 |
 Previous Article | Next Article 
The Journal of Neuroscience, September 15, 2000, 20(18):7024-7036
Profound Amnesia After Damage to the Medial Temporal Lobe: A
Neuroanatomical and Neuropsychological Profile of Patient E. P.
Lisa
Stefanacci1,
Elizabeth A.
Buffalo2,
Heike
Schmolck1, and
Larry
R.
Squire1, 2, 3, 4
Departments of 1 Psychiatry,
2 Neurosciences, and 3 Department of
Psychology, University of California, La Jolla, California 92093, and
4 Veterans Affairs Medical Center, San Diego, California
92161
 |
ABSTRACT |
E. P. became profoundly amnesic in 1992 after viral
encephalitis, which damaged his medial temporal lobe bilaterally.
Because of the rarity of such patients, we have performed a detailed
neuroanatomical analysis of E. P.'s lesion using magnetic
resonance imaging, and we have assessed his cognitive abilities with a
wide range of neuropsychological tests. Finally, we have compared and
contrasted the findings for E. P. with the noted amnesic patient
H.M, whose surgical lesion is strikingly similar to E. P.'s lesion.
Key words:
memory; hippocampus; amnesia; E. P.; medial temporal
lobe; encephalitis
| |
INTRODUCTION |
In the earliest collected case
reports of human memory impairment (Winslow, 1861 ; Ribot, 1881), it was
recognized that the study of memory disorders can provide valuable
insights into the structure and organization of normal memory. During
the past 100 years, cumulative study of groups of amnesic patients and
a few notable single cases have repeatedly illustrated this principle (Rapaport, 1942; Scoville and Milner, 1957; Talland, 1965; Butters and
Cermak, 1980; Mayes, 1988; Baddeley et al., 1995).
The best known and most thoroughly studied case of human amnesia is
patient H. M. (Scoville and Milner, 1957), who in 1953 sustained a
bilateral resection of the medial temporal lobe in an effort to relieve
severe epilepsy. More recently, the surgical lesion was described in
considerable detail using magnetic resonance imaging (MRI) (Corkin et
al., 1997). Comprehensive study of this patient over the years
established the fundamental principle that the ability to acquire new
memories is a distinct cerebral function, separable from other
perceptual and cognitive abilities (Milner et al., 1998).
Most amnesic patients who have been available for study are less
impaired than H. M., because their damage is less extensive than
his. Nevertheless, a few very severely impaired patients have been
described in the neuropsychological literature. Each of these patients
became amnesic after an episode of viral encephalitis (patient S. S., Cermak, 1976; patient D. R. B., Damasio et al., 1985; and
patient R. F. R., Warrington and McCarthy, 1988). However, in
these cases, either no anatomical information is available about the
patient or extensive damage has occurred outside the medial temporal
lobe, and cognitive functions in addition to memory are impaired.
We here present neuroanatomical and neuropsychological findings for
patient E. P. Patient E. P. became profoundly amnesic in 1992 after viral encephalitis, which damaged his medial temporal lobe
bilaterally. After H. M., he is the only profoundly amnesic patient known to us for whom detailed neuroanatomical and
neuropsychological information is available and for whom damage is
limited primarily to the medial aspect of the temporal lobe,
bilaterally (Fig. 1). We have performed a
qualitative and quantitative analysis of E. P.'s brain lesions
using MRI, and we have assessed his cognitive abilities with a wide
range of neuropsychological tests. Finally, we have compared and
contrasted the findings for E. P. with the considerable body of
information available for patient H. M.
View larger version (103K):
[in this window]
[in a new window]
|
Figure 1.
T2-weighted axial MRIs of patients E. P. (right) and H. M. (left), through
the level of the temporal lobes. Damaged tissue is indicated by bright
signal. Images are oriented according to radiological convention (the
right side of the brain is on the left side of the image).
Both patients sustained extensive damage to medial temporal lobe
structures. Scale bar, 2 cm (applies to both panels). The MR
image for H. M. is reprinted from Corkin et al. (1997), their
Figure 4D.
|
|
| |
MATERIALS AND METHODS |
Case history
Patient E. P. is a right-handed male who was born in 1922 and grew up in a central California agricultural community. He has 12 years of education. From 1941 to 1950, he traveled at sea as a radio
operator for an oil company. Afterward, he lived in Los Angeles County,
working for 28 years as a technician in the aerospace industry, then
for 5 years as a part-time consultant. In 1993 he moved to San Diego
County. E. P. has been married since 1950, and he currently lives
at home with his wife. He has two grown children.
In November of 1992, at the age of 70, E. P. was diagnosed with
herpes simplex encephalitis. His illness began with flu-like symptoms
(fever and lethargy) and an episode of memory loss (he could not
remember the names of some family members), which appeared to recover
for a few days. However, his memory then worsened, and he was admitted
to the hospital, where he received a 10 d course of intravenous
Acyclovir. In the months immediately after, E. P. experienced
severe loss of appetite and a 20-30 lb weight loss. By June, 1993 his
clinical condition had stabilized; however, profound memory impairment
has persisted to the present time.
Upon first meeting E. P., one is impressed by his healthy, well
groomed appearance and his pleasant demeanor. E. P. stands 6 feet,
2 1/2 inches tall and weighs 192 lbs. He walks with a slight limp
caused by arthritis in his left knee. He is always agreeable and
cooperative during testing sessions, and he particularly enjoys
participating in computer-aided tests. During testing sessions, he will
repeatedly marvel at the invention of the portable computer, often
commenting that he "was born too early". His conversation is
limited to events from his early life, e.g., his childhood on a farm,
his teenage hobby as a ham radio operator, and his travels during World
War II. Within a 1 hr testing session, E. P. may recount the same
story almost verbatim as many as 10 times.
Like patient H. M. (Corkin et al., 1997), E. P. is socially
interactive but lacks initiative. On a typical day, E. P. has a
light breakfast when he wakes up, and then he returns to bed where he
listens to the radio. His wife reports that when he arises a second
time, he will often return to the kitchen and have breakfast again, and
sometimes he again returns to bed. He has had breakfast as many as
three times in one morning before staying up for the day. E. P. chooses his own clothes and dresses himself. He needs no assistance in
bathing or shaving, although he often needs reminders about these
activities from his wife. In the morning, he alternates between taking
short walks around his neighborhood and sitting in his backyard or in
the living room. After lunch, he watches television or reads the
newspaper or a magazine. Often, he will suggest that he and his wife go
out, but once they leave the house (to go shopping, for example), he
will become confused and ask to return home. He watches television
after dinner, and retires early (7:00 P.M. or 8:00 P.M.).
Medical history
E. P. has a history of hypertension, arthritis (right
elbow, left knee), hernia repair, and an uncomplicated myocardial
infarction with complete recovery and without indication of cerebral
ischemia. E. P. has no history of diabetes, heart or lung disease,
headaches, seizures, stroke, or traumatic loss of consciousness. He
currently takes medication for hypertension (Metoprolol; 50 mg/d), for
anxiety (Paroxetine; 20 mg/d), and for high cholesterol (Atorvastatine; 10 mg/d). E. P. stopped smoking in 1959. He does not currently drink alcohol, and his wife reports that he was never a heavy drinker.
Neurological examination
E. P.'s neurological status has remained stable since his
diagnosis of encephalitis in 1992. On his most recent examination in
1995 he was found to be alert and attentive, but disoriented to place
and time (month and year). His language output was fluent and
nonparaphasic. He was able to copy nonsense figures and a cube, and
showed no signs of spatial neglect. Examination of the cranial nerves
revealed anosmia and mild difficulty hearing conversational speech.
(This mild hearing loss is barely noticeable in conversation with
E. P. and has never interfered with neuropsychological testing.) Examination of reflexes and posture, motor and somatosensory function, and coordination was unremarkable.
Magnetic resonance imaging
Patient E. P. We obtained MR images of EP's
brain on two occasions, in 1994 and 1998, and summaries of these
findings have appeared previously (Squire and Knowlton, 1995; Hamann
and Squire, 1997; Reed and Squire, 1998; Buffalo et al., 1998; Schmolck
et al., 2000a). MRIs were acquired in a 1.5 tesla GE Signa clinical scanner at the University of California San Diego Medical Center, using
four different scanning protocols: (1) sagittal three-dimensional (3-D)
MP-RAGE images, field of view (FOV) = 20 cm, matrix = 256 × 256 (0.781 mm in-plane resolution), 1.2-mm-thick sections;
(2) coronal oblique, T1-weighted images perpendicular to the long axis
of the hippocampus (Press et al., 1989), FOV = 16, matrix = 256 × 256 (0.625 mm in-plane resolution), 5-mm-thick, interleaved sections; (3) coronal oblique, T2-weighted, proton density fast spin
echo (FSE) images, perpendicular to the long axis of the hippocampus,
FOV = 20, matrix = 128 × 256 (1.56 × 0.781 mm
in-plane resolution), 5-mm-thick, interleaved sections; (4) axial
T2-weighted, proton density FSE images, FOV = 20, matrix = 256 × 256 (0.781 mm in-plane resolution), 5-mm-thick sections.
