the case study of hm (henry molaison) and clive wearing

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

Erin Heaning

Clinical Safety Strategist at Bristol Myers Squibb

Psychology Graduate, Princeton University

Erin Heaning, a holder of a BA (Hons) in Psychology from Princeton University, has experienced as a research assistant at the Princeton Baby Lab.

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Saul Mcleod, PhD

Editor-in-Chief for Simply Psychology

BSc (Hons) Psychology, MRes, PhD, University of Manchester

Saul Mcleod, PhD., is a qualified psychology teacher with over 18 years of experience in further and higher education. He has been published in peer-reviewed journals, including the Journal of Clinical Psychology.

Olivia Guy-Evans, MSc

Associate Editor for Simply Psychology

BSc (Hons) Psychology, MSc Psychology of Education

Olivia Guy-Evans is a writer and associate editor for Simply Psychology. She has previously worked in healthcare and educational sectors.

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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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Clive Wearing (Amnesia Patient)

Imagine waking up every day without remembering anything from your past and then immediately forgetting that you woke up at all. This life without memories is the reality for British musician Clive Wearing who suffers from one of the most severe case of amnesia ever known.

Who is Clive Wearing?

Clive Wearing was born on 11 May 1938. He was an accomplished musicologist, keyboardist, conductor, music producer, and professional tenor at the Westminster Cathedral. When on 27 March 1985 he contracted a virus that attacked his central nervous system resulting in a brain infection, Clive’s life was changed forever.

The rare neurological condition called herpes encephalitis caused profound and irreparable damage to Clive’s hippocampus. The hippocampus is a part of the brain that plays an important role in consolidating short-term memory into long-term memory. It is essential for recalling facts and remembering how, where, and when an event happened.

Clive’s hippocampus and medial temporal lobes where it is located were ravaged by the disease. As a consequence, he was left with both anterograde amnesia, the inability to make or keep memories, and retrograde amnesia, the loss of past memories. Most patients suffer one or the other, so it's notable that Clive suffered both.

Clive Wearing and Dual Retrograde-Anterograde Amnesia

Clive’s rare dual retrograde-anterograde amnesia, also known as global or total amnesia, is one of the most extreme cases of memory loss ever recorded. In psychology, the phenomenon is often referred to as "30-second Clive" in reference to Clive Wearing’s case.

Anterograde amnesia

Anterograde amnesia is the loss of the possibility to make new memories after the event that caused the condition, such as an injury or illness. People with anterograde amnesia don’t recall their recent past and are not able to retain any new information. (If you have ever seen the movie  50 First Dates,  you might be familiar with this type of condition.)

The duration of Clive’s short-term memory is anywhere between 7 seconds and 30 seconds. He can’t remember what he was doing only a few minutes earlier nor recognize people he had just seen. By the time he gets to the end of a sentence, Clive may have already forgotten what he was talking about. It is impossible for him to watch a movie or read a book since he can’t remember any sentences before the last one.

Because he has no memory of any previous events, Clive constantly thinks that he has just awoken from a coma. In a way, his consciousness is rebooted every 30 seconds. It restarts as soon as the time span of his short-term memory has elapsed.

Retrograde amnesia

Retrograde amnesia is a loss of memory of events that occurred before its onset. Retrograde amnesia is usually gradual and recent memories are more likely to be lost than the older ones .

Due to his severe case of retrograde amnesia, however, Clive doesn’t remember anything that has happened in his entire life. He completely lacks the episodic or autobiographical memory, the memory of his personal experience.

But although he can’t remember them, Clive does know that certain events have occurred in his life. He is aware, for example, that he has children from a previous marriage, even though he doesn’t remember their names or any other detail about them. He knows that he used to be a musician, yet he has no recollection of any part of his career.

Clive also knows that he has a wife. In fact, his second wife Deborah is the only person he recognizes. Whenever Deborah enters the room, Clive greets her with great joy and affection. He has no episodic memories of Deborah, and no memory of their life together. For him, each meeting with her is the first one. But he knows that she is his wife and that he is happy to see her. His memory of emotions associated with Deborah provokes his reactions even in the absence of the episodic memory.

In spite of his complex amnesia, Clive still has some types of memories that remain intact, including semantic and procedural memory.

Clive Wearing’s Semantic and Procedural Memories

Clive Wearing’s example shows that memory is not as simple as we might think. Although the physical location of memory remains largely unknown, scientists believe that different types of memories are stored in neural networks in various parts of the brain.

Semantic memory

Semantic memory is our general factual knowledge, like knowing the capital of France, or the months of the year. Studies show that retrieving episodic and semantic memories activate different areas of the brain. Despite his amnesia, therefore, Clive still has much of his semantic memory and retains his humor and intelligence.

Procedural memory

Clive may not have any episodic memories of his life before the illness, but he has a largely unimpaired procedural memory and some residual learning capacity.

Procedural or muscle memory is remembering how to perform everyday actions like tying shoelaces, writing, or using a knife and fork. People can retain procedural memories even after they have forgotten being taught how to do them. This is why Clive’s procedure memory including language abilities and performing motor tasks that he learned prior to his brain damage are unchanged.

Using procedural memory, Clive can learn new skills and facts through repetition. If he hears a piece of information repeated over and over again, he can eventually retain it although he doesn’t know when or where he had heard it.

While episodic memory is mainly encoded in the hippocampus, the encoding of the procedural memory takes place in different brain areas and in particular the cerebellum, which in Clive’s case has not been damaged.

Musical memory

What’s more, Clive’s musical memory has been perfectly preserved even decades after the onset of his amnesia. In fact, people who suffer from amnesia often have exceptional musical memories. Research shows that these memories are stored in a part of the brain separate from the regions involved in long-term memory.

That’s why Clive is capable of reading music, playing complex piano and organ pieces, and even conducting a choir. But just minutes after the performance, he has no more recollection of ever having played an instrument or having any musical knowledge at all.

Is Clive Wearing Still Alive?

Yes! Clive Wearing is in his early 80s and lives in a residential care facility. Recent reports show that he continues to approve. He renewed his vows with his wife in 2002, and his wife wrote a memoir about her experiences with him.

You can take a look at Clive Wearing's diary entry, as well as access a documentary on him, by checking out this Reddit post .

Not Just Clive Wearing: Other Cases of Amnesia 

Clive Wearing is one of the most famous patients with amnesia, but he is far from the only one. Amnesia can affect people temporarily or permanently, and it doesn’t discriminate. Famous authors, former NFL players, and just regular people going to the dentist may deal with a bout of amnesia at one point in their lives. And some of these stories are so stranger than fiction that they are doubted by medical professionals and the general public! 

Neuroscientists have been carefully studying amnesia since the 1950s. One of their first notable patients was a man named Henry Molaison, or “H.M.” H.M. suffered amnesia after having surgery at the age of 27. H.M. forgot things almost as soon as they took place. His condition was the subject of studies for decades until he died in 2008. Many scientists still refer to his case when discussing amnesia and other memory disorders. 

Scott Bolzan 

Imagine waking up one day in the hospital with little to no memories of your life. You’re 47, the woman by your bedside is telling you that you have been married for 25 years. The terms “marriage” and “wife” don’t even register in your brain! As your family tells you about your life, you learn that you spent two years playing in the NFL, have two teenage children, and have decades of memories that just aren’t accessible. This is what happened to Scott Bolzan. 

Scott Bolzan developed retrograde amnesia after a simple slip and fall. Little to no blood flow and damaged brain cells in the right temporal lobe erased many of Bolzan’s long-term memories. He knew basic skills, like eating with utensils, but memories of people and events completely disappeared. His case is one of the most severe cases of retrograde amnesia in history, but even his story is doubted by some neurologists. Since his fall, he has written a book about his memory loss and is now a motivational speaker. 

Agatha Christie

The story of Agatha Christie’s amnesia is largely buried under her other accomplishments. She’s one of the world’s best-selling authors (only outsold by the Bible and Shakespeare!) Her brain was always in use as she wrote 66 detective novels, but before that, she may have suffered great memory loss. Did she have total amnesia? The jury is actually out on that. I’ll explain why.  

Christie found out that her husband was cheating on her shortly after the death of Christie’s mother. The stress was tough for Christie to handle, so it’s not surprising that she fled home after an argument with her husband. Her car turned up in a ditch, and after 11 days of searching, she was found at a hotel. Christie had checked into the hotel using the same name as the “other woman” in her husband’s affair. 

Upon discovering Christie, her husband reported that she was suffering from amnesia and had no idea who she was. Two doctors confirmed the diagnosis, but it did not debilitate her for life, like Clive Wearing. This alleged bout with amnesia happened in 1926, years before she wrote the genius novels that we still know today. Some sources are not sure whether she suffered amnesia, was faking the condition to seek revenge on her husband or was simply experiencing a dissociative state after traumatic events. It would not be completely unusual if she did experience memory loss while staying in that hotel. Dissociative amnesia can affect anyone who has been through trauma or extreme levels of stress. 

One patient, identified only as “ WO ,” started living the life of Drew Barrymore’s character in 50 First Dates after a…root canal? While anterograde amnesia was the result of a car crash in the popular movie, other types of trauma or events can bring on this condition. For WO, it was a routine root canal. Nothing dramatic happened during the procedure. Nothing dramatic took place in WO’s brain after they went home. And yet, the patient wakes up every day believing it is March 14, 2005. They were 38 years old at the time of the root canal. 

Every day, the patient must wake up and remind themselves that it is not 2005, but much later. An electronic journal keeps them up to date with their life and the events of the past years. Although the cause behind their amnesia is truly baffling, it goes to show that our brains can be fragile and there is still a lot to learn about them!

Related posts:

• Long Term Memory
• Semantic Memory (Definition + Examples + Pics)
• Memory (Types + Models + Overview)
• Short Term Memory
• Declarative Memory (Definition + Examples)

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38 Clive Wearing and Henry Molaison Reconsidered

• Published: September 2022
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Varying extents of damage to the hippocampi and amygdalas of Henry Molaison and Clive Wearing may account for the differences in severity of their respective memory losses and consequent behaviours.

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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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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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Travis Dixon September 26, 2017 Cognitive Psychology

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There’s never enough time to cover everything in our IB Psychology course, so here are a few resources that might not fit in normal classes, but you might find interesting nonetheless.

Clive Wearing is very similar to the famous case of HM (Henry Molaison). However, whereas HM’s hippocampus was damaged due to surgery, Wearing’s was damaged due to an illness. The results were similar though: Wearing has no short-term memory but his procedural memory remains in-tact.

You can learn more about Mr Wearing by watching the following video from 44:02-57:40.

There are no documentaries (that I’m aware of) that feature filmed footage of HM. Wearing, on the other hand, has been the subject of multiple documentaries. This is perhaps due to the fact that his wife is able to sign consent forms to appear in such films, whereas HM was never married.

Here is another documentary on Clive Wearing from 1986:

This article in the New Yorker called “The Abyss” also explores the case of Wearing.

Deborah Wearing also wrote a book about her and Clive’s experiences, called “Forever Today,” which is available on Amazon.

A Word of Warning about Wearing

You might be tempted to use details of Clive Wearing’s case in an exam, just as you would HM’s. However, you need to be careful. The above documentaries are not peer-reviewed academic literature, so we need to be wary of basing our conclusions on this evidence. I would recommend using details of HM’s case study (Milner, 1957 and Corkin, 1997) in IB exam answers.

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

H.M.; Also the Case of H.M., Molaison, Henry (1926–2008)

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Landmark Clinical, Scientific, and Professional Contributions

Investigations of Henry Molaison’s (HM) neurocognitive functioning following his surgical intervention have revolutionized our understanding of learning and memory processes. HM’s specific surgical intervention and associated cognitive impairments provided information not only about differential memory activities but also about the neural substrates involved in the mediation of these processes. Investigations of the alterations in HM’s memory led to a landmark paper by Brenda Milner, a psychologist working with HM, and William Scoville, his neurosurgeon. The paper, entitled Loss of recent memory after bilateral hippocampal lesions , was published in the Journal of Neurology, Neurosurgery, and Psychiatry in 1957; it brought about a sea change in the understanding of the neural substrates of memory. This paper has been cited more than 1800 times since its initial publication.

In this landmark paper, as well as in many others...

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References and Readings

Corkin, S. (2002). Whats new with amnesic patient H.M.? Nature Reviews Neuroscience, 3 , 153–160.

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Ogden, J. A. (2005). Fractured minds . New York: Oxford University Press.

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Scoville, W. B. (1968). Amnesia after bilateral mesial temporal-lobe excision: Introduction to case H.M. Neuropsychologica, 6 , 211–213.

