippocampus and related structures, but once memory is fully consolidated, reactivation can occur independently in neocortex.

A considerable body of evidence supporting the reactivation view has come from studies using fMRI (see Buckner & Wheeler 2001 , Danker & Anderson 2010 for reviews). For example, several studies have found that the modality-specific or category-specific processes engaged at encoding tend to be re-engaged at retrieval (e.g., Polyn et al. 2005 , Wheeler et al. 2000 , Woodruff et al. 2005 ). This perspective of remembering implies that the dedicated processing areas of the neocortex can also be viewed as memory areas. However, rather than broadly encoding and consolidating memories, like the structures of the medial temporal lobe, each neocortical region operates within a very specific domain, and each region stores only specific features of an experience. It follows then that the same neocortical lesions that selectively impair processing in one particular domain should also cause correspondingly specific anterograde and retrograde memory impairments within the same domain. Although an extensive literature documents the selective information-processing deficits that are associated with different cortical lesions, the effects of those lesions on new learning and past remembering are only rarely considered. Here, we consider the cognitive effects of selective processing deficits with a view toward also identifying the effects on memory.

Achromatopsia

Finding selective anterograde memory impairment in association with a selective perceptual processing deficit would not be surprising. That is, if a perceptual deficit is present in one modality (e.g., visual perception), it should also be difficult to learn new material presented in the same modality. In addition, there should be consequences for remembering the past. Specifically, a selective deficit in processing particular features of visual material should selectively compromise the ability to recollect the same features in a previous memory, while leaving other aspects of the memory intact. This idea is illustrated by “The Case of the Color-blind Painter” ( Sacks 1995 ). An accomplished painter was involved in an automobile accident at the age of 65, which rendered him completely color blind. Although the anatomical basis of his disability was not identified, it was thought to have been caused by damage to regions dedicated to the perception of color (possibly including area V4). The disability itself was striking. The patient could discriminate between wavelengths of light, even though the different wavelengths no longer gave rise to the perception of different colors. Instead, different wavelengths gave rise to the perception of different shades of gray. Because this was a case of acquired cerebral achromatopsia (i.e., cortical color blindness), it was possible to ask about the status of previously established memories that had once included the subjective experience of color. If color in early memories depends on the same cortical structures that support the perception of color, then previously intact memories that were once retrieved in color should now be retrieved in black and white. Indeed, the case description leaves little doubt that the patient’s experience—both going forward and looking back—was now completely (and selectively) devoid of color. Although he retained abstract semantic knowledge of color, he could neither perceive nor later remember the color of objects presented to him (anterograde impairment). In addition, he could not subjectively experience color in his earlier (and once chromatic) memories (retrograde impairment). For example, he knew that his lawn was green, but he reported that he could no longer visualize it in green when he tried to remember what it once looked like.

Prosopagnosia

Similar effects have been documented by formal testing in cases of acquired prosopagnosia (impaired recognition of faces, or face blindness). The cardinal complaint of patients diagnosed with prosopagnosia is that they have a selective retrograde memory deficit. That is, once-recognizable faces no longer yield a memory signal, even though other aspects of one’s memory for the same individuals are preserved. For example, a patient who could not recognize his mother’s face might continue to recognize the sound of her voice and still be able to recall his prior experiences with her.

Patient L.H., a 37-year-old man, sustained a severe closed-head injury in an automobile accident at the age of 18 ( Farah et al. 1995a , b ). His brain damage involved bilateral inferior temporo-occipital regions, as well as the right inferior frontal lobe and right anterior temporal lobe. Although general intellectual and elementary visual capabilities were preserved following the accident, L.H. became profoundly impaired at recognizing previously familiar faces. Along with this retrograde memory deficit, L.H. also exhibited a perceptual processing deficit that was selective for upright faces. For example, on a same/different face discrimination task, L.H. performed worse than controls at discriminating upright faces (consistent with a face perception deficit), but he performed unexpectedly better than controls at discriminating inverted faces (indicating that general perceptual abilities were preserved). Patient L.H. also exhibited anterograde amnesia for new faces. For example, L.H. and controls were presented with black and white photographs of both faces and common objects and asked to memorize them ( Farah et al. 1995a ). On a later recognition test, control subjects performed at the same level for faces and nonface objects. L.H’s ability to remember faces was selectively impaired.

The retrograde memory deficit associated with acquired prosopagnosia is not confined to recognition memory but applies as well to recalling and imaging the past. In one study, ( Barton & Cherkasova 2003 ), seven patients with adult-onset prosopagnosia performed comparative judgments about the configuration of famous faces that they tried to retrieve from memory (e.g., “Who has the more angular face: George Washington or Abraham Lincoln?”). The famous faces used in this test were presumably familiar before the onset of prosopagnosia. Even so, the patients were severely impaired on the face imagery task. Together, the findings from acquired prosopagnosia—a modular perceptual processing deficit associated with selective anterograde and retrograde amnesia—suggest that the same areas that support the perception of faces also support the long-term memory of faces.

This same set of findings, whereby an acquired and relatively modular processing deficit is associated with corresponding memory deficits (both anterograde and retrograde), has also been reported in a patient who lost the ability to recognize familiar music while retaining other perceptual and intellectual functions (amusia). Patient I.R. suffered bilateral brain damage at the age of 28 after undergoing a series of operations to clip aneurysms on the left and right middle cerebral arteries ( Peretz et al. 1998 , Peretz & Gagnon 1999 ). At the time she was tested (in her early 40s), CT scans indicated that the superior temporal gyrus was severely damaged bilaterally, and the lesion also extended to involve structures in the frontal cortex and anterior inferior parietal lobule.

I.R. was of normal intelligence, and her overall memory ability was normal as well. In addition, she exhibited no evidence of a hearing impairment according to standard audiometric tests, and except for music she had no difficulty recognizing familiar environmental sounds. However, tunes that were once familiar to her were now unrecognizable, and she could no longer sing music from memory (which she had previously been able to do). Her selective retrograde amnesia for previously familiar music was also accompanied by a selective perceptual deficit for music. Musical perception was tested using a same/different format in which two short excerpts were presented in succession (e.g., Mozart’s piano concerto #27 followed by Mozart’s piano concerto #23). Controls found this task so easy that they made no errors even when the interstimulus interval was long (20 s) and filled with conversation, but I.R.’s performance was no better than 80% correct even when the interstimulus interval was short (4 s).

She also exhibited anterograde amnesia for new music. A list of 15 briefly presented melodies was presented for study. On a subsequent old/new recognition test involving the 15 old melodies intermixed with 15 new ones, her memory performance was no better than chance (whereas control performance exceeded 85% correct). Thus, as with the cases of acquired achromatopsia and acquired prosopagnosia discussed earlier, impairments associated with acquired amusia imply a close connection between information processing and storage. The specificity of her anterograde and retrograde memory deficits corresponded directly to the specificity of her perceptual deficit.

Knowledge Systems

The findings considered here are consistent with the idea that memory storage in the neocortex reflects the outcome of the perceptual processing and analysis that occurred at the time of learning. A related literature concerns the status of stored semantic knowledge and its relation to information processing. These studies do not document a deficit in specific perceptual processing modules. Instead, they document the effects of cortical lesions (e.g., to posterior temporal cortex) on previously acquired knowledge within specific semantic categories, and they relate these deficits to the kinds of processing involved when the knowledge was first acquired.

The idea that knowledge systems may be organized by semantic categories was discussed by Warrington & Shallice (1984) . They described four patients with widespread bilateral lesions (following herpes simplex encephalitis) that included the medial and lateral temporal lobes. In addition to having global amnesia, all four patients exhibited an asymmetry in their ability to identify animate and inanimate objects. They had a selective impairment in the ability to name or describe pictures of animate objects (e.g., animals and plants). By contrast, their ability to name or describe pictures of inanimate objects (e.g., broom, pencil, umbrella) appeared to be preserved. Assuming that all the objects were previously familiar to the patients, the findings describe a category-specific retrograde memory impairment.

Other patients exhibited the opposite impairment. For example, patient Y.O.T., who had damage to the left temporoparietal region (thought to have resulted from a thromboembolism), showed relatively preserved knowledge of living things and poor knowledge of inanimate objects ( Warrington & McCarthy 1987 ). However, her comprehension of body parts and fabrics was anomalous in that she exhibited knowledge about fabric names (non-living things) and poor knowledge about body parts (living things). In addition, Warrington & McCarthy (1987) noted that patient J.B.R. [one of the four patients previously described by Warrington & Shallice (1984) ], who had exhibited a selective loss of knowledge about living things, nevertheless had preserved knowledge about body parts (living things) and poor knowledge about fabrics (nonliving things). These findings suggested that the principle by which knowledge is organized in the brain concerns whether objects are identified mainly by their physical features (form, color, texture, etc.) or by their function and how they are used. Generally, the animate/inanimate distinction fits this principle, but the exceptions are telling. Most animals are identified by their physical attributes, not by what can be done with them. By contrast, small inanimate objects are usually identified by their functions and how they are used (e.g., sweep with a broom, write with a pencil). However, some living things (such as body parts) are identified largely by their function, and some nonliving things (such as fabrics) are identified largely by their texture and shape. A recent comprehensive review of neuroimaging evidence strongly supports this account of stored semantic knowledge ( Martin 2007 ).

If these category-specific retrograde memory deficits reflect the loss of knowledge that was initially acquired through category-specific processing, then a corresponding anterograde memory deficit would be expected, as well. Thus, for example, a patient who exhibits a selective deficit in naming or describing objects that are defined by how they are used should also exhibit a selective deficit in learning novel objects that are defined by how they are used. To our knowledge, this prediction has not been tested.

RECOLLECTION AND FAMILIARITY

In recent years, there has been extended investigation of the idea that the different medial temporal lobe structures (hippocampus, entorhinal cortex, perirhinal cortex, and parahippocampal cortex) may support different memory functions. The study of H.M. could not address this issue because his bilateral lesions included most of these structures. However, other patients, especially patients with limited hippocampal lesions, have been useful in this regard.

One issue that has commanded considerable attention concerns the roles played by the hippocampus and perirhinal cortex in recognition memory. Recognition memory is thought to be supported by two processes, recollection and familiarity ( Atkinson & Juola 1974 , Mandler 1980 ). Recollection involves remembering specific contextual details about a prior learning episode; familiarity involves simply knowing that an item was presented without having available any additional information about the learning episode. According to one view, both the hippocampus and the perirhinal cortex contribute to recollection and familiarity ( Squire et al. 2007 , Wixted & Squire 2010 ). According to a different view, the hippocampus and perirhinal cortex selectively support recollection and familiarity, respectively ( Brown & Aggleton 2001 , Eichenbaum et al. 2007 ).

Recall versus Recognition

One approach to investigating this issue has been to compare performance on an old/new recognition task, which is widely thought to be supported by both recollection and familiarity, with performance on a task of free recall, which is thought to depend mainly on recollection. (In a free recall task, subjects are presented with a list of items to memorize and are later asked to recall those items in any order they wish.) Because old/new recognition can be partially supported by familiarity, the question of interest is whether the performance of patients with hippocampal lesions is disproportionately better on an old/new recognition task in comparison to free recall.

Several case studies and group studies have asked this question of patients with adult-onset bilateral lesions that, according to quantitative MRI, are limited to the hippocampus. The case studies differ in their findings about the status of old/new recognition memory ( Aggleton et al. 2005 , Cipolotti et al. 2006 , Mayes et al. 2002 ). Because the differing results may reflect individual differences, group studies are more informative. Two group studies have shown that the degree of impairment is similar when old/new recognition and free recall are compared ( Kopelman et al. 2007 , Manns et al. 2003a ) ( Figure 5 ). Another group study involved 56 hypoxic patients with damage believed to be limited to the hippocampus (no radiological information was available) ( Yonelinas et al. 2002 ). The patients were less impaired on old/new recognition than on free recall. However, this conclusion was later shown to result from the remarkably aberrant recognition performance of a single 1 of the 55 control subjects ( Wixted & Squire 2004 ). With that one outlier removed from the analysis, the patients and controls exhibited similar levels of impairment on recall and recognition. The recognition z-score for the patients was −0.59 (before removal of the outlier, z = −0.39), and the recall z-score was a statistically indistinguishable −0.68. Thus, the available group studies are consistent in showing that the degree of memory impairment in patients with lesions limited to the hippocampus is similar for old/new recognition (which is substantially supported by familiarity) and for free recall (which is fully dependent on recollection). These findings suggest that the hippocampus is important for both recollection and familiarity.

Individual recognition ( a ) and recall scores ( b ) for hippocampal patients ( n = 7) and healthy controls ( n = 8) from Manns et al. (2003a) . When the patient scores for recognition and recall are converted to z-scores based on the mean and standard deviation of the corresponding control scores, the recognition deficit (−1.59) is statistically indistinguishable from the recall deficit (−1.81), p > 0.60. d ′ = discriminability.

Remember/Know Procedure

Another method that has been used to investigate the role of the medial temporal lobe in recollection and familiarity is the Remember/ Know procedure, which is based on subjective reports of whether recollection is available when an item is declared old. Participants report Remember when they can recollect something about the original encounter with the item (e.g., its context, what thoughts they had), and they report Know when they judge the item to be familiar but cannot recollect anything about its presentation. The Remember/Know judgments made by patients and controls are often converted into quantitative estimates of recollection and familiarity based on a widely used but controversial model of recognition memory ( Yonelinas 1994 ). Using this method, some studies have reported that recollection is selectively impaired in patients with hippocampal lesions ( Yonelinas et al. 2002 ), whereas other studies have found impairments in both recollection and familiarity ( Manns et al. 2003a ). A difficulty with deriving quantitative estimates of recollection and familiarity from Remember/Know judgments is that the assumptions of the model that is used to derive estimates have generally not been supported by empirical test (e.g., Heathcote 2003 , Rotello et al. 2005 , Slotnick 2010 , Slotnick & Dodson 2005 ). In particular, Know judgments reflect weaker memory than do Remember judgments, as measured by both confidence and accuracy (e.g., Dunn 2004 , Squire et al. 2007 ). Thus, a supposed impairment in recollection (Remembering) after hippocampal lesions could simply mean that the patients have few strong memories (and that what would have been strong memories are now weak memories), not that recollection is selectively affected. The Remember/Know procedure could be used to study recollection and familiarity effectively if Remember and Know judgments were first equated for confidence and accuracy, but this approach has not been used in patient studies to date.

