Neuron
NeuroView
The Legacy of Patient H.M. for Neuroscience
Larry R. Squire1,2,*
1Veterans Affairs Healthcare System, San Diego, CA 92161, USA
2Departments of Psychiatry, Neurosciences, and Psychology, University of California, San Diego, La Jolla, CA 92093, USA
*Correspondence: lsquire@ucsd.edu
DOI 10.1016/j.neuron.2008.12.023
H.M. is probably the best known single patient in the history of neuroscience. His severe memory impairment,
which resulted from experimental neurosurgery to control seizures, was the subject of study for five decades
until his death in December 2008. Work with H.M. established fundamental principles about how memory
functions are organized in the brain.
In 1952, Brenda Milner was completing
her doctoral research at McGill University
under the direction of Donald Hebb. At
about this time, she encountered two
patients (P.B. and F.C.) who had become
severely amnesic following unilateral
removal of the medial structures of the
left temporal lobe for the treatment of
epileptic seizures (Penfield and Milner,
1958). This unfortunate outcome was
entirely unexpected, and it was proposed
that in each case there had been a preexistent,
but unsuspected, atrophic lesion in
the medial temporal lobe of the opposite
hemisphere. In that way, the unilateral
surgery would have resulted in a bilateral
lesion, an idea that was confirmed at
autopsy some years later for patient P.B.
After the two cases were presented at
the 1955 meeting of the American Neurological
Association, Wilder Penfield (the
neurosurgeon in both cases) received
a call from William Scoville, a neurosurgeon
in Hartford, Connecticut. Scoville
told Penfield that he had seen a similar
memory impairment in one of his own
patients (H.M.) in whom he had carried
out a bilateral medial temporal lobe resection
in an attempt to control epileptic
seizures. As a result of this conversation,
Brenda Milner was invited to travel to
Hartford to study H.M.
H.M. had been knocked down by
a bicycle at the age of 7, began to have
minor seizures at age 10, and had major
seizures after age 16. (The age of the
bicycle accident is given as 9 in some
reports; for clarification see Corkin,
1984.) He worked for a time on an
assembly line but, finally, in 1953 at the
age of 27 he had become so incapacitated
by his seizures, despite high doses
of anticonvulsant medication, that he
could not work or lead a normal life. Scoville
offered H.M. an experimental procedure
that he had carried out previously in
psychotic patients, and the surgery was
then performed with the approval of the
patient and his family.
When Milner first visited H.M., she saw
that the epilepsy was now controlled but
that his memory impairment was even
more severe than in Penfield’s two
patients, P.B. and F.C. What she
observed was someone who forgot daily
events nearly as fast as they occurred,
apparently in the absence of any general
intellectual loss or perceptual disorder.
He underestimated his own age, apologized
for forgetting the names of persons
to whom he had just been introduced, and
described his state as ‘‘like waking from
a dream . every day is alone in itself.’’
(Milner et al., 1968, p. 217).
The first observations of H.M., and the
results of formal testing, were reported
a few years later (Scoville and Milner,
1957). This publication became one of
the most cited papers in neuroscience
(nearly 2500 citations) and is still cited
with high frequency. H.M. continued to
be studied for five decades, principally
by Brenda Milner, her former student
Suzanne Corkin, and their colleagues
(Corkin, 1984, 2002; Milner et al., 1968).
He died on December 2, 2008, at the
age of 82. It can be said that the early
descriptions of H.M. inaugurated the
modern era of memory research. Before
H.M., due particularly to the influence of
Karl Lashley, memory functions were
thought to be widely distributed in the
cortex and to be integrated with
intellectual and perceptual functions.
The findings from H.M. established the
fundamental principle that memory is
a distinct cerebral function, separable
from other perceptual and cognitive abilities,
and identified the medial aspect of
the temporal lobe as important for
memory. The implication was that the
brain has to some extent separated its
perceptual and intellectual functions
from its capacity to lay down in memory
the records that ordinarily result from
engaging in perceptual and intellectual
work.