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Scoville, W. B., & Milner, B. (1957). Loss of recent memory after bilateral hippocampal lesions. Journal of Neurology, Neurosurgery, and Psychiatry, 20 , 11–21.

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Scoville, W. B., & Milner, B. (2000). Loss of recent memory after bilateral hippocampal lesions. Journal of Neuropsychiatry and Clinical Neuroscience, 12 (1), 103–113.

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Alderson, A. (2018). H.M.; Also the Case of H.M., Molaison, Henry (1926–2008). In: Kreutzer, J.S., DeLuca, J., Caplan, B. (eds) Encyclopedia of Clinical Neuropsychology. Springer, Cham. https://doi.org/10.1007/978-3-319-57111-9_622

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Author Interviews

The lobotomy of patient h.m: a personal tragedy and scientific breakthrough.

Patient H. M.

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Counting the cost of medical advances in 'patient h.m.'.

The story of Henry Molaison is a sad one. Known as Patient H.M. to the medical community, he lost the ability to create memories after he underwent a lobotomy to treat his seizures.

He did earn a place in history, though. His case taught scientists a lot about how the brain creates and stores memories.

"A lot of what we know about how memory work came from more than a half-century of experimentation that was conducted on Patient H.M.," says Luke Dittrich, author of the book Patient H.M. : A Story of Memory, Madness and Family Secrets .

Dittrich, who is also the grandson of William Scoville, the doctor who performed Patient H.M.'s lobotomy, tells NPR's Allison Aubrey that the story is one of both personal tragedy and scientific breakthrough.

"It's hard to argue that it was a good outcome for him. But it's one of those sort of murky cases that you find in the history of medicine, in the history of science, where his tragedy — it was a boon to science," Dittrich says. "We're still learning from him now."

Interview highlights contain web-only extended answers.

Interview Highlights

On Patient H.M.'s backstory and his contributions to medicine

Before he was Patient H.M., he was a man named Henry Molaison. He grew up in the Hartford area in Connecticut, and his story really begins when he was 8 or 9 years old, in the mid-1930s.

He was walking home from the park late one night, got knocked down by a bicyclist and hit his head. And shortly after that, he began experiencing seizures.

His seizures got worse and worse over the years, until by the time he was 27 years old, he was deeply and almost catastrophically epileptic. He would have these major seizures, sometimes multiple times a day, and it had a terrible impact on sort of all aspects of his life — his social life, his professional life.

His high school principal wouldn't let him walk across the stage during graduation because he worried that Henry would have a seizure and cause a scene. And so in the midst of this terrible and debilitating epilepsy, my grandfather, who was a renowned neurosurgeon, offered Henry's family hope in the form of an experimental brain operation.

He told them that he might be able to take Henry's epilepsy away by removing several mysterious and and deep-seated structures in Henry's brain. And they, in their desperation, said yes.

So my grandfather went in and he removed a significant portions of Henry's hippocampus, amygdala ... and what happened was that although it may have had some effect of alleviating the seizures, the main thing that the surgery did was render Henry completely and profoundly amnesiac.

He lived the rest of his life, a half-century or so, in more or less 30-second increments. You could meet him and have a conversation with him and then walk out of the room and come back in and, you know, introduce yourself to him for the first time all over again.

On his grandfather, the neurosurgeon William Scoville

He died when I was 9 years old, and so I knew him, but I didn't know him very well. But he always loomed large, even when I was a kid, as this sort of charismatic and dashing character. He had this rotating fleet of sports cars. He was a world traveler.

His passion was neurosurgery, and he was this gifted surgeon. He was one of the leading proponents in America of so-called psycho-surgery, which we commonly think of as lobotomy — that is, surgical treatment for mental illness.

One of the things I discovered during the course of researching my book was that his sort of passion for psycho-surgery, for the lobotomy, grew out of a sort of a personal desperation for my grandmother. His wife was herself mentally ill and institutionalized.

On the treatments that his grandmother — and many other mental health patients — endured in asylums

My grandmother was institutionalized at ... the Institute of Living in Hartford Conn., and it was, at the time, a very assertive, upscale asylum. It had an almost country club environment on the surface.

That asylum had its own operating room devoted exclusively to surgery. And then, once you had your surgery, you were put in a special sort of education ward, where the idea was that your personality had been wiped clean and then the doctors could sort of build you up again and create a new personality for you in that ward.

I had to go to dig deep into the records of this one particular asylum that she was institutionalized at to come up with information about all the treatments that she endured back then. ... What she endured was really terrifying.

I mean, to be to be a woman in a mental institution in the 1940s was, in some ways, to be living a horror story. She underwent something called pyretotherapy, for example, which I hadn't even heard of. It's otherwise known as fever therapy, and in the early days of fever therapy, they would they would literally inject you with the malaria parasite in order to induce high fevers, which were supposed to bring about some sort of mental clarity.

But by the time she was institutionalized, they had what they considered to be a more modern version of it, where they would lock you into like a brass coffin and then heat up the inside until you developed a fever of as high as 105 degrees. And they would keep you there for eight hours a day, sometimes for a week straight, and that was thought to have somehow a pacifying effect on patients who were mentally disturbed.

A lot of the treatments of the time, looking back on them, you can't help but be horrified by them.

On the kinds of people who received lobotomies

If you break down the patients by sex, the vast majority were women. It's an open question as to why that was, but one possible answer is that the side effects of the consequences of lobotomy — tractability, passivity, docility — were in some senses viewed by certain men of that era as being almost ideal feminine characteristics.

Anyway, it was a way of changing personality. It was done with the intent of addressing mental illness

Some people operated on people as young as 7 years. They would do it for what we would consider to be almost a normal childlike behavior, to treat juvenile delinquency, hyperactivity, misbehavior. It was definitely extreme, it was definitely irreversible, and it was also used to treat "conditions" that were not conditions at all. People were lobotomized for homosexuality.

On whether or not the patients consented

Notions of informed consent really did not exist in the 1940s. ... So it's safe to say that that a lot of these patients who were submitted to surgical procedures did not consent in any sense of the word that we would I understand now.

Probably the most prolific lobotomist then, Walter Freeman, argued that the more a patient fought against being lobotomized, the more that indicated that that patient should be lobotomized.

On what it was like to research and publish his own family secrets

It was a unique experience and a hard experience in a lot of ways. I have done a lot of investigative journalism in the past. Some of the stories you write are going to cause some level of pain to people, but I'm not used to causing pain to the people closest to me, the people that, you know, I love most of all. I came up with information that ultimately was not only shocking to me but hard to process for my own mother.

I'm having to sort of confront and decide that, well, the story is worth telling, and so I can't keep anything really off-limits. I mean, there's a few things I kept off-limits, but I put a lot in there that certain members of my family probably would wish that I would not.

This is a book that I wrote about memory and how memory works, and one of the one of the strange sort of side effects of working on this book is that it has in some ways I have shifted and change some of my own memories from my childhood.

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H.M.’s Contributions to Neuroscience: A Review and Autopsy Studies

Jean c. augustinack.

1 Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts

André J.W. van der Kouwe

David h. salat, thomas benner, allison a. stevens, jacopo annese.

2 The Brain Observatory, San Diego, California 92101, USA and Department of Radiology, University of California San Diego, San Diego, California 92093, USA

Bruce Fischl

3 CSAIL, Massachusetts Institute of Technology, Cambridge, Massachusetts

Matthew P. Frosch

4 C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, Massachusetts

Suzanne Corkin

5 Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts

H.M., Henry Molaison, was one of the world’s most famous amnesic patients. His amnesia was caused by an experimental brain operation, bilateral medial temporal lobe resection, carried out in 1953 to relieve intractable epilepsy. He died on December 2, 2008, and that night we conducted a wide variety of in situ MRI scans in a 3 T scanner at the Massachusetts General Hospital (Mass General) Athinoula A. Martinos Center for Biomedical Imaging. For the in situ experiments, we acquired a full set of standard clinical scans, 1 mm isotropic anatomical scans, and multiple averages of 440 µm isotropic anatomical scans. The next morning, H.M.’s body was transported to the Mass General Morgue for autopsy. The photographs taken at that time provided the first documentation of H.M.’s lesions in his physical brain. After tissue fixation, we obtained ex vivo structural data at ultra-high resolution using 3 T and 7 T magnets. For the ex vivo acquisitions, the highest resolution images were 210 µm isotropic. Based on the MRI data, the anatomical areas removed during H.M.’s experimental operation were the medial temporopolar cortex, piriform cortex, virtually all of the entorhinal cortex, most of the perirhinal cortex and subiculum, the amygdala (except parts of the dorsal-most nuclei—central and medial), anterior half of the hippocampus, and the dentate gyrus (posterior head and body). The posterior parahippocampal gyrus and medial temporal stem were partially damaged. Spared medial temporal lobe tissue included the dorsal-most amygdala, the hippocampal-amygdalotransition- area, ~2 cm of the tail of the hippocampus, a small part of perirhinal cortex, a small portion of medial hippocampal tissue, and ~2 cm of posterior parahippocampal gyrus. H.M.’s impact on the field of memory has been remarkable, and his contributions to neuroscience continue with a unique dataset that includes in vivo, in situ, and ex vivo high-resolution MRI.

INTRODUCTION

This review chronicles H.M.’s history, his contributions to the neuroscience of memory, neuroimaging studies past and present, and his autopsy. In the following paragraphs, we walk through the anatomical details of the medial temporal lobe, describe the specific structures removed and spared in H.M., and provide the only glimpse of his intact, fresh brain. We recount the critical discoveries that made him one of the most famous amnesic patients in the world, and illustrate, with high-resolution imaging, the age-related white matter disease that likely accounts for his dementia in the final part of his life. We also identify key questions to be addressed in the forthcoming neuropathological examination and in future histological studies.

On August 25, 1953, the neurosurgeon William Beecher Scoville performed an experimental operation in a 27-year-old man, Henry Gustave Molaison (H.M.), in the hope of curing his medically intractable epilepsy ( Scoville, 1954 ; Scoville and Milner, 1957 ). H.M. had experienced petit mal seizures from the age of 10 and grand mal seizures that began on his 15th birthday. The etiology of his seizures was unclear—as a young boy, he had sustained a minor head injury and, in addition, several of his father’s relatives had epilepsy. H.M. graduated from high school when he was 21 and later repaired electric motors and worked on a typewriter assembly line. He took large doses of anti-epilepsy drugs, but they did not quell his attacks. Because numerous EEG studies failed to reveal a precise surgical target for seizure control, Scoville proposed a psychosurgical procedure that he had devised, bilateral medial temporal lobotomy ( Scoville and Milner, 1957 ). He had previously performed the operation in patients with psychiatric disorders, mainly schizophrenia, with mixed results. H.M. was the first patient to undergo this procedure for intractable epilepsy. Scoville later renamed the operation bilateral medial temporal lobe resection.

Postoperatively, H.M.’s petit and grand mal attacks continued, and although their frequency decreased markedly, he required anti-epilepsy drugs for the rest of his life. His seizure control, however, was accompanied by a devastating loss. For the next 55 years, H.M. was trapped in the moment because of profound anterograde amnesia. His amnesia was pure—unconfounded by other cognitive deficits. His IQ was above average, and his language, reasoning, and perceptual capacities were normal. The exceptions were impaired olfactory function, caused by the operation, and cerebellar symptoms, a side effect of his anti-seizure medication, Dilantin.

The discrete nature and severity of H.M.’s amnesia made him the topic of scientific scrutiny for the remainder of his life and even after his death. Over 100 researchers participated in collaborative projects to study him, integrating behavioral testing, standardized interviews, and structural and functional imaging. In 1955, Brenda Milner conducted the first postoperative psychological testing of H.M., providing quantitative evidence of profound memory loss with preserved intelligence and immediate memory ( Scoville and Milner, 1957 ). She and Scoville concluded, “The findings reported herein have led us to attribute a special importance to the anterior hippocampus and hippocampal gyrus in the retention of new experience” (p. 21). Milner later introduced the idea that some memory processes were not hippocampus dependent by showing that H.M.’s error scores decreased across three days of testing on a motor skill-learning task, mirror tracing ( Milner, 1962 ). This discovery constituted the first experimental demonstration of preserved learning in amnesia.