Analysis of the Receiver Operating Characteristic

Still another method that has been used to estimate recollection and familiarity has been to fit the Yonelinas (1994) dual-process model to receiver operating characteristic (ROC) data. This is the same model that has often been used to estimate recollection and familiarity using the Remember/Know procedure. An ROC is a plot of the hit rate versus the false alarm rate across different decision criteria. Typically, multiple pairs of hit and false alarm rates are obtained by asking subjects to provide confidence ratings for their old/new recognition decisions. A pair of hit and false alarm rates is then computed for each level of confidence, and the paired values are plotted across the confidence levels. The points of an ROC typically trace out a curvilinear path that can be characterized in terms of its symmetry relative to the negative diagonal ( Figure 6 ). The dual-process model proposed by Yonelinas (1994) holds that the degree of asymmetry in an ROC directly reflects the degree to which the recollection process is involved in recognition decisions. Accordingly, a symmetrical ROC indicates that recognition decisions were based solely on familiarity, and an asymmetrical ROC indicates that recollection occurred for some of the items, as well.

Symmetrical ( a ) and asymmetrical ( b ) receiver operating characteristic (ROC) plots with hypothetical data shown as filled red circles. The axis of symmetry is the negative diagonal ( dashed gray line ), and chance performance is indicated by the positive diagonal ( solid blue line ). The symmetrical ROC ( a ) reflects relatively weak memory (the data fall close to the positive diagonal), and the asymmetrical ROC ( b ) reflects stronger memory (the data fall farther from the positive diagonal).

The finding that memory-impaired patients produce symmetrically curvilinear ROCs, whereas controls produce asymmetrical curvilinear ROCs, has been interpreted to mean that the recollection process is selectively impaired by hippocampal lesions ( Yonelinas et al. 1998 , 2000). However, once again, this is a model-dependent interpretation, and much evidence that has accumulated against this model in recent years instead supports an alternative signal-detection model (e.g., Dunn 2004 , 2008 ; Wixted 2007 ; Wixted & Mickes 2010 ). According to the signal-detection model, a symmetrical ROC does not indicate familiarity-based responding but simply reflects weaker memory. Because patients have weaker memory than do controls, the fact that patients tend to exhibit symmetrical ROCs is not surprising.

The question is whether patients can exhibit asymmetrical ROCs (like controls) once the strength of memory is equated. In one study, patients with lesions limited to the hippocampus were studied under two conditions (weak and strong memory) ( Wais et al. 2006 ). In the weak condition, patients studied 50-item word lists, as did matched controls. As expected, the controls performed better than the patients did. In addition (again as expected), the control ROC was asymmetrical, and the patient ROC was symmetrical. To equate for overall memory strength, patients also studied lists of 10 items, which improved their memory performance to a level similar to that of the controls who had studied 50-item lists. In this condition, the patient ROC and the control ROC were similarly asymmetrical. These results show that patients can exhibit asymmetric ROCs, which have been taken to denote performance based on recollection. The results further suggest that the typical finding of asymmetrical ROCs for controls and symmetrical ROCs for patients does not necessarily indicate a selective deficit in recollection but can reflect a difference in overall memory strength.

Newer (Model-Free) Methods

The effects of hippocampal lesions on recollection and familiarity can also be studied in a way that does not depend on the assumptions of any specific psychological model. If hippocampal lesions selectively impair recollection, and preserve familiarity, then patients with hippocampal lesions should commonly experience strong, familiarity-based recognition that is unaccompanied by recollection. Furthermore, this experience should occur even more frequently in patients than controls because ordinarily when strong, familiarity-based recognition occurs (e.g., seeing a familiar face), details about prior encounters are remembered, as well.

In a formal test of this prediction, five patients with circumscribed hippocampal damage studied 25 words in one of two contexts (source A or source B) ( Kirwan et al. 2010 ). Old/new recognition memory for the words was then tested using a six-point confidence scale (1 = sure new, 6 = sure old). For items endorsed as old, participants were also asked to make a source recollection decision (was the item learned in context A or B?). Old decisions made with high confidence but in the absence of successful source recollection would thus correspond to strong, familiarity-based recognition without recollection. The results were that there was no increased tendency for this experience to occur in patients relative to controls. If anything, the experience was less frequent in the patients. The simplest explanation for this result is that hippocampal damage impairs familiarity as well as recollection.

In summary, a large body of evidence based on the Remember/Know procedure and ROC analysis has been interpreted to mean that the hippocampus subserves recollection and plays no role in familiarity. It is often not appreciated that this interpretation is based on a specific model that equates weak memory with familiarity and strong memory with recollection [the model proposed by Yonelinas (1994) ]. However, familiarity can sometimes be strong, and recollection can sometimes be weak ( Wixted & Mickes 2010 ). In studies that do not depend on this model, the results suggest that hippocampal lesions impair both recollection and familiarity ( Kirwan et al. 2010 , Wais et al. 2006 ).

The fact that a memory strength confound can explain why earlier studies have failed to detect impaired familiarity in hippocampal patients should not be taken to mean that “memory strength” is a concept that usefully informs the functional organization of medial temporal lobe structures. Consideration of how these structures contribute differently to memory properly begins with neuroanatomy. Information from neocortex enters the medial temporal lobe at different points ( Suzuki & Amaral 1994 ). Perirhinal cortex receives strong input from unimodal visual areas, and the parahippocampal cortex receives prominent projections from areas important for spatial cognition, including posterior parietal cortex. This anatomical specialization suggests that perirhinal cortex may be especially important for visual memory (regardless whether a task requires recollection), and the parahippocampal cortex may be important for spatial memory. The finding of severe impairment in monkeys in visual associative tasks after perirhinal lesions ( Murray et al. 1993 ) and in spatial tasks after parahippocampal cortex lesions ( Malkova & Mishkin 2003 ) conforms to this suggestion. The hippocampus itself receives input from the adjacent cortex and is thus in a position to combine the operations of memory formation that are carried out by the more specialized structures that project to it. As expected, hippocampal lesions impair both visual memories and spatial memories. The impairment in memory formation is only modestly severe because many memory functions can be carried out by the adjacent cortex [for additional discussion of differences in the function of medial temporal lobe structures, see Squire et al. (2007) , Wixted & Squire (2011) ].

GROUP STUDIES AND MULTIPLE METHODS

The study of patients with medial temporal lobe lesions (especially the severely impaired patient H.M.) has led to dramatic advances in understanding the structure and organization of memory. As work progressed, many studies came to focus on smaller lesions and less severe impairments. Furthermore, many of these studies were based on single cases and investigated specific questions about particular aspects of the impairment (for example, recall versus recognition or recollection versus familiarity). Such questions are difficult to settle from individual case studies because the expected effects are relatively small. Under such conditions, a deficit may reflect (unmeasured) premorbid individual differences rather than the effect of a focal brain lesion. Accordingly, for many questions single case studies are more suggestive than conclusive, and group studies are needed to answer experimental questions in a compelling way.

The advantage of group studies is that individual variability tends to be averaged out. However, group studies are useful only to the extent that the lesions can be documented and quantified with MRI. Some group studies have studied patients with assumed lesions, such as patients with modest memory impairments due to hypoxia who are studied on the untested assumption that their lesions are limited to the hippocampus. Given techniques currently available for quantifying the locus and extent of lesions, the use of such techniques in both single-case and group studies should become standard practice.

It is important to emphasize that studies of patients with lesions provide only one of many experimental approaches to investigating the organization of memory. The same issues have been usefully investigated in experimental animals with lesions (e.g., rats and monkeys), in single-unit recording studies of animals and humans, in studies using functional neuroimaging or transcranial magnetic stimulation (TMS), and in studies of genetically modified mice. Each approach has its own advantages and disadvantages, such that one can expect that their combined application will provide the best opportunity for further discovery.

CONCLUSIONS

The early descriptions of H.M. changed how human memory was understood. What became clear as a result of work with H.M.—and what remains clear today—is that the structures of the medial temporal lobe are essential for normal memory function. Specifically, these structures are thought to be important for the formation of memory and for the maintenance of memory for a period of time after learning. Although active lines of research investigate the possibility that these structures also contribute to other domains of cognitive function (e.g., visual perception, working memory, and online computations supporting spatial cognition), the half-century of research that began with H.M. has shown that profound impairment after medial temporal lobe damage occurs in only one domain, specifically, in what is now termed declarative memory.

The elements of long-term memory are stored in the neocortex (not in the medial temporal lobe) as products of the distributed, domain-specific processing that occurred in different regions of neocortex at the time of learning. Thus, long-term memory for whole events is widely represented, but the multiple areas that are involved each store distinct components of information. In addition, acts of remembering involve the reactivation of the same neocortical regions that initially processed and stored what was learned. The role of the medial temporal lobe is to consolidate the distributed elements of memory into a coherent and stable ensemble (a process that can take years). Many questions remain about how consolidation occurs, as well as about memory storage, memory retrieval, and the specific functions of the different medial temporal lobe structures and the different areas of neocortex. These topics encompass what has become a substantial and fruitful tradition of research within systems and cognitive neuroscience—a tradition that began with the study of H.M.

Acknowledgments

This work was supported by the Medical Research Service of the Department of Veterans Affairs, NIMH grant MH24600 to L.R.S., and NIMH grant MH082892 to J.T.W.

DISCLOSURE STATEMENT

The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

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• Study protocol
• Open access
• Published: 18 June 2024

The effect of an online acceptance and commitment intervention on the meaning-making process in cancer patients following hematopoietic cell transplantation: study protocol for a randomized controlled trial enhanced with single-case experimental design

• Aleksandra Kroemeke   ORCID: orcid.org/0000-0001-8707-742X 1 ,
• Joanna Dudek 2 ,
• Marta Kijowska 1 ,
• Ray Owen 3 &
• Małgorzata Sobczyk-Kruszelnicka 4  

Trials volume  25 , Article number:  392 ( 2024 ) Cite this article

58 Accesses

Metrics details

Hematopoietic cell transplantation (HCT) is a highly invasive and life-threatening treatment for hematological neoplasms and some types of cancer that can challenge the patient’s meaning structures. Restoring meaning (i.e., building more flexible and significant explanations of the disease and treatment burden) can be aided by strengthening psychological flexibility by means of an Acceptance and Commitment Therapy (ACT) intervention. Thus, this trial aims to examine the effect of the ACT intervention on the meaning-making process and the underlying mechanisms of change in patients following HCT compared to a minimally enhanced usual care (mEUC) control group. The trial will be enhanced with a single-case experimental design (SCED), where ACT interventions will be compared between individuals with various pre-intervention intervals.

In total, 192 patients who qualify for the first autologous or allogeneic HCT will be recruited for a two-armed parallel randomized controlled trial comparing an online self-help 14-day ACT training to education sessions (recommendations following HCT). In both conditions, participants will receive once a day a short survey and intervention proposal (about 5–10 min a day) in the outpatient period. Double-blinded assessment will be conducted at baseline, during the intervention, immediately, 1 month, and 3 months after the intervention. In addition, 6–9 participants will be invited to SCED and randomly assigned to pre-intervention measurement length (1–3 weeks) before completing ACT intervention, followed by 7-day observations at the 2nd and 3rd post-intervention measure. The primary outcome is meaning-related distress. Secondary outcomes include psychological flexibility, meaning-making coping, meanings made, and well-being as well as global and situational meaning.

This trial represents the first study that integrates the ACT and meaning-making frameworks to reduce meaning-related distress, stimulate the meaning-making process, and enhance the well-being of HCT recipients. Testing of an intervention to address existential concerns unique to patients undergoing HCT will be reinforced by a statistically rigorous idiographic approach to see what works for whom and when. Since access to interventions in the HCT population is limited, the web-based ACT self-help program could potentially fill this gap.

Trial registration

ClinicalTrials.gov ID: NCT06266182. Registered on February 20, 2024.

Peer Review reports

Administrative information

Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/ ).

Introduction

Background and rationale {6a}.

Hematologic neoplasms (e.g., lymphomas or acute leukemias) due to unique and sometimes increased challenges are highly stressful conditions. Treatment-related challenges can impede the realization of life goals and violate general beliefs and a sense of meaning as defined by the integrative meaning-making model [ 1 ]. A significant point on the trajectory of coping, challenging the patient meaning structures, may be hematopoietic cell transplantation (HCT). HCT is a highly invasive and life-threatening treatment for hematological neoplasms and some types of cancer (e.g., testicular cancer). In the acute phase, HCT involves the destruction of the patient hematopoietic system through radio and/or chemotherapy and then its restoration via autologous or allogeneic cell transplantation [ 2 , 3 ]. During in- and outpatient conditions, patients usually experience burdensome adverse effects and have to follow strong medical regimens [ 2 , 4 ]. Evidence suggests that HCT affects a patient physical (e.g., fatigue), psychological (e.g., anxiety and depression symptoms), social (e.g., financial concerns, employment disruptions), and spiritual (e.g., existential concerns) well-being [ 5 ]. HCT recipients may confront fear of death, loss of control, feelings of uncertainty and social isolation, increased dependence, or disabling physical symptoms in the short and long term after transplantation [ 6 , 7 ]. Some models of adaptation and adjustment argue that restoring meaning is central to adapting to these conditions [ 8 ].

Meaning-making process following HCT

The most commonly mentioned factors of meaning reconstruction are meaning-making coping and meanings made [ 1 , 9 ]. Meaning-making is related to the process of searching for meaning and explanation for adversity (i.e., seeking understanding of disease), whereas meanings made is the product of the meaning-making process (i.e., giving meaning to the disease, acceptance, finding benefits, or change of identity due to disease). According to the integrative meaning-making model [ 1 , 10 ], distress related to the discrepancy between global meaning (i.e., basic goals and beliefs, and fundamental assumptions about life) and situational meaning (i.e., the personal significance of a particular situation) initiates meaning-making coping, which impacts the meanings made and then well-being. However, a prolonged unsuccessful search for meaning can be maladaptive. Indeed, the adaptability of meaning-making coping depends on whether the meaning has been found or restored [ 10 ].

A review of the narratives shows that HCT recipients who were able to find meaning in their experience were better able to cope with physical symptoms and were less likely to report unfavorable psychological outcomes after transplant than those who had difficulty finding meaning [ 6 ]. Meanings made was also an essential link connecting meaning-making and well-being in HCT recipients in a daily diary study lasting 28 days after hospital discharge [ 11 ]. The direct effect of average meaning-making coping was unfavorable but positive when mediated by meanings made. In another study among HCT recipients in the late outpatient period with a 4-month follow-up interval, only changes in meaning-making coping were associated with changes in well-being, and these correlates were positive and negative [ 12 ]. The role of meanings made in these relationships was, however, not tested. Indeed, few studies tested the assumptions of the integrative meaning-making model in the context of HCT. More often, the focus is on the global meaning which turns out to be a dynamic construct. In a longitudinal study, sense of meaning decreased 1 month post-HCT and returned to pre-transplant levels by 6 months post-HCT. Moreover, a greater pre-HCT sense of meaning predicted more favorable psychological and physical outcomes during the 12 months following HCT [ 13 ].

