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Dorsal thalamic lesion in a noted case of human memory dysfunction.

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Dorsal Thalamic Lesion in a Noted Case
of Human Memory Dysfunction
Larry R. Squire, PhD, and Robert Y.Moore, MD, P h D
The extensively studied patient N. A. has had a severe verbal memory deficit since 1960, when he sustained a stab
wound to the brain with a miniature fencing foil. His amnesia occurs in the absence of any other known cognitive
defect. Recent CT scans have localized a lesion in the left dorsal thalamus of this patient in a position corresponding
to the dorsomedial nucleus; there is no radiographic evidence of other damage in the diencephalon or cerebral
cortex. The dorsomedial thalamus may be critical in the neuropathology of diencephalic amnesia and, in humans,
may be required for normal memory functions.
Squire LR, Moore RY: Dorsal thalamic lesion in a noted case of human memory dysfunction.
Ann Neurol 6:503-506, 1979
Clinicopathological studies of human memory disturbances have provided a great deal of information
about the organization of normal memory and its
neurological basis [l, 281. Amnesia can occur as
a relatively pure cognitive deficit, and damage to
specific brain regions can produce memory dysfunction. For example, the reported distribution of lesions in the well-known amnesic patient H. M. has
suggested that the hippocampal zone is involved in
the formation of long-term memory [261.
Damage to the midline diencephalon can cause
memory dysfunction, but here it has been more
difficult t o identify the critical regions. In the alcoholic Korsakoff syndrome the areas most frequently damaged are dorsal medial thalamus, mammillary bodies, pulvinar, and terminal aspects of the
fornix [38]. Since Korsakoff syndrome involves cognitive defects in addition to amnesia [33], the lesions
specifically responsible for memory dysfunction have
been difficult to identify with certainty. The mammillary bodies have long been considered critical in
the pathophysiology of this memory loss [2, 31, but
some neuropathological studies of patients with Korsakoff syndrome have suggested that destruction of
the mammillary bodies may not be sufficient to produce amnesia and that the important lesions are those
of the dorsal medial thalamus [38]. Nevertheless,
there is disagreement about which of these structures
deserves the greater emphasis. O n one hand, damage
to the mammillary bodies has been reported not to
result in memory disturbances [ 3 5 , 38, 411; on the
other, damage reportedly confined t o the mammillary bodies was said to produce memory disturbances
in 4 patients [ 5 , 9, 10, 241.
Studies of diencephalic tumor have suggested that
damage to dorsal thalamic and periventricular structures is sufficient t o produce memory dysfunction
[15, 391, and in 1 recent case the mammillary bodies
appeared normal at autopsy [17]. In tumor cases,
however, there is often involvement of adjacent
structures as well as widespread edema or increased
intracranial pressure, so that clear interpretation of
the neuropathology of amnesia is not possible.
We report here the localization of neuroanatomical
changes in the diencephalon of a well-studied patient
(N. A.) who exhibits chronic amnesia for verbal material. This patient’s amnesia is not as severe as that of
Patient H. M., but it is strikingly pure and therefore
of potential value for identifying possible neuroanatomical substrates of amnesia.
From the Veterans Administration Hospital, San Diego, and the
Departments of Psychiatry and Neurosciences, University of
California, San Diego, School of Medicine, La Jolla, CA.
Accepted for publication Feb 26, 1979.
Case Report
N. A. has been described in detail previously and his memory defect has been extensively documented [29, 341. In
1960, at the age of 22 years, this individual sustained a stab
wound to the brain with a miniature fencing foil. He has
since exhibited a marked incapacity for recalling day-to-day
events and has not been employed. His verbal memory is
poorer than his nonverbal memory. Yet his I Q is 124 and
he has scored above normal levels in a number of perceptual and cognitive tests. In formal memory testing he failed
at paired associate learning, improving only slightly after
three repetitions of the same list of ten word pairs. He also
exhibited deficient recall of remote events that had occurred since his accident in 1960, though he recalled normally from the premorbid period prior to 1960 [29].
In 1977, N. A. voluntarily submitted to three CT scans.
The first two were performed in January and March and
were carried out with and without contrast material, using
Address reprint requests to Dr Squire, Veterans Administration
Hospital (V-116), 3350 La Jolla Village Dr, San Diego, CA 92161.
0364-5134/79/120503-04$01.25 @ 1979 by Larry R. Squire 503
scans, this would lie in the dorsomedial nucleus of the
thalamus. In addition, the anterior horn of the left lateral
ventricle is slightly larger than that on the right. Since considerable asymmetry between the anterior horns can occur
normally [ 111, the meaning of this observation is uncertain.
The remainder of the CT scan is normal. In particular,
there is no evidence of cortical atrophy. The sylvian fissures
are present but normal in size o n both sides. Cuts through
the temporal lobes appear normal. The bodies and temporal horn of the lateral ventricles are symmetrical and of
normal size, and the third ventricle lies in the midline and is
of normal width. T h e fornix appears entirely intact at the
center of the lesion (see the Figure).
(A) C?’ scan perfornied o n Patient N . A. in November, 1977.
The cut shouw i.r through the maximal area of the lesion,
which lies lateral and anterior t o the pineal body. (B) Line
interpretation of the scan, showing the major featltres of the
lesion: reduction of the Left thalamic mass and a cavity continuous with the rubarachnoid space. See text for description.
( C = cavitj; CI = interpositus cistern; F = fornix; IF =
interhemispheric fEssure; LV = lateral ventricle; P = pineal
body; T = thalamus.)
standard 8 mm cuts from the vertex to the skull base. These
demonstrated a lesion in the region of the left thalamus.