Dissociable Memory Processes

Subsequent research with H.M. extended Milner’s pioneering work and established several firm conclusions. The evidence supported the dual process theory of memory proposed by James (1890) and Hebb (1949) . They viewed short-term and long-term memory as separate processes. Accordingly, H.M.’s short-term memory was preserved, while his long-term memory was impaired. His episodic and semantic learning were both deficient, indicating overlapping neural substrates ( Gabrieli et al., 1988 ; Steinvorth et al., 2005 ). Tests that distinguished two forms of recognition memory—recollection and familiarity—revealed that H.M. could make familiarity-based judgments to recognize complex pictures, even six months after encoding. This surprising result showed that recollection depends on the hippocampus, but familiarity does not. Examinations of H.M.’s retrograde amnesia led to the discovery that he could remember only two preoperatively experienced autobiographical episodes, whereas his semantic memory for the same time period was normal ( Steinvorth et al., 2005 ; Corkin, 2013 ). This dissociation implicates the hippocampus as necessary for the retrieval of premorbid autobiographical but not semantic information. At the same time, certain kinds of nondeclarative learning—motor skill learning, classical conditioning, and repetition priming—were preserved.

The issues that motivated decades of research with H.M. were to understand the scope of his amnesia, to elucidate the kinds of learning and memory that were spared, and to establish a causal link between his amnesia and specific brain circuits. Some information about the integrity of his brain was available even before his operation. H.M. had a pneumoencephalogram in 1946 and another in 1953, both of which were read as normal. At the time of his operation in 1953, information about the damage to his brain came exclusively from Scoville’s account of what he had removed. His notes and drawings formed the basis of a set of detailed drawings by another neurosurgeon, Lamar Roberts, which accompanied Scoville and Milner’s 1957 paper ( Scoville and Milner, 1957 ). Scoville estimated that the medial temporal lobe resection extended 8 cm back from the tip of each temporal lobe, but subsequent MRI scans indicated that the removal was much less extensive.

Postoperative In Vivo Imaging

CT scans carried out in 1977 and 1984 showed metallic clips from the operation, minimal atrophic change in the anterior temporal region bilaterally, cerebellar atrophy, and, in the 1984 scan when he was 58, mild to moderate cortical atrophy ( Corkin, 1984 ). Specific brain structures were not visualized. A SPECT scan conducted in 1992 at Brigham and Women’s Hospital in Boston confirmed his bilateral medial temporal lobe resection and cerebellar atrophy.

H.M.’s first MRI scans occurred in 1992 at Brigham and Women’s Hospital and in 1993 at Mass General, when he was 66 and 67 years old, respectively ( Corkin et al., 1997 ). These images showed that the removal extended back about 5.4 cm from the tip of the temporal lobe on the left and about 5.1 cm on the right. The bilaterally symmetrical lesion damaged most of the amygdaloid complex, the entorhinal cortex, part of perirhinal cortex, the uncal and rostral portions of the hippocampal complex, and part of parahippocampal cortex. Some of the ventral perirhinal and posterior parahippocampal cortices were intact. Approximately 2 cm of caudal hippocampal tissue was also spared, but it appeared atrophic and was likely deafferented due to removal of the entorhinal cortex. The subcortical white matter associated with the most anterior portions of the superior, middle, and inferior temporal gyri may have been compromised by the resection. The cerebellar atrophy was dramatic, but the cortical surface appeared normal for H.M.’s age ( Corkin et al., 1997 ).

A decade later, in 2002 to 2004, Salat and colleagues scanned H.M. at the Mass General Martinos Center, using improved MRI data acquisition and analysis tools—higher resolution, quantitative measures of tissue morphometry, and indices of tissue integrity ( Salat et al., 2004 , 2006 ; van der Kouwe et al., 2005 , 2006 ; Wiggins et al., 2006 ). By then, H.M. was 74 to 77 years old, and we uncovered new age-related abnormalities that were not connected to his 1953 resection—cortical thinning and abnormal signal in white matter and deep gray matter. H.M.’s T1 morphometry images showed significant atrophy of the cerebral ribbon, ranging from ~0.3 mm to ~0.7 mm relative to control participants. The atrophy that occurred between 1998 and 2003 was greater than that between 1993 and 1998, suggesting an aging-related degenerative process ( Salat et al., 2006 ). T1-weighted images also revealed infarcts in a number of subcortical gray matter structures, including the thalamus and putamen. Consistent with earlier imaging studies, H.M.’s cerebellum was severely atrophied. In T2-weighted images, Salat et al. noted significant white matter hyperintensities throughout H.M.’s brain that were especially pronounced in the inferior frontal gyrus near the corpus callosum. These new abnormalities appeared to be the result of high blood pressure and small vessel disease. We also collected the first diffusion MRI scans of H.M.’s brain, allowing the examination of fractional anisotropy (FA) maps to quantify the microstructural integrity of the white matter. Overall, H.M. had decreased FA compared to matched controls, and the focal areas of white matter damage had reduced FA. We never found any abnormality that would account for his original seizure disorder.

Current Study

H.M. died on December 2, 2008. That night, we conducted a wide variety of in situ MRI scans in a 3 T scanner at the Mass General Athinoula A. Martinos Center for Biomedical Imaging. The next morning, H.M.’s body was transported to the Mass General Morgue where Matthew Frosch, Director of the Neuropathology Unit, performed an autopsy. Jacopo Annese assisted with the autopsy. Photographs taken immediately afterward provided the first documentation of H.M.’s lesions in his physical brain. After ~10 weeks of tissue fixation, we obtained ex vivo structural data at ultra-high resolution using 3 T and 7 T magnets. This postmortem research had two goals—to document the specific structures that were removed and spared in H.M.’s brain, based on the gross examination of the fresh brain and analysis of the MRI images, and to relate the behavioral dissociations documented during H.M.’s life to the precisely established sparing and loss of brain tissue. An additional motivation for the ex vivo imaging was to provide an MRI-based method to later register the histological sections in 3D. The Partners Human Research Committee approved all studies described here. In this report, we first introduce the anatomical structures that define the medial temporal lobe region and then describe H.M.’s autopsy and MRI results.

MATERIALS AND METHODS

Participant, h.m.

At the time of his death, H.M. was 82 years old. The cause of death was arteriosclerotic cardiovascular disease. In 1992, H.M. and his court-appointed conservator had signed a brain donation form authorizing Mass General and MIT to perform a postmortem examination upon his death, and the conservator gave consent for the autopsy the evening H.M. died.

Neuroanatomy of the Intact Adult Medial Temporal Lobe—Terminology

To establish the terminology used in this report, we first describe pertinent structures in an intact adult brain, focusing on the medial temporal lobe region ( Rosene and Van Hoesen, 1987 ; Gloor, 1995 ; Insausti et al., 1995 ; Van Hoesen, 1995 ; Insausti et al., 1998 ). To educate the reader on the relevant structures, we selected nine blockface images from a control case (60 year old, male) in our MGH brain collection and labeled them ( Fig. 1 ). The areas include the piriform cortex (primary olfactory cortex), mesocortices of the parahippocampal gyrus (entorhinal and perirhinal cortices), and temporal polar cortex; the hippocampal formation—hippocampus, subiculum, and dentate gyrus; and the subcortical collection of nuclei that comprise the amygdala ( Fig. 1 ). The structures and slices are described from anterior to posterior.

Blockface images of medial temporal lobe structures from a control case (60-year-old, male). Nine levels represent the anterior-posterior extent of the medial temporal lobe. Level (A) temporal pole, (B) pyriform (olfactory) cortex, anterior-most entorhinal cortex, (C) anterior amygdala, (D) mid-amygdala, (E) anterior hippocampal head (pes), (F) posterior hippocampal head, (G) posterior hippocampal head and anterior hippocampal body, (H) hippocampal body, (I) posterior hippocampal body, hippocampal tail (not illustrated). Numerical labels correspond to Brodmann areas, and letter abbreviations are defined as: AAA = anterior amygdala area, AB = accessory basal nucleus of amygdala, B = basal nucleus of amygdala, CA = cornu ammonis (1–4), CAT = cortical amygdala transition area, Ce = central nucleus of amygdala, Co = cortical nucleus of amygdala, CS = collateral sulcus, DG = dentate gyrus, ES = endorhinal sulcus, fm = fimbria, HATA = hippocampal amygdala transition area, HF = hippocampal fissure, L = lateral nucleus of amygdala, LV = lateral ventricle, M = medial nucleus of amygdala, Pre = presubiculum, Par = parasubiculum, SUB = subiculum, TP = temporal pole, and Un = uncus. Magnification bar = 1 cm.

The temporal pole is divided into four regions: dorsal, ventral, medial, and lateral. Anteriorly, the temporal polar cortex hangs unattached to other brain tissue for ~1.5 cm ( Fig. 1A ), after which the temporal lobe joins the frontal cortex at the level of the limen insula. At this level, several features are noteworthy. The frontal insula and temporal insula merge together, the temporal polar cortex ends, and the piriform cortex begins to occupy the medial temporal area ( Fig. 1B ). The sulcal configuration in this region is complicated because the rhinal sulcus is incipient in humans and not present in all brains. The main sulci that outline the parahippocampal gyrus include the rhinal sulcus anteriorly, albeit variably, and the collateral sulcus laterally. The control case illustrated in Figure 1 does not exhibit a rhinal sulcus. If a rhinal sulcus were present, it would reside approximately at level B, at the level of the piriform cortex. Deep to the parahippocampal gyrus, the endorhinal sulcus dorsally separates the corticomedial nuclei of the amygdala from the optic tract area, the sulcus semi-annularis separates the medial parahippocampal cortex from the corticoamygdala-transition-area, and the hippocampal fissure separates the parahippocampal gyrus from the hippocampus ( Figs. 1C–F ). At the point where the frontal and temporal lobar regions connect, the temporal stem, one of the major white matter conduits for the temporal lobe, appears.

The amygdala lies posterior and slightly dorsal to the piriform cortex, which is situated deep beneath the parahippocampal cortex between the olfactory cortex anteriorly and the hippocampus posteriorly. The key amygdala nuclei are (from lateral to medial) the lateral nucleus, basal nucleus, accessory basal nucleus, paralaminar nucleus, medial nucleus, cortical nucleus, and corticoamygdala-transition-area ( Figs. 1C,D ). At the medial most edge of the amygdala, three nuclei line up from superior to inferior: medial nucleus, cortical nucleus, and corticoamygdala-transition area ( Figs. 1C,D ).

At the amygdala’s broadest part, immediately anterior and slightly dorsal to the hippocampus, the parahippocampal gyrus is also at its largest width. The anterior parahippocampal gyrus contains two Brodmann areas, area 34 medially and area 28 laterally ( Brodmann, 1909 ; Lorente de No, 1934 ). Brodmann area 34 corresponds to the gyrus ambiens and sometimes has a bulbar configuration that is often mistaken for the uncus of the hippocampus, but the uncus resides deep to the gyrus ambiens and slightly posterior ( Fig. 1D ). The hippocampal fissure borders the uncus and lower bank of the parahippocampal gyrus where the subicular cortices are located ( Fig. 1E ). Brodmann area 28 makes up a substantial component of the parahippocampal territory and occupies the entire crown of the anterior parahippocampal gyrus, commonly referred to as the entorhinal cortex. Equally prominent within the parahippocampal cortex is the entorhinal cortex’s neighbor laterally, the perirhinal cortex ( Figs. 1B–I ). The perirhinal cortex (Brodmann area 35, Braak’s transentorhinal) ( Braak and Braak, 1985 ) is sometimes slightly larger than the entorhinal cortex and surrounds it anteriorly, laterally, and posteriorly ( Insausti et al., 1998 ; Van Hoesen et al., 2000 ; Ding and Van Hoesen, 2010 ). The perirhinal cortex lies lateral to the rhinal sulcus but medial relative to the collateral sulcus, once the collateral sulcus has begun ( Van Hoesen et al., 2000 ; Ding et al., 2009 ). The ectorhinal cortex (Brodmann area 36) is temporal isocortex; we classify it separately from perirhinal cortex based on the fact that perirhinal area 35 is agranular and dysgranular (area 35a periallocortex and 35b proisocortex, respectively), whereas temporal isocortex (area 36) contains a granular layer. On the crown of the posterior parahippocampal gyrus, areas TH and TF ( von Economo and Koskinas, 1925 ; von Bonin and Bailey, 1947 ) make up the remaining parahippocampal cortex as it ends caudally at the retrosplenial cortex and calcarine sulcus (TH-TF, not illustrated).