Hence, an intervention targeting the ability to successfully search for meaning and find it holds promise in terms of facilitating recovery following HCT and adjustment. To date, no trials tested such interventions among patients undergoing HCT. To the best of our knowledge, two studies are currently underway in HCT recipients that include modules directed at searching for meaning i.e., identifying benefits and meaning. The first one examines the effect of one-on-one, in-person intervention promoting resilience in stress management [ 14 ], whereas the second is a phone-delivered positive psychology intervention [ 15 ]. Both, however, will not evaluate the outcomes from the perspective of the meaning-making model. A systematic review shows that various psychosocial interventions can promote meaning and purpose in the cancer population [ 16 ]. Nevertheless, these targeting meaning enhancements demonstrate a higher effect size. One of the promising approaches potentially fostering meaning-making in disease is Acceptance and Commitment Therapy [ 17 ].

Acceptance and Commitment Therapy (ACT) intervention

Acceptance and Commitment Therapy (ACT) is a transdiagnostic therapeutic approach rooted in the contextual behavioral science that aims to improve the psychological functioning and well-being of individual by increasing psychological flexibility (i.e., the ability to engage in values-based actions even in the presence of unpleasant or difficult experiences) [ 17 ]. To achieve this goal ACT targets six core processes: ( 1 ) contact with the present moment—paying attention to different aspects of the internal and external environment; ( 2 ) self-as-context—the ability to look at one’s internal experiences from a broader perspective; ( 3 ) acceptance—making room for thoughts, feelings, and sensations, even those that are unpleasant; ( 4 ) defusion—noticing thoughts instead of being controlled by them; ( 5 ) values—knowing what really matters; and ( 6 ) committed action—taking values-congruent actions even in the presence of difficulties. During the therapy, the individual learns to assess the workability of strategies used to cope with difficult, unwanted private experiences and to use mindfulness and acceptance skills when necessary. Those skills allow the individual to recognize moments when they have an opportunity to engage in behaviors consistent with their values and fully immerse themselves in those activities, even in the presence of painful thoughts, feelings, or sensations. Individuals are not asked to accept painful private experiences (e.g., physical pain) if there is an effective way to get rid of the pain; acceptance means embracing painful private experiences only when there is no effective way of escaping painful experiences on a long-term basis or when the means of escape comes at too high a cost in terms of valued living. Techniques used in ACT to obtain the aforementioned changes include using metaphors, experiential exercises, and functional analysis [ 17 ].

Besides the typical use of ACT as an individual face-to-face therapy, ACT was also tested in a group format (e.g., for anxiety and depression [ 18 ] or chronic pain [ 19 ]), as a self-help form [ 20 ] as well as technology-supported intervention (using online materials, web or phone applications, telephone) with or without therapeutic guidance [ 21 ].

ACT has been proven to be an effective intervention for various conditions [ 22 ], with the growing number of randomized controlled trials [ 23 ] and mediational studies showing that psychological flexibility is a mediator of the intervention [ 24 ]. Several systematic reviews and metanalyses provide evidence for ACT effectiveness in improving the quality of life and decreasing psychological distress among cancer patients [ 25 , 26 , 27 , 28 , 29 ]. Other systematic reviews support ACT efficacy in improving quality of life and symptoms for long-term chronic conditions [ 30 , 31 ], also including the technology-supported delivery of ACT [ 21 ]. Finally, ACT is considered to be an effective treatment for chronic pain, being recognized by the American Psychological Association as an evidence-based treatment with “strong research support” [ 32 ].

The links between ACT and the meaning-making process

ACT and meaning-making frameworks share common philosophical roots, including constructivism and existentialism [ 9 ]. The ACT model promotes acceptance of what is difficult to change or is not subject to change (such as chronic disease or burden of toxic treatment), taking responsibility for one’s own experiences and actions and creating a meaningful life by engaging in activities that match one’s values [ 33 ]. While meaning-making is not an explicit goal of ACT, creating psychological flexibility should foster meaning-making in disease or following HCT by building more flexible and workable meaning-making explanations of disease [ 34 ]. ACT emphasizes increased awareness of what matters most to the individual and a stepping back from automatic patterns of thought and behavior. Both of these abilities should facilitate meaning-making, i.e., changing global meaning or a reappraisal of situational meaning to achieve congruence, thus alleviating the distress of the event such as HCT. Achieving congruence should end meaning-making coping and be associated with meanings made and improved well-being.

Objectives {7}

This trial aims to examine the effect of an online self-help ACT intervention on the meaning-making process and the underlying mechanisms of change in patients following HCT compared to a minimally enhanced usual care (mEUC) control group. The trial will be enhanced with a single-case experimental design (SCED), where ACT interventions will be compared between individuals with various pre-intervention intervals. As the change process is characterized by complexity, traditional examination of intervention efficacy will be enriched with a temporal perspective (i.e., examination of trajectories of change in primary and secondary outcomes over time) and a systems perspective (i.e., network analysis depicting the pattern of connections between components of the system). The latter assumes that an intervention transforms the connectivity of the networks of intervention goals, the outcome of the intervention, and the connections between the two networks [ 35 , 36 ].

It is hypothesized that the ACT intervention group would show increased psychological flexibility and decreased meaning-related distress compared with the control group (hypothesis 1). Additionally, an increase in meanings made and well-being is anticipated (hypothesis 2). In more exploratory terms, the moderating effect of individual resources (i.e., global and situational meaning, baseline well-being) and demographic and clinical factors on the effect of the intervention will also be examined. Moreover, it is hypothesized that psychological flexibility and meaning-making coping would mediate the ACT intervention effects on meaning-related distress, meanings made, and well-being in HCT recipients (hypothesis 3). Finally, following the network theory, it is hypothesized that the ACT intervention group will display more robust positive connections within the psychological flexibility and meaning-making coping network (hypothesis 4), weaker connections within the distress network (hypothesis 5), more negative connections of distress with psychological flexibility and meaning-making coping (hypothesis 6), and more positive connections between psychological flexibility, meaning-making coping, meanings made, and well-being as compared to control conditions (hypothesis 7).

Trial design {8}

A two-armed parallel randomized controlled trial (RCT) will be conducted to determine the effects of an online Acceptance and Commitment Therapy ACT intervention on the meaning-making process in patients following HCT. Participants will be randomly assigned in a double-blinded manner to ACT intervention and education conditions at a ratio of 1:1. RCT will be enhanced with a randomized multiple-baseline single-case experimental design (SCED). SCED will proceed according to the AB + post-intervention design, where A is the pre-intervention phase and B is the intervention phase, followed by the post-intervention phase. Participants will be randomly assigned to one of three pre-intervention measurement lengths (7 days, 14 days, 21 days) followed by 7-day observations at the 2nd and 3rd post-intervention measure.

Methods: participants, interventions and outcomes

Study setting {9}.

Recruitment will take place in the Department of Bone Marrow Transplantation and Oncohematology of the Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO) Gliwice Branch. MSCNRIO branch in Gliwice is the leading facility in Poland that performs HCT. Approximately 150 primary transplants are performed there annually (approx. 200 HCT in total).

Eligibility criteria {10}

The participation criteria will include ( a ) qualification for the first autologous or allogeneic HCT due to hematologic malignancies or solid tumors, ( b ) age ≥ 18 years, ( c ) signed written informed consent, ( d ) ability to read and write in Polish, and ( e ) daily access to the Internet by computer and/or mobile device. The exclusion criteria will be as follows: ( a ) major psychiatric or cognitive disorder that would impede providing informed consent and study participation, ( b ) inability to cooperate and give informed consent, ( c ) hearing, seeing, or movement impairment that precludes participation, ( d ) current participation in any form of psychotherapy, ( e ) no access to the Internet and computer and/or mobile device, and ( f ) inability to use a computer and/or mobile device and the Internet.

Who will take informed consent? {26a}

Written informed consent to participate in the study will be obtained by the recruiter (member of the research team), in direct contact with the participant and after an extensive briefing.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

N/A. Biological specimens will not be collected.

Interventions

Explanation for the choice of comparators {6b}.

In RCT, the ACT intervention will be compared with minimally enhanced usual care (mEUC). Standard psychological care following HCT does not include a standard psychological care protocol. Psychological care for HCT recipients is provided if needed according to the physician’s recommendation in the event of the patient’s functioning deteriorating. Thus, to maintain the same conditions in both trials, participants in the control condition will receive cognitively neutral tasks (education) from which no effects are expected for the meaning-making process. In SCED, comparisons between participants with different pre-intervention measurement lengths will be conducted.

Intervention description {11a}

ACT intervention “The Path to Health” will start on the second day after hospital discharge for individuals in RCT or after 7–21-day pre-intervention measurement in individuals in SCED. It will take 14 days (+ day 0 with organizational information). Each day, participants will receive a web-based intervention consisting of the theoretical introduction (including examples of patients’ experiences and metaphors) and practical ACT activity (e.g., reflective questions, experiential exercise, values card sorting test). Most of the activities are followed by a debrief that includes the patient’s reactions to this particular exercise and practical tips. On some days, participants will also receive additional exercise (optional).

Using the metaphor of life as a journey, participants will learn to recognize where they are headed (values), when there is a moment of choice between actions that lead towards values or away from them, and how to use attention flexibly to free themselves from the power of thoughts, to open up and accept emotions so that they can effectively take action in line with their values (Table  1 ). Each introduction and each activity will be available in written form and audio. The ACT intervention is built from standard ACT activities [ 37 , 38 , 39 , 40 ] and tailored to the context of the disease and treatment. Participants will be advised to do one activity a day, but they will be able to come back to the chosen activities or practice them a couple of times if necessary.

During the same period, participants allocated to the education in RCT will receive an online guide to post-HCT recommendations. Each day, participants will receive information about post-transplant prescriptions along with exercises. Participants will receive guidelines in several areas: diet, physical activity, hygiene, rest, social interactions, and sexual health. During the first 3 days, nutrition will be discussed, including the principles of healthy diet after HCT. On the fourth day, participants will learn the rules of personal hygiene. The fifth day is devoted to presenting the rules aimed at preventing infection. On the sixth day, the issue of body fatigue will be discussed. For the next 3 days, the main topic will be the resumption of activity, mostly physical activity. The tenth day is devoted to safe social contacts. On the eleventh day, participants will work on their sleep. On the twelfth day, sexual health will be discussed. Day 13 is devoted to discussing the issue of rest. And the last day will be a summary of all the guidelines. The exercises serve as an extension of the topic (e.g., watching a video presenting the principles of nutrition) or the emphasis is on practice to support the implementation (e.g., preparing a sequence of exercises and performing them several times a day). The content is prepared based on available guides for HCT recipients. It was also verified by a hemato-oncologist.

Criteria for discontinuing or modifying allocated interventions {11b}

Modification of assigned interventions is not provided for. Disease recurrence will be the criteria for discontinuation of the intervention. The participant can also discontinue the intervention at any time without any negative consequences.

Strategies to improve adherence to interventions {11c}

To improve adherence to the intervention, participants will receive daily reminders about the intervention. Also, direct technical support will be available 24/7. If participants drop out or stop using the intervention, they will be asked for the reason(s) why they decided to quit the intervention and/or study.

Relevant concomitant care permitted or prohibited during the trial {11d}

Individuals participating in any form of psychotherapy will not be eligible for the study. Participation in forms of psychological support will be monitored on an ongoing basis.

Provisions for post-trial care {30}

Upon completion of the study, all participants will have access to the self-help ACT intervention booklet with written and recorded exercises.

Outcomes {12}

The primary and secondary outcomes will be assessed at baseline (before HCT), during the intervention, immediately, 1 month, and 3 months after the intervention (Table  2 ). In SCED, 1 month and 3 months post-intervention assessments will be preceded by 7-day daily diaries. A summary of the outcome measures that will be used in this study is available in Table  3 .

Primary outcomes

The primary outcome will be the changes compared to the baseline in meaning-related distress as assessed by the Global Meaning Violation Scale (GMVS) [ 41 ].

Secondary outcomes

The secondary outcomes will be changes from baseline in global meaning, situational meaning, meanings made, and well-being. Global meaning will be measured by cognitive and emotional representations of illness and global presence of meaning using the Brief-Illness Perception Questionnaire (B-IBP) [ 42 ] and Meaning in Life Questionnaire (MLQ) [ 43 ], respectively. Coping self-efficacy, an indicator of situational meaning, will be assessed with the Perceived Coping Self-Efficacy (CSE) Scale [ 44 ]. Meanings made will be assessed using the “current standing” Post-Traumatic Growth Inventory-Short Form (C-PTGI-SF) [ 45 , 46 ] and 3-item scale based on the Meaning of Loss Codebook (MLC) [ 47 ]. Depressive and anxiety symptoms will be assessed with the Patient Health Questionnaire (PHQ-4) [ 48 ], while loneliness, as recommended by the British Office for National Statistics [ 49 ], will be evaluated with the enhanced R-UCLA 3-item Loneliness Scale [ 50 ] and direct question from the Community Life Survey [ 51 ].

Mediators and moderators

To assess putative mechanisms of change and change moderators, meaning-making coping and psychological flexibility will be measured longitudinally. In this scheme, deliberate and automatic meaning-making coping will be assessed with the Core Beliefs Inventory (CBI) [ 52 ] and the intrusive ruminations subscale from the Event-Related Rumination Inventory (ERRI) [ 53 ], respectively. Psychological flexibility will be measured using the Comprehensive Assessment of Acceptance and Commitment Therapy Processes (CompACT-9) [ 54 ]. In addition, fluctuations in meaning-making coping, meanings made, psychological flexibility, and well-being (i.e., subjective health and positive and negative affect) will be measured in an intensive longitudinal manner (i.e., daily) throughout the intervention in RCT and pre- to post-intervention in SCED. Daily meaning-making coping (deliberate and automatic) will be measured with an abbreviated and tailored to the daily measurement and context of the study 4-item version of the ERRI questionnaire. Daily meanings made will be evaluated using a contextualized 3-item scale based on the Meaning of Loss Codebook (MLC). Daily psychological flexibility will be measured using a shortened to 4-item version of the CompACT questionnaire. Daily subjective health will be assessed by a single-item statement “Generally, I can say my health today was…” on a 5-point scale ranging from 1 (bad) to 5 (excellent). Daily positive and negative affect will be assessed with two positive (happy, cheerful) and two negative adjectives (sad, gloomy) based on the Circumplex Model of Emotion [ 55 ].

