I remember meeting H.M. in the spring of 1967, when he was perhaps 40 years old and I was 16 years his junior. My mentor, Hans-Lucas Teuber, brought him to my tiny office across from the psychology department library at the Massachusetts Institute of Technology. I recall H.M.'s thin, smiling, rather handsome face as he squeezed into the doorway with Teuber, who introduced us as “Don” and “Henry,” as if we might become buddies. I think I called Henry “sir” as we shook hands because he was already a minor M.I.T. celebrity. Teuber assured Henry that he would enjoy taking part in my experiment on sentence comprehension, something he was good at, and excused himself.

As we climbed the stairs to the testing room, it never crossed my mind that this quiet man would become a major focus of my research during the next half a century. I unlocked the door and seated Henry at a wooden desk facing mine, sunlight streaming into the room from large windows to my right. In front of me I had two stopwatches and a stack of 32 short sentences typed onto three-by-five index cards. I started a tape recorder and began what I thought would be a fairly routine experiment.

Since 1967 Henry's initials have become the most famous in the history of the brain sciences. (The public only learned his full name, Henry Molaison, after his death in 2008.) Henry's rise to fame began about 13 years earlier at age 27, when a neurosurgeon removed a small portion of his midbrain known as the hippocampal region. This removal largely cured Henry's life-threatening epilepsy but had an unintended side effect: for the remainder of his life, Henry could no longer learn new information in a normal manner, a condition that revolutionized the study of memory and the brain.

Studying Henry helped others before me to clarify the role of the hippocampal region in forming complex memories for novel, personally experienced events. My research with Henry showed that the hippocampal region also helps us to retain established memories, by essentially forming damaged memories anew. Without such renovation, we would forget forever.

At age 27, Henry Molaison, known to the public as H.M. until his death in 2008, underwent surgery that removed the brain's engines of memory formation. As a result, he could no longer remember new experiences in a normal way. As he aged, his established memories degraded abnormally as well, a mystery that an evolving body of work has begun to solve. Clockwise from left: H.M. appears as a high school senior, in his early 30s, at about age 50, at age 60, and as an old man. Credit: © Suzanne Corkin, Used by Permission of the Wylie Agency LLC

This idea sweeps away the notion of memory degradation as a passive, inexorable process. The mechanism by which we revive old memories appears to offset some of the recollection difficulties that occur during normal aging. Rather than allowing the pieces of our past to simply drift away with time, the brain stays actively involved in restoring damaged memories. These insights also solve a 100-year-old mystery in psychological research on amnesia. Until now, no one clearly understood why people with amnesia, who by definition have difficulty learning information encountered after their brain damage, usually have problems remembering information they learned many years before that damage.

“Who are You?”

In the 1987 film Overboard, a socialite played by Goldie Hawn bumps her head falling from her yacht and suffers memory loss so complete that it destroys her identity. Movie plots invoking amnesia often feature dramatic scenes in which trauma immediately wipes out a character's past, but the protagonist can still form memories of new facts and experiences. Such cases are pure fiction. Real amnesic individuals have difficulty learning new information but (except for cases of Alzheimer's disease) never lose all of their past, whether caused by a brain lesion, a concussion, alcohol poisoning or a viral infection.

Henry became amnesic in 1953 after his operation, which removed the brain's central engines for memory formation. His ability to remember new experiences became severely impaired. Brief interruptions wiped out his extremely fragile memories for recent events (his episodic memories). If a knock at the door during your experiment called you away for even a minute, when you returned Henry might ask, “Who are you?” You needed then to reintroduce yourself and once again describe the task you wanted him to continue.

Henry could not make mental impressions of ephemeral experiences stick. In documenting such memory deficits, my mentor and others established the critical role of the hippocampal region in forming new long-term memories. Yet Henry's recollection of events and facts learned before his lesion seemed perfectly normal, at first. He pronounced everyday words fluently, easily asked questions such as “Have we met before?” and lucidly answered questions about where he went to high school and where he was born.

In the 1960s psychologist Wayne Wickelgren, then at M.I.T., proposed that the hippocampal region facilitates the creation of permanent memories in the brain's exterior rind, the neocortex. These cortical memories take the form of strengthened connections among neurons. The neocortex thus resembles the repository, and the hippocampus acts like a builder of memories, whether these are episodic, such as my memory of meeting Henry, or factual (semantic), such as the meaning of a word. This idea, which emerged in large part from work with Henry, was a dramatic revision of earlier thinking. Previously researchers had conceived of the hippocampal region as a direct storehouse of memories. Because Henry's neocortex was unimpaired, it therefore made sense that his word memories, stored before his operation, would be intact.

So the day I met Henry, I assumed he would perform well on my sentence comprehension test. I instructed Henry to read 32 ambiguous sentences. For example, the sentence “I just don't feel like pleasing salesmen” could mean either “I don't want to please salesmen” or “I don't want agreeable salesmen around.” Henry's task was to find and describe both meanings for each sentence as quickly as possible.