Control subjects. MR images of the brains of three
right-handed, male control subjects (mean age, 78.6 years; mean
education, 16 years) were acquired in a 1.5 tesla GE Signa clinical
scanner at the Veterans Affairs Medical Center (San Diego, CA). A 3-D spoiled gradient-recalled acquisition in a steady state (SPGR) scanning
protocol was used to collect images in the coronal
(1.5-mm-thick sections) or the sagittal (1.2-mm-thick sections) planes.
For all images, the in-plane resolution was 1.0 mm, and FOV = 24 cm.
Data analysis. We first performed a qualitative analysis of
the MR images of each participant using primarily T1-weighted sagittal,
T1-weighted coronal oblique, and T2-weighted axial images. We also
imported the sagittal MP-RAGE images into the Analysis of Functional
NeuroImages (AFNI) software program (Cox, 1996), so that the images
could be reconstructed and analyzed in all three planes. Our
qualitative analysis focused mainly on the temporal lobe, which was
extensively damaged in E. P. A quantitative analysis was also
accomplished by capturing AFNI images at 2 mm (subject C2) or 3 mm
intervals (E. P., and controls C1 and C3) throughout the brain and
importing them into the Canvas 5.0 software program. Images were
reconstructed so that the voxel dimensions were the same across brains.
We then calculated for each participant the volume of the frontal
lobes, lateral temporal lobes, parietal lobes, occipital lobes, and
insula in the following manner. First, we outlined each of these
regions with the Canvas 5.0 polygon tool and calculated the total area
by summing the areas for each hemisphere. The area of the ventricles
was subtracted from relevant sections. We then multiplied the total
area of each region by the image thickness.
The measuring technique described above was also used to calculate the
volume of the lateral and third ventricles. We excluded the temporal
horns of the lateral ventricles from these measurements, because they
were substantially enlarged in E. P. (consistent with the tissue
damage and atrophy in his medial temporal lobes). Excluding the
temporal horns allowed for an estimate of cortical atrophy that was not
influenced by E. P.'s medial temporal lobe abnormalities.
We measured the frontal lobe from the frontal pole to the caudal limit
of the central sulcus. The ventral border of the frontal lobe is formed
by the fundus of the superior limiting sulcus until the central sulcus
appears more caudally. Measurement of the lateral temporal lobe
included the inferior, middle, and superior temporal gyri, as they
extend from the temporal pole to the splenium of the corpus callosum.
On coronal sections, the outline for the lateral temporal lobe thus
extended from the fundus of the lateral occipitotemporal sulcus
(medially) to the fundus of the inferior limiting sulcus (laterally).
The parietal lobe measurement extended rostrally to the central sulcus.
Caudally, it extended beyond the caudal extent of the lateral sulcus to
meet with the temporal and occipital lobes. The occipital lobe
measurement extended to the parietal lobe at the level of the
parieto-occipital fissure and to the temporal lobe at approximately the
level of the splenium of the corpus callosum where the calcarine sulcus
merges with the parieto-occipital fissure.
In the case of the insula, the presence of white matter damage deep to
the insula (see Results) made it difficult to determine the gray-white
matter border of this region, and therefore difficult to make a
satisfactory volume estimate. We calculated total insula area by
measuring the perimeter of the insula from the superior limiting sulcus
to the inferior limiting sulcus in 2-3mm intervals, and then
multiplied the sum perimeter by the image thickness.
| |
Neuropsychology |
E. P. was assessed on a number of tests of anterograde and
retrograde memory, as well as on other tests of cognitive function. For
many of the tests, E. P.'s performance was compared to the performance of four healthy, age- and education-matched men who were
volunteers or employees at the San Diego Veterans Affairs Medical
Center. As a group they averaged 75.3 years of age and had 12.8 years
of education. For other tests, E. P.'s performance was compared
to previously published scores of normal subjects.
| |
RESULTS |
Magnetic resonance imaging
Terminology
The description of E. P.'s medial temporal lobe follows the
nomenclature used by Amaral and Insausti (1990) and Corkin et al.
(1997). The hippocampal formation comprises the dentate gyrus, hippocampus, subicular complex (parasubiculum, presubiculum, and subiculum proper), and entorhinal cortex. Rostrally, the
intraventricular portion of the hippocampal formation (dentate gyrus,
hippocampus, and subiculum) begins ~3.5 cm from the temporal pole and
continues for ~4.0 cm caudally, to a point ~7.5 cm from the
temporal pole. The entorhinal cortex begins ~2.5 cm from the temporal
pole, on the parahippocampal gyrus, and continues for ~2.5 cm
caudally to the anterior limit of the lateral geniculate nucleus. The
entorhinal cortex is bounded medially by the subicular complex and
laterally by the perirhinal cortex. The perirhinal cortex extends from
the temporal pole and continues ventrocaudally, for ~5 cm, ending at
the posterior border of the medially situated entorhinal cortex; that
is, at about the anterior limit of the lateral geniculate nucleus. The
perirhinal cortex lies on both banks of the collateral sulcus for most
of its rostrocaudal extent (the collateral sulcus is located between
the medially situated parahippocampal gyrus and the laterally situated
fusiform gyrus). The perirhinal cortex is bordered caudally by the
parahippocampal cortex, which comprises the caudal portion of the
parahippocampal gyrus and extends to the caudal extent of the temporal
lobe (i.e., to the level of the splenium of the corpus callosum). The
amygdala is located ~3 cm caudal to the temporal pole and is
immediately dorsal to the entorhinal and perirhinal cortices.
General appearance of the brain
The most striking feature of E. P.'s brain is severe,
bilateral medial temporal lobe pathology (Figs.
2-4).
The damage is most severe in the anterior temporal lobe, and includes
the amygdala, hippocampus, entorhinal, and perirhinal cortices,
bilaterally (Figs. 2E-J,
5A-C). There is also
involvement of the rostral fusiform gyrus and the rostral
parahippocampal cortex, bilaterally (Fig. 5B-E). Beyond the
caudal limit of the fusiform and parahippocampal damage (5.1 cm from
the temporal pole on the left side, and 6.3 cm from the pole on the
right side), the hippocampal lesion continues bilaterally to a point 7 cm from the tip of the temporal poles and includes the full
rostrocaudal extent of the hippocampus (Fig. 4B,C).
View larger version (206K):
[in this window]
[in a new window]
|
Figure 2.
T1-weighted coronal images arranged from rostral
(A) to caudal (P) through
E. P.'s brain. Images are 0.781-mm-thick and are spaced 8.6 mm
apart. Damaged tissue is indicated by dark signal. Images are oriented
as in Figure 1. E. P.'s temporal lobe damage can be seen in
D-K. Scale bar: A, 2 cm (applies to all
panels).
|
|
View larger version (162K):
[in this window]
[in a new window]
|
Figure 3.
T2-weighted axial images, arranged from ventral
(A) to dorsal (D),
indicating the extent of damage in E. P.'s anterior temporal
lobes (bright signal areas). Images are 5-mm-thick and are spaced 7.5 mm apart. Images are oriented as in Figure 1. Scale bar:
A, 2 cm (applies to all panels).
|
|
View larger version (72K):
[in this window]
[in a new window]
|
Figure 4.
A shows a T1-weighted parasagittal
image from the left hemisphere of a 74-year-old control subject.
B and C show parasagittal images through
the left and right hemispheres, respectively, of E. P.'s brain.
Compare the intraventricular portion of the hippocampal formation of
the control subject (A, black arrow), with the absence
of hippocampal tissue in E. P.'s ventricles (B,
C). The damaged portion of E. P.'s anterior temporal
lobes is indicated with white arrows in B
and C. Scale bars: A, 2 cm;
B, 2 cm (also applies to C).
|
|
View larger version (318K):
[in this window]
[in a new window]
|
Figure 5.