The hippocampal formation comprises the hippocampus proper, subicular cortices (subiculum, presubiculum, and parasubiculum), and dentate gyrus ( Rosene and van Hoesen, 1987 ). The hippocampus proper contains subfields CA1, CA2, CA3, and CA4, named for cornu ammonis because it resembles a ram’s horn. The hippocampus, which contains four main structural parts, genu ( Fig. 1D ), head ( Figs. 1E–G ), body ( Figs. 1G–I ), and tail (not illustrated), sits deep beneath the parahippocampal cortex. Its structure changes significantly from anterior to posterior, with the head being disproportionately larger than the body and tail. The head of the hippocampus is made up of several convolutions, the pes hippocampi, where the medial-most convolution defines the uncus ( Figs. 1E,F ). The inferior horn of the lateral ventricle makes its first appearance at the level of the amygdala and hippocampal head.

Autopsy and Fixation

On December 4, 2008, when the postmortem interval was ~19 hrs, Matthew Frosch conducted the autopsy. H.M.’s brain was fixed in standard 10% formalin for several hours and was then transferred to buffered 4% paraformaldehyde. The fixative solution was changed twice during the two months that it remained in the Mass General Department of Pathology, allowing the brain tissue to fix thoroughly. On February 12, 2009, when it was transferred to the Martinos Center for ex vivo scanning, it remained in 4% paraformaldehyde.

In Situ MRI Acquisition

On the evening of December 2, 2008, just under 4 hr after H.M.’s death in Windsor Locks, Connecticut, we collected in situ scans at the Mass General Martinos Center. In situ refers here to postmortem imaging of the brain in the head. Images were collected in a 3 T Siemens (Erlangen, Germany) TIM Trio MRI scanner with a 32-channel head coil. We determined beforehand that the configuration of this system (in particular, the imaging gradient switching and RF energy deposition) would not damage the brain by heating the tissue or by heating or vibrating the surgical clips.

Because subject fatigue and motion were not an issue and scanning could continue for several hours, we collected high-quality, high-resolution images that would not be possible in a living subject. The in situ 3 T session lasted 9 hr. We obtained a wide range of contrasts of the unfixed brain with different scan types and high-resolution anatomical images.

We first acquired a full set of standard clinical scans for comparison with antemortem images. In addition, we obtained a 2 mm isotropic diffusion scan, 1 mm isotropic single and multiecho MPRAGEs ( Mugler and Brookeman, 1990 ; van der Kouwe et al., 2008 ), 1 mm isotropic multi-flip angle multiecho FLASH scans with 2 mm isotropic B1± maps, and multiple averages of a 440 µm isotropic single-echo multi-flip angle FLASH scan. All scans were automatically localized for acquisition using AutoAlign ( van der Kouwe et al., 2005 ; Benner et al., 2006 ). The synthetic images presented in this report were generated using estimates of intrinsic tissue parameters derived from a combination of acquired multiecho FLASH images with native contrast ( Fischl et al., 2004 ).

Clinical scans

We obtained five standard clinical scans: (1) sagittal T1-weighted spin-echo, (2) axial T2-weighted turbo-spin-echo, (3) axial FLAIR, (4) susceptibility weighted imaging (SWI), and (5) diffusion with matching B0 field map. Prescan intensity normalization was applied to all scans.

• T1-weighted 2D-encoded spin-echo ( T acq 4 m 20 s); 24 sagittal slices of 5 mm with 1 mm gap, 240 mm field of view with 256 matrix and 75% phase resolution, phase encode AP (1.3 × 0.9 × 5 mm). TE 7.1 ms, TR 550 ms, BW 201 Hz/px, FA 120°, two concatenations.
• T2-weighted 2D-encoded turbo-spin-echo ( T acq 5 m 27 s); 23 axial slices of 5 mm with 1 mm gap, 230 × 172.5 mm field of view with 512 matrix and 75% phase resolution, phase encode RL (0.6 × 0.4 × 5 mm). TE 91 ms, TR 5 s, BW 100 Hz/px, FA 134°, two averages, flow compensation in slice direction.
• FLAIR 2D-encoded turbo-spin-echo ( T acq 6 m 52 s); 23 axial slices of 5 mm with 1 mm gap, 230 × 172.5 mm field of view with 384 matrix and 75% phase resolution, phase encode RL (0.8 × 0.6 × 5 mm). TE 71 ms, TR 10 s, TI 2,500 ms, BW 130 Hz/px, FA 150°, two averages, flow compensation in slice direction.
• Susceptibility-weighted 3D-encoded gradient echo ( T acq 6 m 59 s). 96 axial partitions (k-space slices) of 1.5 mm, 220 × 171.9 mm field of view with 448 × 350 matrix, phase encode RL (0.5 × 0.5 × 1.5 mm). TE 20 ms, TR 28 ms, BW 120 Hz/px, FA 15° (slab-selective), flow compensation.

Standard anatomical scans for morphometry

We collected a standard set of 1 mm isotropic anatomical scans designed to elucidate brain morphometry using FreeSurfer ( http://surfer.nmr.mgh.harvard.edu ) ( Dale et al., 1999 ; Fischl et al., 2002 , 2004 ). The set consisted of T1-weighted multiecho MPRAGE (MEMPR) for cortical modeling and subcortical segmentation, multiecho FLASH (MEF) for tissue parameter quantification, and T2-SPACE and FLAIR T2-SPACE for T2 contrast. Prescan normalization was applied to all scans, and, for accurate alignment, scans were matched with respect to geometry and bandwidth (thus, degree of distortion).

• T1-weighted 3D-encoded 4-echo MEMPR ( van der Kouwe et al., 2008 ) ( T acq 6 m 3 s); 176 sagittal partitions of 1 mm, 256 mm field of view with 256 × 256 matrix, phase encode AP (1 mm isotropic), 2× GRAPPA with 32 reference lines. TE 1.64/3.5/5.36/7.22 ms, TR 2,530 ms, TI 1,200 ms (non-selective), BW 651 Hz/px, FA 7° (nonselective).
• T1-weighted 3D-encoded 8-echo FLASH ( T acq 13 m 25 s at each of three flip angles); 176 sagittal partitions of 1 mm, 256 mm field of view with 256 × 256 matrix, phase encode AP, 50% phase oversampling (1 mm isotropic), 2× GRAPPA with 32 reference lines. TE (1.85 + n × 2.0 + n × ( n −1)/2×0.1) ms ( n = 0,…,7) (uneven spacing for phase unwrapping), TR 22 ms, BW 651 Hz/px, FA 5/20/30° (nonselective), magnitude and phase images.
• T2-weighted variable flip angle 3D-encoded turbo-spin-echo (T2-SPACE) ( Mugler et al., 2000 ) (T acq 4 m 43 s); 176 sagittal partitions of 1 mm, 192 mm field of view with 192 × 192 matrix, phase encode AP (1 mm isotropic), 2× GRAPPA with 24 reference lines. TE 368 ms, TR 3,200 ms, BW 651 Hz/px, FA variable (nonselective).
• T2-weighted variable flip angle 3D-encoded turbo-spin-echo with fluid attenuation (FLAIR T2-SPACE) ( Mugler et al., 2000 ) ( T acq 7 m 22 s). 176 sagittal partitions of 1 mm, 192 mm field of view with 192 × 192 matrix, phase encode AP (1 mm isotropic), 2× GRAPPA with 24 reference lines. TE 352 ms, TR 5 s, TI 1,800 ms, BW 789 Hz/px, FA variable (nonselective).

T2*-weighted anatomical scans

To quantify tissue T2*, we carried out a multiecho FLASH scan according to a protocol that had a longer TR and more widely spaced echoes than the 8-echo FLASH described above. We also repeated the 8-echo FLASH protocol at 2 mm isotropic resolution (two repetitions of T acq 6 m 42 s with 128 × 128 matrix).

• 3D-encoded 8-echo FLASH ( T acq 14 m 15 s). 128 sagittal partitions of 1.33 mm, 256 mm field of view with 192 × 192 matrix, phase encode AP (1.33 mm isotropic), 2× GRAPPA with 32 reference lines. TE (3.41 + n × 6.9 + n × ( n − 1)/2 × 0.1) ms ( n = 0,․,7) (uneven spacing for phase unwrapping), TR 60 ms, BW 202 Hz/px, FA 20° (nonselective), magnitude and phase images.

High-resolution anatomical scans

We dedicated ~5 hr of the in situ scanning time to obtaining high-resolution anatomical scans, using a single-echo FLASH protocol with an isotropic resolution of 440 µm.

• T1-weighted 3D-encoded FLASH ( T acq 24 m 19 s at each of 6 flip angles); 384 sagittal partitions of 0.44 mm, 225 mm field of view with 512 × 512 matrix, phase encode AP, 50% phase oversampling (1 mm isotropic), 2× GRAPPA with 32 reference lines. TE 4.09 ms, TR 9.5 ms, BW 199 Hz/px, FA 3/5/8/10/15/18° (non-selective), magnitude and phase images.

Quality control scans

We obtained additional scans to correct artifacts. For the diffusion scans, matching B0 field maps were acquired. We collected data for 1 mm isotropic DESPOT1, DESPOT2, and HiFi analyses ( Deoni et al., 2003 , 2005 ; Deoni, 2007 ). Based on these results, we chose the optimal range of flip angles for the subsequent FLASH scans. We obtained a B1 transmit map using Actual Flip Angle Imaging ( Yarnykh, 2007 ) at 2.5 mm isotropic resolution and a B1 transmit/receive map by imaging at 2 mm isotropic resolution with the body coil and with each element of the 32-channel array. In addition, we acquired a gradient echo EPI series of volumes (TR 3 s, 192 measurements, 3 mm resolution with 0.6 mm gap between slices, 42 slices). Two additional runs used an experimental radial and Cartesian-encoded gradient echo protocol with an ultrashort echo (FLUSTER) ( Van der Kouwe, 2008 ) (data not shown).

Ex Vivo Imaging

Ex vivo imaging occurred after H.M.’s brain had been stored in 10% formalin for ~10 weeks. The fixed brain was placed in a custom-made Plexiglas chamber and imaged at high field ( Annese et al., 2014 ). We repeated the in situ scans ex vivo, and as expected the images confirmed the observations made in in situ.

High-resolution scans (7 T)

We used a 7 T Siemens scanner based on the Avanto platform for high-resolution imaging with a 31-channel custom-built head coil. The highest resolution images were 210 µm isotropic single-echo multi-flip angle FLASH scans. We measured coil covariance for image reconstruction and obtained 1.68 mm isotropic B1 transmit/receive maps and a two-echo gradient echo field map (2 mm × 2 mm × 3 mm resolution) for image correction.

We dedicated 15.5 hr of scan time to collecting high-resolution images of the entire fixed brain. Encoding at 210 µm isotropic resolution with the 31-channel head coil required offline image reconstruction because the k-space data volumes were larger than the 32 GB of RAM available on the scanner image reconstruction computer. The k -space data were streamed to an external storage site during acquisition because the total amount of data per scan exceeded the 320 GB of disk space available on the scanner RAID. We used the coil covariance matrix to combine the signals from the 31 head coil channels to form a single image volume ( Roemer et al., 1990 ).

• T1-weighted 3D-encoded FLASH ( T acq 4 h 50 m at each of three flip angles); 704 partitions of 210 µm, 175 × 153 mm field of view with 832 × 728 matrix (210 µm isotropic). TE 15.1 ms, TR 34 ms, BW 40 Hz/px, FA 10/20/30° (nonselective).

Temperature Monitoring

From the time of H.M.’s death until his body reached the Martinos Center, his head was enclosed in a Cryopak Ice Blanket to keep his brain cool. During the in situ scanning, room temperature was maintained at ~18°C. During ex vivo scanning, we monitored temperature carefully, keeping it below 19°C on the outer surface of the chamber at 3 T and 7 T. Temperature was a concern because RF energy deposition during MR imaging can heat the sample. To ensure that temperature fluctuations due to imaging would be well below normal fluctuations in room temperature, we previously monitored a test sample (whole brain) during imaging with the highest specific absorption rate sequences. A multichannel fiber optic temperature sensor (Neoptix, Inc., Quebec, Canada) recorded the temperature in four areas—deep in the tissue, close to the inner wall of the chamber, on the outer surface of the chamber, and in the room air. As expected, even during high (100%) specific absorption rate protocols, the temperature inside the tissue never increased more than 4°C relative to the inside and outside of the container. The specific absorption rate of RF energy for the 3 T diffusion sequence was close to 100% of the clinically safe value imposed by the scanner hardware, and it was substantially lower for the other protocols. The room temperature was at the minimum thermostat setting (18°C), and an additional fan was used to dissipate heat from around the chamber. The temperatures of the outer surface of the chamber and the surrounding air were monitored with the fiber optic system. Because these temperatures never exceeded 19°C, we reasoned that the temperature of the brain tissue never went above 23°C during imaging. We believe that the temperature differentials were even smaller during in situ imaging because the imaging session was shorter, the protocols were less energy intensive, and the energy could dissipate throughout the body.