The Medial Temporal Lobe Memory
System
The early paper is sometimes cited incorrectly
as evidence that the hippocampus
is important for memory, but this particular
point could not of course be established
from a lesion that, by the surgeon’s
description, included the hippocampus,
amygdala, and the adjacent parahippocampal
gyrus. As Milner subsequently
wrote, ‘‘Despite the use of the word
‘hippocampal’ in the titles of my papers
with Scoville and Penfield, I have never
claimed that the memory loss was solely
attributable to the hippocampal lesions’’
(Milner, 1998). Indeed, the original paper
ends, quite appropriately, with the state-
ment:
It is concluded that the anterior
hippocampus and hippocampal
gyrus, either separately or together,
are critically concerned in the
retention of current experience. It
is not known whether the amygdala
plays any part in this mechanism,
since the hippocampal complex
has not been removed alone, but
6 Neuron 61, January 15, 2009 ª2009 Elsevier Inc.
always together with uncus and
amygdala. (Scoville and Milner,
1957, p. 21).
The findings from H.M. were initially
met with some resistance, especially
because of the difficulty for many years
of demonstrating anything resembling
his impairment in the experimental animal.
Efforts to establish an animal model in fact
began almost immediately when Scoville
himself came to Montreal and did the
same surgery in monkeys that he had
done with H.M. But these monkeys and
others with medial temporal lesions
seemed able to learn tasks that H.M.
could not learn. Only much later did it
become understood that apparently
similar tasks can be learned in different
ways by humans and monkeys. For
example, the visual discrimination task,
which is learned gradually by the monkey
over hundreds of trials, proved to involve
what one would now call habit learning.
In the monkey, this kind of learning
depends on the basal ganglia, not the
medial temporal lobe. Eventually, tasks
were developed for the monkey that
were exquisitely sensitive to medial
temporal lobe lesions (for example, the
one-trial, delayed nonmatching to sample
task), and an animal model of human
memory impairment thereby became
available (Mishkin, 1978).
Cumulative work with the animal model
over the next decade, together with
neuroanatomical studies, succeeded in
identifying the anatomical components
of what is now termed the medial
temporal lobe memory system (Squire
and Zola-Morgan, 1991): the hippocampus
and the adjacent perirhinal, entorhinal,
and parahippocampal cortices that
make up much of the parahippocampal
gyrus. This information showed which
structures within H.M.’s large lesion
were important for understanding his
impairment and, more broadly, what
structures are important for memory.
A few years later, an improved description
of H.M.’s lesion was obtained with
magnetic resonance imaging (MRI) (Corkin
et al., 1997). MRI had been delayed
because of concerns that clips placed
on the dura during surgery made H.M.
ineligible for imaging. However, thorough
inquiry revealed that the dural clips
constituted no risk.
At this juncture, several points became
clear. First, H.M.’s lesion was less
extensive than described originally by the
surgeon in that it extended a little more
than 5 cm caudally from the temporal
pole (not 8 cm). As a result the posterior
parahippocampal gyrus was largely
spared (specifically, the parahippocampal
cortex or what in the monkey is termed
area TH TF). Second, the reason that
H.M.’s memory impairment was so severe
was that the bilateral damage included the
parahippocampal gyrus (anteriorly) and
was not restricted to the hippocampus.
Damage limited to the hippocampus
causes significant memory impairment
but considerably less impairment than in
H.M. Third, memory impairment more
severe than H.M.’s could now be understood,
as when the damage includes the
structures damaged in H.M. but also
extends far enough posteriorly to involve
the parahippocampal cortex (patients
E.P. and G.P.; Kirwan et al., 2008).
In the early years, the anatomy of the
medial temporal lobe was poorly understood,
and terms like hippocampal zone
and hippocampal complex were often
used to identify the area of damage. With
the elucidation of the boundaries and
connectivity of the structures adjacent to
the hippocampus and the discovery that
these structures are important for
memory, vague terms like hippocampal
complex became unnecessary (though
one can still find them in contemporary
writing). It is now possible to achieve careful
descriptions based on anatomical
measurement and modern terminology.
H.M. not only motivated the development
of an animal model of human
memory impairment and the subsequent
delineation of the medial temporal lobe
memory system. As described next, the
study of H.M. also led to fundamental
insights into the function of the medial
temporal lobe and the larger matter of
how memory is organized in the brain.
Immediate Memory and Long-Term
Memory
H.M.’s intact intellectual and perceptual
functions, and similar findings in other
patients with large medial temporal
lesions, have been well documented.