Five T1-weighted coronal images through the
temporal lobes of E. P. are presented from rostral
(A) to caudal (E). Coronal
images from the same 74-year-old control shown in Figure 4 are
presented in panels F-J. Damaged tissue in E. P. is indicated by dark signal. Images for E. P. were selected at
4-6 mm intervals, and images from the control brain were selected to
match as closely as possible the levels illustrated for E. P. Images are oriented as in Figure 1. Scale bar: A, 2 cm
(applies to all panels). In A and
B, the amygdala, rostral hippocampus, parahippocampal
gyrus (comprising the entorhinal and perirhinal cortices at this
level), and the fusiform gyrus are extensively damaged bilaterally. In
C, the temporal horns of the lateral ventricles are
grossly dilated, and nothing remains of the intraventricular portion of
the hippocampal formation except perhaps a thin remnant of tissue
bilaterally. The damage to the fusiform gyrus can be seen on both
sides, although the damage appears less severe on the left. The
entorhinal and perirhinal cortices are severely compromised
bilaterally. In D, the temporal horns remain enlarged
bilaterally, and only a tag of tissue is present within the ventricles.
The appearance of the fusiform gyrus is improved on the left side,
although the medially adjacent parahippocampal gyrus is damaged and
severely atrophic bilaterally. In E, the hippocampus
continues to be severely compromised bilaterally. The right temporal
cortex is more atrophic than the left, although an abnormal (dark)
signal is present in the parahippocampal gyrus (comprising the
parahippocampal cortex at this level) on the left. The left fusiform
gyrus appears to be intact. A, Amygdala;
cs, collateral sulcus; EC, entorhinal
cortex; fg, fusiform gyrus; H,
hippocampus; PR, perirhinal cortex; PH,
parahippocampal cortex; V, ventricle. Figure
continues.
|
|
There is some white matter damage in E. P.'s brain, visible as
significant hyperintensity on T2-weighted images. The abnormalities are
apparent in the external capsule, in the white matter deep to the
insula, the corona radiata, and in periventricular regions. It is not
clear whether this fiber damage is directly related to the encephalitis
or whether it represents premorbid leukoencephalopathy (white matter
disease), or both. In the temporal lobe, the subcortical lesions invade
portions of the laterally adjacent white matter, at the level of the
amygdala and the rostral hippocampus. This damage may likely encroach
on a portion of an area referred to as the temporal stem, a somewhat
vaguely defined fiber bundle that contains afferent and efferent
connections of the temporal cortex and amygdala.
There is also notable volume loss in some regions of E. P.'s
brain, as indicated by the presence of prominent sulci. In particular, the Sylvian fissures are enlarged in the anterior region of the temporal lobes (Fig. 5A-E). The atrophy is more prominent
in the cerebral hemispheres than in the brainstem or cerebellum.
Additionally, the temporal lobes appear disproportionately shrunken
when compared to other cortical regions, and this volume loss appears
to be associated with the focal brain damage in the temporal lobes. The
volume of E. P.'s frontal lobes, occipital lobes, right parietal lobe, and ventricles are comparable in volume to the control brains, whereas his insula, lateral temporal lobes, and left parietal lobe are
reduced in volume (Table 1).
There are no other gross abnormalities in E. P.'s brain, with the
exception of a small area of abnormal signal intensity in the vicinity
of the caudal medulla, which is unlikely to be related to his encephalitis.
Temporal lobe findings
Starting at the temporal poles, there is extensive bilateral
damage to the medial temporal lobe, which at this level includes the
polar portion of the perirhinal cortex. The abnormal tissue appears
dark on the T1-weighted images (Figs. 2, 5). Lateral aspects of the
cortex, including the inferior, middle, and superior temporal gyri, are
intact. The damage continues caudally to include all of the amygdala,
all of the entorhinal cortex, and all of the perirhinal cortex,
bilaterally. At the level of the amygdala, the cortical damage extends
lateral to the parahippocampal gyrus to include the fusiform gyrus,
bilaterally. This pattern remains constant through the caudal amygdala
and rostral hippocampus (4-5 cm from the temporal pole), where the
damage on the left becomes more localized to the medially situated
parahippocampal cortex. Here, the left collateral sulcus is visible for
the first time, and the signal within the left fusiform gyrus becomes
less abnormal. The left parahippocampal cortex continues to be severely
atrophic (with hypointense signal) for ~1.0 cm further caudally, at
which point it develops a more normal appearance. On the right side, the cortical damage extends further caudally than on the left. Damage
to the right fusiform gyrus continues to ~5.0 cm from the temporal
pole. Additionally, damage to the right parahippocampal cortex
continues for ~1.0 cm beyond the caudal limit of the right fusiform damage.
The temporal horns of the lateral ventricles are grossly enlarged at
the most rostral aspect of the hippocampus (Fig. 5C). Within
the ventricles, nothing remains of the hippocampus except a small tag
of vestigial tissue on each side (Fig. 5C-E). The total
volume of this tissue remnant is ~10% of the average volume of the
hippocampus of the three control brains that were analyzed (0.28 vs
2.64 cm3). The abnormal appearance of this
tissue and the absence of the entorhinal cortex (which originates the
major cortical afferents of the hippocampus) make it quite unlikely
that the remnant tissue is functional.
We also quantified the amount of intact cortical tissue in the
parahippocampal cortex and the fusiform gyrus, which sustained incomplete damage. These results are described below.
Summary for parahippocampal cortex. There is bilateral
damage to the anterior portion of the parahippocampal cortex, which is
more extensive on the right side than on the left (Fig. 5E). On the left, the damage includes the rostral 5 mm of the
parahippocampal cortex (18%), and on the right the damage includes the
rostral 1.6 cm (57%) of the parahippocampal cortex.
Summary for fusiform gyrus. There is bilateral damage to the
anterior portion of the fusiform gyrus, which is more extensive on the
right side than on the left side (Fig. 5A-D). On the left, the damage includes the rostral 4 cm of the fusiform gyrus (40% damage). On the right, the damage includes the rostral 5 cm of the
fusiform gyrus (53% damage).
Cortical atrophy (Table 1)
Inferior, middle, and superior temporal gyri. E. P.'s lateral temporal lobes (inferior, middle, and superior temporal
gyri) are smaller than the lateral temporal lobes of the three control brains. The average volume for E. P.'s right and left lateral temporal lobes (52 cm3) falls outside the
95% confidence interval of the control volume (mean volume, 64 cm3; range, 61-66).
Frontal lobes. E. P.'s frontal lobe volume is
comparable to the frontal lobe volume of the three controls. The
average volume for E. P.'s right and left frontal lobes (156 cm3) is well within the range of control
values (mean volume, 153 cm3; range,
145-167 cm3).
Parietal lobes. E. P.'s parietal lobe volume is
smaller than the parietal lobe volume of the control brains. The
average volume for E. P.'s right and left parietal lobes (144 cm3) falls outside the 95% confidence
interval of the control volume (mean volume, 180 cm3, range 169-190
cm3). However, E. P.'s right
parietal lobe volume is within the control range.
Occipital lobes. E. P.'s occipital lobe volume is also
comparable to the occipital lobe volume of the three
controls. The average volume for E. P.'s right and left occipital
lobes (81 cm3) is well within the range of
control values (mean volume, 77 cm3;
range, 57.0-88 cm3).
Insula. E. P.'s insula is smaller bilaterally than the
insula of the control subjects. The average area for E. P.'s
right and left insula (13.8 cm2) is
outside the 95% confidence interval of the control area (mean area,
15.8 cm2; range = 15.6-16.0
cm2).
Ventricles. As noted above, the temporal horns of E. P.'s lateral ventricles are grossly enlarged. The remaining portions of E. P.'s lateral ventricles and his third ventricle have a
total volume of 26.3 cm3, which falls
within the 95% confidence interval of the control volume (mean volume,
47 cm3; range, 33-71
cm3).
Neuropsychological findings
Intellectual function
In 1994, E. P. obtained a full-scale IQ score of 103 on a
standard test of intellectual function [Weschler Adult Intelligence Scale-Revised (WAIS-R)]. His performance was low on two
subtests (WAIS-R: information, 17; vocabulary, 33; E. P.'s four
controls averaged 23 and 56, respectively), consistent with his mild
impairment on tests of semantic knowledge (see below). E. P.'s
performance on standard tests of intellectual function has remained
stable during the 6 years that he has been tested in our laboratory. E. P.'s premorbid reading ability, measured by the Wide Range Achievement test (WRAT 3), was estimated to be at the 12th grade level,
consistent with his education. Finally, E. P. obtained a total
score of 118 (81.9%) on the Dementia Rating Scale (DRS; Mattis, 1976),
with most points lost on the memory subportion of the test (15 points
lost). Eleven normal controls (mean age, 60.8 years) averaged 139.7 (97%) on this same test (Janowsky et al., 1989).