Lesions in the Fresh

Brain The unfixed brain weighed 1,100 g, ~200 g less than one would expect for a 6-foot-tall, healthy man. Photographs of the brain taken immediately after its removal from the skull showed the overall topography of the gross brain to be relatively preserved. Notably, the olfactory bulbs and tracts were intact, and we saw no explicit damage, with the obvious exceptions of the medial temporal lobe excisions and a shriveled cerebellum ( Fig. 2 ). The dashed white lines drawn laterally and posteriorly illustrate where a normal sized cerebellum would be. The blood vessels appeared mildly atherosclerotic. In the right ventral temporal lobe, we identified a black surgical clip, which we believe was intentionally left behind by Scoville to prevent bleeding ( Scoville and Milner, 1957 ). A second clip was located in the left temporal lobe.

Photograph of the whole fresh brain (inferior surface) taken at H.M.’s autopsy. In the ventral view, the white arrows on both sides of the brain indicate the lines of cut in the coronal MRI slices in Figure 5 . These slices (white arrows) correspond to the in situ MRI ( Figs. 5A–L ). Note the area of excision and additional fibrous tissue (i.e., scar tissue) bilaterally, and the residual medial most tissue (bilaterally but larger on the left) in the medial temporal area, next to cranial nerve III. Abbreviations: B = basilar artery, M = medulla, MB = mammillary bodies, OB = olfactory bulb, OC = optic chiasm, ON = optic nerve, TP = temporal pole, V = vertebral artery, and III = cranial nerve III (oculomotor nerve). White arrowheads point to posterior temporal artery on both right and left. Dashed white lines illustrate atrophy in the cerebellum. Note the black surgical clip on right temporal lobe. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com .]

Figure 3 magnifies the ventromedial view to reveal a close-up of the right (A) and left (B) medial temporal lobe lesions. The photographs show slightly different views, a consequence of the unfixed state. (An unfixed brain collapses or widens slightly and does not retain the classical formation until fixed.) The medial temporal lobe lesions began immediately to the left and right of the optic nerves, which had been cut during the autopsy so the brain could be pulled out of the skull, leaving the eyes intact. On both sides, the lesion extended posteriorly from the temporal polar cortex through the parahippocampal gyrus until about the level of the halfway point of the basilar artery. In a normal case, the gyrus ambiens would reside immediately and slightly anterior to the uncus. In H.M., medial tissue remained on both sides but to a greater extent on the left ( Figs. 3A,B ). We could not determine definitively whether the remaining medial tissue on the left was uncus or gyrus ambiens because the banks of the hippocampal fissure and other landmarks had been surgically removed. The histological analysis, which will be the topic of a later report, will reveal whether the cytoarchitecture of this tissue is hippocampal (allocortical) or cortical (periallocortical). Continuing posteriorly, significant scar tissue occupied the medial temporal areas bilaterally.

Close-up photographs of H.M.’s medial temporal lobe showing a ventral view of the right and left temporal regions (A and B). Tissue was splayed out (due to being unfixed) to reveal a slightly different viewpoint of the extent of the lesion. In A and B, the lesion extends from the temporal pole to the midparahippocampal gyrus. Note the absence of tissue and the abundant scar tissue bilaterally. The basilar and vertebral arteries contain several atherosclerotic plaques. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com .]

In Situ MRI

The several different contrasts acquired in situ provided an MEMPR (T1-weighted) image ( Fig. 4A ) with the classic MRI contrast that shows CSF as dark and white matter as white. In the T2-SPACE acquisition ( Fig. 4B ), white matter was relatively dark, gray matter was brighter, and CSF was brightest. Because the lesion void was filled with CSF, it appeared bright in the image. In the T2-SPACE acquisition with fluid attenuation (FLAIR) ( Fig. 4C ), the CSF in the region of the lesion was dark, but the remaining tissue fragments were relatively bright and clearest compared to other contrasts. The bottom panels of Figure 4 show quantitative proton density (PD) ( Fig. 4D ) and T1 estimates ( Fig. 4E ) together with a synthetic image constructed from the corresponding 440 µm volumes ( Fig. 4F ) ( Fischl et al., 2004 ). We estimated the T1 and PD volumes from a combination of multiecho FLASH scans with different flip angles. Figure 4D shows only PD contrast (arbitrary units, but proportional to spin density); Figure 4E shows estimated T1 relaxation time (sec). PD reflected only the proton (or spin) density and was a relatively flat contrast. The lesions appeared fairly bright because CSF is relatively dense in free water, while the PD of white matter is slightly less than that of gray matter. Both appeared darker than CSF in the PD image. Because higher T1 produces darker voxels in T1-weighted images, the image showing the absolute T1 value had the opposite contrast of the MEMPR (i.e., white matter is darker than gray matter and CSF in the quantitative image because white matter has a shorter T1 relaxation time). To optimize contrast and increase signal-to-noise, we created a synthetic image from the FLASH scans ( Deoni et al., 2003 ; Fischl et al., 2004 ). Figure 4F shows the synthetic FLASH image that would result if the TR had been 22 ms, flip angle had been 20°, and TE had been 0. This image was synthesized from the PD and T1 estimates by applying the steady-state FLASH model, in the reverse of the estimation procedure. We chose the TR and flip angle to achieve optimal discrimination between the structures segmented by FreeSurfer ( http://www.surfer.nmr.mgh.harvard.edu/ ), based on contrast (TE 0 implies no signal decay due to T2* relaxation). The synthetic image in Figure 4F has a T1-weighted contrast similar to the MPRAGE.

Various MRI contrasts acquired at 3.0 T in situ. (A) multiecho MPRAGE (MEMPR), (B) T2-SPACE, (C) T2-SPACE FLAIR, (D) quantitative PD, (E) quantitative T1, (F) synthetic FLASH. Note the lesion in all contrasts, with the borders especially clear in the multiecho MPRAGE and synthetic FLASH images. T1 and T2-SPACE FLAIR revealed scar tissue faintly in addition to the lesion.

Lesions in medial temporal lobe structures

Here we describe the specific medial temporal lobe areas that were explicitly removed and identify other structures that remained. The 12 coronal MR images ( Fig. 5 ) highlight the lesion extent and illustrate remaining anatomical structures, based on remaining landmarks ( Figs. 5A–L ). Levels are spaced 4 mm apart. The first image shows the temporal pole where the anterior-most portion of the lesion began ( Fig. 5A ). The medial temporopolar cortex, mainly dysgranular area 38 and area 36, were removed. The temporal polar sulcus, located dorsally, was partially destroyed.

Twelve coronal MR images showing the anterior and posterior extent of H.M.’s medial temporal lobe lesion. Images were synthesized from multi-echo FLASH scans acquired in situ and are ordered from anterior (A) to posterior (L). In all images, note the enlarged ventricles, general atrophy, and a plethora of regional white matter signal abnormalities. We identify particular structures (present or absent) in each panel. A, B, C: medial temporal pole removed; D: anterior entorhinal cortex removed (i.e. piriform cortex), E: cortical amygdala and possibly central nucleus remained; F: gyrus ambiens or uncus remained; G and H: perirhinal cortex and damaged parahippocampal cortex; I: the body of the hippocampus visible; J: first full observation of parahippocampal cortex (right side) and fimbria; K: posterior tip of the lesion (right side is past the lesion), and L: the undamaged parahippocampal cortex posterior to the lesion. Magnification bar = 1 cm.

In the second image ( Fig. 5B ), the lesion entered prime temporal polar cortex territory, where we observed the optic nerves (slightly off the midline) and the caudate nucleus. Here, the limen insula had not yet connected to the frontal and temporal lobes. The temporal polar areas, 38 and area 36, were still absent at this level. The olfactory tract, seen inferiorly to the orbitofrontal gyrus, appeared normal. The third image ( Fig. 5C ) was approximately at the level of the anterior amygdala.

The fourth image ( Fig. 5D ) fell at the level of the optic chiasm. Presumptive medial structures were the posterior piriform cortex, part of perirhinal cortex (area 35), and temporal isocortical area 36. In all slices described thus far, the medial temporal stem was partially damaged bilaterally, and the white matter quality appeared compromised, with the lesion in the left hemisphere extending farther medially than in the right. The collateral sulcus appeared in images four through eight ( Figs. 5D–H ), and perirhinal cortex occupied its medial bank.

A small part of the entorhinal cortex appeared in the fifth and sixth images ( Figs. 5E,F ), but only on the extreme lateral convexity of the gyrus. The border between the entorhinal and perirhinal cortices typically falls on the corner of the parahippocampal gyrus near the collateral sulcus. The fifth image captured the emerging optic tracts, anterior commissure (midline), and caudate/putamen ( Fig. 5E ). The anterior-most amygdala—specifically parts of the endopiriform nucleus and the corticoamygdalo-transition-area—might have been present in this image. Noticeably, the anterior-amygdala-area was lacking at this level. The landmarks in the sixth image included the optic tract, anterior commissure laterally (very subtle), caudate/putamen/anterior limb of the internal capsule, globus pallidus, hypothalamus, and columns of the fornix, indicating that this slice was at the level of the mid-amygdala ( Fig. 5F ). In a healthy brain, this level would represent the amygdala at its largest extent along with the gyrus ambiens (Brodmann area 34 in humans). The left side may have contained a portion of the semilunar gyrus slightly dorsal to gyrus ambiens; this possibility will be examined in the histological analysis. Figure 5F shows the best MRI example of the medial tissue that remained. The hypothalamus appeared atrophied, likely due to the lack of hippocampal input, and the fornix and hippocampal commissure showed significant atrophy.

The seventh image is where one would expect to see the posterior amygdala, subiculum, and anterior-most hippocampus, given that other landmarks usually present at this level are visible—the mammillary bodies of the hypothalamus, the thalamus, putamen, globus pallidus, and the optic tract (tucked in medially) ( Fig. 5G ). The spared posterior hippocampal tissue first appeared in this slice, with the right side showing more hippocampal head than the left ( Fig. 5G ).

The eighth image ( Fig. 5H ) embodied the presumptive uncal hippocampus and anterior dentate gyrus level, where neighboring anatomical landmarks were the cerebral peduncles, red nucleus, substantia nigra in the brainstem, anterior nucleus of the thalamus and posterior putamen. In the ninth image ( Fig. 5I ), the right hippocampus began to resemble the classic hippocampal shape, and this slice showed the body of the hippocampus for the first time. The tenth image exposed the body of the hippocampus where the lateral geniculate nucleus of the thalamus made its first appearance, defining the end of the entorhinal cortex ( Fig. 5J ). Images ten and eleven revealed badly damaged parahippocampal gyri, especially on the left side ( Figs. 5J,K ). Images eleven and twelve showed the shrunken posterior body and tail of the hippocampus ( Figs. 5K,L ). In the twelfth image, the posterior thalamus (pulvinar), fimbria-fornix, and posterior commissure all came into view ( Fig. 5L ).

In summary, the high-resolution, high-contrast images reported here indicated that the areas removed bilaterally by suction during H.M.’s experimental operation were the medial temporopolar cortex, piriform cortex, virtually all of the entorhinal cortex, most of the perirhinal cortex (area 35), a large amount of subiculum, amygdala, except the dorsal most nuclei (i.e., central and medial), most of the hippocampus (head and body), and the dentate gyrus (posterior head and body). Parts of posterior parahippocampal gyrus (roughly equivalent to TH and TF) remained but were damaged. Other medial temporal lobe areas spared bilaterally were: the dorsal-most amygdala, part of the hippocampal-amygdalo-transition-area, a portion of perirhinal area 35, a medial portion of the hippocampus or gyrus ambiens, and the posterior body and tail of the hippocampus. The major sulci in the medial temporal lobe were remarkably well preserved bilaterally, with the exception of the hippocampal fissure. The collateral sulci were partially present, but shallow. The endorhinal sulci were present dorsally and medially, the sulci semi-annularis were spared medially, but the rhinal sulci were absent rostrally.

Ex Vivo MRI

At higher field strength (7.0 T), we acquired ultra-high-resolution images at 210 µm for the whole brain. Because the brain was suspended in 4% paraformaldehyde during scanning, the background contained some MRI signal from the water molecules in the solution. The contrast to noise ratio (CNR) and signal to noise ratio (SNR) were compromised for two reasons—the tissue contrast and solution contrast were similar, and the resolution was high. Due to the preciousness of this brain, we chose not to subject it to a proton-free liquid, such as Fomblin. Had we used a proton-free liquid, we would have avoided the unsatisfactory background observed in the 7.0 T images ( Fig. 6 ). Even with the high background, however, the ex vivo scans showed new details, and we delineated specific landmarks, such as the endorhinal sulcus and collateral sulcus, which helped determine the exact boundaries of the lesion. We outlined the lesion with dotted lines at three pertinent anterior-posterior levels: the anterior commissure, columns of fornix, and mammillary bodies. The high-resolution ex vivo scans provided additional information about the exact shape of H.M.’s lesions.