A key additional finding was that H.M.
had a remarkable capacity for sustained
attention, including the ability to retain
information for a period of time after it
was presented. Thus, he could carry on
a conversation, and he exhibited an intact
digit span (i.e., the ability to repeat back
a string of six or seven digits). Indeed,
information remained available so long
as it could be actively maintained by
rehearsal. For example, H.M. could retain
a three-digit number for as long as 15 min
by continuous rehearsal, organizing the
digits according to an elaborate
mnemonic scheme. Yet when his attention
was diverted to a new topic, he forgot
the whole event. In contrast, when the
material was not easy to rehearse (in the
case of nonverbal stimuli like faces or
designs), information slipped away in
less than a minute. These findings supported
a fundamental distinction between
immediate memory and long-term
memory (what William James termed
primary memory and secondary memory).
Primary memory [immediate memory]
.comes to us as belonging to the
rearward portion of the present
space of time, and not to the
genuine past (James, 1890, p. 647).
Secondary memory [long-term memory] is
quite different.
An object which has been recollected
. is one which has been
absent from consciousness altogether,
and now revives anew. It is
brought back, recalled, fished up,
so to speak, from a reservoir in
which, with countless other
objects, it lay buried and lost from
view. (James, 1890, p. 648).
Notably, time is not the key factor that
determines how long patients like H.M.
can retaininformationin memory. The relevant
factors are the capacity of immediate
memory and attention, i.e., the amount of
material that can be held in mind and
how successfully it can be rehearsed.
The work with H.M. demonstrated that
the psychological distinction between
immediate memory and long-term
memory is a prominent feature of how the
brain has organized its memory functions.
Multiple Memory Systems
Perhaps the most unexpected discovery
about H.M., given his profound and global
Neuron
NeuroView
Neuron 61, January 15, 2009 ª2009 Elsevier Inc. 7
memory impairment, came when Brenda
Milner tested his ability to acquire a visuomotor
skill (Milner, 1962). H.M. was shown
a five-pointed star, with a double contour,
and asked to trace its outline with a pencil,
but in a condition when he could only
see his hand and the star as reflected
in a mirror. H.M. acquired this mirrordrawing
skill during ten trials and
exhibited excellent retention across 3
days. Yet at the end of testing, he had
no recollection of having done the task
before. This demonstration provided the
first hint that there was more than one
kind of memory in the brain and suggested
that some kinds of memory (motor
skills) must lie outside the province of the
medial temporal lobe.
For a time, it was rather thought that
motor skills were a special case and that
all the rest of memory is impaired in
patients like H.M. Later it became appreciated
that motor skills are but a subset
of a larger domain of skill-like abilities, all
of which are preserved in amnesia. The
demonstration of a fully preserved ability
to learn the perceptual skill of mirror
reading suggested a distinction between
two broad classes of knowledge: declarative
and procedural (Cohen and Squire,
1980). Declarative memory is what is
meant when the term ‘‘memory’’ is used
in everyday language, i.e., conscious
knowledge of facts and events. Procedural
memory refers to skill-based knowledge
that develops gradually but with little
ability to report what is being learned.
In the years that followed, other
preserved learning abilities began to be
reported for amnesic patients, and the
perspective shifted to a framework that
accommodated multiple (i.e., more than
two) memory systems. As Endel Tulving
wrote:
But even if we accept the broad
division of memory into procedural
and propositional forms . there
are phenomena that do not seem
to fit readily into such a taxonomy
(Tulving et al., 1982, p.336).
Subsequently, the terms declarative
and nondeclarative were introduced with
the idea that declarative memory refers
to the kind of memory that is impaired in
H.M. and is dependent on the medial
temporal lobe. Nondeclarative memory
is an umbrella term referring to additional
memory systems. These include systems
that support skill learning, habit learning,
simple conditioning, emotional learning,
as well as priming and perceptual
learning. The structures with special
importance for these kinds of memory
include the basal ganglia, the cerebellum,
the amygdala, and the neocortex. The
starting point for these developments
was the early discovery that motor skill
learning was preserved in H.M. This
finding revealed that memory is not
a single faculty of the mind and led ultimately
to the identification of the multiple
memory systems of the mammalian brain.