Feasibility will be examined via attrition and adherence rates as well as questions about intervention engagement. Acceptability will be measured by intervention satisfaction and evaluation (attractiveness and easiness). Adherence to the intervention will be estimated based on the dropout rate (i.e., the percentage of participants who do not log in to the intervention on a given day) and self-reported questions about engagement in the intervention: ( 1 ) the number of days on which the proposed exercises were done seriously, ( 2 ) the number of minutes spent on average in training, and ( 3 ) the use of various training components. Satisfaction with the intervention will be measured using 4 questions (no. 3, 4, 7, and 8) from the Client Satisfaction Questionnaire (CSQ-8) [ 56 ] modified to the intervention context and online form. Evaluation of the intervention will be assessed using questions of the author’s own measuring the ease and attractiveness of the training.

The cost-effectiveness of the intervention will be examined by estimating health-related quality of life as measured by the Quality of Life Questionnaire of the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) [ 57 ].

Other measures

At the baseline, demographic data (e.g., age, sex, education, marital status, employment) will also be collected and partially measured using the Diversity Minimal Item Set (DiMIS) [ 58 ]. Clinical data (e.g., diagnosis, time since diagnosis, conditioning, concomitant diseases) will be obtained from the medical records.

Participant timeline {13}

Figure  1 describes the project timeline.

Timeline for RCT and SCED study

Sample size {14}

In RCT, the sample size was calculated based on an analysis of variance with two groups (ACT versus mEUC) and four repeated measures of variance (ANOVA) with within-between interaction (group x time) using the G*Power calculator [ 59 ] and simulation study of the time course with dichotomous between-person level predictor [ 60 ]. Given the large effects of ACT on psychological well-being, including hope (Hedge’s g  = 0.88–2.17) and medium effects on psychological flexibility among cancer patients (Hedge’s g  = 0.58) [ 29 ], the stronger effects in the population of women with breast cancer compared to patients with other types of cancer (large versus medium effect sizes) [ 31 ], and medium effect sizes of technology-supported ACT interventions (Hedges’ g  = 0.44–0.48) [ 21 ], moderate differences between conditions were expected. Assuming a medium effect size of f  = 0.25, a power of 0.80, and an alpha level of 0.05 in repeated measures of ANOVA, a total sample size of N  = 178 is required. In turn, on the basis of a simulation study, a total sample size of N  = 136 is required for multilevel modeling. Therefore, the minimum sample size was assumed of N  = 160 (80 per condition). Allowing for the potential attrition rate of 20%, this leads to a sample size of N  = 192 participants, including 96 in each arm. In SCED, 6–9 participants will be investigated, a minimum of 2 per condition. According to the simulation study [ 61 ], sufficient power (0.80) can be reached in SCED with six to eight participants, depending on the assumed effect size (large versus medium, respectively).

Recruitment {15}

Recruitment will take place at a single center, after elective admission to the bone marrow transplantation and oncohematology unit due to HCT before the start of conditioning treatment. Recruitment will take place on average on the 2nd day after admission. Every 2 days, the transplant coordinator, PI, and physician (members of the research team) will review the lists of patients enrolled for HCT. Those who meet the inclusion criteria will be initially informed of the purpose of the study and invited for an extensive briefing by a recruiter (member of the research team). Patients will also be allowed to ask any remaining questions about the aim of the study and the study procedures. After receiving an extensive briefing, all patients who give written informed consent will proceed with baseline. Recruitment will be carried out until the desired sample size is achieved. The flowchart of the study is depicted in Fig.  2 .

Participant flowchart in RCT and SCED study. ACT, Acceptance and Commitment Therapy; mEUC, minimally enhanced usual care

Assignment of interventions: allocation

Sequence generation {16a}.

The allocation sequence will be generated using the method of minimization. Minimization can be classified as dynamic allocation or covariate adaptive methods because the allocation depends on the characteristics of the patients and is performed continuously [ 62 ]. Randomization will be stratified by type of transplant (autologous versus allogeneic) to ensure a balanced representation between the study conditions because autologous and allogeneic HCT recipients experience different recovery trajectories and HCT impact on well-being [ 63 , 64 ].

Concealment mechanism {16b}

The mechanism of implementing the allocation sequence will be central randomization. It means generating an allocation sequence after the patient is enrolled [ 65 ]. This way, randomization will not affect the recruitment process.

Implementation {16c}

The trial coordinator (member of the research team) will enroll participants, generate the allocation sequence, and assign participants to interventions. Other members of the team will be blind to the allocation of the participants to the conditions.

Assignment of interventions: blinding

Who will be blinded {17a}.

In RCT, trial participants, care providers, outcome assessors, and data analysts will be blinded after assignment to interventions. Blinding will be performed using two separate databases: one containing participant allocation information (blinded) and the other containing the remaining information (unblinded). Only the trial coordinator will have access to the blinded database.

Procedure for unblinding if needed {17b}

Disclosure of the participant allocation will take place after the completion of the study and analysis of the first results examining the efficacy of the online ACT intervention.

Data collection and management

Plans for assessment and collection of outcomes {18a}.

Data will be collected via self-reported online questionnaires at the baseline (before HCT), post-intervention, and 1 and 3-month follow-ups (Table  2 ). In addition, to assess momentary changes and mechanisms of change, participants will complete daily diaries throughout the intervention. SCED participants will complete 7-day daily diaries repeatedly, i.e., before 1 and 3-month follow-ups. The detailed characteristics of the study instruments are presented in Table  3 .

We intend to collect clinical data (e.g., diagnosis, time from diagnosis, type of transplant and conditioning treatment, comorbidities) from the patient’s medical records. The participants will give their additional consent for the data to be collected from their medical history by a physician (team member). If the participant does not approve of access to the data from medical records, they will be requested to provide information themselves.

Plans to promote participant retention and complete follow-up {18b}

To improve participant retention and complete follow-up, participants will receive email and phone reminders about the survey and subsequent measurements. If participants fail to complete study assessments, motivational reminders will be sent repeatedly by email. In daily diary measurements, participants who give written consent will receive SMS reminders. Since the daily diaries will not be filled retrospectively, a single reminder with the mailing of the survey will be used.

During the study, direct technical support will be available 24/7, and a research team member will contact the participant by phone to resolve any issues and answer questions. If participants drop out of the study, they will be asked for the reason(s). Any other attritions (e.g., disqualification from HCT, death) along with the reasons will be recorded.

Data management {19}

Questionnaire data collection will be done electronically (using the SurveyMonkey platform, which encrypts and secures data during transit and the data stored; the accounts are password-protected with available complexity controls). Medical data will be collected electronically directly from the medical records registry by the physician (member of the research team). Only informed consents will be paper documents, collected and entered by recruiter (member of the research team). The PI will be responsible for the secure delivery of the documents to the trial office. The PI and trial coordinator will oversee the quality of the data. Data and metadata storage will take place in the university’s central resources according to the 3–2-1 rule. The detailed data management plan is available at OSF .

Confidentiality {27}

Personal data such as phone numbers and email addresses of the participants will be encrypted (using individual trial identification number) and stored only during the data collection period. Written informed consent and the data identifying the participants will be stored separately under lock and key and will be kept strictly confidential. The data will be accessed by the PI of the project and selected team members who will be contacting the participants (trained in the General Data Protection Regulation). Access to the data will be monitored and possible only after obtaining the access rights that the PI of the project will grant. Once data collection is completed, the data will be anonymized and in this form will be analyzed statistically.

Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

N/a. Biological specimens will not be collected.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}.

Analyses will be conducted using the latest Mplus statistical package [ 66 ], R [ 67 ], and IBM SPSS (IBM Corp.; Armonk, NY). We will use the standard α  = 0.05 or 95% confidence interval for the determination of value probability. All data analysis will be performed according to the intention-to-treat principle, where all randomized participants are included in the analysis assuming missing data at random. The collected data will be first analyzed in terms of sample characteristics and comparisons (frequency, descriptive statistics; ANOVA, t -test or their nonparametric counterparts; χ 2 ; Pearson’s or Kendall’s correlation), missing data (frequency, multilevel modeling), and sample attrition (logistic regression analysis). Multilevel confirmatory factor analysis (MCFA) will be performed to establish the respective measurement models and calculate the indicator reliabilities (omega coefficient) at the within- and between-person levels [ 60 , 68 ]. To examine hypotheses 1–3, latent curve growth modeling (LCGM) [ 69 ] and multilevel (MSEM) and dynamic structural equation modeling (DSEM) will be applied [ 60 , 70 ]. All methods allow for the examination of the time course. In addition, MSEM and DSEM allow for the calculation of simple between- and within-person associations and more advanced associations such as mediations and moderations. Hypotheses 4–7 will be verified using a multilevel vector autoregressive (mlVAR) model [ 71 ]. mlVAR allows for the examination of a temporal network (i.e., lagged predictive relations between each node in the network and each node in the network at the next measurement occasion), a contemporaneous network (i.e., partial correlations within the same measurement occasion), and a between-person network (i.e., associations between nodes that are averaged across measurement occasion).

Interim analyses {21b}

Due to a known minimal risk, i.e., testing interventions with known positive effects, an interim analysis plan was not created. The principal investigator (PI) will make the final decision to terminate the study once the optimal number of study participants has been obtained.

Methods for additional analyses (e.g., subgroup analyses) {20b}

All analyses will be supplemented by sensitivity analyses. In all models, possible confounders (i.e., demographics, clinical factors, and other confounders) will be considered after preliminary selection.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

The statistical methods used (i.e., MSEM, DSEM) will allow the most recent flexible approach to the missing data (the full information maximum likelihood) [ 72 , 73 ]. In less sophisticated analyses, missing data will be multiple imputed in advance.

Plans to give access to the full protocol, participant-level data and statistical code {31c}

The full protocol, dataset, statistical codes, and outputs will be made available at the Open Science Framework (OSF). Participant-level datasets will be publicly available, however without demographics and clinical data due to privacy or ethical restrictions (the possibility of identification of participants).

Oversight and monitoring

Composition of the coordinating center and trial steering committee {5d}.

The study’s coordinating center is SWPS University. The study’s steering committee will consist of a health psychologist, a certified cognitive behavioral therapist (CBT) and ACT therapist, and a doctoral student (master’s degree in psychology). The committee’s responsibilities will be to develop the intervention and then implement it and monitor implementation. The committee will meet 2–4 times a month.

Composition of the data monitoring committee, its role and reporting structure {21a}

Due to known minimal risks, a formal committee of data monitoring is not needed.

Adverse event reporting and harms {22}

In this study, an adverse event will be defined as any deterioration in mood that requires specialized treatment, collected after the individual has received the intervention, and reported to the local institutional review board (IRB).

Frequency and plans for auditing trial conduct {23}

No audit procedures are planned. An independent audit may be conducted by the local IRB and the sponsor.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

Communication of significant protocol modifications and study outcomes will be done to the funder, the ethics committee, and the public through ClinicalTrials.gov.

Dissemination plans {31a}

The results will be published in peer-reviewed journals and presented at thematic international scientific conferences. Also, during the debriefing, participants will be informed of the web address of the project website, where a lay summary of the study updated with the results (when available) will be posted.

Effective treatment of patients undergoing HCT likely requires a focus also on those mechanisms that support the reconstruction of meaning damaged by medical treatment and the disease itself. An intervention based on ACT, an empirically validated theoretical model [ 17 ], appears to be a promising psychological therapy to support the reconstruction of meanings [ 33 , 34 ]. This trial represents the first study that aims to integrate the ACT and meaning-making frameworks to reduce meaning-related distress, stimulate the meaning-making process, and enhance the well-being of HCT recipients. It builds on previous successful ACT interventions that strengthened cancer patient well-being albeit outside the context of meaning reconstruction [ 25 , 26 , 27 , 28 , 29 ]. Moreover, testing a specific theory-based intervention to address existential concerns unique to patients undergoing HCT will be reinforced by a statistically rigorous idiographic approach. SCED will allow us to go beyond aggregate group effects and see how a specific person responds to an ACT intervention, thereby providing clinical input into what works for whom and when . Beyond this, since access to interventions in the HCT population is limited, the web-based ACT self-help program we designed has the potential to fill that gap. Self-directed ACT interventions are considered cost-effective, flexible, and accessible for cancer patients [ 21 ]. They allow patients to self-determine what (content), when (time), where (location), and how (read or listen) to use ACT intervention booklets.

Despite these strengths, we expect several challenges and limitations. First, recruiting the HCT recipients will be challenging. Therefore, we allow for the possibility of recruiting at a second oncohematology center with identical credentials. Retaining participants in the study can be also a challenge, hence the contact maintenance and participation reminder activities we have planned. In addition, we plan to compensate participants for their participation at a rate of PLN 150 (approx. 34.5 Euros) in RCT and PLN 300 (approx. 69 Euros) in SCED. Another limitation is the targeting of the trial to all willing HCT recipients, regardless of the level of distress or the stage of the meaning reconstruction process. However, we are guided by pragmatic (restrictive inclusion/exclusion criteria would prolong the already long data collection time) and cognitive considerations (to our knowledge, this is the first study that will test the relationship of ACT interventions to meaning reconstruction processes) hoping that this will result in further research in this area.

Trial status

ClinicalTrials.gov, NCT06266182. Registered 20 February 2024, https://clinicaltrials.gov/study/NCT06266182 . Version 3.0 dated May 13, 2024. Patient recruitment began on March 6, 2024. Recruitment is expected to be completed in December 2025.

Availability of data and materials {29}

Data that will be collected during the current study (without demographics and clinical data due to the possibility of identification of participants), full protocol, statistical codes, and outputs will be made available at the Open Science Framework (OSF).

Abbreviations

• Acceptance and Commitment Therapy

Analysis of variance

Brief-Illness Perception Questionnaire

Core Beliefs Inventory

Cognitive behavioral therapy

Comprehensive Assessment of Acceptance and Commitment Therapy Processes

The “current standing” Post-Traumatic Growth Inventory-Short Form

Coping Self-Efficacy Scale

Client Satisfaction Questionnaire

Diversity Minimal Item Set

Dynamic structural equation modeling

Quality of Life Questionnaire of the European Organization for Research and Treatment of Cancer

Event-Related Rumination Inventory

Global Meaning Violation Scale

• Hematopoietic cell transplantation

Institutional review board

Latent curve growth modeling

Multilevel confirmatory factor analysis

Minimally enhanced usual care

Meaning of Loss Codebook

Meaning in Life Questionnaire

Multilevel vector autoregressive

Maria Sklodowska-Curie National Research Institute of Oncology

Multilevel structural equation modeling

Open Science Framework

Patient Health Questionnaire

Principal investigator

• Randomized controlled trial

Revised UCLA Loneliness Scale

• Single-case experimental design

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Acknowledgements

Not applicable.