Ex vivo images of medial temporal lobe areas acquired at 7 T. Images at 210 µm isotropic show the extent of the lesion and remaining medial structures. For level-of-cut cross reference, see Figure 5 . Panels A, B, and C correspond to the MRI slices in Figures 5E–G . A shows H.M.’s lesion approximately at the level of the amygdala. The lesion shape is relatively uniform at this level. Note the square corners at the dorsal-most part of the lesion. B demonstrates the lesion where the posterior amygdala-anterior hippocampal level would have been. Note the fornix columns medially in the hypothalamus and the irregular lesion shape. The large round black structures in C are regions of susceptibility surrounding air bubbles. C illustrates the lesion at the level of the mammillary bodies where the head of the hippocampus (i.e., pes hippocampus) would normally reside. At level C the lesion narrows. The shape of the lesion changes considerably from anterior to posterior, scar tissue is visible. The white arrowheads point to the collateral sulcus. Numbers represent Brodmann areas. Abbreviations: AC = anterior commissure, ES = endorhinal sulcus, FX = fornix, MB = mammillary bodies, OC = optic chiasm, RN = red nucleus, and SN = substantia nigra.

At the level of the anterior commissure, the anterior-most levels of the entorhinal cortex (i.e., the piriform cortex) and the extreme anterior parts of amygdala were removed ( Fig. 6A ). It is noteworthy that at this level, the lesion represented a rectangular shape and showed sharp 90° angles at the innermost (and superior) borders.

The second level is at the columns of the fornix ( Fig. 6B ). At this mid-amygdala level, the lesion shape, indicated by the dotted white lines, became irregular, especially on the left ( Fig. 6B ). The white arrow points to tissue that was likely the anterior hippocampus.

The third medial temporal lobe level is at the mammillary bodies of the hypothalamus, where the hippocampal head is largest. The right lesion appeared significantly larger than the left in the medial-lateral direction, consistent with our lesion measurements. Based on the quantitative data and these qualitative data, the right-sided lesion was slightly shorter than the left-sided in the anterior-posterior plane but slightly wider in the medial-lateral plane.

Lesion Size

We defined the overall length and width of H.M.’s lesion as the distance parallel to the anterior-posterior direction and left-right direction, respectively. We considered the lesion measurements in two ways, the total ablation and the total ablation plus damaged cortex. For the left-sided lesion, the length from the tip of the temporal lobe was 4.6 cm for the ablation and 6.0 cm for the ablation and damaged cortex ( Fig. 7 ). For the right-sided lesion, the length from the tip of the temporal lobe was 4.2 cm for the ablation and 5.5 cm for the ablation and damaged cortex ( Fig. 7 ). These dimensions indicated that the left medial temporal lobe lesion was larger than the right. The width was 2.04 cm on the left and 1.89 cm on the right at the temporal pole, 1.54 cm on the left and 1.63 cm on the right at the amygdala/uncus, and 1.02 cm on the left and 0.95 cm on the right at the hippocampal tail. The overall shape of the lesion matched a truncated cone with the wide base anterior and the narrow end posterior.

Axial view of the multiecho FLASH images. Line measurements were acquired in the axial plane to assess the anterior-posterior lesion size. The ablation on the right side measured 5.5 cm while the left measured 6.0 cm. The left temporal lobe lost considerably more cortex during surgery. Note the cerebellar atrophy due to Dilantin.

We also obtained two high-resolution anatomical volumes—the 440 µm in situ volume and the 210 µm ex vivo volume. Both were synthesized from multiple FLASH scans collected at different flip angles. The in situ 440 µm volume had near in vivo contrast, with gray matter appearing darker than white matter and CSF that was dark, but not black (visible also in the vicinity of the lesion).

The ex vivo 210 µm volume had a different contrast because the tissue was fixed (tissue classes are better distinguished by T2* contrast in fixed ex vivo brain tissue) ( Tovi and Ericsson, 1992 ). In these images, gray matter was brighter than white matter and exhibited distinct layers, such as the stria Gennari , which were not visible in the in situ scans. Because the brain was packed in paraformaldehyde, which generated a relatively strong signal that was comparable to white matter, the ventricles and region of the lesion were not extremely distinct from the adjacent structures. The cotton packing and the brain contained small bubbles, and the latter gave rise to spin dephasing artifacts, which were exaggerated by the choice of a long TE, a consequence of the low bandwidth needed to obtain reasonable SNR and gradient strengths at the required high resolution.

The white matter was noticeably inhomogeneous in both the in situ and ex vivo images, presumably a consequence of aging-related white matter disease. In the ex vivo images, B1 + (RF transmit field) inhomogeneities due to the dielectric resonance effect at high field contributed further to overall image non-uniformity. Despite the fact that we invested 15.5 hrs in the 210 µm volumes vs. 2.5 hrs for the 440 µm, SNR was higher for the 440 µm volume because SNR falls dramatically with increasing isotropic resolution. SNR was roughly 20 to 50 and 130 to 150 for brain tissue in the 210 µm and 440 µm volumes, respectively. These values are approximate because SNR varies spatially, and the noise distribution is not precisely Gaussian. We selected protocols that would give reasonable SNR in the time available. The CNR (gray/white) for the 440 µm data was 14.7. In the 210 µm data, CNR measures for gray/white matter were 15.1 for high signal areas and 5.7 for medium signal areas. The SNR measures in these regions were 4.24 and 3.39, respectively ( Fig. 4 ).

Structures Outside the Medial Temporal Lobes

The cerebellum was severely atrophic and at autopsy appeared nearly half the size of a healthy cerebellum. The cerebellar atrophy seemed uniform with the flocculonodulus, vermis, and lateral hemispheres all reduced in size. In the in situ MRI images, we observed the dentate nucleus, the largest of the deep cerebellar nuclei, in its usual location, but we could not detect the other nuclei (fastigial, globose, emboliform), given the resolution (440 um) 3 .

Aging-related changes

At the end of his life, H.M. became demented. Multiple small strokes due to untreated hypertension and white matter atrophy likely contributed to his mental deterioration. The black spots in the MRI images indicate hypertensive disease and were particularly notable in the brainstem in Figure 4A . As a consequence of the untreated hypertension and perhaps other aging processes, we observed extensive isocortical and subcortical atrophy in all structures. Limbic structures such as the fornix, hippocampal commissure, and mammillary bodies, which were connected to the hippocampus before the surgery, were markedly degenerated ( Fig. 5G ). Similarly, the extended amygdala (centromedial amygdala and bed nucleus of stria terminalis) and other structures (i.e., the substantia inominata, including the nucleus basalis of Meynert and the diagonal band of Broca) showed noteworthy deterioration, as did the ventral striatopallidal areas. In the basal forebrain, the atrophy was so extensive that it was difficult to discern the location of nuclei. Degeneration went beyond the limbic cortices and limbic-related areas. We observed severe atrophy in the striatopallidum (caudate, putamen, globus pallidus) and thalamus (anterior nucleus, ventral anterior nucleus, mediodorsal nucleus, lateral posterior, lateral dorsal nucleus, pulvinar nucleus, medial geniculate nucleus and lateral geniculate nucleus) as demonstrated by the large size of the third ventricle ( Figs. 5H–J ). We noted atrophy of the anterior commissure and all parts of the corpus callosum. The corpus callosum appeared so thin that it resembled the thickness of a healthy anterior commissure. We found isocortical thinning in all areas, including primary and secondary sensory and motor cortices. Shrinkage was especially pronounced in prefrontal, temporal, parietal, and occipital association areas.

White Matter Integrity

The diffusion imaging data acquired as part of the imaging sessions will be reported at a later time. The structural images, however, demonstrated a clear and substantial deterioration of the connective integrity of H.M.’s brain, with overt macrostructural white matter lesions throughout several portions of the cerebrum ( Fig. 5 ). We previously described this damage and noted that hints of white matter deterioration were apparent as far back as 1998 when he was 72 ( Corkin et al., 1997 ; Salat et al., 2006 ). In the 2008 imaging sessions, dark bands of hypointense white matter in T1 images were obvious throughout the periventricular regions. Such changes are commonly observed in older adults, but the degree of alterations here was well beyond what could be considered a benign consequence of aging.

Blood Supply

We did not explicitly trace the blood vessels in H.M.’s brain, but based on the anatomical areas that were surgically removed, it is likely that the blood supply was also interrupted. The arterial origins of the vascular supply to the medial temporal lobe include the middle cerebral artery, internal carotid artery, anterior choroidal artery, and posterior cerebral artery. From the fresh brain, it appeared that the anterior temporal artery, a branch of the posterior cerebral artery was removed bilaterally. The anterior choroidal artery, known to supply the anterior hippocampus, was absent on both sides, as was the anteroinferior parahippocampal artery, which supplies the anterior parahippocampal gyrus (i.e., entorhinal cortex). The posterior temporal artery was spared on both sides ( Figs. 2 and ​ and3) 3 ) as well as the posterior parahippocampal artery, which supplies the posterior parahippocampal gyrus (i.e., TH and TF). Further tissue damage suggested that the posterior hippocampal artery, which supplies the posterior hippocampus, was compromised bilaterally.

The onset of H.M.’s profound memory impairment immediately after the operation established for the first time that removal of the hippocampus and surrounding structures causes amnesia ( Scoville and Milner, 1957 ). The postmortem studies reported here are part of an ongoing effort to characterize the damage as precisely as possible. Our first goal was to document in detail the medial temporal lobe lesions, and the second was to examine the integrity of other structures that likely supported his intact intellect and preserved learning capacities. Bearing this anatomical information in mind, we associate specific cognitive processes that were impaired or spared in H.M. to particular circuits inside and outside the medial temporal lobe. Many of the findings with H.M. informed ongoing controversies in cognitive neuroscience concerning dissociations of function.

This report extends previous anatomical findings in MRI by revealing more detail and specific anatomy about what structures were removed or spared. The autopsy photographs showed the dense scar tissue in H.M.’s lesion and the marked cerebellar atrophy, while the MRI data, including in situ and ex vivo images, capitalized on improved contrast and resolution to reveal the lesion shape (or remaining tissue shape) and the precise measurements for lesion size. For example, the improved contrast highlighted tissue that may be the gyrus ambiens or a sliver of the anterior uncus. It is difficult to estimate whether this tissue is gyrus ambiens (medial part of entorhinal cortex) or uncal hippocampal tissue (i.e., medial CA1) and this new finding must be evaluated histologically. The high-resolution MRI also showed contrast differences between damaged and undamaged tissue that allowed more precise measurement of overall lesion size and shape. In this report, the lesion, measured from 440 µm 3 MRI, was 6.0 cm on the right and 5.5 cm on the left, suggesting that Scoville ( Scoville and Milner, 1957 ) overestimated the lesion at 8 cm while Corkin and colleagues ( Corkin et al., 1997 ) slightly underestimated the right-sided lesion at 5.1 cm. The high-resolution MRI also revealed the shape of the lesions, which exactly followed the contour of the parahippocampal gyrus, wider anteriorly and narrower posteriorly. Previous in vivo MRI images showed that H.M. developed significant white matter damage and cortical thinning as he aged ( Salat et al., 2006 ). The new in situ MRI findings provide evidence of white matter disease progression, showing that at the time of H.M.’s death, his white matter was riddled with white matter signal abnormalities and extensive cortical thinning. Cortical thinning and white matter signal abnormalities were widespread, and no structure was spared. The following paragraphs review how H.M.’s lesions relate to the rich body of behavioral data collected over 55 years.

Lesion Dimensions

Overall lesion size.

At the time of H.M.’s operation, Scoville estimated that the lesion extended 8 cm back from the tip of the temporal lobe. If this had been the case, then the damage would have invaded visual cortex, which it did not. With the advent of MRI, we were able to get a more accurate idea of lesion size. The in vivo MRI estimates in the rostrocaudal extent, based on 1 mm MRI data, were ~5.4 cm on the left and ~5.1 cm on the right ( Corkin et al., 1997 ). The comparable postmortem MRI dimensions were slightly greater, showing that H.M.’s lesion was 6.0 cm on the left and 5.5 cm on the right ( Fig. 7 ). The high-resolution in situ data allowed us to measure the excision and the damaged tissue more precisely. In the left temporal lobe, the excised region measured 4.6 cm, the damaged area an additional ~1.5 cm, and the entire lesion 6.0 cm. On the right side, the excision measured 4.2 cm, the damaged region an additional ~1.4 cm, and the whole lesion 5.5 cm. The ex vivo measures were more accurate because of the superior resolution we could obtain in long scan sessions at 3 T and 7 T that would not have been feasible in vivo. We hypothesize that the greater lesion size was due in part to age- and disease-related degeneration. The in situ MRI findings reported here are the most accurate measures of H.M.’s lesion size because the brain had not yet been distorted by removal and fixation procedures.