Immediate memory
Like other amnesic patients (Baddeley and Warrington, 1970; Cave
and Squire, 1992), E. P.'s immediate memory is intact as measured
by digit span. The digit span test, which was given to E. P. on 12 occasions, was taken from the forward digit span subtests of the WAIS-R
(given nine times), the Wechsler Memory Scale-Revised (WMS-R)
(given twice), and the WAIS-III (given once). E. P.'s average
forward digit span was 6.6 (range, 5-8), which was within the range of
scores obtained by the four healthy control subjects (mean digit span
of controls, 7.3; range, 4-9). In addition, E. P.'s digit span
performance was comparable to the performance of six amnesic patients
with confirmed or suspected damage to the hippocampal formation (mean
digit span, 6.8; Cave and Squire, 1992), and comparable to the
performance of the densely amnesic patient H. M., who obtained a
digit span of 6.0 on the WMS-R (Keane et al., 1995).
The Spatial Span task from the WMS-III provides a nonverbal measure of
immediate memory. The experimenter points to a series of blocks on a
three-dimensional board, and the participant must then point to the
same blocks in the same order. E. P. and his four controls were
given the spatial span task on four different occasions. E. P. had
an average spatial span of 5.5 blocks (range, 4-6), and the controls
had an average spatial span of 5.9 blocks (range, 4-7).
Declarative memory
Despite E. P.'s intact performance on tests of immediate
memory, his declarative memory is profoundly impaired, as documented by
every test of delayed recall and recognition that he has ever been
given (Squire and Knowlton, 1995; Hamann et al., 1997; Hamann and
Squire, 1997; Reed et al., 1997; Reber and Squire, 1998; Buffalo et
al., 1998; Teng and Squire, 1999; Stark and Squire, 2000). E. P. obtained scores of 94, 57, 82, 61, and 56 on the five indices of the
WMS-R (attention-concentration, verbal memory, nonverbal memory,
general memory, and delayed memory). These five indices yield means of
100 in the normal population (SD, 15). Table
2 and Figure
6 show a sample of E. P.'s
performance on other memory tests. He exhibited no capacity for
declarative memory on any of the tests. E. P.'s severe memory
impairment is particularly well illustrated by his poor performance on
tests of recognition memory (Fig. 7). In
two different studies (Hamann and Squire, 1997; Stark and Squire,
2000), E. P. saw 20 or 24 words and after a 5 or 10 min delay was
given a test of either yes-no recognition or forced-choice
recognition. A total of 42 such tests were given, and his average score
across all tests was 49.3% correct. That is, he performed at chance
levels.
View larger version (18K):
[in this window]
[in a new window]
|
Figure 6.
The Rey-Osterrieth figure. Subjects are asked to
copy the figure illustrated in the small box in the
left panel and, 10-15 min later, to reproduce it from
memory. The copy (top) and reproduction
(bottom) for E. P., for amnesic patient L. M. (Rempel-Clower et al., 1996) and for a representative control
are shown in the larger panels at right. E. P. did not recall copying the figure. Encouraged to draw whatever came
to mind, he declined to try.
|
|
View larger version (13K):
[in this window]
[in a new window]
|
Figure 7.
E. P.'s average performance on 42 different
tests of recognition memory for words (Hamann and Squire, 1997, 12 tests; Stark and Squire, 2000, 30 tests). Half of the tests were
two-alternative forced choice, and half were yes-no recognition. The
same five healthy control subjects took all 42 tests.
Brackets for E. P. indicate the SEM. The data
points for the control group (CON) indicate each
participant's mean score across all 42 recognition memory tests.
E. P.'s average performance (49.3% correct) was >5 SDs below
the average performance of control subjects (81.1% correct; SD, 6.3)
and not different from chance.
|
|
E. P. moved to his present home in 1993, after he became amnesic.
A final example of E. P.'s anterograde memory impairment is his
inability to describe how he would travel from his home to locations in
his neighborhood that he visits with his wife (e.g., the supermarket,
the post office; Teng and Squire, 1999). Moreover, in 1999, he was
unable to draw a floor plan of his present home. Finally, although he
lives <2 miles from the Pacific Ocean, he cannot when asked point in
the direction of the ocean.
Unlike other amnesic patients, including patient H. M. (Freed et
al., 1987), E. P.'s recognition memory performance did not benefit by extended exposure to study items (Reed et al., 1997). On
three separate occasions, E. P. viewed 40 pictures for either 0.2 sec each (short exposure) or 20 sec each (extended exposure), and 10 min later took a yes-no recognition memory test. He was not able to
recognize the pictures after seeing them in the extended exposure
condition, and he obtained an average score of 50.6% correct across
the three tests. In contrast to E. P., H. M. benefited from
extended study time (H. M.'s average score across four tests, 78.8%; Freed et al., 1987). The procedures for the tests given to
E. P. and H. M. were the same, with the exception that
E. P. was presented with a shorter list of pictures (EP, 40;
H. M., 120). E. P.'s recognition memory performance was
similarly poor when he was tested in a two-alternative, forced-choice
format, and when the tests involved shorter lists of to-be-remembered items, increased study time, or increased numbers of exposures to each item.
Retrograde memory
Patient E. P. has severe and extensive retrograde amnesia for
facts and events but is capable of retrieving memories from his early
life. For example, he is extremely impaired on tests of recall and
recognition for public events, famous faces, and famous names that came
into the news after 1950. His performance is somewhat better, however,
when the tests involve subject matter that came into the news before
1950 (Reed and Squire, 1998).
E. P.'s performance on the Autobiographical Memory Interview
(AMI) (Kopelman et al., 1989) provides a particularly striking illustration of his retrograde amnesia (Fig.
8). The AMI is a structured interview
that asks for detailed information about three periods of life (i.e.,
childhood, early adult life, and recent life). Within each of these
periods E. P.'s memory was tested for both personal semantic
knowledge (e.g., What was your home address while attending high
school?) and autobiographical memory (e.g., Describe an incident that
occurred while you were attending elementary school). The accuracy of
all his responses was corroborated by at least two family members.
View larger version (23K):
[in this window]
[in a new window]
|
Figure 8.
Performance of E. P. (open
bars) and controls (black bars,
n = 4) on the AMI (Kopelman et al., 1989; scores
from Reed and Squire, 1998). A, Scores for items that
assessed memory for personal semantic knowledge (maximum, 21 for each
time period). B, Scores for items that assessed memory for
autobiographical memory (maximum, 9 for each time period). Test items
associated with the recent time period assessed memory for information
that could have been acquired only subsequent to the onset of his
amnesia. The scores from the other two periods reflect retrograde
memory function. For controls, brackets indicate the
SEM.
|
|
For the recent time period, E. P. performed extremely poorly. He
did better at answering questions about his early adult life, but his
scores were still below (personal semantic memory) or at the low end of
the range (autobiographical memory) of the control scores. In contrast,
E. P. performed normally when answering questions about his
childhood, scoring nearly as high as the highest-scoring control subjects.
Another striking example of E. P.'s capacity to recall memories
from his early life comes from tests of his spatial knowledge about the
town in which he grew up (Fig. 9; Teng
and Squire, 1999). E. P. was asked to describe how he would
navigate from his home to different locations in the area (familiar
navigation), between different locations in the area (novel
navigation), and between these same locations if a main street were
blocked off (alternative routes). He was also asked to imagine himself
in a particular orientation at certain locations and then to point
toward specific landmarks (pointing to landmarks). On all tests, his
performance was comparable to the performance of five individuals who
attended E. P.'s high school at the same time as he did, lived in
the region for about as long as he did, and, like E. P., moved
away from the area as young adults.
View larger version (13K):
[in this window]
[in a new window]
|
Figure 9.