Remote Memory
H.M.’s memory impairment has generally
been taken as reflecting a failure to convert
transient, immediate memory into stable
long-term memory. A key insight about
the organization of memory, and medial
temporal lobe function, came with
a consideration of his capacity to
remember information that he had
acquired before his surgery. The first
exploration of this issue with formal tests
asked H.M. to recognize faces of persons
who had become famous in different
decades, 1920–1970 (Marslen-Wilson
and Teuber, 1975). As expected, H.M.
wasseverelyimpairedatrecognizingfaces
from his postmorbid period (the 1950s and
1960s), but he performed as well as or
better than age-matched controls at
recognizing faces of persons who were in
thenewsbeforehissurgery.Thisimportant
finding implied that the medial temporal
lobe is not the ultimate storage site for
previously acquired knowledge. The early
descriptions of H.M. conform to this view.
Thus, H.M. was described as having
a partial loss of memory (retrograde
amnesia) for the 3 years leading up to his
surgery, with early memories ‘‘seemingly
normal’’ (Scoville and Milner, 1957, p. 17).
Similarly, about 10 years later it was
remarked that there did not appear
to have been any change in H.M.’s
capacity to recall remote events
antedating his operation, such as
incidents from his early school
years, a high-school attachment,
or jobs he had held in his late teens
and early twenties (Milner et al.,
1968, p. 216).
Subsequently, a particular interest
developed in the status of autobiographical
memories for unique events, which
are specific to time and place, and
methods were developed to assess the
specificity and the detail with which such
recollections could be reproduced. In
the earliest efforts along these lines, as
summarized by Suzanne Corkin (Corkin,
1984), H.M. produced well-formed autobiographical
memories, from age 16 years
or younger. It was concluded that H.M’s
remote memory impairment now
extended back to 11 years before his
surgery. The situation seemed to change
further as H.M. aged. In an update
prepared nearly 20 years later (Corkin,
2002), H.M. (now 76 years old) was
described as having memories of childhood,
but his memories appeared more
like remembered facts than like memories
of specific episodes. It was also said that
he could not narrate a single event that
occurred at a specific time and place.
Essentially the same conclusion was
reached a few years later when new
methods, intended to be particularly
sensitive, were used to assess H.M.’s
remote memory for autobiographical
events (Steinvorth et al., 2005). These
later findings led to the proposal that,
whatever might be the case for fact
memory, autobiographical memories,
i.e., memories that are specific to time
and place, depend on the medial temporal
lobe so long as the memories persist.
There are reasons to be cautious about
this idea. In 2002–2003, new MRI scans of
H.M. were obtained (Salat et al., 2006).
These scans documented a number of
changes since his first MRI scans from
1992–1993 (Corkin et al., 1997), including
cortical thinning, subcortical atrophy,
large amounts of abnormal white matter,
and subcortical infarcts. These findings
were thought to have appeared during
the past decade, and they complicate
the interpretation of neuropsychological
data collected during the same time
period. Another consideration is that
remote memories could have been intact
in the early years after surgery but then
have faded with time because they could
not be strengthened through rehearsal
and relearning. In any case, the optimal
time to assess the status of past memory
is soon after the onset of memory
impairment.
8 Neuron 61, January 15, 2009 ª2009 Elsevier Inc.
Neuron
NeuroView
Other work has tended to support the
earlier estimates that H.M.’s remote
memories were intact. First, Penfield’s
two patients described above, P.B. and
F.C., were reported after their surgeries
to have memory loss extending back
a few months and 4 years, respectively,
and intact memory from before that time
(Penfield and Milner, 1958). Second,
methods like those used recently to
assess H.M. have also been used to evaluate
autobiographical memory in other
patients, including patients like E.P. and
G.P. who have very severe memory
impairment (Kirwan et al., 2008). In these
cases, autobiographical recollection was
impaired when memories were drawn
from the recent past but fully intact when
memories were drawn from the remote
past.
