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Previous Article | Next Article
Volume 16, Number 16, Issue of August 15, 1996 pp. 5233-5255
Copyright ©1996 Society for NeuroscienceThree Cases of Enduring Memory Impairment after Bilateral Damage Limited to the Hippocampal Formation
Nancy L. Rempel-Clower3, Stuart M. Zola1, 2, 3, Larry R. Squire1, 2, 3, and David G. Amaral4 1 Veterans Affairs Medical Center, San Diego, California 92161, Departments of 2 Psychiatry and 3 Neurosciences, University of California at San Diego, La Jolla, California 92093, and 4 Department of Psychiatry and Center for Neuroscience, University of California at Davis, Davis, California 95616
ABSTRACT
Patient RB (Human amnesia and the medial temporal region: enduring memory impairment following a bilaterial lesion limited to field CA1 of the hippocampus, S. Zola-Morgan, L. R. Squire, and D. G. Amaral, 1986, J Neurosci 6:2950-2967) w as the first reported case of human amnesia in which detailed neuropsychological analyses and detailed postmortem neuropathological analyses demonstrated that damage limited to the hippocampal formation was sufficient to produce anterograde memory impairment. Neuropsychological and postmortem neuropathological findings are described here for three additional amnesic patients with bilateral damage limited to the hippocampal formation. Findings from these patients, taken together with the findings from patient RB and other amnesic patients, make three important points about memory. (1) Bilateral damage limited primarily to the CA1 region of the hippocampal formation is sufficient to produce moderately severe anterograde memory impairment. (2) Bilateral damage beyond the CA1 region, but still limited to the hippocampal formation, can produce more severe anterograde memory impairment. (3) Extensive, temporally graded retrograde amnesia covering 15 years or more can occur after damage limited to the hippocampal formation. Findings from studies with experimental animals are consistent with the findings from amnesic patients. The present results substantiate the idea that severity of memory impairment is dependent on locus and extent of damage within the hippocampal formation and that damage to the hippocampal formation can cause temporally graded retrograde amnesia.
Key words: hippocampal formation; CA1 region; human amnesia; anterograde memory impairment; retrograde memory impairment; temporally graded retrograde amnesiaAnterograde memory Table 2 shows the scores for six measures of anterograde memory function. The mean scores for a group of eight control subjects are also included (Shimamura and Squire, 1986
INTRODUCTION
The medial temporal lobe has been recognized as important for memory for nearly a century (von Bechterew, 1900; Grunthal, 1947
Patient RB (Zola-Morgan et al., 1986
Patient RB had little detectable retrograde amnesia (Zola-Morgan et al., 1986
These results from the available studies of amnesic patients with damage to the hippocampal formation raise a number of questions. First, patient RB exhibited moderately severe anterograde amnesia in association with a circumscribed CA1 hippocampal lesion. Is this a typical and repeatable finding after global ischemia? Does damage limited to the CA1 region ordinarily result in moderately severe anterograde memory impairment? Second, does damage beyond the CA1 region, but still limited to the hippocampal formation, produce more severe anterograde memory impairment? Third, RB's CA1 lesion resulted in quite limited retrograde amnesia. What damage is required to produce the more extensive, temporally graded retrograde amnesia that can be documented in formal testing (Beatty et al., 1987a
Neuropsychological and postmortem neuropathological findings are described here for three amnesic patients with bilateral medial temporal lobe damage. They varied in the severity of their anterograde amnesia and in the extent of their retrograde amnesia. The patients survived for more than 6 years after the onset of amnesia, during which time they received extensive neuropsychological testing of memory and other cognitive functions.
MATERIALS AND METHODS
Three amnesic patients (GD, LM, and WH) were studied from the onset of amnesia until their deaths 6 to 9.5 years later. Their case histories are described below. Patient GD Case history. Patient GD was a Caucasian male born in 1940. He joined the Navy after graduating from high school and served for 16 years, ultimately as a navigator. After his service in the Navy, he owned a wrecking business. In 1976, GD was diagnosed with hypertension thought to be secondary to nephrosclerosis. In August 1981, he was diagnosed with chronic renal failure. A biopsy showed focal crescentic glomerulonephritis, and hemodialysis was begun in February 1982. He received hemodialysis three times a week for the remainder of his life.In May 1983, GD was hospitalized for elective parathyroidectomy to relieve severe itching attributable to hyperparathyroidism. (His parathyroid hormone level was 78,000 pg/ml compared with normal levels of <150 pg/ml.) The 5 hr procedure consisted of a total parathyroidectomy with autotransplantation of some parathyroid tissue to the right forearm. He also underwent left thyroid lobectomy because of loss of blood to the left lobe of the thyroid during removal of the parathyroids. Two and a half hours into surgery he experienced cardiac arrhythmia (a junctional rhythm), and his heart rate dropped to 45 beats/min. For a period of 15 min at that time, his blood pressure was 100-110/50-60 mmHg. His recorded blood pressure sometimes had also been low immediately after dialysis treatment during the 7 months before surgery (80-150/50-100 mmHg).