The work is supported by the National Science Centre, Poland [grant number 2020/39/B/HS6/01927 awarded to AK]. The funders had no role in the study design, data collection, analysis, and interpretation, decision to publish, or preparation of the manuscript.

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Aleksandra Kroemeke & Marta Kijowska

Faculty of Psychology, SWPS University, Warsaw, Poland

Joanna Dudek

Gloucester, UK

Department of Bone Marrow Transplantation and Oncohematology, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland

Małgorzata Sobczyk-Kruszelnicka

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Contributions

AK is a principal investigator, who led the proposal and protocol development. JD developed the ACT intervention and contributed to the study design. MK developed cognitively neutral tasks (education) for the control group and assisted in the development of the ACT intervention. RO offered review and advice on ACT intervention component. MSK reviewed the manuscript. AK, MK, and MSK will be involved in the recruitment of participants and data collection. AK, JD, and MK drafted the manuscript. All authors have approved the manuscript.

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Correspondence to Aleksandra Kroemeke .

Ethics declarations

Ethics approval and consent to participate {24}.

The study has been reviewed and approved by the Ethical Review Board at SWPS University, Faculty of Psychology in Warsaw (Decision No. 52/2023 of December 12, 2023), and adheres to the ethical guidelines of the Declaration of Helsinki. All participants will be requested to give written informed consent before participation (assessment and randomization).

Consent for publication {32}

Not applicable—no identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. The participant information materials and informed consent form are available from the authors on request.

Competing interests {28}

The authors declare that they have no competing interests.

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Kroemeke, A., Dudek, J., Kijowska, M. et al. The effect of an online acceptance and commitment intervention on the meaning-making process in cancer patients following hematopoietic cell transplantation: study protocol for a randomized controlled trial enhanced with single-case experimental design. Trials 25 , 392 (2024). https://doi.org/10.1186/s13063-024-08235-1

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DOI : https://doi.org/10.1186/s13063-024-08235-1

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Published on 19.6.2024 in Vol 12 (2024)

Effect of Implementing an Informatization Case Management Model on the Management of Chronic Respiratory Diseases in a General Hospital: Retrospective Controlled Study

Authors of this article:

• Yi-Zhen Xiao 1 , MBBS ; 
• Xiao-Jia Chen 1 , MBBS ; 
• Xiao-Ling Sun 1 , MBBS ; 
• Huan Chen 1 , MM ; 
• Yu-Xia Luo 1 , MBBS ; 
• Yuan Chen 1 , MBBS ; 
• Ye-Mei Liang 2 , MM

1 Department of Pulmonary and Critical Care Medicine, Yulin First People’s Hospital, , Yulin, , China

2 Department of Nursing, Yulin First People’s Hospital, , Yulin, , China

Corresponding Author:

Ye-Mei Liang, MM

Background: The use of chronic disease information systems in hospitals and communities plays a significant role in disease prevention, control, and monitoring. However, there are several limitations to these systems, including that the platforms are generally isolated, the patient health information and medical resources are not effectively integrated, and the “Internet Plus Healthcare” technology model is not implemented throughout the patient consultation process.

Objective: The aim of this study was to evaluate the efficiency of the application of a hospital case management information system in a general hospital in the context of chronic respiratory diseases as a model case.

Methods: A chronic disease management information system was developed for use in general hospitals based on internet technology, a chronic disease case management model, and an overall quality management model. Using this system, the case managers provided sophisticated inpatient, outpatient, and home medical services for patients with chronic respiratory diseases. Chronic respiratory disease case management quality indicators (number of managed cases, number of patients accepting routine follow-up services, follow-up visit rate, pulmonary function test rate, admission rate for acute exacerbations, chronic respiratory diseases knowledge awareness rate, and patient satisfaction) were evaluated before (2019‐2020) and after (2021‐2022) implementation of the chronic disease management information system.

Results: Before implementation of the chronic disease management information system, 1808 cases were managed in the general hospital, and an average of 603 (SD 137) people were provided with routine follow-up services. After use of the information system, 5868 cases were managed and 2056 (SD 211) patients were routinely followed-up, representing a significant increase of 3.2 and 3.4 times the respective values before use ( U =342.779; P <.001). With respect to the quality of case management, compared to the indicators measured before use, the achievement rate of follow-up examination increased by 50.2%, the achievement rate of the pulmonary function test increased by 26.2%, the awareness rate of chronic respiratory disease knowledge increased by 20.1%, the retention rate increased by 16.3%, and the patient satisfaction rate increased by 9.6% (all P <.001), while the admission rate of acute exacerbation decreased by 42.4% (P <.001) after use of the chronic disease management information system.

Conclusions: Use of a chronic disease management information system improves the quality of chronic respiratory disease case management and reduces the admission rate of patients owing to acute exacerbations of their diseases.

Introduction

Chronic obstructive pulmonary disease (COPD) and asthma are examples of common chronic respiratory diseases. The prevalence of COPD among people 40 years and older in China is estimated to be 13.7%, with the total number of patients reaching nearly 100 million. The lengthy disease cycle, recurrent acute exacerbations, and low control rate were found to have a significant impact on the prognosis and quality of life of middle-aged and older patients with COPD [ 1 , 2 ]. Therefore, to decrease the morbidity and disability rates and enhance the quality of life of all patients with chronic respiratory diseases, it is crucial to investigate effective prevention and treatment methods and establish a life cycle management model for chronic respiratory diseases.

Since the development of information technology, the internet and medical technology have been applied to the management of chronic diseases [ 3 ]. The chronic disease information systems adopted in hospitals and communities, along with mobile medical apps, can enhance the self-management capabilities of patients and play a significant role in disease prevention, control, and monitoring [ 4 - 9 ]. However, the existing platforms are generally isolated, the patient health information and medical resources are not effectively integrated, and the Internet Plus Healthcare technology model is not implemented throughout the patient consultation process [ 3 , 9 ].

Yulin First People’s Hospital developed a chronic disease management information system based on the hospital information system (HIS) to fully and effectively utilize the medical resources in hospitals and to better support and adapt the system to the needs of patients with chronic diseases. In this study, we evaluated the impact of the use of this system on the efficacy of case management for patients with chronic respiratory diseases.

Chronic Respiratory Diseases Case Management Model Prior to Implementation of the Chronic Disease Management Information System

Yulin First People’s Hospital is a public grade-3 general hospital with 2460 open beds, a specialty clinic in the Department of Pulmonary and Critical Care Medicine, and 180 beds in the Inpatient Department. Chronic respiratory diseases case management was initiated in 2019, which did not involve the use of an information system and was implemented by a chronic respiratory diseases case management team led by two nurses qualified as case managers, one chief physician, two supervisor nurses, and one technician. Under this system, patients with COPD, bronchial asthma, bronchiectasis, pulmonary thromboembolism, lung cancer, and lung nodules were managed using the traditional inpatient-outpatient-home chronic respiratory diseases case management model, including 1024 cases managed from 2019 to 2020. Except for medical prescriptions and electronic medical records, the patient case management information such as the basic information form, follow-up form, patient enrollment form, inpatient follow-up register, patient medication and inhalation device use records, smoking cessation and vaccination records, and pulmonary rehabilitation and health education records was managed using Microsoft Excel forms that were regularly printed for filing.

Establishment of a Management Information System for Chronic Diseases

The information carrier forming the basis of the management information system is constituted by the model of internet technology, chronic disease case management models, and overall quality management. The key technology is to establish a scientific, refined, and feasible follow-up pathway according to the methods and procedures of chronic disease case management based on the guidelines for the diagnosis and treatment of single chronic diseases. The closed-loop management of the clinical pathway was conducted in accordance with the Deming cycle (plan-do-check-act), and dynamic monitoring of single-disease health-sensitive and quality-sensitive indicators was carried out. The successfully developed system was installed on the hospital server to connect personal terminals (medical terminals and customer apps) to the existing HIS, which includes electronic medical records and medical advice.

Using the single-disease path assessment or plan scale as a framework, the system can automatically collect and integrate the majority of the medical information of patients with chronic respiratory diseases and provide these patients with inpatient, outpatient, and home intelligent medical services. Patients with chronic diseases who enroll in use of the system can use the app to schedule appointments for medical guidance, payment, and result queries; receive health guidance information; perform self-health assessments; write a treatment diary; and obtain medical communication materials.

The medical terminal consists of five functional modules: user entry, data statistics and query, quality control, knowledge base, and module management. As the core of the system, the user entry module can manage case information in seven steps: enrollment, assessment, planning, implementation, feedback, evaluation, and settlement [ 10 - 14 ]. Each step has a corresponding assessment record scale as well as the health-sensitive and quality-sensitive indicators. The structure of the HIS-based chronic disease management information system is shown in Figure 1 .

Implementation of the Chronic Disease Information Management System

Using the chronic disease management information system, two full-time case managers oversaw the case management of 2747 patients diagnosed with six diseases among chronic respiratory diseases between 2021 and 2022. The operation process was broken down into enrollment, assessment, planning, implementation, evaluation, feedback, and settlement stages.

Case managers entered the system through the medical app, selected a disease and an enrolled patient from the list of patients (the system automatically captures the patient’s name and ID number according to the International Classification of Diseases [ ICD ] code) in accordance with the chronic respiratory diseases diagnostic criteria to sign the enrollment contract and determine the relationship between the personal information and data [ 15 - 19 ].

The system can be seamlessly integrated with multiple workstations on the HIS to automatically capture the basic information, electronic medical records, medical advice, and inspection materials, and can generate questionnaires or assessment scales for patients with chronic respiratory diseases such as the COPD Assessment Test, Asthma Control Test, modified Medical Research Council scale, form for lung function test results, inhalation device technique evaluation form, 6-minute walk test record, rehabilitation assessment form, health promotion form, and nutritional assessment form. The above materials can be added or removed based on the requirements for individual patients.

The case managers drafted the follow-up plan based on the patient assessment criteria and included the patients on the 1-, 3-, 6-, and 12-month follow-up lists. If the patient satisfied the self-management and indicator control requirements after follow-up, they could be settled and included in the annual follow-up cohort. Case managers can set up follow-up warning and treatment, involving the return visit plan, health education, follow-up content, pathway, and time, and notify the patients and nurses on day 7 and at months 1, 3, 6, and 12 after discharge. The nurses should promptly deal with patients who miss their scheduled follow-up visit.

Implementation

During the inpatient or outpatient care, supervising physicians, nurses, and patients collaborated with each other to implement the treatment. Case managers monitored the patients, evaluated them, documented the results, interpreted various test indicators, and provided health guidance. The chronic disease management information system acquired the corresponding data for chronic disease–sensitive indicators from outpatient and inpatient orders and medical records automatically. The chronic respiratory diseases management team reviewed the patients’ conditions and the dynamics of chronic disease–sensitive indicators to make accurate decisions based on the current situation. The outpatient physicians obtained the single-disease package advice and personalized prescriptions to modify the diagnosis and treatment scheme.

Case managers highlighted evaluation and health education. First, they assessed and examined the content of the previous education and recorded and analyzed the patients’ conditions, medication, diet, nutrition, rehabilitation exercises, and self-management. Second, they prepared the personalized health education plan, return visit plan, and rehabilitation plan, and used standardized courseware, educational videos, and health prescriptions to provide the patients with one-on-one health guidance. Finally, they sent the management tasks and educational contents to the phones of the patients for consolidating the learning in the hospital, as an outpatient, and at home.

Patients can access their biochemical, physical, and chemical data as well as chronic disease–sensitive indicators in the hospital, as an outpatient, and at home for self-health management. Case managers can also perform online assessment, appraisal, and guidance via telephone, WeChat, and the chronic disease information system and record the data. Client mobile terminals can receive SMS text message alerts and the main interface of the chronic disease information system would display reminders of follow-up and return visits within ±7 days.

If a patient was out of contact for 3 months, died, or refused to accept the treatment, case managers could settle the case.

Evaluation of the Effect of Implementing the Chronic Disease Management Information System

Evaluation method.

In accordance with case quality management indicators [ 20 ], two full-time case managers collected and evaluated data in the process of the follow-up procedure. To reduce the potential for evaluation bias, the case managers consistently communicated and learned to standardize the evaluation method. The cases were divided based on different chronic respiratory diseases case management models (ie, before and after use of the chronic disease information system). The following case management quality indicators were evaluated under the noninformation system management model (2019‐2020) and under the chronic disease management information system model (2021‐2022): number of managed cases, number of patients accepting routine follow-up services, follow-up visit rate, pulmonary function test rate, admission rate for acute exacerbations, chronic respiratory diseases knowledge awareness rate, and patient satisfaction. Excel sheets were used to acquire data prior to incorporation of the chronic disease management information system into the new information system.

Evaluation Indicators

The annual number of cases was calculated as the sum of the number of newly enrolled patients and the number of initially enrolled patients. The number of cases was calculated as the sum of the number of cases in different years. The number of routine follow-up visits represents the number of patients who completed the treatment plan. The follow-up visit rate was calculated as the number of completed follow-up visits in the year divided by the number of planned follow-up visits in the same year. The pulmonary function test rate was calculated as the number of pulmonary function tests completed for patients scheduled for follow-up during the year divided by the number of pulmonary function tests for patients scheduled for follow-up during the year. The admission rate for acute exacerbations was calculated as the number of recorded patients admitted to the hospital due to acute exacerbations divided by the total number of patients recorded. The chronic respiratory diseases knowledge awareness rate was determined by the number of people having sufficient knowledge divided by the total number of people tested. This knowledge indicator was based on the self-prepared chronic respiratory diseases knowledge test scale, which consists of 10 items determined using the Delphi method (following expert consultation) through review of the literature, including common symptoms, disease hazards, treatment medication, diet, living habits, exercise, negative habits affecting the disease, regular review items, effective methods for cough and sputum removal, appointments, and follow-ups. The content of the questionnaire was refined by disease type, and the reviewers included 11 personnel with the title of Deputy Chief Nurse or above in the Internal Medicine Department of the hospital. The expert authority coefficients were 0.85 and 0.87 and the coordination coefficients were 0.50 and 0.67 for the two rounds of review, respectively; the χ 2 test showed a statistically significant value of P =.01. Patient satisfaction was assessed with a self-made questionnaire that showed good internal reliability (Cronbach α=0.78) and content validity (0.86). The questionnaire items included the reminder of return visits, practicability of health education content, and service attitude of medical staff; the full-time case managers surveyed the patients (or their caregivers) at the time of return visits after the third quarter of each year. Satisfaction items were rated using a 5-point Likert scale with a score of 1‐5, and a mean ≥4 points for an individual indicated satisfaction. Patient satisfaction was then calculated as the number of satisfied patients divided by the total number of managed patients.