Memory loss can sometimes extend
back for decades in the case of large
medial temporal lobe lesions (though
additional damage to anterolateral
temporal cortex may be important in this
circumstance). In any case, memories
from early life appear to be intact unless
the damage extends well into the lateral
temporal lobe or the frontal lobe. These
findings are typically interpreted to mean
that the structures damaged in H.M. are
important for the formation of long-term
memory and its maintenance for a period
of time after learning. During this period
gradual changes are thought to occur in
neocortex (memory consolidation) that
increase the complexity, distribution,
and connectivity among multiple cortical
regions. Eventually, memory can be supported
by the neocortex and becomes
independent of the medial temporal
lobe. The surprising observation that
H.M. had access to old memories, in the
face of an inability to establish new
ones, motivated an enormous body of
work, both in humans and experimental
animals, on the topic of remote memory
and continues to stimulate discussion
about the nature and significance of retrograde
amnesia.
Perspective
H.M. was likely the most studied
individual in the history of neuroscience.
Interest in the case can be attributed to
a number of factors, including the unusual
purity and severity of the memory impairment,
its stability, its well-described
anatomical basis, and H.M.’s willingness
to be studied. He was a quiet and courteous
man with a sense of humor and
insight into his condition. Speaking of his
neurosurgeon, he once said, ‘‘What he
learned about me helped others, and I’m
glad about that.’’ (Corkin, 2002, p. 159).
An additional aspect of H.M.’s circumstance,
which assured his eventual place
in the history of neuroscience, was the
fact that Brenda Milner was the young
scientist who first studied him. She is
a superb experimentalist with a strong
conceptual orientation that allowed her
to draw from her data deep insights about
the organization of memory. Because he
was the first well-studied patient with
amnesia, H.M. became the yardstick
against which other patients with memory
impairment would be compared. It is now
clear that his memory impairment was not
absolute and that he was able to acquire
significant new knowledge (Corkin,
2002). Thus, memory impairment can be
either more severe or less severe than in
H.M. But the study of H.M. established
key principles about how memory is organized
that continue to guide the discipline.
ACKNOWLEDGMENTS
Supported by the Medical Research Service of the
Department of Veterans Affairs, The National Institute
of Mental Health (MH24600), and the Metropolitan
Life Foundation. I thank Nicola Broadbent,
Robert Clark, Christine Smith, Ryan Squire, and
Wendy Suzuki for their helpful comments.
REFERENCES
Cohen, N., and Squire, L.R. (1980). Science 210,
207–209.
Corkin, S. (1984). Semin. Neurol. 4, 249–259.
Corkin, S. (2002). Nat. Rev. Neurosci. 3, 153–160.
Corkin, S., Amaral, D.G., Gonzalez, R.G., Johnson,
K.A., and Hyman, B.T. (1997). J. Neurosci. 17,
3964–3979.
James, W. (1890). Principles of Psychology, Dover
Edition, Volume One (New York: Holt).
Kirwan, C.B., Bayley, P.J., Galva´ n, V.V., and
Squire, L.R. (2008). Proc. Natl. Acad. Sci. USA
105, 2676–2680.
Marslen-Wilson, W.D., and Teuber, H.L. (1975).
Neuropsychologia 13, 353–364.
Milner, B. (1962). Physiologie de l’hippocampe,
P. Passouant, ed. (Paris: Centre National de la
Recherche Scientifique), pp. 257–272.
Milner, B. (1998). The History of Neuroscience in
Autobiography, Volume 2, L.R. Squire, ed. (San
Diego: Academic Press), pp. 276–305.
Milner, B., Corkin, S., and Teuber, H.L. (1968).
Neuropsychologia 6, 215–234.
Mishkin, M. (1978). Nature 273, 297–298.
Penfield, W., and Milner, B. (1958). AMA Arch.
Neurol. Psychiatry 79, 475–497.
Salat, D.H., van der Kouwe, A.J.W., Tuch, D.S.,
Quinn, B.T., Fischl, B., Dale, A.M., and Corkin, S.
(2006). Hippocampus 16, 936–945.
Scoville, W.B., and Milner, B. (1957). J. Neurol.
Neurosurg. Psychiatry 20, 11–21.
Squire, L.R., and Zola-Morgan, S. (1991). Science
253, 1380–1386.
Steinvorth, S., Levine, B., and Corkin, S. (2005).
Neuropsychologia 43, 479–496.
Tulving, E., Schacter, D.L., and Stark, H.A. (1982).
J. Exp. Psychol. Learn. Mem. Cogn. 8, 336–342.
Neuron 61, January 15, 2009 ª2009 Elsevier Inc. 9
Neuron
NeuroView