Correlation between lesion size, distribution, and severity of amnesia

H.M. had both extensive amnesia and large medial temporal lesions, suggesting that amnesia severity is related to lesion size. His amnesia was more profound than that of Penfield and Milner’s patients F.C. and P.B., whose excisions for epilepsy and pre-existing damage spared a considerable amount of medial temporal tissue ( Penfield and Milner, 1958 ; Milner, 1959 ). More recent findings from Squire’s laboratory extend the evidence concerning correlations with lesion size and support the view that lesions restricted to the hippocampus produce less severe memory loss than lesions of the hippocampus plus other temporal lobe areas. R.B.’s lesion, limited to the CA1 field, resulted in moderately severe amnesia ( Zola-Morgan and Squire, 1986 ), whereas two other patients, G.P. and E.P., with damage to their entire medial temporal lobes bilaterally, were profoundly amnesic ( Stefanacci et al., 2000 ; Bayley and Squire, 2005 ). Notably, E.P.’s lesion included the temporal pole, amygdala, entorhinal cortex, hippocampus, perirhinal cortex, and rostral parahippocampal cortex and also extended into lateral temporal neocortex; his declarative memory was even more impaired than H.M.’s ( Insausti et al., 2013 ).

Medial Temporal Lobe Structures Excised and Spared

After H.M.’s death in 2008, we assessed his lesion using high-resolution in situ and ex vivo MRI. These images showed that the following areas were removed or damaged: substantial portions of the medial temporopolar, piriform, entorhinal, perirhinal, and parahippocampal cortices, as well as the subiculum, presubiculum, parasubiculum, amygdala, hippocampal fields CA1, CA2, CA3, and CA4 (in the hippocampal head and body), and dentate gyrus (posterior head and body). Further, our analyses suggested that a few noteworthy structures survived the medial temporal lobe surgery and may have been more difficult to discern with in vivo MRI scans due to lower resolution ( Corkin et al., 1997 ; Salat et al., 2006 ). Notably, several areas within the amygdala were spared—parts of the amygdalar medial nucleus, cortical nucleus, cortical amygdaloid transition area, amygdala-striatal zone, endopiriform nucleus, and a portion of the central nucleus. Also visible were the hippocampal-amygdalo-transition-area (HATA), a small portion of the uncus, the tail of the hippocampus (~2 cm), a small part of the perirhinal cortex (Brodmann area 35), the entire ectorhinal cortex (Brodmann area 36), and ~2 cm of the posterior parahippocampal gyrus. Although the residual hippocampal, perirhinal, and parahippocampal tissue was first documented in the 1992 and 1993 MRI images ( Corkin et al., 1997 ), the present findings further specify the locus and extent of the spared tissue.

Neural Substrate for H.M.’s Amnesia

Parahippocampal cortices and hippocampal formation.

After his operation in 1953, H.M. could not consolidate and retrieve new facts and events, documenting for the first time that circuits within the medial temporal lobe are necessary for the establishment of long-term declarative memory ( Scoville and Milner, 1957 ). Memory experiments carried out over the next five decades showed that H.M.’s deficits were severe and extensive, affecting the acquisition of verbal and nonverbal material presented via four sensory modalities ( Milner, 1968 ; Corkin, 1984 , 2002 ). He could not learn new episodic or semantic information ( Gabrieli et al., 1988 ; O’Kane et al., 2004 ), highlighting the critical role of medial temporal lobe structures in all kinds of declarative memory. Further support for this brain-behavior correlation came from MRI studies carried out in the 1990s, which gave a more accurate picture of the specific structures that were excised and spared in H.M.’s brain. The postmortem studies reported here provide new details of his lesions that could not be gleaned from the in vivo imaging studies.

By far the greatest territory removed on the day of surgery was the parahippocampal gyrus, in particular, the anterior parts of the perirhinal cortex and the entire entorhinal cortex. In a normal brain, the entorhinal cortex receives input from several secondary and tertiary association cortices and multimodal areas (in prefrontal cortex and superior temporal association cortex) and acts as the ultimate end station before extrinsic sensory afferents converge prior to entering the hippocampus ( Van Hoesen, 1997 ; Van Hoesen et al., 1972 ). After this convergence on the entorhinal cortex, entorhinal layer II and superficial layer III then project to the hippocampus via the perforant pathway ( Van Hoesen and Pandya, 1975 ).

Scoville’s resection included the mesocortices of the anterior parahippocampal gyrus (entorhinal and perirhinal cortices (perirhinal area 35)) and also the hippocampal head and body. As a result, H.M.’s perforant pathway was destroyed at its origin and termination, thereby eliminating the entire circuitry necessary for long-term declarative memory. The remaining ~2 cm of hippocampal tissue was deafferented, and, therefore, not able to support long-term memory formation, storage, and retrieval. A preliminary histological study showed that the remaining hippocampal tissue contained substantial gliosis, which would further compromise the residual tissue ( Annese et al., 2014 ).

H.M.’s pervasive memory impairment resulted from the removal of a significant portion of his hippocampi, including all CA subfields, the anterior dentate gyrus, anterior subiculum, anterior presubiculum, and prosubiculum. The hippocampal remnants included the hippocampal-amygdala-transition-area (HATA), the tail of the hippocampus, and a small portion of medial hippocampal tissue. Subsequent histological studies will clarify whether the small medial remnant is uncus or gyrus ambiens. Also spared were the posterior portions of the subiculum, dentate gyrus, and hippocampal body and tail. The posterior portion of the subiculum appeared to be intact, possibly leaving the subicular projections to the anterior, lateral dorsal, reuniens, and paraventricular nuclei of the thalamus untouched ( Aggleton et al., 1986 ). It is clear, however, that this modest input, if it existed, was not sufficient to support normal memory function in H.M.

A new finding in the postmortem scans concerned the medial temporal stem. In 1997, we reported that the temporal stem was intact ( Corkin et al., 1997 ), although Gaffan disagreed ( Gaffan, 2001 ). In the current study, major advances in technology allowed us to examine the temporal stem with greater precision in the in situ and ex vivo images. We noted that this structure was markedly deteriorated in H.M. in situ and showed decreased contrast in MPRAGE (see Figs. 5C–E ). It is unclear whether these lesions dated back to the surgical excision or were caused by degenerative disease late in life, but we favor the view that this damage was due to aging and white matter deterioration as noted in previous MRIs ( Salat et al., 2006 ) and not to Scoville’s original resection. The role of the temporal stem in amnesia has been somewhat controversial ( Horel, 1978 ; Gaffan et al., 2001 ; Gaffan, 2001 ), but a study by Zola-Morgan, Squire, and Mishkin ( Zola-Morgan et al., 1982 ) appeared to be irrefutable. They found that monkeys in whom the temporal stem white matter had been cut bilaterally were unimpaired on a delayed nonmatching-to-sample task, whereas animals with bilateral lesions of the amygdala, hippocampus, and parahippocampal gyrus showed severe impairment. A later study by Gaffan et al. was consistent with this view ( Gaffan et al., 2001 ). On a delayed matching-to-sample task, the performance of monkeys with transection of the anterior temporal stem alone did not differ significantly from their preoperative levels. It is, therefore, unlikely that H.M.’s temporal stem lesions contributed to his declarative memory impairment. Rather, his profound amnesia was caused by the excision of the parahippocampal cortices and hippocampal formation. H.M.’s performance on delayed-match-to-sample and delayed-nonmatch-to-sample tasks was comparable to that of control participants 6 months after learning ( Freed et al., 1987 ; Freed and Corkin, 1988 ), suggesting that his partially intact perirhinal cortex may have been engaged to carry out these tasks.

Aging, Cortical Thinning, and White Matter Damage

Previous in vivo MRIs characterized H.M.’s cortical and white matter damage ( Salat et al., 2006 ). At the time of his death, he was demented, and his entire brain was severely atrophied, with no structure escaping degeneration. As noted previously ( Annese et al., 2014 ), we observed a small lesion in the left orbitofrontal region in the in situ and ex vivo MRI scans that was not described in Scoville’s original report ( Scoville and Milner, 1957 ). The etiology of this lesion is unclear, but we are confident that planned histological studies will reveal the cause. The possibilities include damage by the retractor used to elevate H.M.’s left frontal lobe, deafferentation of a medial temporal lobe projection, or white matter disease, possibly due to small vessel ischemic disease, such as untreated hypertension. The white matter damage throughout H.M.’s brain was severe in the in situ and ex vivo images, and it was far worse than in other untreated hypertensive cases at his age (JCA and DHS, personal observation) ( Fazekas et al., 1993 ; Young et al., 2008 ). Substantial contrast changes in older adults may be due to significant dysfunction of vascular regulatory mechanisms ( Braffman et al., 1988 ; Breteler et al., 1994b ; Longstreth et al., 1996 ; Erkinjuntti, 2007 ), and given the substantial white matter abnormalities that we observed in H.M.’s brain ex vivo, it is likely that white matter damage caused his dementia.

Neural Substrates for H.M.’s Preserved Memory Capacities

H.M.’s deep and lasting amnesia attests to the fact that the spared medial temporal lobe structures were unable to support normal memory function or anything approaching it. Still, over the years, he occasionally surprised his examiners by retrieving episodic and semantic information that he encountered after his operation. The most astonishing example came from a picture recognition experiment in which we asked him to look at and remember complex colorful pictures for 20 sec each. Not only did he achieve normal recognition at 10 min, 24 hrs, 72 hrs, and 1 wk after encoding, but he also scored within 1 SD of the control mean 6 months later ( Freed et al., 1987 ; Freed and Corkin, 1988 ).

We attribute H.M.’s ability to recognize the complex pictures to the engagement of familiarity–based processes supported by his residual perirhinal and parahippocampal cortices in communication with his preserved cortical circuitry. Our MRI data obtained in vivo and in situ showed some remnants of perirhinal and parahippocampal cortices bilaterally ( Figs. 5E–G ) ( Corkin et al., 1997 ). Evidence accumulated over the last 20 years strongly suggests that recollection and familiarity engage different medial temporal lobe areas, with recollection mediated by the hippocampus and familiarity by perirhinal and parahippocampal cortices ( Aggleton and Brown, 1999 , 2005 ; Yonelinas and Jacoby, 2012 ). H.M.’s ability to recognize complex visual stimuli underscores the point that the hippocampus is not necessary for recognition memory based on familiarity.

H.M. was also able to recognize and provide a few distinguishing details about celebrities and politicians who rose to fame after his operation, such as JFK, Ray Charles, and Liza Minnelli ( Gabrieli et al., 1988 ; O’Kane et al., 2004 ). We attribute these glimmers of memory formation in part to processing in preserved medial temporal lobe structures seen in the in situ and ex vivo MRI images: part of perirhinal cortex, posterior parahippocampal cortex, dorsal-most amygdala, and the medial-most uncus. It is possible that these small pieces of medial temporal lobe that remained, especially posteriorly, helped support declarative memory formation on rare occasions. H.M. spent a lot of time watching television and leafing through magazines, which exposed him to a wealth of information about celebrities. This repeated stimulation over months and years enabled him to build up meager representations of a handful of famous people; he acquired this knowledge slowly over time and not via the fast declarative memory processes that healthy individuals would employ.

H.M.’s preserved memory capacities also included those now classified as nondeclarative. Milner’s 1962 groundbreaking report that he showed procedural learning over three days introduced the idea that the human brain houses dissociable memory circuits ( Milner, 1970 ). Subsequent experiments extended this result, showing that H.M. could acquire a variety of motor skills ( Corkin, 1968 ). Studies in patients with Parkinson disease, Huntington disease, and cerebellar degeneration later indicated that the striatum and cerebellum mediate motor skill learning ( Sanes et al., 1990 ; Knopman and Nissen, 1991 ; Pascual-Leone et al., 1993 ; Breteler et al., 1994a , b ; Corkin, 2013 ). Our in vivo MRI results confirmed that the striatum was not damaged in H.M.’s operation, and although his cerebellum was atrophied, it did not appear grossly abnormal.