Statistical Analysis

SPSS 16.0 software was used for data analysis. The Mann-Whitney U test was performed to compare continuous variables between groups and the χ 2 test was performed to compare categorical variables between groups. P <.05 indicated that the difference was statistically significant.

Ethical Considerations

The study was conducted in accordance with the principles of the Declaration of Helsinki. This study received approval from the Ethics Committee of Yulin First People’s Hospital (approval number: YLSY-IRB-RP-2024005). The study did not interfere with routine diagnosis and treatment, did not affect patients’ medical rights, and did not pose any additional risks to patients. Therefore, after discussion with the Ethics Committee of Yulin First People’s Hospital, it was decided to waive the requirement for informed consent from patients. Patients’ personal privacy and data confidentiality have been upheld throughout the study.

Characteristics of Patient Populations Before and After Implementation of the Information System

There was no significant difference in age and gender distributions in the patient populations that received care before and after implementation of the chronic disease management information system ( Table 1 ).

Comparison of Workload Before and After Implementation of the Information Management System

Before use of the system, 1808 cases were managed, with a mean of 603 (SD 137) cases having routine follow-up visits. After use of the system, 5868 cases were managed, with a mean of 2056 (SD 211) routine follow-up visits. Therefore, the number of managed cases and the number of follow-up visits significantly increased by 3.2 and 3.4 times, respectively, after use of the system (U =342.779; P< .001).

Comparison of Quality Indicators of Managed Cases Before and After Implementation of the Information System

The quality indicators in the two groups are summarized in Table 2 . Compared with the corresponding indicators before use of the system, the follow-up visit rate increased by 50.2%, the pulmonary function test rate increased by 26.2%, the chronic respiratory diseases knowledge awareness rate increased by 20.1%, the retention rate increased by 16.3%, and the patient satisfaction increased by 9.6%; moreover, the admission rate for acute exacerbations decreased by 42.4%.

a CRD: chronic respiratory disease.

Principal Findings

The main purpose of this study was to build a chronic disease management information system and apply it to the case management of chronic respiratory diseases. Our evaluation showed that the chronic disease management information system not only improves the efficiency and quality of case management but also has a benefit for maintaining the stability of the condition for patients with respiratory diseases, reduces the number of acute disease exacerbations, increases the rate of outpatient return, and improves patients’ adherence with disease self-management. Thus, a chronic disease management information system is worth popularizing and applying widely.

Value of the HIS-Based Chronic Disease Management Information System

Chronic diseases constitute a significant public health issue in China. Public hospitals play important roles in the health service system, particularly large-scale public hospitals with the most advanced technologies, equipment, and enormous medical human resources, which can greatly aid in the diagnosis and treatment of diseases and also serve as important hubs for the graded treatment of chronic diseases. Moreover, a significant number of patients with chronic diseases visit large hospitals, making them important sources of big data on chronic diseases [ 21 ]. Adoption of an HIS-based chronic disease management information system can make full use of and exert the advantages of large-scale public hospitals in terms of labor, technology, and equipment in the diagnosis, treatment, and prevention of chronic diseases; enhance the cohesiveness of the case management team in chronic disease management; and achieve prehospital, in-hospital, and posthospital continuity of care for patients with chronic diseases. Overall, use of a chronic disease management information system can enhance the quality and efficiency of chronic disease management and lay a good foundation for teaching and research on chronic diseases.

Improved Efficiency of Case Management

China was relatively late in applying case management practices, and chronic disease management has traditionally been primarily conducted offline [ 14 , 20 ] or supplemented by management with apps and WeChat [ 7 , 8 ]. Traditional case management methods require case managers to manually search, record, store, query, count, and analyze information. This manual process necessitates substantial time and makes it challenging to realize a comprehensive, systematic, and dynamic understanding of patient information, resulting in a small number of managed cases and follow-up visits. With the application of information technology, use of an HIS-based chronic disease monitoring and case management system can automatically extract and integrate patient information, thereby increasing the efficiency of chronic disease management and reduce costs [ 4 , 22 ]. In this study, two case managers played leading roles both before and after implementation of the information system; however, compared with the situation before the use of the system, the numbers of both managed cases and of follow-up visits increased, reaching 3.2 and 3.4 times the preimplementation values, respectively. The information system can automatically obtain a patient’s name and ID number based on the ICD code, which can expand the range of enrollment screening and appoint the register of patients as planned. In addition, the information system can automatically obtain outpatient, inpatient, and home medical information for the postillness life cycle management of patients. Moreover, the intuitive, clear, and dynamic indicator charts on the system can save a significant amount of time for diagnosis and treatment by medical staff, while the paperless office and online data-sharing functions can essentially solve the problem of managing files by case managers to ultimately enhance efficiency.

Improved Quality of Case Management

According to evidence-based medicine, the seven steps of case management represent the optimal clinical pathway [ 10 - 14 , 22 ]. In this study, the concept of an Internet-Plus medical service was introduced; that is, the chronic disease management information system was established based on the HIS data and case management model [ 22 ] and the function of a mobile medical terminal app was incorporated in the system [ 6 , 7 ]. Compared with the noninformation system case management model, this system has several advantages. First, owing to the swift management mode, it can overcome the limitations of time and space [ 4 - 8 ]. Second, multichannel health education and communication can enhance patients’ knowledge and skills, as well as their compliance with self-management, based on diversified forms of image data such as graphics and audio [ 6 , 22 ]. Third, the use of intelligent management can remind doctors and patients to complete management work and follow-up visits as planned, and to perform intelligent pushes of patient outcome indicators to improve confidence in the treatment [ 22 ]. Fourth, this system enables information sharing and big data analysis, as well as multidisciplinary diagnosis and treatment based on the matching of doctor-patient responsibility management, which can be more conducive to the precise health management of patients.

Compared with the traditional case management model, information-based case management significantly increased the follow-up visit rate, lung function test rate, chronic respiratory diseases knowledge awareness rate of patients, patient satisfaction rate, and retention rate. Among these indicators, the follow-up visit rate and lung function test rate represent aspects related to the patients’ own management of their condition [ 1 ]. The results of this study are consistent with previous findings related to information-based management of chronic diseases in China, demonstrating that such a management system was more conducive to planned, systematic, and personalized education and follow-up by the case management team, thereby promoting the virtuous cycle of compliance with self-management and reducing the number of acute exacerbations among patients with chronic respiratory diseases, ultimately enhancing the precision of medical resource allocation and hospital management [ 22 , 23 ].

Helping Patients With COPD Maintain Stability of Their Condition

The admission rate for acute exacerbations serves as a common indicator of the quality of the treatment of chronic respiratory diseases [ 23 ]. The deployment of a clinical pathway–based hospital case management information system significantly reduced the admission rate for acute exacerbations and enhanced the quality of treatment for chronic respiratory diseases, indicating its high clinical significance. There are several reasons for these observed benefits. First, home care and self-management are essential in the management of chronic respiratory diseases. The information-based case management model improved the patients’ knowledge and skills along with their compliance with self-management. Consequently, the standardized self-management process helped to reduce the number of acute exacerbations of chronic respiratory diseases and thus lowered the admission rate. Second, the information-based case management model increased the regular return rate, which allowed the medical staff to identify the potential risk factors for acute exacerbations in a timely manner, deal with them when they occur, and prepare personalized treatment plans and precise health management schemes. This consequently enabled adjustment of treatment schemes in real time, reduced the number of admissions due to acute exacerbations, and lowered the readmission rate. For hospitals interested in implementing a similar model, we suggest first conducting a detailed review of the current situation prior to making adequate changes based on the relevant disease and patient populations.

Consequently, the HIS-based case information management model could improve efficiency, enhance the quality of case management, and aid in stabilizing the conditions of patients with chronic respiratory diseases. In contrast to the hospital case management information system reported by Yuan et al [ 22 ], the system described in this study includes a personal terminal app. Previous studies confirmed that a stand-alone mobile health app could improve patient compliance and disease control [ 6 - 8 ]; thus, whether this system can be used to manage specialized disease cohorts for patients with chronic diseases remains to be determined. In this study, the effect on the retention rate of patients was confirmed; however, the overall operational indicators for the diagnosis and treatment of chronic diseases should be further determined.

With the advancement of information technology, the internet and medical technology have been applied to the management of chronic diseases. As an information-based platform for the case management of patients with chronic respiratory diseases, a newly developed chronic disease management information system was introduced in this study. This system is capable of designing the follow-up time registration, follow-up content, approaches, methods, quality control, and feedback process for a single chronic respiratory disease via the single-disease clinical pathway following the case management process (enrollment, assessment, planning, implementation, feedback, and evaluation). Use of this system can encourage patients with chronic respiratory diseases to adhere to regular follow-up and form an outpatient-inpatient-home chronic disease management strategy. This can help in reducing the admission rate for acute exacerbations, increase the return visit rate, and improve the correctness and compliance of home self-management of patients with chronic respiratory diseases. Owing to these benefits, wide adoption of such information systems for the management of chronic diseases can offer substantial economic and social value.

Acknowledgments

We are particularly grateful to all the people who provided help with our article. This study was supported by a grant from Yulin City Science and Technology Planning Project (20202002).

Data Availability

The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' Contributions

YML, YZX, XLS, and YXL designed this study. XLS and XJC wrote the draft of the paper. YML, YZX, and YC contributed final revisions to the article. XJC, HC, and YC collected the data. XJC, YML, YXL, and HC performed the statistical analysis. YML received funding support. All authors read and approved the final draft of the article.

Conflicts of Interest

None declared.

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Abbreviations

Edited by Christian Lovis; submitted 15.06.23; peer-reviewed by Kuang-Ming Kuo; final revised version received 14.04.24; accepted 17.04.24; published 19.06.24.

© Yi-Zhen Xiao, Xiao-Jia Chen, Xiao-Ling Sun, Huan Chen, Yu-Xia Luo, Yuan Chen, Ye-Mei Liang. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 19.6.2024.

This is an open-access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Medical Informatics, is properly cited. The complete bibliographic information, a link to the original publication on https://medinform.jmir.org/ , as well as this copyright and license information must be included.

• Open access
• Published: 20 June 2024

Association of interleukin-2 and interleukin-10 with the pathophysiology and development of generalized anxiety disorder: a case-control study

• Nisat Sarmin 1   na1 ,
• A. S. M. Roknuzzaman 2   na1 ,
• Rapty Sarker 1   na1 ,
• Mamun -or-Rashid 1 ,
• MMA Shalahuddin Qusar 3 ,
• Sitesh Chandra Bachar 4 ,
• Eva Rahman Kabir 5 ,
• Md. Rabiul Islam 5 &
• Zobaer Al Mahmud 1  

BMC Psychiatry volume  24 , Article number:  462 ( 2024 ) Cite this article

Metrics details

Generalized anxiety disorder (GAD) is a devastating mental health condition characterized by constant, uncontrolled worrying. Recent hypotheses indicate that pro-inflammatory cytokines and chemokines are potential contributors to the pathogenesis of GAD. Here, we aimed to assess the role of interleukin-2 (IL-2) and interleukin-10 (IL-10) in the pathophysiology and development of GAD.

This study recruited 50 GAD patients diagnosed according to the DSM-5 criteria and 38 age-sex-matched healthy controls (HCs). A qualified psychiatrist evaluated all study subjects. The socio-demographic and clinical characteristics of the study population were determined using pre-structured questionnaires or interviews, and cytokine serum levels were estimated using commercially available ELISA kits.

We observed reduced serum IL-10 levels in GAD patients compared to HCs (33.69 ± 1.37 pg/ml vs. 44.12 ± 3.16 pg/ml). Also, we observed a significant negative correlation between altered IL-10 levels and GAD-7 scores ( r =-0.315, p  = 0.039). Moreover, IL-10 serum measurement exhibited good predictive value in receiver operating characteristics (ROC) analysis with an area under the curve (AUC) value of 0.793 ( p  < 0.001) with 80.65% sensitivity and 62.79% specificity at a cutoff value of 33.93 pg/ml. Conversely, we noticed elevated serum IL-2 levels in GAD patients than in HCs (14.81 ± 2.88 pg/ml vs. 8.08 ± 1.1 pg/ml); however, it failed to maintain any significant association with GAD-7 scores, implying that IL-2 might not be involved in GAD pathogenesis. The lower AUC value (0.640; p  > 0.05) exhibited by IL-2 serum measurement in ROC analysis further supported that IL-2 might not be associated with GAD.

This study provides new insights into the complex interplay between anti-inflammatory cytokines and GAD pathogenesis. Based on the present findings, we can assume that IL-10 but not IL-2 may be associated with the pathophysiology and development of GAD. However, further research with a larger population size and longitudinal design is required to confirm the potential diagnostic efficacy of IL-10.

Peer Review reports

Generalized anxiety disorder (GAD) is a chronic neuropsychiatric disorder characterized by persistent and excessive uncontrollable fear or worry (occurs for at least 6 months) about various aspects/activities of daily life, affecting the educational, occupational, or social lives of the affected people [ 1 ]. If a person is excessively worried about anything for most days over at least 6 months, he/she is considered to have GAD. Though currently the prevalence rate of GAD is 3–6% worldwide [ 1 , 2 , 3 ], the prevalence is increasing day by day due to the complexity of modern lifestyles and thus warrants attention from national and international authorities to take interventions for mitigating and managing this disorder properly. If it remains undiagnosed or untreated, the uncontrollable and persistently intense anxiety can lead to a marked reduction in cognitive functions or a reduced capacity to work properly in all spheres of life, including educational, family, social, and individual routine work. As such, chronic GAD leads to a reduced quality of life and thereby poses a significant mental health concern globally.

Despite its high prevalence, significant morbidity, and socioeconomic burden, GAD remains poorly characterized in terms of its pathophysiology or effective treatment options. Though the precise cause and mechanism of pathogenesis are still unknown, evidence suggests that multiple factors, including disrupted serotonergic, dopaminergic, and GABAergic neurotransmission and excessive glutamatergic neurotransmission in the brain, genetic factors, family or environmental stress, chronic diseases, hyperthyroidism, childhood trauma, and special personality traits, are linked to GAD. Alterations in monoaminergic neurotransmissions in limbic systems (cingulate gyrus, hippocampus, amygdala, thalamus, and hypothalamus) due to the lower synaptic availability of serotonin, norepinephrine, and dopamine are thought to be associated with anxiety symptoms. Besides, decreased GABA-mediated inhibitory neurotransmission in the amygdala or excessive activation of excitatory glutamatergic neurotransmission are also suggested to be involved in GAD pathology.