Performance on four tasks of topographical memory
(Teng and Squire, 1999). Open circles show the scores of
five control subjects. Filled circles show E. P.'s
average score for two different testing sessions. A,
Percent correct score on three verbal navigation tasks that required
negotiating either familiar routes, novel routes, or alternative routes
(when the most direct route was blocked). B, Median
error in degrees on a task in which subjects pointed to particular
locations while imagining themselves oriented at other locations in the
neighborhood.
|
|
Nondeclarative memory
Patient E. P.'s nondeclarative memory is intact as measured
by several tests, including perceptual priming (word-stem completion and perceptual identification; Hamann and Squire, 1997, Stark and
Squire, 2000), learning of a visuomotor skill (Reber and Squire, 1998),
and learning of category prototypes (Squire and Knowlton, 1995). In
word-stem completion priming (Hamann and Squire, 1997; Fig.
10a), E. P. first saw
24 words. Then, after a 5 min delay, he saw 48 three-letter word stems
(e.g., MOT) and was asked to complete each stem to form the first
English word that came to mind. Twenty-four stems corresponded to study
list words, and the remaining 24 stems corresponded to words that had
not been studied (baseline items). On six separate tests, E. P. tended to complete word stems with words he had read earlier and
exhibited this effect to the same extent as controls. Similarly, he
performed like controls on 12 separate tests of perceptual
identification priming (Fig. 10b). Specifically, when asked
to identify 48 briefly flashed words, he identified successfully the
words that he had read earlier much more frequently than newly
presented words.
View larger version (16K):
[in this window]
[in a new window]
|
Figure 10.
A, Stem-completion priming. Six
tests were given to patient E. P. and normal controls
(CON; n = 7). Priming scores were
calculated as percent correct for studied items minus percent correct
for baseline items. B, Perceptual identification
priming. Twelve tests were given to patient E. P. and controls
(CON; n = 7). Priming scores were
calculated as percent correct identification of studied items minus
percent correct identification of nonstudied items.
Brackets for E. P. indicate the SEM. The data
points for the CON group indicate means of individual subjects across
all the tests (Hamann and Squire, 1997).
|
|
E. P. also learned a visuomotor skill (the serial reaction task)
at the same rate as controls (Reber and Squire, 1998). In this task, a
cue (an asterisk) was presented on a computer screen in any of four
possible locations. A response key was located directly below each cue
location. E. P. was asked to respond to the cue as rapidly as
possible by pressing the key beneath the cue. A correct keypress caused
the cue to disappear and then reappear in a new location after a 250 msec delay. The task was administered in 60-trial blocks, and each
block contained five repetitions of a 12-location sequence. Across a
20-block session (1200 trials), E. P.'s reaction time for making
keypresses gradually decreased at the same rate as control subjects.
We have also noted at least two ways in which E. P.'s behavior
has changed during the time that we have known him, both of which may
be attributable to his capacity for nondeclarative memory. The first
example concerns his reactions to his testers. During the first 2 or 3 years in which we visited his house, he was wary and slow to accept the
idea that we wished to talk to him and administer tests. After some
conversation, and with encouragement from his wife, E. P. would
after a number of minutes seat himself at a table for testing. During
the subsequent years, the same tester has visited his house more than
150 times. Now, when she arrives he greets her in a friendly manner and
moves readily and promptly to the testing table even when his wife is
not present. Yet, his pattern of greeting and acceptance occurs without
any recognition of who the tester is, and he will repeatedly deny that
he has seen her before.
The second example concerns E. P.'s reactions to the test
materials. One particular test, which E. P. has worked on more
than 90 times over the course of several years, requires him to use the
eraser-end of a pencil to touch a computer screen. After approximately 50 repetitions of this test procedure, E. P. began regularly to pick up the pencil and orient the eraser-end toward the computer screen
before he was told even that he was to use a pencil in the test. Yet,
E. P. always denies that he has taken the test before and
disclaims any sense of familiarity toward it.
We take these examples of behavioral change to be instances of habit
learning, which E. P. has acquired gradually and which has allowed
him to modify his behavior in response to regularities in his environment.
Frontal lobe function
Dementia rating scale (DRS). The initiation and
perseveration subscale of the DRS is sensitive to frontal lobe damage
(Janowsky et al., 1989). E. P.'s score on this subscale was
comparable to the score of control subjects [E. P.'s score, 36 (97.3%); control score, 36.5 (98.7%), range, 33-37]. He performed
better than amnesic patients with alcoholic Korsakoff's syndrome, who
have both diencephalic lesions and frontal lobe atrophy (mean, 88%;
range, 78-97%) and better than patients with left or bilateral
frontal lobe lesions (mean, 78%; range, 70-86%; Janowsky et al.,
1989).
WMS-R. Like other amnesic patients (Janowsky et al., 1989),
E. P. scored well on the attention-concentration index (E. P., 94; 12 other amnesic patients, 96.8) and low on the delayed memory index (E. P., 56; other amnesic patients, 56). In contrast,
patients with frontal lobe lesions scored low on the
attention-concentration index and better on the delayed memory index
(attention-concentration, 83.3 vs delayed memory, 94.5;
n = 7; Janowsky et al., 1989).
Wisconsin card-sorting task. E. P. was given the
Wisconsin Card Sorting Test (WCST) in 1994 and again in 1998. On both
occasions he was unable to sort any categories, and he committed 50.8 and 73.4% perseverative errors, respectively. Although this test is often considered to be diagnostic of frontal lobe dysfunction, Anderson
et al. (1991) found no consistent relationship between poor WCST
performance and structural damage to the frontal lobes in 91 patients
with focal brain lesions resulting from cerebrovascular accident
(n = 71) or from neurosurgical resection for treatment of a tumor or seizures (n = 20). Likewise, Teuber et
al. (1951) found no differences in card-sorting ability among 131 World
War II veterans with brain lesions caused by either frontal, posterior, or intermediate battle wounds.
Semantic knowledge
Naming objects. We tested E. P.'s naming ability
in several ways. On four separate administrations of the standard,
60-item version of the Boston Naming Test (Kaplan et al., 1983),
E. P. named an average of 41.3 items correctly (68.8%; range,
65-73%; four controls = 54.5 items; 90.8% correct; range,
86.7-95.0%; Reed and Squire, 1998). His performance improved on a
four-alternative, multiple-choice version of the Boston Naming Test,
but he still scored lower than controls (E. P., 93.3%; controls,
99.7%, range, 98.3-100%; Reed and Squire, 1998). We also gave
E. P. the same 84-item version of the Boston Naming Test that had
been given to patient H. M. E. P. scored 63% correct,
H. M. scored 83% correct, and E. P.'s controls scored
87.3% correct (range, 83-91%) (S. Corkin, personal
communication; Kensinger et al., 1999).
Word and category fluency. The FAS Test asks subjects
to provide as many words as possible in 1 min beginning with the letter F (then A, then S; Lezak, 1976). The category fluency test asks subjects to provide as many words as possible in 1 min that belong to
the category "animal" (then "fruits", then "vegetables";
Monsch et al., 1992). On both tests, E. P. produced fewer items
than controls. On the FAS test, he produced 18 words plus four
perseverative errors, whereas controls produced an average of 42 words
plus two perseverative errors (range, 30-53 words; 0-5 perseverative errors). He performed better on the category test (33 words produced, 7 perseverative errors) but still scored outside the range of the
controls (mean = 38.8 words, 1.5 perseverative errors; range, 37-44, 0-4 perseverative errors).
Detecting and explaining ambiguity in sentences. E. P. was given a series of 65 ambiguous sentences (e.g., "He looked over the old stone wall"), together with 25 unambiguous sentences
(Schmolck et al., 2000a). Whereas eleven controls detected correctly
78.6% of the ambiguous sentences (range, 54.0-96.9%), E. P. was
successful for only 31%. Patient H. M., who was tested earlier on
the same task, obtained a similar score (33.8%; Lackner, 1974).
Controls could explain spontaneously 68.5% of the ambiguous sentences
(range, 35.4-87.7%), whereas E. P. could explain 41.5%, and
H. M. could explain 37.5% (MacKay et al., 1998).
Other tests of semantic knowledge. We tested E. P. and
his four controls on four tasks of semantic knowledge (for the first three tasks, see Hodges et al., 1992; Hodges and Patterson, 1995). The
first test presented verbal descriptions of each of 48 items and asked
participants to name the item [naming (cue: description)]. The second
test presented the name of each item, together with its picture and
seven other pictures from the same category. Participants were asked to
point to the appropriate picture [pointing to picture (cue: name)].