In this postmortem photograph of the brain of the amnesic H.M., white lines highlight the regions of the medial temporal lobes where a surgeon suctioned out part of his hippocampus, a brain region that governs long-term memory storage. From “Postmortem Examination of Patient H.M.'s Brain Based on Histological Sectioning and Digital 3D Reconstruction,” by Jacopo Annese et al., in Nature Communications, Vol. 5; January 2014

Henry discovered both meanings for just 20 percent of the sentences, whereas Harvard University students had no trouble identifying any of the ambiguities. Henry also took 10 times as long as the college students had—more than 49 seconds, on average—to begin his descriptions. And Henry's descriptions tended to be incomplete, inaccurate and difficult to understand. For example, at one point Henry explained the two meanings of “I just don't feel like pleasing salesmen” as follows: “The person doesn't like salesmen that are pleasing to him. Uh, and that personally he doesn't like them, and and [sic] personally he doesn't like them [sic], and then I think of a phrase that he would say himself, he doesn't, uh, pleasing, as conglamo [sic], of all of pleasing salesmen.”

At the time, I did not know what to make of these observations. A confusing array of questions came to mind that I only later categorized and addressed. Why did Henry have difficulties understanding my sentences? Neurologists since 1874 had believed that a region of the cortex now known as Wernicke's area carries out sentence comprehension. Yet Henry's neocortex was undamaged. His incoherence also baffled me because Broca's area, in another part of the neocortex, was thought to be the engine that created grammatical sentences. And what did Henry mean by “conglamo”—a conglomeration? A concatenation? Or a fusion of both words?

At age 40, Henry seemed too young to be experiencing word-finding difficulties, but something was clearly happening to his lexical memories. I just had no idea what that was. Only later would I discover a connection between Henry's damaged hippocampal region and his memory for words he had learned in adolescence.

A type of Fastener Made of Nylon

After earning my Ph.D. from M.I.T. in 1967, I became a professor at the University of California, Los Angeles. For me, language proved to be a useful way to study many aspects of memory, including the impact of aging on our ability to remember familiar words. Unlike memories for personal experiences, which vary from person to person, we all learn the same spelling, meaning and pronunciation for words. The uniformity of word knowledge in young adults made it easy for me to determine whether aging was responsible for the deteriorating word memories of older adults.

My research during subsequent years delineated specific age-related changes in how we remember words. In 1990, for example, my colleagues and I reported that as we age, the ability to recall pronunciations of familiar but rarely used words declines systematically. When we gave people a definition such as “a type of interlocking fastener made of nylon,” adults aged 65 and older could not bring to mind the word “Velcro” as often or as readily as adults 18 to 20 years old. For the older adults, the word more often remained on the tip of their tongue: they knew the meaning of the word, often its first speech sound (V) and its number of syllables but could not retrieve the entire word.

In 1998 my team published a related discovery: the ability to spell familiar but irregularly written words such as “rhythm,” “physicist” and “yacht” also declines with aging. Adults 60 years or older in our experiments produced reliably more misspellings than young adults. Even though the older adults realized that they once spelled “bicycle” without difficulty, they could no longer remember whether it was spelled “bicycle,” “bysicle” or “bisykle” until they reencountered “bicycle” in print.

Our discoveries indicated that normal adults older than 65 experience slight but reliable difficulties in retrieving lexical information learned decades earlier, difficulties that become progressively more severe with aging. At first, the information would come to mind after a delay, but as the memory grew more fragile over time, it often became irretrievable. At the extreme, even seeing the word failed to bring to mind its correct pronunciation, spelling and meaning. (To learn what aspects of memory decline with age and what to do about it, see "Memory's Fountain of Youth" below.)

Click or tap to enlarge

Credit: Tami Tolpa

Tip-of-the-tongue and tip-of-the-pen experiences are thought to arise when the relevant neural connections in the neocortex degrade. The representations of our knowledge of how to spell “rhythm” or pronounce “Velcro” weaken with time if these words are rarely spoken, seen or heard. Frequent use or recent exposure to a word strengthens those connections and prevents forgetting. Older people show no deficits in understanding, spelling or recalling words they often use, hear or write.

An Aging Amnesic

As I investigated the effects of normal aging on word memories, I returned to my 1967 questions about Henry's lexical memories. I reexamined a 178-page transcript of interviews with Henry recorded in 1970 by William Marslen-Wilson, then a fellow graduate student at M.I.T. The recording revealed that at age 44, Henry experienced unusual difficulties retrieving rarely used words. Instead of describing people as “more relaxed,” Henry said they were “more eased.” Similarly, he referred to a model airplane as made of “bamboo” or “like wood” rather than “balsa.” These errors haunted me, as I had never seen such lapses in someone so young. It was as if Henry's lexical memories were undergoing premature deterioration.