Currently, available pharmacotherapies for GAD include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), pregabalin, and benzodiazepines, which act by reversing these altered monoaminergic neurotransmitter systems. Alongside these drug treatments, non-pharmacological therapies such as several psychological interventions, including cognitive-behavioral therapy, and the acquisition and application of stress management skills, including relaxation and mindfulness skills are also widely used for the management of GAD. However, currently, available pharmacotherapies (SSRIs, SNRIs, pregabalin, and benzodiazepines) have failed to demonstrate the required efficacy in treating anxiety disorders, as 50% of patients failed to respond to these drugs, and at least in 30% of cases, there is a recurrence of the disease following the pharmacological treatment [ 1 , 4 , 5 ]. Moreover, studies reported a higher rate of discontinuity from these pharmacotherapies with low patient adherence or compliance due to the adverse effects, including sexual dysfunction for SSRIs and SNRIs, nausea and dizziness for pregabalin, demonstrating an urgent need for searching for novel anxiolytics [ 3 ]. These findings raised questions about the validity of the currently available mechanism of pathogenesis and suggested that the altered monoaminergic neurotransmitter system might not fully explain the molecular mechanism of GAD development, suggesting other pathophysiological factors might be involved in GAD. Recently, dysregulated immune systems have attracted great interest as an important pathophysiological factor for the development of GAD [ 4 , 6 , 7 , 8 ]. Several clinical and preclinical studies suggest a link between the altered immune system and GAD pathology. Preclinical studies in mice also demonstrated that administration of pro-inflammatory cytokines (including IL-1β, TNF-α, and IL-6) in mice resulted in anxiety-like behaviors that were attenuated or normalized after injecting either anti-inflammatory cytokines or antagonists for the concerned cytokines [ 9 , 10 , 11 , 12 , 13 ]. A recent prospective cohort study conducted by Hou et al., (2019) demonstrated that administration of selective serotonin reuptake inhibitors (escitalopram or sertraline) resulted in a significant reduction in peripheral pro-inflammatory cytokines, and the authors suggested that the anxiolytic effects of these SSRIs might partly be based on their acute anti-inflammatory activities [ 14 ], implicating a significant association between dysregulated peripheral immune systems and GAD development. The development of anxiety-like symptoms in IL-4 gene knock-out mice, reduced levels of IL-4 in anxious mice, and the significant attenuation of anxiety-like behaviors following IL-4 injection demonstrated a positive association between anti-inflammatory cytokines, IL-4 levels, and anxiety pathology [ 15 , 16 , 17 , 18 ]. This immune hypothesis of GAD development is further potentiated by findings from several clinical studies that reported that GAD patients showed significantly higher levels of pro-inflammatory cytokines ( IL-1Ra, IL-1, IL-6, TNF-α, etc.) compared to healthy controls (HCs) [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ] along with decreased levels of anti-inflammatory cytokines, including IL-4 and IL-10 [ 25 ]. Besides, pro-inflammatory cytokines such as TNF-α, and IL-6 were significantly associated with anxiety scores [ 29 ]. Consistent with this, a randomized clinical trial in humans demonstrated that LPS administration resulted in enhanced anxiety scores, and the authors suggested a significant correlation between pro-inflammatory cytokine levels and anxiety severity [ 30 ]. LPS-mediated microglia activation causes enhanced release of excessive pro-inflammatory cytokines in the basolateral amygdala, which ultimately leads to neuroinflammation in mice, resulting in the development of anxiety and depression-like behaviors by modulating neuronal plasticity. The authors found that anxiety pathogenesis was due to the excessive release of excitatory neurotransmitter glutamate from presynaptic axonal terminals of the prefrontal cortex, leading to neuroplasticity [ 31 ]. However, some studies reported either no significant variation in pro-inflammatory or anti-inflammatory cytokine serum levels between GAD patients and HCs [ 32 ] or that pro-inflammatory cytokines including IL-1, IL-2, and IL-6 were significantly reduced in GAD patients than HCs [ 33 , 34 ]. This discrepancy in altered levels of inflammatory cytokines across clinical studies necessitates a further examination of the role of these cytokines in GAD pathophysiology.

Interleukin-2 (IL-2) is one of the major pro-inflammatory cytokines implicated in T cell activation, proliferation, and differentiation and is thus linked to excessive neuro-inflammatory processes [ 35 ]. IL-2 has been shown to impair synaptic plasticity and cause neuroinflammation, which ultimately leads to neuronal damage in neurocircuits associated with fear and anxiety signal transduction. IL-2 was also reported to act as a potent modulator of NMDA and kainite-mediated excitability in mesolimbic or mesostriatal systems [ 36 , 37 , 38 ] and thus affect neuroplasticity. As IL-2 was found to be positively associated with major depressive disorder [ 38 , 39 ], probably, IL-2 might also be correlated with anxiety disorders like GAD, as MDD and GAD are highly co-morbid themselves and thus might share common pathophysiological factors. Recently, a preclinical study conducted by Gilio et al., (2022) observed that IL-2 administration in experimentally healthy mice triggered marked anxiety and depression-like behaviors, and the authors suggested that inhibition of GABA-mediated synaptic inhibitory neurotransmission was involved in the pathology of anxiety [ 40 ].

Interleukin-10 (IL-10) is one of the major anti-inflammatory cytokines that is secreted from Treg cells, Th2 cells, CD4 + T cells, CD8 + T cells, monocytes, macrophages, dendritic cells, B cells, neutrophils in the peripheral nervous system, and from microglia, astrocytes in the central nervous system (CNS) [ 41 ]. IL-10 signaling triggers anti-inflammatory, immunosuppressive, and immunoregulatory activities, including downregulating the production and secretion of pro-inflammatory cytokines and chemokines from activated macrophages, neutrophils, mast cells, Th1 cells, and DCS, decreasing the expression of MHC class II and co-stimulatory molecules on macrophages, and thereby suppressing the antigen presentation capacity of APCS [ 42 , 43 , 44 , 45 , 46 ]. In the CNS, it inhibits the production of such cytokines and chemokines by activated microglia and thereby counteracts cellular and tissue damage in response to excessive neuroinflammation [ 47 , 48 ]. IL-10 has also been shown to stimulate axonal regeneration and activate wound healing through tissue repair [ 48 ]. Research also indicates its role as an inhibitor for microglial hyperactivation in response to LPS-induced inflammatory stimulus [ 49 ]. Based on its anti-inflammatory and immunoregulatory functions, researchers suggested an intricate role for IL-10 in several auto-immune and neuropsychiatric disorders. For example, Mesquita et al., (2008) observed that IL-10 KO mice developed markedly enhanced depressive-like behavior, which was attenuated after IL-10 administration, and that overexpression of IL-10 resulted in reduced depressive behaviors in mice [ 50 ]. Moreover, administration of IL-10 into rats attenuated the pro-inflammatory cytokine IL-1β-induced anxiety-like symptoms in male rats [ 10 ], demonstrating that IL-10 possesses anxiolytic activities. Preclinical research using an experimental animal model also suggests that the observed anxiolytic effect of several anti-anxiety drugs, including 3’-deoxyadenosine (3’-dA), imipramine, fluoxetine, and chlordiazepoxide, stems from their ability to upregulate anti-inflammatory cytokine (IL-4, IL-10) expression in the prefrontal cortex and locus coeruleus and simultaneous down-regulation of proinflammatory cytokine gene expression, leading to a correction of the imbalance between proinflammatory and anti-inflammatory states [ 51 , 52 ]. Though several preclinical studies suggest a potential link between IL-10 levels and anxiety disorder, there is a scarcity of clinical studies aimed at evaluating such an association between IL-10 and GAD development [ 10 ].

Currently, there is no objective and cost-effective diagnostic or prognostic biomarker for GAD, which poses challenges in early diagnosis or risk prediction and leads to misdiagnosis or underdiagnosis, hampering the proper management of the disease. Currently available diagnostic tools, including self-reported symptoms and scoring severity based on the patient’s response to the 7-item questionnaire (GAD-7 scores), are subjective. Though neuroimaging techniques such as positron emission tomography (PET) and functional MRI can be used for the proper and objective diagnosis of GAD, due to their high cost and sophistication or complexities, these diagnostic tools are not suitable for either mass-level screening or are not easy to conduct multiple times to monitor the disease progression or therapeutic drug response. As such, the investigation of cost-effective objective biomarkers for GAD is one of the major focuses of current research on GAD. Finding a suitable biomarker is essential for early diagnosis and initiating psychotherapy and pharmacotherapy as early as possible [ 3 ]. Several studies were performed investigating the potential association between altered pro-inflammatory cytokines or anti-inflammatory cytokines and the pathogenesis of GAD. However, the actual role of inflammatory cytokines in GAD patients is not well explained. Therefore, the present study aims to explore the role of pro-inflammatory cytokines (IL-2) and anti-inflammatory cytokines (IL-10) in the pathophysiology and development of GAD. Also, we aim to find the potential associations of IL-2 and IL-10 with the severity of GAD patients. We believe the present study results would help to understand the pathophysiology and development of GAD.

Study population

We recruited 88 participants for this case-control study (50 GAD patients and 38 HCs matched by age and sex). Patients were collected from the Department of Psychiatry, Bangabandhu Sheikh Mujib Medical University Hospital, Dhaka, Bangladesh, and HCs from nearby areas of Dhaka city. A professional psychiatrist diagnosed patients and evaluated HCs based on DSM-5 criteria. We applied a 7-item GAD scale to assess the severity of anxiety symptoms [ 53 ]. The total scores range from 0 to 21, and it classifies the anxiety severity into four categories: minimal anxiety (0–4 scores), mild anxiety (5–9 scores), moderate anxiety (10–14 scores), and severe anxiety (15–21 scores). We excluded subjects with a co-morbidity of other psychiatric disorders, such as MDD, panic disorder, post-traumatic stress disorder, and social phobia, from the study. Additional exclusion criteria for participants were chronic liver and kidney diseases, infectious diseases, and alcohol or substance abuse. We also excluded patients who were exposed to anxiolytics or antidepressant medications within at least two weeks prior to the study that might have an impact on cytokine levels. We recorded the sociodemographic profile of the study population using a pre-designed questionnaire. The objectives of the study were explained to each participant, and informed written consent was obtained from them before their participation in this study. The study was conducted in accordance with the Declaration of Helsinki.

Blood sample collection and serum isolation

A 5 ml blood sample was collected from the cephalic vein of each participant. The blood samples were kept at room temperature for 1 hour to ensure coagulation and were then subjected to centrifugation at 3000 rpm for 15 minutes at room temperature to collect serum samples. The collected serum was then placed in the Eppendorf tube and stored at -80 °C until further analysis.

Estimation of serum cytokine levels

We estimated the serum levels of IL-2 and IL-10 by ELISA methods (Boster Bio, USA). We followed the manufacturer’s protocol for the ELISA assays. At first, we added 100 µl of standard cytokine solution, samples, and controls to each well of a pre-coated 96-well microplate. The microplates were covered with a plate sealer and incubated for 90 min at 37⁰C. After that, the cover was removed, and the liquid in each well was discarded. Subsequently, 100 µl of biotinylated anti-IL-2 antibody or anti-IL-10 antibody was incorporated into each well and incubated for 60 min at 37⁰C. After discarding the liquid from each well and washing it three times with 300 µl of wash buffer, 100 µl of avidin-biotin-peroxidase complex was added to each well, and the microplate was then again incubated for 30 min at 37⁰C. After the incubation period, the liquid was again discarded, and the plate was washed again with 300 µl of wash buffer five times. Following the addition of 90 µl color-developing reagent (TMB) into each well, the plate was incubated in a dark place for 30 min at RT, followed by the addition of 90 µl of stop solution to each well to stop the reaction process. We measured the absorbance with a microplate reader at 450 nm. We calculated the cytokine levels using standard curves and expressed them as pg/ml.

Data presentation and statistical analysis

GraphPad Prism (version 8.0.1) and Statistical Package for the Social Sciences (version 24.0) were used for data analysis. We used descriptive statistics to find the variations in sociodemographic profiles and clinical characteristics between the groups. A T-test and a Chi-square test were employed to determine the statistical level of significance between the mean differences for variables across patients versus HC groups in the case of continuous variables and categorical variables, respectively. We used boxplot graphs for comparisons of analyzed cytokines between patients and HCs. We also generated scatter plot graphs for several clinical variables in GAD patients to show the correlations among the clinical parameters. A correlation analysis was performed to assess the potential association between several demographic and clinical variables in GAD patients. Receiver operating characteristics (ROC) analysis was conducted to determine the diagnostic efficacy of serum IL-2 or IL-10 levels in discriminating GAD patients from HCs. In all cases, statistical significance was considered at p  < 0.05.

Sociodemographic characteristics of the study population

The sociodemographic characteristics of the study population are presented in Table  1 . The GAD patients and HCs were similar in terms of their age, sex, and BMI. Among the participants, about 60% were male and from urban areas. The majority of patients (60.00%) and HCs (68.42%) were unmarried. There was no significant variation between patients and HCs for their education level, occupation, economic status, or smoking status. In contrast, there was a difference between patients and HCs for their family history and previous history of the disease. In GAD patients, 20.00% had a family history, and 40.00% had a previous history of the disease.

Clinical characteristics and laboratory findings

Clinical characteristics and laboratory analysis results are presented in Table  2 . GAD patients displayed markedly higher serum levels of IL-2 (14.81 ± 2.88 pg/ml) compared to HCs (8.08 ± 1.10 pg/ml), and the difference reached the statistically significant level ( p  = 0.037, two-tailed unpaired t-test) (Table  2 ; Fig.  1 ). Though male GAD patients exhibited markedly higher levels of IL-2 compared to male HCs ( p  = 0.048), there was no significant variation in IL-2 levels between female patients and female HCs ( p  > 0.05) (Fig.  1 ). Though some 1.8-fold higher IL-2 serum levels were observed in male GAD patients compared to female GAD patients, the difference did not reach the statistical significance level ( p  = 0.198, two-tailed unpaired t-test). In contrast to the results obtained for IL-2, IL-10 showed a statistically significant ( p  < 0.001) reduction in GAD patients (33.69 ± 1.37 pg/ml) compared to HCs (44.12 ± 3.16 pg/ml) (Fig.  1 ). Similar to the results obtained for IL-2, IL-10 levels showed a statistically significant difference between patients versus HCs when male people were considered (Fig.  1 ). In contrast, there was no significant variation in IL-10 levels between female GAD patients and female HCs ( p  > 0.05).