The third test (semantic features) consisted of eight yes-no questions
about each item (e.g., "Does an elephant lay eggs?"). The fourth
test presented verbal descriptions of each item, together with its
picture and seven other pictures from the same category, and asked
participants to point to the appropriate item [pointing to picture
(cue: description)]. Across all four tasks, E. P. was mildly
impaired (Fig. 11). For example, on the
naming task, he correctly named 37 of 48 items (control range, 42-47
items correctly named). On the pointing to picture tasks, he correctly
pointed to 43 of 48 items (cue:name; control range, 47-48 items
correct) and 41 of 48 items (cue:description; all controls correctly
pointed to 48 items). On the semantic features task, E. P. answered all the questions correctly for six of 24 total items
presented (control range, all questions answered correctly for 8-18
items).
View larger version (54K):
[in this window]
[in a new window]
|
Figure 11.
Performance of four control subjects
(gray bars) and E. P. (open
bars) on four tests of semantic knowledge. The filled
circles show individual scores of the controls for each
test.
|
|
Using other tests of semantic knowledge, we also compared E. P.'s performance to the performance of patient D. M., whose
semantic dementia has been extensively documented (Breedin et al.,
1994; Srinivas et al., 1997). Like E. P., D. M. has
radiologically confirmed damage to the anterior inferior temporal
lobes, but D. M.'s damage includes more lateral temporal cortex
than is damaged in E. P. E. P. performed normally on
tests that D. M. performed poorly. One task required that real
objects be discriminated from nonobjects (created by combining parts of
real objects, such as a violin with a duck's head; Breedin et al.,
1994; Riddoch and Humphreys, 1997). E. P. made one incorrect
judgment of 60 trials, for a score of 98.3% correct. (E. P.'s
four controls scored 95.8%, range, 93.3-98.3; D. M., 78.3%). In
a second task, E. P. was presented with 60 objects and asked if
the objects were larger or smaller than a typical chair. E. P. scored 100% correct (control average, 99.2%; range, 98.3-100%;
D. M., 78.3%). E. P. also judged the typical weight of
objects normally, scoring 96.7% (control average, 95.8%; range,
93.3-100%; D. M., 88.3%).
| |
DISCUSSION |
Summary
Patient E. P. has extensive, bilateral damage to the medial
temporal lobe, including the amygdala, the hippocampus, the entorhinal and perirhinal cortices, and the rostral parahippocampal cortex. He
also has damage to the rostral fusiform gyrus, bilaterally. In addition
to these lesions, the cortical volume of the insula, lateral temporal
lobes, and left parietal lobe is reduced.
E. P. has normal or near-normal intellectual functions as measured
by standard tests. His immediate memory and nondeclarative memory are
intact. In contrast, he has profound anterograde amnesia and is
impaired on a wide variety of verbal and nonverbal tests of recall and
recognition. He also has severe and extensive retrograde amnesia for
facts and events, personal semantic knowledge, and autobiographical memory, but he appears fully capable of retrieving memories acquired in his early life, including detailed spatial memories of his childhood neighborhood. Finally, he is mildly impaired
on tests of semantic knowledge, including tests of object naming, tests
involving the detection and explanation of ambiguous sentences, and
tests that asked about the features of common objects.
Comparison with patient H. M.
Damage to the medial temporal lobe
Corkin et al. (1997) recently described H. M.'s surgical
lesion in considerable detail using MRI. These findings, compared with
the findings for E. P. presented here, indicate that E. P.'s medial temporal lobe lesion is more extensive than H. M.'s,
particularly with regard to the perirhinal cortex, the parahippocampal
cortex, and hippocampus (Fig. 1).
With respect to the perirhinal cortex, E. P. sustained complete
damage bilaterally, whereas H. M. has some sparing of its ventrocaudal aspect. With respect to the parahippocampal cortex, the
damage in E. P. includes the rostral 18% on the left side and the
rostral 57% on the right side, whereas this region is almost
completely spared bilaterally in H. M. With respect to the
hippocampus, we identified in E. P. a tag of severely atrophic tissue within the temporal horn of the lateral ventricle bilaterally, and the volume of this tissue remnant is ~10% of the average volume of the hippocampus of control brains. In H. M., the posterior portion of the hippocampus (~50% of the normal intraventricular extent) is present, although the tissue appears to be "somewhat atrophic bilaterally" (Corkin et al., 1997, page 3976). Both patients sustained similar (i.e., virtually complete) damage to the entorhinal cortex and the amygdaloid complex.
At the level of the rostral hippocampus, E. P.'s temporal white
matter damage may invade a portion of his temporal stem. The "temporal stem" hypothesis of medial temporal lobe amnesia (Horel, 1978) proposes that bilateral temporal stem damage is crucial to memory
impairment. However, it is unlikely that the minor damage to this
massive fiber bundle present in E. P. is sufficient to produce the
devastating amnesic syndrome that we have observed. Moreover, patient
H. M. has profound amnesia, but H. M. has no temporal stem
damage (Corkin et al., 1997). Thus, the findings from E. P. and
H. M. provide no support for the temporal stem hypothesis of
medial temporal lobe amnesia.
Damage outside of the medial temporal lobe
In the temporal lobe, E. P.'s lesion extends laterally to
involve the fusiform gyrus, bilaterally. In addition, there is some cortical volume loss in the inferior, middle, and superior temporal gyri, particularly on the right side. H. M.'s lesion does not involve the fusiform gyrus, but there is damage at the temporal pole
that involves the middle and superior temporal gyri (Fig. 1; also see
Corkin et al., 1997, their Figs. 2K, 4C,D, pages
3967 and 3970). In addition, in H. M. "the subcortical
white matter associated with the anterior portions of the superior,
middle, and inferior temporal gyri may also have been compromised by
the resection" (page 3975).
There is also some cortical volume loss in E. P.'s insula and
left parietal lobe. Whereas Corkin et al. (1997) did not perform volumetric measurements of H. M.'s cortex, they did compare his brain with an age-matched control brain and reported slight neocortical atrophy in H. M. that was judged to be consistent with his age. Finally, H. M. has marked atrophy of his cerebellum (vermis and hemispheres) that is not present in E. P.
Neuropsychology
In many ways, E. P. and H. M. have strikingly similar
neuropsychological profiles. They have similar intellectual function (E. P.'s full scale WAIS-R IQ, 103; H. M.'s WAIS-R IQ in
1997, 101; Corkin, personal communication). They also have comparable scores on the information and vocabulary subtests of the WAIS-R (E. P., 17 and 33, respectively; in 1997 H. M. scored 18 and
39, respectively; Corkin, personal communication). They both perform normally on tests of immediate memory (for H. M., see Keane et al., 1995). Additionally, both patients have intact nondeclarative memory, as measured by perceptual priming tasks (for H. M.,
word-stem completion, Gabrieli et al., 1994; perceptual identification, Keane et al., 1995), and skill learning tasks (for H. M., Parsons et al., 1988). The fact that E. P. and H. M. perform normally on a wide range of cognitive tasks is consistent with the circumscribed nature of their brain lesions, which in both cases are largely restricted to the medial temporal lobe.
Both E. P. and H. M. have profoundly impaired anterograde memory (Table
3). Nevertheless, on tests of recognition
memory that used the same procedures, H. M. benefited from
extended study time (Freed et al., 1987), whereas E. P. did not
(Reed et al., 1997). E. P. has more extensive medial temporal lobe
damage than H. M., and this more extensive damage may account for
E. P.'s poorer anterograde memory performance on these tests.
With regard to retrograde memory, E. P. and H. M. both have
access to early memories. E. P.'s retrograde amnesia covers
~40-50 years before the onset of his encephalitis. Whereas H. M.'s retrograde amnesia has been described as covering only 11 years
before his surgery (Corkin, 1984), 11 years of retrograde amnesia would
for H. M. extend back to age 16. Note that E. P., who became
amnesic at the age of 70, can also retrieve memories from before the
age of 16 (Reed and Squire, 1998; Teng and Squire, 1999). Perhaps if
H. M. had become amnesic in middle age, he also would have exhibited more extensive retrograde amnesia.
E. P. is mildly but unequivocally impaired on some tests of
semantic knowledge, including tests of object naming and tests involving the detection and explanation of ambiguous sentences. H. M. is also impaired on tests of ambiguous sentences (Lackner, 1974;
MacKay et al., 1998), but his naming ability (which falls within 1 SD
of the mean of his control group tested at MIT), is superior to E. P.'s (Corkin, personal communication; Kensinger et al., 1999). What
damage might account for E. P.'s impairment in semantic
knowledge? We suggest that damage to the lateral temporal lobes, and in
particular damage to the fusiform gyrus, is responsible for E. P.'s impairment. Damage to anterior lateral inferotemporal cortex,
including the fusiform gyrus, has been reported to produce the kinds of
semantic deficits that we observed in E. P. (Hodges et al., 1992;
Garrard et al., 1997; Srinivas et al., 1997). Note also that patient
D. M., and other patients with extensive lateral temporal lobe
damage, perform more poorly than E. P. on tests of semantic
knowledge. Finally, the idea that the fusiform gyrus itself is
important for semantic knowledge is supported by imaging studies
demonstrating activation of the fusiform gyrus during object naming and
during other tasks that depend on semantic knowledge (Moore et al.,
1996; Vandenberghe et al., 1996; Henry et al., 1998; Moore and Price,
1999).