The third scan was performed without contrast in
November in order to obtain better definition of the lesion. A number of 10 m m cuts were made from just dorsal
to the lesion, through it, and ventral to the lesion. The
principal finding on these scans is shown in the Figure.
There is marked reduction in the mass of the left thalamus,
which appears restricted to the anterior two-thirds of its
dorsal portion. The center of this region contains a lucent
area with the same density as the third ventricle. T h e lucency appears to communicate with the third ventricle and
with the subarachnoid cistern lying just above.
By measurement, the center of the cavity within the lesion lies approxiniately 2 cm rostra1 to the center of the
pineal calcification and 1 cm lateral to the midline. As projected from fixeJ human brains cut in the plane of the C T
The available history of the injury and the findings on
C T scan suggest that the fencing foil penetrated the
right nostril and entered the cranial cavity through
the ethmoid bone. The probable course of the foil
was to cross the midline and pass through the orbitofrontal cortex, the rostrum of the corpus callosum, the
anterior horn of the left lateral ventricle, and through
the neostriatum into the thalamus. The cystic nature
of the defect on CT scan and the decrease in thalamic
mass suggest that the initial damage may have been
hemorrhagic. The discrete nature of the lesion provides support for attributing this patient’s memory
deficit to damage of the left thalamus and suggests
that the damage is largely localized to the dorsomedial nucleus. A precise definition of the lesion and
the extent of damage to the structures involved cannot be determined without pathological confirmation. Nevertheless, the findings on CT scan provide a
reasonable basis for the conclusions presented here.
The finding that the lesion in this case is situated
entirely to the left of midline, and that the amnesia
affects verbal material more than nonverbal material,
is of considerable interest. Hemispheric specialization of function in memory has been well established
for anterior temporal neocortex [ 191. Functional
asymmetry of the left and right thalamus has been
demonstrated for verbal and nonverbal skills, respectively [2 11, and electrical stimulation of the right
thalamus in humans has been shown to impair the
formation of nonverbal memory [20]. The present
findings imply that left thalamic dysfunction can disrupt the formation of verbal memory and support the
notion that hemispheric specialization of function in
memory extends to the thalamus.
The present findings agree with recent discussions
of Korsakoff syndrome and amnesia, which have emphasized the role of the dorsomedial nucleus of the
thalamus [38]. In addition, memory disturbances
have been noted in clinical reports of patients who
received surgical lesions in the dorsomedial nucleus
[ 2 7 ] . Memory loss, in association with vertical gaze
apraxia and decreased alertness, has also been re-
504 Annals of Neurology Vol 6 No 6 December 1979
ported in patients with infarctions in the territory of
the thalamosubthalamic paramedian arteries [ 181.
This territory includes portions of the dorsomedial
nuclei and other thalamic nuclei. In every report we
have found, dorsal thalamic lesions in humans have
resulted in memory disturbances. The results of animal studies have also tended to minimize the role of
the mammillary bodies in memory functions [40],but
dorsomedial thalamic lesions have been reported to
affect learning and memory [23,25].Taken together,
the evidence suggests that damage to the dorsal
thalamus is sufficient to cause memory dysfunction.
There is an additional reason for thinking that the
mammillary bodies might not be of central importance in diencephalic amnesia. The mammillary
bodies receive connections from the subicular region
of the hippocampal formation via the postcommissural fornix [31].Yet findings from both neurosurgical procedures and tumor cases indicate that bilateral
interruption of the fornix does not result in amnesia
[4,6,8,30,36,41]. We have found a total of 47 cases
in which surgical interruption of the anterior fornix
produced no noticeable effects on memory and only
3 in which memory dysfunction was noted [12, 13,
321. It has been suggested that in the negative cases
damage was restricted to the postcommissural fornix
and that the 3 positive cases either had damage to
both the precommissural and postcommissural fornix
or had additional damage [ 131. This view is supported
by the finding that section of the dorsal fornix in
monkeys, which interrupts both precommissural
and postcommissural fibers, can impair recognition
memory [7].Unfortunately, interpretation of human
cases is complicated by the fact that they are often
presented with inadequate psychological testing or
insufficient neuropathological information. Therefore, the possibility cannot be excluded that lesions
in the dorsal thalamus, as well as in the fornix or
mammillary bodies, can cause some memory defect.
In any case, it seems likely that the functional link
between hippocampus, postcommissural fornix, and
mammillary bodies may not be as strong as was once
believed [22], and the traditional view that the
mammillary bodies are preeminent in the neuropathology of diencephalic amnesia may need to be
It is not y e t clear what functional relationship
might exist between the dorsomedial thalamus and
the hippocampus, which has previously been implicated in memory functions based on results of medial temporal surgery [26].Evidence for connections
between the hippocampus and dorsomedial nucleus
is sparse, but a projection via the precommissural
fornix to the dorsomedial nucleus has been reported
in monkeys [37].It has also been proposed recently
that the critical structure in medial temporal amnesia
is not the hippocampal formation, but the adjacent
temporal stem or albal stalk 1141. The temporal stem
connects the amygdala and temporal neocortex to a
variety of brainstem structures, including the pulvinar and dorsomedial nucleus [16].
It has been possible to obtain extensive neuropsychological evidence for a circumscribed memory
impairment in a patient with damage apparently
confined to the dorsal thalamus. The results indicate
that damage in this region, sparing both the fornix
and the mammillary bodies, is sufficient to cause
strikingly pure anterograde amnesia for verbal material. The results suggest that in humans, the dorsal
thalamus has a role in the formation of long-term
Supported by the Medical Research Service of the Veterans Administration, by Grant MH24600 and Mental Health Clinical Research Center Grant lP50 M H 30914 01 from the National Institute of Mental Health, and by US Public Health Service Grant
We thank Dr F. Brahme for assistance in interpreting the CT
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