Distribution of serum IL-2 ( a i ) and IL-10 ( b i ) levels in GAD patients and healthy controls. Comparison of IL-2 and IL-10 levels between GAD patients and their counterparts in control subjects are showed in a i and b i . Comparison of IL-2 and IL-10 levels between male or female GAD patients and their counterparts in control subjects are presented in a ii and b ii

Correlation analysis among different study parameters

We then performed a series of correlation analyses to investigate the association of altered cytokine serum levels with several demographic and clinical variables, such as age, BMI, DSM-5, and GAD-7 scores (Table  3 ). Serum IL-2 levels did not show any positive or negative association with either DSM-5 or GAD-7 scores ( p  > 0.05), suggesting that despite its significant enhancement in GAD patients compared to HCs, IL-2 may not associate with GAD pathophysiology. We also observed no significant association between the ages of the patients and IL-2 serum levels. In contrast, the IL-2 levels of GAD patients maintained a significant and positive correlation with BMI levels of patients ( r  = 0.390, p  < 0.05) which is consistent with the intricate relationship between body mass and enhanced pro-inflammatory responses. Contrary to the results obtained for IL-2, reduced serum IL-10 levels maintained a significant but negative association with both DSM-5 scores ( r =-0.300, p  = 0.045) and GAD-7 scores ( r =-0.315, p  = 0.039), implicating that altered IL-10 levels are linked to GAD development or pathogenesis. However, the age and BMI levels of GAD patients failed to show any positive or negative association with IL-10 serum levels. Analysis also showed a significant and strong positive association between IL-2 and IL-10 serum levels ( r  = 0.471, p  = 0.011) in GAD patients, which might be due to the compensatory enhancement of anti-inflammatory cytokine, IL-10 in response to elevated pro-inflammatory cytokine, IL-2 levels. Also, we displayed these correlations among several clinical variables of GAD patients by scatter plot graphs (Fig.  2 ).

Scatter plot graphs for several clinical variables of GAD patients showing existence or absence of correlation between the clinical parameters. Scatter plot for serum IL-2 levels versus GAD-7 scores ( a ) or DSM-5 scores ( b ) expressing no significant association between IL-2 and both clinical parameters. Scatter plot graphs showing significant association between IL-2 levels and BMI ( c ), IL-10 levels and GAD-7 scores ( d ), IL-10 levels and DSM-5 scores and IL-10 and IL-2 levels ( f )

Receiver operating characteristic curve analysis

Serum IL-10 measurement showed a good performance in differentiating GAD patients from HCs, which was evidenced by its significantly higher area under the curve (AUC) value of 0.793 ( p  < 0.001) with 80.65% sensitivity and 62.79% specificity at a cut-off value of 33.93 pg/ml, in which the cytokine levels below this point indicate disease states (Table  4 ; Fig.  3 ). ROC analysis of serum IL-2 levels failed to discriminate GAD patients from HCs as the AUC value was below the acceptable range (AUC: 0.640; p  = 0.108) with 54.17% sensitivity and 68.18% specificity at a cut-off value of 8.83 pg/ml) (Fig.  3 ; Table  4 ).

Receiver operating characteristic curve (ROC) for serum IL-2 ( a ) and IL-10 levels ( b )

To the best of our knowledge, this is the first case-control study to investigate the potential association between the pathophysiology of GAD and the pro-inflammatory cytokine, IL-2, and the anti-inflammatory cytokine, IL-10, among the Bangladeshi population. We observed that IL-10 serum levels were significantly lower in GAD patients than in HCs, and this reduction was found to be significantly but negatively associated with both DSM-5 scores and GAD-7 scores, demonstrating potential involvement of this anti-inflammatory cytokine in disease severity and symptoms. Our results of a significant reduction in IL-10 levels in GAD patients are in good agreement with those observed in other studies [ 23 , 25 ]. In contrast, our results diverge from those reported by others [ 33 , 54 ] who either reported no significant variation in IL-10 levels between GAD patients and HCs or that IL-10 levels were enhanced in GAD patients compared to HCs. ROC analysis also demonstrated the good predictive value of IL-10 serum measurement in discriminating diseased patients from HCs, suggesting that IL-10 serum level might be a potential biomarker for diagnosis, anti-anxiety drug response monitoring, or disease progression monitoring. Recently, Hou et al. (2019) demonstrated that peripheral serum levels of the pro-inflammatory cytokine IL-6 could be used to monitor the treatment response of SSRIs in GAD [ 14 ]. Similarly, IL-10 might be used as a marker for therapeutic drug monitoring in GAD. However, further longitudinal studies are required to find any causal relationship between IL-10 and disease severity or pathogenesis. On the other hand, serum IL-2 levels were significantly elevated in GAD patients compared to HCs, but they failed to demonstrate any significant association with either DSM-5 scores or GAD-7 scores in Pearson correlation analysis, implying that IL-2 levels might not be associated with the pathophysiology and development of GAD. Consistent with this, ROC analysis showed that IL-2 levels have no significant diagnostic efficacy in differentiating GAD patients from HCs. Further analysis with a larger population size is required to explore the role of IL-2 in the context of GAD severity. Our results are consistent with those reported by Tang et al. (2018), who also observed that GAD patients exhibited significantly higher serum levels of IL-2 compared to HCs [ 19 ]. However, our results are not in agreement with those reported by others who observed either no significant variation in IL-2 levels [ 54 ] or a significant reduction in GAD patients compared to HCs [ 25 , 33 , 34 , 55 ]. We also observed a significant positive correlation between IL-2 and IL-10 levels in GAD patients, which indicates a compensatory mechanism [ 56 ].

Our study provides some valuable insights into the complex and intricate relationship between the dysregulated immune system and GAD. The observed reduction in IL-10 levels in GAD patients in our study suggests a potential immunoregulatory imbalance in GAD, with IL-10 playing a role in modulating anxiety severity. The lack of a significant association between IL-2 serum levels and anxiety severity highlights the nuanced nature of immune dysregulation in GAD, warranting further exploration into the specific mechanisms involved. Elevated levels of pro-inflammatory cytokine, IL-2, and decreased levels of anti-inflammatory cytokine, IL-10, in GAD patients compared to HCs indicate that GAD individuals of the Bangladeshi cohort are characterized by heightened inflammatory responses derived from the imbalance between pro-inflammatory and anti-inflammatory states. Our study finding provides further support for the cytokine hypothesis of anxiety disorder, which proposes that pro-inflammatory cytokine-mediated neuroinflammatory processes can lead to anxiety symptoms or behaviors by downregulating serotonin biosynthesis or enhancing the reuptake of serotonin, resulting in an altered serotonergic neurotransmitter system in the CNS [ 15 ]. The observed significant negative correlation between IL-10 and DSM-5 scores or GAD-7 scores suggests that lowering IL-10 levels might be involved in the pathogenesis of GAD. One of the major implications of our study findings is that IL-10 signaling might be targeted to explore potential novel immunological/immunomodulatory therapies against GAD. The diminished IL-10 levels and their negative correlation with GAD severity suggest a potential avenue for therapeutic intervention. IL-10 might also be used as an anti-inflammatory adjunctive therapy with other pharmacotherapies including SSRIs/SNRIs. However, at this moment, we don’t know the exact mechanism by which lowered levels of IL-10 are linked to higher anxiety severity in GAD patients.

As IL-10 has anti-inflammatory and immunoregulatory activities such as suppression of production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) from microglia and astrocytes, reduction in IL-10 levels in GAD patients in our study led to an imbalance between pro-inflammatory and anti-inflammatory states and resulted in enhanced pro-inflammatory responses, which might be the cause of enhanced anxiety symptoms as inflammatory cytokine-mediated neuroinflammation was reported to be linked with disrupted monoaminergic neurotransmission in the brain. Besides, elevated levels of IL-10 were shown to attenuate anxiety-like behaviors by modulating GABAergic neurotransmission in the amygdala (Patel et al., 2021). IL-10 was also reported to display some neuroprotective activities and has been shown to inhibit neuronal apoptosis and promote neurite outgrowth, axonal outgrowth, and synapse formation in the brain by the JAK1-STAT3 signaling pathway [ 57 ]. In a preclinical study, IL-4 has been shown to cause the shifting of microglia and macrophages from pro-inflammatory to anti-inflammatory neuroprotective phenotypes characterized by excessive production of arginase-1 and PPARγ receptor expression in microglia and macrophage and thereby attenuating brain-injury-mediated anxiety by inhibiting neuronal loss and nerve tracts in the limbic system [ 58 ]. A similar mechanism might be involved in IL-10-mediated anxiety symptom improvement in GAD patients. Further research is required to unravel the exact mechanisms of IL-10-mediated anxiety symptom attenuation in GAD patients.

In terms of diagnostic marker development, as IL-10 serum level measurement demonstrated good performance in discriminating GAD patients from HCs and as IL-10 levels maintained a significant and negative correlation with disease severity, IL-10 serum level raised the possibility of being an objective biomarker for GAD. However, the diagnostic efficacy of this cytokine should be investigated thoroughly using a range of longitudinal studies. Despite this, at this time we can conclude that IL-10 might be used as a risk indicator for assessment of susceptibility to anxiety disorder, resulting in early detection of the disease and prompting the initiation of intervention strategies. This early detection will reduce treatment costs and decrease the prevalence and morbidity associated with this chronic disorder.

The strength of our study is that we designed a set of inclusion and exclusion criteria for the recruitment of participants and followed those criteria in such a way that homogenous population data could be obtained. The strict study design helped us enormously to minimize the potential impact of several confounding variables, including age, sex, BMI, co-morbid diseases, and immunomodulatory drugs, on cytokine levels. However, our study also has some limitations that should be acknowledged. The major limitation of this study is the smaller sample size. We recruited 50 patients and 38 HCs, which does not represent the whole Bangladeshi demographic. It would be better if we could enroll an equal number of cases and controls. For example, we observed that cytokine levels maintained a statistically significant difference between male GAD patients and male HCs. In contrast, no significant variation in cytokine levels was observed when female data were considered. As we have included more male participants (60%) than female participants (40%), the lower sample size of female participants might generate a higher background noise, resulting in lower statistical power, warranting further studies recruiting a larger population size to investigate sex-specific differences in cytokine levels in GAD patients. Our case-control study design is inherently correlational and thus not able to evaluate the causal relationship between altered cytokine levels and GAD. So, at this moment, we cannot conclude whether the altered levels of serum cytokines are the causes of anxiety development or just the outcome of pathophysiological changes.

Longitudinal studies are required to investigate whether altered cytokine levels precede GAD or if it’s just a mere reflection of GAD pathology. Though we have restricted the impacts of several co-variates, other confounding variables, including genetic polymorphism in cytokine genes, the effect of lifestyle or xenobiotics, and dietary habits, were not considered, which might have modulatory effects on serum cytokine levels.

The study provides valuable insights for understanding the pathogenesis of GAD. Despite having elevated IL-2 levels in GAD patients compared to HCs, it failed to demonstrate a significant association with anxiety severity as assessed by GAD-7 scores. In contrast, serum IL-10 levels were significantly reduced in GAD patients compared to HCs and showed a significant negative correlation with anxiety severity, implicating a potential link with the GAD pathophysiology. Our results support the immune hypothesis of GAD development. Our study findings also suggest that IL-10 serum level measurement might offer an objective blood-based biomarker or risk assessment indicator for GAD. We recommend further research employing a larger population size and homogenous data from different areas of Bangladesh to confirm our study findings.

Data availability

All the relevant data and information will be available from the corresponding author upon reasonable request.

Abbreviations

Body mass index

Chronic energy deficiency

Confidence interval

Central nervous system

Diagnostic and statistical manual for mental disorders, 5th edition

Enzyme-linked immunosorbent assay

• Generalized anxiety disorder

Generalized anxiety disorder 7-item scores

Healthy control

• Interleukin-2
• Interleukin-10

Receiver operating characteristic

Standard error mean

Statistical package for social science

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Acknowledgements

The authors are thankful to all the participants of this study. They are also thankful to the staff and physicians at the Department of Psychiatry, BSMMU, for their technical and administrative support. The authors are also thankful for the laboratory support provided by the Department of Pharmacy, University of Asia Pacific, Dhaka Bangladesh.

This research received no specific grant from any funding agency. However, we received partial funding from University of Dhaka, Bangladesh (Centennial Research grant (2nd Phase) for the year of 2020–2021, project title: “Investigation of peripheral pro-inflammatory and anti-inflammatory cytokines and immune balance in Bangladeshi patients with Generalized Anxiety Disorder”).

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Nisat Sarmin, A. S. M. Roknuzzaman and Rapty Sarker contributed equally to this work.

Authors and Affiliations

Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh

Nisat Sarmin, Rapty Sarker, Mamun -or-Rashid & Zobaer Al Mahmud

Department of Pharmacy, University of Asia Pacific, Dhaka, 1205, Bangladesh

A. S. M. Roknuzzaman

Department of Psychiatry, Bangabandhu Sheikh Mujib Medical University, Shahabagh, Dhaka, 1000, Bangladesh

MMA Shalahuddin Qusar

Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh

Sitesh Chandra Bachar

School of Pharmacy, BRAC University, Kha 224 Bir Uttam Rafiqul Islam Avenue, Merul Badda, Dhaka, 1212, Bangladesh

Eva Rahman Kabir & Md. Rabiul Islam

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Contributions

NS, ASMR, RS, MRI, and ZAM: Conceptualization, Data curation, Investigation, Writing – original draft. MR, MMASQ, SCB, and ZAM: Funding acquisition, Project administration, Validation. ERK, MRI, and ZAM: Conceptualization, Formal analysis, Methodology, Supervision, Writing – review & editing.

Corresponding authors

Correspondence to Md. Rabiul Islam or Zobaer Al Mahmud .

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The research protocol was approved by the Research Ethics Committee (REC) of the University of Asia Pacific, Dhaka, Bangladesh (Ref: UAP/REC/2023/202-S). We briefed the objectives of the study to the participants, and informed consent was obtained from each of them. We conducted this investigation following the Helsinki Declaration’s guiding principles.

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Sarmin, N., Roknuzzaman, A.S.M., Sarker, R. et al. Association of interleukin-2 and interleukin-10 with the pathophysiology and development of generalized anxiety disorder: a case-control study. BMC Psychiatry 24 , 462 (2024). https://doi.org/10.1186/s12888-024-05911-z

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Received : 31 December 2023

Accepted : 13 June 2024

Published : 20 June 2024

DOI : https://doi.org/10.1186/s12888-024-05911-z

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