H. M. does not have damage to the fusiform gyrus and is better
than E. P. at confrontational naming. H. M. does, however, have difficulty with ambiguous sentences, which could be attributable to the damage he has to the lateral aspect of the temporal pole. Yet,
H. M. also exhibits difficulties on language tests that E. P. does not exhibit (Schmolck et al., 2000a,b). For example, on a test
that asked patients to provide definitions of common items, H. M. exhibited many grammatical and linguistic errors, whereas E. P. and other patients with more extensive medial and lateral temporal lobe
damage performed like controls. It is also true that H. M.'s
seizures began at age 10, and his education was interrupted at age 16 (he received a high school diploma at age 21). Accordingly, it is
possible that H. M. did not develop fully normal language abilities. In any case, his language shortcomings appear to be unrelated to his temporal lobe pathology.
In summary, E. P. has profound and relatively circumscribed
amnesia as the result of viral encephalitis that damaged his medial temporal lobe, bilaterally. There are striking similarities between E. P. and the surgical patient H. M., both with respect to
the neuroanatomy of their lesions and their cognitive
neuropsychological profiles. For more than 40 years, neuropsychological
studies of memory have depended crucially on the ideas and the findings
derived from a single, well studied patient (H. M.). E. P. provides a second example, based on a different etiology, of profound
memory impairment after medial temporal lobe damage. The detailed
neuroanatomical and neuropsychological information obtained from
E. P. is useful in three respects. First, the findings from
E. P. largely confirm what has been learned from H. M. about
the importance of the medial temporal lobe for memory. Second, E. P.'s difficulties on some tests of semantic knowledge suggest the
importance of lateral temporal cortex, including the fusiform gyrus,
for performance on these tests. Third, it has been difficult to know
which features of H. M.'s performance are central to his memory
impairment and which features are unrelated. The findings from E. P. suggest that H. M.'s difficulties with language expression are
unrelated either to his memory impairment or his temporal lobe pathology.
| |
FOOTNOTES |
Received May 5, 2000; revised June 19, 2000; accepted June 26, 2000.
This research was supported by the National Institute of Mental Health
(NIMH) (5 T32 MH18399, MH24600, and 2T32AG00216), the Medical Research
Service of the Department of Veterans Affairs, the McDonnell-Pew Center
for Cognitive Neuroscience at San Diego, the National Alliance for
Research on Schizophrenia and Depression, and the Metropolitan Life
Foundation. E.A.B. is now at the Laboratory of Neuropsychology, NIMH
(Bethesda, MD). We thank D. Amaral, D. Delis, J. Frascino, J. Hodges,
T. Jernigan, M. Kritchevsky, C. F. Notestine, G. Press, C. Stark,
S. Zola, and J. Zouzounis for assistance, and S. Corkin and E. Kensinger for discussions about patient H. M.
Correspondence should be addressed to Larry Squire, Department of
Psychiatry, 0603, University of California at San Diego, La
Jolla, CA 92093. E-mail: lsquire{at}ucsd.edu.
| |
REFERENCES |
-
Amaral DG,
Insausti R
(1990)
Hippocampal formation.
In: The human nervous system (Paxinos G,
ed). San Diego: Academic.
-
Anderson SW,
Damasio H,
Jones RD,
Tranel D
(1991)
Wisconsin card- sorting test performance as a measure of frontal lobe damage.
J Clin Exp Neuropsychol
13:909-922[Web of Science][Medline].
-
Baddeley AD,
Warrington EK
(1970)
Amnesia and the distinction between long- and short-term memory.
J Verb Learning Verb Behav
9:176-189.
-
Baddeley AD,
Wilson BA,
Watts FN
(1995)
In: Handbook of memory disorders. Chichester, NY: Wiley.
-
Breedin SD,
Saffran EM,
Coslett HB
(1994)
Reversal of the concreteness effect in a patient with semantic dementia.
Cognit Neuropsychol
11:617-660.
-
Buffalo EA,
Reber PJ,
Squire LR
(1998)
The human perirhinal cortex and recognition memory.
Hippocampus
8:330-339[Web of Science][Medline].
-
Butters N,
Cermak L
(1980)
In: Alcoholic Korsakoff's syndrome. An information processing approach to amnesia. New York: Academic.
-
Cave CB,
Squire LR
(1992)
Intact verbal and nonverbal short-term memory following damage to the human hippocampus.
Hippocampus
2:151-163[Web of Science][Medline].
-
Cermak LS
(1976)
The encoding capacity of a patient with amnesia due to encephalitis.
Neuropsychologia
14:311-326[Web of Science][Medline].
-
Corkin S
(1984)
Lasting consequences of bilateral medial temporal lobectomy: clinical course and experimental findings in H. M.
Semin Neurol
4:249-259[Web of Science].
-
Corkin S,
Amaral DG,
Gonzalez RG,
Johnson KA,
Hyman BT
(1997)
H. M.'s medial temporal lobe lesion: findings from magnetic resonance imaging.
J Neurosci
17:3964-3979[Abstract/Free Full Text].
-
Cox RW
(1996)
AFNI: software for analysis and visualization of functional magnetic resonance neuroimages.
Comput Biomed Res
29:162-173[Web of Science][Medline].
-
Damasio AR,
Eslinger PJ,
Damasio H,
Van Hoesen GW
(1985)
Multimodal amnesic syndrome following bilateral temporal and basal forebrain damage.
Arch Neurol
42:252-259[Abstract/Free Full Text].
-
Freed DM,
Corkin S,
Cohen NJ
(1987)
Forgetting in H. M.: a second look.
Neuropsychologia
25:461-471[Web of Science][Medline].
-
Gabrieli JDE,
Keane MM,
Stanger BZ,
Kjelgaard MM,
Corkin S,
Growdon JH
(1994)
Dissociations among structural-perceptual, lexical-semantic, and event-fact memory systems in Alzheimer, amnesic, and normal subjects.
Cortex
30:75-103[Web of Science][Medline].
-
Garrard P,
Perry R,
Hodges JR
(1997)
Disorders of semantic memory.
J Neurol Neurosurg Psychiatry
62:431-435[Free Full Text].
-
Hamann SB,
Squire LR
(1997)
Intact perceptual memory in the absence of conscious memory.
Behav Neurosci
111:850-854[Web of Science][Medline].
-
Hamann SB,
Cahill L,
Squire LR
(1997)
Emotional perception and memory in amnesia.
Neuropsychology
11:104-113[Web of Science][Medline].
-
Henry TR,
Buchtel HA,
Koeppe RA,
Pennell PB,
Kluin KJ,
Minoshima S
(1998)
Absence of normal activation of the left anterior fusiform gyrus during naming in left temporal lobe epilepsy.
Neurology
50:787-790[Abstract/Free Full Text].
-
Hodges JR,
Patterson K
(1995)
Is semantic memory consistently impaired early in the course of Alzheimer's disease? Neuroanatomical and diagnostic implications.
Neuropsychologia
33:441-459[Web of Science][Medline].
-
Hodges JR,
Salmon DP,
Butters N
(1992)
Semantic memory impairment in Alzheimer's disease: failure of access or degraded knowledge?
Neuropsychologia
30:301-314[Web of Science][Medline].
-
Horel JA
(1978)
The neuroanatomy of amnesia. A critique of the hippocampal memory hypothesis.
Brain
101:403-445[Free Full Text].
-
Janowsky JS,
Shimamura AP,
Kritchevsky M,
Squire LR
(1989)
Cognitive impairment following frontal lobe damage and its relevance to human amnesia.
Behav Neurosci
103:548-560[Web of Science][Medline].
-
Kaplan EF,
Goodglass H,
Weintraub S
(1983)
In: The Boston naming test. Philadelphia: Lea and Febiger.
-
Keane MM,
Gabrieli JDE,
Mapstone HC,
Johnson KA,
Corkin S
(1995)
Double dissociation of memory capacities after bilateral occipital-lobe or medial temporal-lobe lesions.