Then an idea came to me. Perhaps Henry's word-finding problems reflected an inability to relearn information he had completely forgotten. After all, his fundamental deficit was an inability to represent new information in his cortex. I reasoned that Henry's hippocampal damage may have prevented him from offsetting the degradation that accompanies normal aging. This inability could have transformed the usually minor word-retrieval problems of older adults into major impairments.

But so far I only had hints that Henry suffered such severe memory gaps. To determine whether Henry's memories were in fact fading abnormally, I needed to compare his word knowledge in his early 70s with that of people with normal memory who resembled Henry in all other respects. I also needed to document how Henry's lexical memories changed during his lifetime. Evidence of unusual memory degradation might for the first time explain why most individuals suffering damage to the hippocampal region end up forgetting information learned before their lesion.

When Henry was 71 and 73 years old, I asked my postdoctoral fellow, Lori E. James, now a psychologist at the University of Colorado Colorado Springs, to fly to Boston to test Henry's lexical memory at M.I.T. I wanted to assess Henry's ability to define words, with questions such as “What does 'squander' mean?” and to see whether he could tell which words—“squander,” say—are real and meaningful rather than invented. I also wished to evaluate how well Henry could retrieve the sounds of words for the purpose of naming familiar objects in pictures and reading rarely used words aloud. Finally, I was curious whether Henry could recall irregular spellings of words such as “rhythm.”

James and I created sets of words that Henry had almost certainly used earlier in his life, based on the age at which each word is normally acquired and the extensive Marslen-Wilson transcript of words Henry had used in conversation at age 44. We categorized our words as high frequency or low frequency based on available statistics on how often people use them. (I discuss only our results for low-frequency words because Henry's performance for common words was unremarkable.)

Testing Henry was the easy part. I, along with my wife, Deborah M. Burke, a psychologist at Pomona College, and our colleagues then spent many years finding healthy individuals aged 71 or 73 years with normal memory whose education, intelligence, occupation and socioeconomic background were similar to Henry's. We culled our candidates from the records of more than 750 older adults in the participant pools of the U.C.L.A. Cognition and Aging Laboratory, the Claremont Project on Memory and Aging, and retirees from clerical or physical plant positions at the Claremont Colleges.

In the end, we found 26 individuals for suitable control groups. Comparing Henry's results with those of these individuals revealed dramatic deficits in Henry's lexical memories, as my colleagues and I reported in a series of papers that culminated in 2009. In our tests of word meaning, for instance, the 73-year-olds without brain damage correctly responded with “a type of bean or pea” to the question “What does ‘lentil’ mean?” Henry, on the other hand, told us: “That's a combination word, in a way, from ‘lent’ and ‘till’ ... (meaning) area and time of.” Henry produced many such remarkable errors and generated fewer correct definitions than our comparison subjects, even for words that he used appropriately when he was younger. Henry also could not reliably distinguish low-frequency words from pseudowords such as “frendlihood” and “quintity.” In contrast, the other 73-year-olds made accurate distinctions 82 percent of the time, and Henry himself scored at the 86 percent level on this same test at age 57.

When we instructed participants to read aloud words typed on index cards, Henry misread “triage” as “triangle,” “thimble” as “tim- ... tim-BO-lee” and “pedestrian” as “ped-AYE-ee-string.” Henry's reading errors were far more numerous than the older adults we later tested. Apparently Henry could not remember how to pronounce multisyllabic words in which variables such as syllable stress patterns and certain letter sounds (such as whether to pronounce the e's in “pedestrian” as long or short) are unspecified.

What's in a Name?

Henry's problems were similarly apparent in the so-called Boston naming test. In this test, people are supposed to identify common objects depicted in line drawings. If a subject cannot recall the name of the object, the experimenter provides phonological cues—for example, “it begins with ‘tr’”—followed by a verification question containing the word itself: “Do you know the word ‘trellis’?” Although he had been familiar with the target names at a younger age, Henry correctly named fewer pictures than others his same age, benefited less than they did from the phonological cues, and produced more erroneous answers involving incorrect speech sounds. For instance, Henry called a snail a “sidion,” indicating severe degradation of his phonological memory for this familiar word.

In our spelling task, participants heard an irregularly spelled word such as “bicycle” and saw it spelled with a missing letter, as “bic_cle.” They were asked to choose one of two letters (“i” or “y”) to correctly fill in the blank. Henry chose the correct letter for 65 percent of the words, whereas our comparison subjects did so 82 percent of the time, suggesting extensive erosion of Henry's memories for irregularly spelled aspects of familiar words.