Subsequent studies evaluated H.M.’s performance on other kinds of nondeclarative memory tasks. In a series of eyeblink classical conditioning experiments, he acquired conditioned responses in both the delay and trace paradigms ( Woodruff-Pak, 1993 ). Although he required more trials to reach criterion than his control, the fact that he showed any conditioned responses is a challenge to explain because previous research has established that the cerebellum, hippocampus, and amygdala play a major role in eyeblink conditioning (Woodruff-Pak et al., 1985; Weisz et al., 1992 ; Thompson and Kim, 1996 ; Clark et al., 2002 ; Christian and Thompson, 2003; Thompson and Steinmetz, 2009). In H.M.’s brain, the hippocampus and amygdala were extirpated, and the cerebellum was markedly atrophied. Still, it is possible that his cerebellum and deep cerebellar nuclei supported the learning, and we will examine these structures microscopically in hope of uncovering clues about his ability to acquire conditioned responses.

Repetition priming refers to a kind of learning in which recent incidental exposure to test stimuli, such as words, pictures, and patterns, facilitates subsequent processing of that information. Priming is evidence that past experience can influence memory unconsciously, that is, when participants are not trying intentionally to recall the past, and it is mediated by cortical pathways undamaged in H.M. In several experiments, he demonstrated intact performance on perceptual and conceptual priming tasks ( Gabrieli et al., 1990 , 1995 ; Keane et al., 1995 ). Companion studies in patients with cortical lesions indicated that conceptual priming is mediated by lateral temporal and parietal circuits, while perceptual priming depends on occipital circuits ( Keane et al., 1991 , 1994 , 1995 ; Gabrieli et al., 1994 ). These cortical networks were intact in H.M. and likely the underpinnings of his intact priming performance. This finding of preserved nondeclarative memory considered side by side with his impoverished declarative memory, measured by tests of recall and recognition, established the validity of cognitive and neural dissociations among memory processes.

Neural Substrates for H.M.’s Nonmnemonic Behavioral Deficits

Examination of H.M.’s fresh brain at autopsy indicated that his olfactory bulbs and tract were undamaged, but the surgical removal did include primary olfactory cortex in the temporal lobe (piriform cortex and periamygdaloid cortex). As a result, H.M. was anosmic. Extensive behavioral testing uncovered limited preserved function and severe deficits on several olfactory tasks ( Eichenbaum et al., 1983 ). His detection of weak odorants was normal as was his threshold for discrimination of intensity differences, and he showed normal adaptation to a strong odor. In contrast, his ability to discriminate odor quality was completely absent on three different measures: signal-detection testing, the triangle match-to-sample task, and a common-odor-matching task, likely due to the absence of piriform and periamygdaloid cortices ( Eichenbaum et al., 1983 ). This striking dissociation of olfactory perceptual capacities established that odor quality discrimination and recognition are not necessary for detection, intensity discrimination, or adaptation.

The in situ and ex vivo MRI studies described here brought to light the details of H.M.’s extensive amygdala resection, which included the lateral, basolateral, accessory basal, and paralaminar nuclei, a portion or all of the central nucleus, and the anterior amygdala area. The result was that most of H.M.’s amygdala output was silenced, and it is likely that the amygdala resection explains a cluster of behavioral abnormalities. H.M.’s perception of pain was diminished in the laboratory and in daily life, he showed no change in his ratings of hunger and thirst from before to after a meal, he was asexual, and he was not fearful of anything ( Hebben et al., 1985 ; Corkin, 2013 ). Nevertheless, he could experience and display a range of emotions, such as happiness, friendliness, sadness, worry, guilt, and aggression, and he was able to label the emotion in various facial expressions ( Corkin, 2013 ). The emotional response system is complex, and the underlying brain mechanisms connecting inputs and outputs engage cortical and subcortical circuits beyond the amygdala ( Price, 2003 ). A goal of future histological studies will be to examine the integrity of these connections and remnants of the amygdala in H.M.’s brain.

Neural Substrate for H.M.’s Preserved Cognitive Capacities

The MR images collected from H.M. in 1992 and 1993, four decades after his operation, showed that his frontal, parietal, and occipital cortices were normal for his age, as was the lateral temporal neocortex. At that time, it was unclear whether the subcortical white matter associated with the most anterior portions of the superior, middle, and inferior temporal gyri was damaged, but our in situ and ex vivo images confirmed that these tracts were abnormal. Nevertheless, the vast expanse of cortex on both sides of H.M.’s brain likely functioned near optimally, allowing the engagement of multiple specialized circuits to support his performance on a broad spectrum of cognitive tasks.

Milner conducted H.M.’s first postoperative psychological examination in 1955, 2 years after his operation ( Scoville and Milner, 1957 ). On the Wechsler-Bellevue Intelligence Scale, he achieved an IQ of 112, but on the Wechsler Memory Scale, his MQ was only 67, indicating normal intelligence coupled with markedly impaired long-term memory ( Wechsler, 1945 ). On subsequent testing with different forms of the Intelligence Scale and Memory Scale, he maintained this pattern of performance through 2000 ( Kensinger et al., 2001 ). This longitudinal analysis firmly established that medial temporal lobe structures are not necessary for optimal performance on IQ tests, indicating a clear dissociation between high-order cognition and long-term declarative memory.

The high-resolution, high-contrast MRI methods highlighted here confirmed that H.M.’s cortical and subcortical language areas remained intact following his surgery, and the results from numerous experimental measures and standardized tests showed that his language functions were largely spared ( Kensinger et al., 2001 ). He successfully completed seven lexical memory tasks: spelling; picture naming, name recognition, and information retrieval; Boston naming test; picture naming; picture judgment; category identification; and landmark identification, and on tests of morphology, he was able to produce and judge regular and irregular inflectional or derivational forms, including plural production, past-tense production, past tense judgment, and derivational morphology production. Two additional tasks measured his syntax processing, and he performed them normally. In general, H.M. maintained his preoperative lexical knowledge without explicit retraining, indicating that medial temporal lobe structures are not necessary for the retention of already learned lexical information. They are, however, critical for the acquisition of new lexical information (e.g., new vocabulary, celebrities) ( Gabrieli et al., 1988 ; Postle and Corkin, 1998 ). Notable exceptions in the language domain were H.M.’s impaired performance on fluency tasks and uneven success in detecting linguistic ambiguities ( Lackner, 1974 ; Corkin, 2013 ). These deficits likely stemmed from a combination of factors: minimal surgical damage to anterolateral temporal cortex, slow responding, substandard education, and lower socioeconomic background ( Kensinger et al., 2001 ; Schmolck et al., 2002 ).

Evidence of preserved problem solving and working memory processes came from H.M.’s consistently excellent performance on the Wisconsin Card Sorting Test ( Milner, 1968 ). During each administration of the task over years of testing, he quickly changed to a new sorting category as needed and had very few perseverative errors, but he was always unaware that he had done the test before. To perform this complex task, H.M. had to recruit multiple cognitive processes and engage circuits in prefrontal cortex and posterior parietal cortex, areas that were spared in the 1953 surgery ( Corkin et al., 1997 ; Salat et al., 2006 ).

H.M.’s bilateral medial temporal lobe resection was circumscribed, and the resulting amnesia was pure. He revolutionized the science of memory through his participation in numerous behavioral and imaging studies, and he continues to illuminate the science of memory. During his lifetime, neuroimaging advanced with specialized sequences and sophisticated multichannel array coils that enabled high resolution MRI. These tools allowed a final and riveting inspection of H.M.’s lesions and remaining anatomy. This postmortem research is consistent with his wishes: He knew he was contributing to science and gladly donated his brain for future study. His mantra was, “Whatever is beneficial.” It is fitting that the field of neuroscience continues to benefit from his contributions, even after his death.

Acknowledgments

The authors are grateful to H.M. and his conservator for the generous tissue donation. The authors also thank M. Dylan Tisdall, Jonathan R. Polimeni, and Thomas Witzel for technical assistance in developing protocols to accommodate extremely large data files and Kristen Huber for photographing the blockface images and laboratory preparations.

Grant sponsor: National Center for Research Resources; Grant number: P41-RR14075; Grant sponsor: NCRR BIRN Morphometric Project; Grant numbers: BIRN002 and U24 RR021382; Grant sponsor: National Institute for Biomedical Imaging and Bioengineering; Grant number: R01EB006758; Grant sponsor: National Institute on Aging; Grant numbers: AG022381 and 5R01AG008122-22; Grant sponsor: NIH Blueprint for Neuroscience Research; Grant number: 5U01-MH093765; Grant sponsors: Part of the Multi-Institutional Human Connectome Project and National Science Foundation; Grant number: NSF-SGER0714660; Grant sponsor: Dana Foundation; Grant number: 2007-4234.

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psychologyrocks

Msm and case studies of people with brain injuries.

In your essay, it is important that you are able to link research evidence to specific theoretical claims. Case studies of people with acquired brain injuries have been particularly useful in providing support for one of MSM’s key claims, but the same studies have also highlighted some of the weaknesses of this model.

What is a case study?

Case studies allow us to gather in-depth information on areas where it may be impossible to carry out experiments. Clearly, from an ethical standpoint we cannot deliberately injure someone purely to see what behavioural and cognitive changes may result! Instead, scientists often make use of naturally occurring cases where someone has an acquired brain injury, meaning they were functioning perfectly well beforehand, i.e. they have been involved in an accident, had an illness that has affected their brain or undergone surgery for a tumour or to treat epilepsy, for example.

Case studies focuses on an individual or small group and use information from a variety of sources including medical and educational reports and records, interviews, standardised tests and observations, and so on to gather a wide range of detailed information. The use of multiple research methods is known as method triangulation.

Case studies generally lack control as the injury was naturally occurring, this said, they can inspire more scientific studies that are able to examine cause and effect.

As you may recall from the localisation topic, case studies focusing on people who have sustained brain damage allow researchers to explore the function of various brain regions through examining the impact of the damage on their behaviour and cognitive functioning.

Can you think of any scientific weaknesses of such studies?

Often there is no valid evidence of the person’s skill level prior to the brain injury, and therefore it is not possible to conclude with certainty that the brain injury has caused any issues the person appears to have, as these problems may have pre-dated the injury. This is clearly not always the case but worth bearing in mind 😉

The table below details three case studies conducted with people with brain injuries. Case studies like these indicate that there are different memory stores but perhaps it is too simple to think that there are only three stores, memory for different types of information seems to be situated in different areas. This is shown by HM and Clive Wearing’s unaffected procedural memories.

Use the worksheet above to find out more about these three case studies and think about how they could be used to support or refute the claims made by Atkinson and Shiffrin’s multistore model, i.e. that there are three separate memory stores through which information flows in a linear fashion, that short and long term memory are single (unitary) stores.

Clive Wearing

Find out more about the case of Clive Wearing using these clips from youtube:

HM – Henry Molaison

One interesting aspects of the HM case study is that although it is claimed HM was incapable of laying down new long term memories (anterograde amnesia) over time it was shown that he was able to learn a new skill; mirror drawing.

Learn more about HM with this podcast form the BBC: https://www.bbc.co.uk/programmes/b00t6zqv

Practice drawing stars like HM: Click below and scroll down to “ Milner Research Replication” .

https://opl.apa.org/src/index.html#/Demonstrations

Practice what you know about the HM case study and how it relates to MSM using this quizizz: https://quizizz.com/admin/quiz/5f74661a1bb349001ba0a3a5

The Case of KF

To learn more about the case of KF why not check out one of the original papers about this patient here :

Case study of KF Original Paper: warrington1969 

A clip of Warrington talking about KF

The following worksheet demonstrates how the case study of KF exemplifies all the key features of the case study as a research method in psychology, but is also useful for adding to your detailed knowledge of the aim, procedure, findings and conclusions of the study itself.

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Clive Wearing and HM - Two Evaluations of Brain Function and memory loss.

Kym Anstey 12.1

Each case study has given us a unique understanding of brain-functioning – outline specifically what each case has done to further our understanding

Studies like these can raise interesting question for further research

If there are enough similar cases then generalisations can start to be made

Very in depth, rich data can be achieved through a variety of research methods

Case studies are often longitudinal meaning that we can see changes in behaviour over time

As each case study is unique, this means that information gained about each of these cases can’t be generalised well to other cases

Researchers can sometimes become so close to participants in studies such as these that their accounts can become subjective

Such investigations are highly time consuming

It is possible that there are ethical implications for research studies such as these

This is a preview of the whole essay

Document Details

• Word Count 1107
• Page Count 3
• Level International Baccalaureate
• Subject Psychology

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