Brain
188:1129-1148.
-
Kensinger EA,
Ullman MT,
Locasio JJ,
Corkin S
(1999)
What is the relation between medial temporal lobe structures and lexical memory? Evidence from amnesic patient H.M.
Soc Neurosci Abstr
25:357.
-
Kopelman MD,
Wilson BA,
Baddeley AD
(1989)
The autobiographical memory interview: a new assessment of autobiographical and personal semantic memory in amnesic patients.
J Clin Exp Neuropsychol
5:724-744.
-
Lackner JR
(1974)
Observations on the speech processing capabilities of an amnesic patient: several aspects of H. M.'s language function.
Neuropsychologia
12:199-207[Web of Science][Medline].
-
Lezak MD
(1976)
In: Neuropsychological assessment. New York: Oxford UP.
-
MacKay DG,
Stewart R,
Burke DM
(1998)
H. M. revisited: relations between language comprehension, memory, and the hippocampal system.
J Cognit Neurosci
10:377-394[Web of Science][Medline].
-
Mattis S
(1976)
Dementia rating scale.
In: Geriatric psychiatry 1 (Bellack R,
Karasu B,
eds), pp 77-121. New York: Grune and Stratton.
-
Mayes
(1988)
In: Human organic memory disorders. Cambridge: Cambridge UP.
-
Milner B,
Squire LR,
Kandel ER
(1998)
Cognitive neuroscience and the study of memory.
Neuron
20:445-468[Web of Science][Medline].
-
Monsch AU,
Bondi MW,
Butters N,
Salmon DP,
Katzman R,
Thal LJ
(1992)
Comparisons of verbal fluency tasks in the detection of dementia of the Alzheimer type.
Arch Neurol
49:1253-1258[Abstract/Free Full Text].
-
Moore CJ,
Price CJ
(1999)
Three distinct ventral occipitotemporal regions for reading and object naming.
NeuroImage
10:181-192[Web of Science][Medline].
-
Moore CJ, Price CJ, Friston KJ, Frackowiak
RSJ (1996) Phonological retrieval and semantic processing
during naming tasks. Paper presented at Second International Conference
on Functional Imaging of the Human Brain, Boston, June.
-
Osterrieth PA
(1944)
Le test de copie d'une figure complexe [The test of copying a complex figure].
Archives de Psychologie
30:206-356.
-
Parsons LM,
Gabrieli JDE,
Yucaitis J,
Corkin S
(1988)
Normal improvement in mental rotation skill in global amnesia.
Soc Neurosci Abstr
14:1290.
-
Press GA,
Amaral DG,
Squire LR
(1989)
Hippocampal abnormalities in amnesic patients revealed by high-resolution magnetic resonance imaging.
Nature
341:54-57[Medline].
-
Rapaport D
(1942)
In: Emotions and memory. Baltimore: Williams and Wilkins.
-
Reber PJ,
Squire LR
(1998)
Encapsulation of implicit and explicit memory in sequence learning.
J Cognit Neurosci
10:248-263[Web of Science][Medline].
-
Reed JM,
Squire LR
(1998)
Retrograde amnesia for facts and events: Findings from four new cases.
J Neurosci
18:3943-3954[Abstract/Free Full Text].
-
Reed JM,
Hamann SB,
Stefanacci L,
Squire LR
(1997)
When amnesic patients perform well on recognition memory tests.
Behav Neurosci
111:1163-1170[Web of Science][Medline].
-
Rempel-Clower N,
Zola SM,
Squire LR,
Amaral DG
(1996)
Three cases of enduring memory impairment after bilateral damage limited to the hippocampal formation.
J Neurosci
16:5233-5255[Abstract/Free Full Text].
-
Ribot T
(1881)
In: Les maladies de la memoire [Diseases of memory]. New York: Appleton-Century-Crofts.
-
Riddoch MJ,
Humphreys GW
(1997)
Visual object processing in optic aphasia: a case of semantic access agnosia.
Cognit Neuropsychol
4:131-185.
-
Schmolck H, Stefanacci L, Squire LR (2000a) Detection and
explanation of sentence ambiguity are unaffected by hippocampal lesions
but are impaired by larger temporal lobe lesions. Hippocampus, in
press.
-
Schmolck H, Stefanacci L, Kensinger L, Corkin S, Squire
LR (2000b) Semantic memory in patient H. M. and other
patients with bilateral medial and lateral temporal lobe lesions. Soc
Neurosci Abstr, in press.
-
Scoville WB,
Milner B
(1957)
Loss of recent memory after bilateral hippocampal lesions.
J Neurol Neurosurg Psychiatr
20:11-21.
-
Squire LR,
Knowlton BJ
(1995)
Learning about categories in the absence of memory.
Proc Natl Acad Sci USA
92:12470-12474[Abstract/Free Full Text].
-
Squire LR,
Shimamura AP
(1986)
Characterizing amnesic patients for neurobehavioral study.
Behav Neurosci
100:866-877[Web of Science][Medline].
-
Srinivas K,
Breedin SD,
Coslett HB,
Saffran EM
(1997)
Intact perceptual priming in a patient with damage to the anterior inferior temporal lobes.
J Cognit Neurosci
9:490-511[Web of Science].
-
Stark CEL,
Squire LR
(2000)
Chance recognition memory performance in severe amnesia: no evidence for the use of repetition priming in familiarity judgments.
Behav Neurosci
114:459-467[Web of Science][Medline].
-
Talland G
(1965)
In: Deranged memory. New York: Academic.
-
Teng E,
Squire LR
(1999)
Memory for places learned long ago is intact after hippocampal damage.
Nature
400:675-677[Medline].
-
Teuber H-L,
Battersby WS,
Bender MB
(1951)
Performance of complex visual tasks after cerebral lesions.
J Nerv Ment Dis
14:413-429.
-
Vandenberghe R,
Price C,
Wise R,
Josephs O,
Frackowiak RSJ
(1996)
Functional anatomy of a common semantic system for words and pictures.
Nature
383:254-256[Medline].
-
Warrington EK
(1984)
In: Recognition memory test. Windsor, England: FER-Nelson.
-
Warrington EK,
McCarthy RA
(1988)
The fractionation of retrograde amnesia.
Brain Cogn
7:184-200[Web of Science][Medline].
-
Winslow F
(1861)
In: On obscure diseases of the brain and disorders of the mind, Ed 2. London: John W. Davies.
Copyright © 2000 Society for Neuroscience 0270-6474/00/20187024-13$05.00/0
This article has been cited by other articles:
|
|
|
|
 
A. Mendelsohn, O. Furman, I. Navon, and Y. Dudai
Subjective vs. documented reality: A case study of long-term real-life autobiographical memory
Learn. Mem.,
January 29, 2009;
16(2):
142 - 146.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. Gold and L. R. Squire
The anatomy of amnesia: Neurohistological analysis of three new cases
Learn. Mem.,
November 1, 2006;
13(6):
699 - 710.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Levy, P. J. Bayley, and L. R. Squire
The anatomy of semantic knowledge: Medial vs. lateral temporal lobe
PNAS,
April 27, 2004;
101(17):
6710 - 6715.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Ecker, P. Stein, Z. Xu, C. J. Williams, G. S. Kopf, W. B. Bilker, T. Abel, and R. M. Schultz
Long-term effects of culture of preimplantation mouse embryos on behavior
PNAS,
February 10, 2004;
101(6):
1595 - 1600.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Kapur and M. D Kopelman
Advanced brain imaging procedures and human memory disorder
Br. Med. Bull.,
March 1, 2003;
65(1):
61 - 81.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J. Bayley and L. R. Squire
Medial Temporal Lobe Amnesia: Gradual Acquisition of Factual Information by Nondeclarative Memory
J. Neurosci.,
July 1, 2002;
22(13):
5741 - 5748.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. R. Squire, H. Schmolck, and S. M. Stark
Impaired Auditory Recognition Memory in Amnesic Patients with Medial Temporal Lobe Lesions
Learn. Mem.,
September 1, 2001;
8(5):
252 - 256.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Manns, C. E. L. Stark, and L. R. Squire
The visual paired-comparison task as a measure of declarative memory
PNAS,
October 4, 2000;
(2000)
220398097.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
J. R. Manns, C. E. L. Stark, and L. R. Squire
The visual paired-comparison task as a measure of declarative memory
PNAS,
October 24, 2000;
97(22):
12375 - 12379.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
Brain Diseases