Our memories are stored in the cerebral cortex as changes in the connections between neurons (shown here). As we age, the neural ties representing our memories weaken, and we forget. Science Picture Company Alamy

We next documented the trajectory of Henry's decline between his 40s and 70s. By comparing our results with those of others, we learned that Henry's lexical memories deteriorated dramatically over the years, beginning in his late 50s. For instance, in a 1983 study by psychologists John Gabrieli, Neal Cohen and Suzanne Corkin, all then at M.I.T., Henry at age 57 showed a small but reliable deficit in distinguishing low-frequency words from pseudowords. At age 73, he showed significantly greater difficulties in the same task. Similarly, Henry had no problems naming pictures at age 54, according to a 1984 study by Corkin. Yet at age 73, Henry produced dramatic word substitutions such as “compass” for “protractor,” circumlocutions such as “ice clippers” for “tongs,” and neologisms such as “trake” for “trellis.”

In word-reading tests, Henry exhibited small deficits at age 67 in a 1993 study by Corkin and her graduate student Bradley R. Postle. In our studies, his losses were more glaring for the identical words. At age 71 he misread 67 percent of the words versus a mean of 9 percent for our control subjects. Just two years later his deficit for the same words was even greater and included new types of errors such as segment-omission errors—for instance, the reading of “affirmation” as “formation.”

Memory Maintenance

Psychologists have known for decades that synaptic connections in the neocortex deteriorate with age, so that memories we have stored there become increasingly weak and fragmented. The memories that suffer most are those we recall infrequently. If we have not thought about, heard or seen something recently, that information is vulnerable—and more so the older we become.

In his 50s, 60s and 70s, Henry's difficulties remembering word knowledge he rarely used or encountered became progressively worse, and the decline for him was much steeper than for typical adults of the same age and background. We reasoned, therefore, that the hippocampal complex must be involved in preserving old memories as well as making new ones. Just as a builder can make a new structure or repair a damaged one, so could the hippocampus craft new memories to replace those that have been degraded or fragmented with time.

Such rebuilding might occur whenever someone reencounters a forgotten word or a personal anecdote from the past. In this way, recent exposure and learning could shore up a shattered memory and reduce the rate of loss. In Henry's case, this hippocampal maintenance system was defunct. Henry had no way of rejuvenating depleted memories through experience and relearning—leading to his accelerated decline.

To support this theory, we would like to determine whether other people with amnesia and hippocampal region damage eventually experience exaggerated or faster than normal degradation of memories for rarely used information. We also want to find out whether healthy older adults re-create memories that have decayed from aging and lack of use as they naturally reencounter the missing information.

From personal experience as an older adult, I believe that we can and often do refurbish fragmented recollections. When I reread my story about meeting Henry, I checked the date of our meeting by looking at my unpublished report, written soon after the experiment. Although I had been absolutely certain that I had met Henry in 1967, the report indicated 1966 as the time of the test, showing we had met one year earlier than I had remembered, a fact that I will not soon forget!

Some episodic memories are impossible to check and correct, however. As I reread my description of Henry and me climbing the stairs to our testing room, I suddenly recalled that Henry had taken out something resembling an oversize business card and proceeded to tell me a story about rifles. I can no longer retrieve the specifics of Henry's rifle story, and I have no way of revisiting this 1966 incident to renew my memory for it. As a result, the details of the rifle story will slide even further into oblivion, much like Henry's own memories did for aspects of the meaning, spelling and pronunciation of rarely used words.

Memory’s Fountain of Youth

Like the rest of the body, the brain tends to decline with age. Yet science suggests ways to lessen the loss

First, a little perspective: not all aspects of memory decay. Older adults are just as able to understand sentences containing familiar words and to relearn forgotten information as when they were younger, though at a slightly slower rate. All behaviors are somewhat slower in older than younger individuals—a difference measured in thousandths of a second.

In some ways, cognitive function even improves with age. For example, vocabularies continue to expand up to age 80 and even beyond. As older individuals, we spontaneously use a greater variety of words and score higher on standardized vocabulary tests.

Older adults do encounter somewhat more trouble learning new uses for old words and remembering such things as a telephone number long enough to dial it. We also experience frustrating lapses in recalling the spelling of familiar, irregular words, such as “rhythm,” and pronunciations—especially for the names of places and people—that we learned decades earlier.

Recent research, including my own, suggests that older adults can counteract these changes. The key is exposure. Engaging in social situations helps to protect numerous language-related, among other, facets of memory. Before meeting up with friends, we can rehearse their names so as to avoid the embarrassment of forgetting them. We can preserve our spelling and word-retrieval skills by playing games such as Scrabble in which we exercise those skills rather than engaging in passive activities such as watching television.

We can prevent the deterioration of areas of expertise—say, public speaking, chess or playing the piano—by continuing to practice or play. More generally, we can engage in lifelong learning of various forms. After all, learning and relearning—reinstating old memories—are ways the hippocampal region keeps all of us young. — D.G.M.