After this ischemic episode, GD was noted in the hospital records to be agitated, disoriented, and very forgetful of events from the preceding 5 min. He was discharged 5 d after the surgery and was still unable to remember what he had recently said or done. Beginning 2 months after surgery and continuing intermittently for 9.5 years, he was given a variety of neuropsychological tests (described below).
GD gave no evidence of intellectual or cognitive deficit other than memory impairment. He exhibited little interest in testing, however, and this complicated the interpretation of some of his memory test scores (see below). His memory impairment remained stable for the next 9.5 years until his death. In December 1992, GD died of congestive heart failure secondary to uremic pericarditis and end-stage renal disease. He was 52 years old.
Acquisition and preparation of tissue. Approximately 3 hr after death, GD's brain was removed and placed in 4% paraformaldehyde with 0.02% picric acid. The carotid arteries were cannulated, and the brain was perfused with the paraformaldehyde solution for 1 hr and then for 3 more hours with fresh 4% paraformaldehyde in 0.1 M phosphate buffer.
Photographs of the whole brain surfaces were taken, and then the brain was cut into ~1-cm-thick coronal blocks and placed in 4% paraformaldehyde in 0.1 M phosphate buffer for 48 hr. The blocks were then stored in cold 10% formalin in 0.1 M phosphate buffer for approximately 9 months. Then, the blocks were placed in a cryoprotectant solution of 20% glycerol and 2% dimethyl sulfoxide in 0.1 M phosphate buffer for 2 d before freezing. Whole coronal blocks were frozen between glass slides by placing them in
Patient LM Case history. Patient LM has been described previously (as patient MRL in Beatty et al., 1987a70°C isopentane for 45 min and stored at
LM had a history of alcohol abuse and was treated in the Alcoholism Treatment Program at the San Diego Veterans Affairs Medical Center (VAMC) in 1980. During the 6 months before treatment, he estimated his average daily intake of alcohol at 16 drinks. He denied using other psychoactive drugs.
LM began to have seizures while on military duty, often associated with alcohol withdrawal. According to his former wife, a nurse at the San Diego VAMC, he experienced generalized tonic clonic seizures in 1964, 1967, 1978, 1980, and 1984. The seizures were usually preceded by visual images of flashing lights sometimes followed by other images. His former wife reported that he fully recovered from the first four seizures, and that his intellectual faculties seemed entirely normal before the 1984 seizures (see below). Periodic neurological evaluations after seizures from 1964 to 1984 were normal. LM began taking anticonvulsants regularly after the 1984 seizures and did not have further tonic clonic seizures. However, according to his former wife, he did have partial seizures that ranged in frequency from once in 2 weeks to sometimes as often as three to four times a day. During these episodes, he would be unresponsive to visual or auditory stimuli and moved his lips in a chewing motion.
Although LM's drinking was reportedly minimal after 1980, his former wife reported that he had six to seven drinks of hard liquor and some beer ~2 d before suffering a series of generalized tonic clonic seizures on September 27, 1984. While LM was riding in an automobile with coworkers, he complained of feeling dizzy and then had at least three tonic clonic seizures. He was brought to the emergency room and was comatose postictally for ~2 hr. There was evidence of respiratory acidosis (pH, 6.8; pCO2, 64), and an electroencephalogram (EEG) revealed diffuse sharp waves and delta activity. LM required respiratory assistance for at least 18 hr. On September 29, he was alert but disoriented to time and place. A neurological exam showed that his pupillary responses were normal and that he had normal reflexes and strength in all extremities, and an appropriate response to pain. One week later, an EEG showed mild-to-moderate generalized nonspecific abnormalities, i.e., slowing, but no focal abnormalities or epileptiform discharges were apparent. A CT brain scan, without contrast, was normal.
In his initial interview with a neuropsychologist (Dr. Nelson Butters, San Diego VAMC), he was oriented to person but not to place. He was unsure whether he was married at present (he was living with his former wife) and did not know which of his children were daughters or stepdaughters. During this initial interview, he even forgot the questions he was attempting to answer. He gave no evidence of intellectual or cognitive deficit other than memory impairment. His memory impairment remained stable for the next 6 years.
In July 1990, LM was diagnosed with a small cell carcinoma of the lung. Neuropsychological tests administered in August 1990 detected no changes in memory or other cognitive functions, and he remained alert and lucid until a few days before his death. LM died of respiratory failure October 27, 1990, at the age of 60.
Acquisition and preparation of tissue. LM's brain was removed at autopsy ~1.5 hr after death and placed in cold 0.9% saline. The carotid arteries were cannulated and the brain was perfused with 0.9% saline for 30 min, then perfused with 4% paraformaldehyde with 0.02% picric acid for 30 min. This was replaced with fresh 4% paraformaldehyde after 30 min, and the perfusion was continued for another 30 min.
Photographs of the whole brain surfaces were taken, and the brain was cut into coronal blocks ~1 cm thick and placed in cold 4% paraformaldehyde with 10% glycerol and 2% dimethylsulfoxide for 2 hr. The brain was cryoprotected in 20% glycerol and 2% dimethylsulfoxide in 0.1 M phosphate buffer for 4 d, and frozen as described for patient GD.
After sections from the anterior blocks (anterior 30% of the brain) were mounted and stained with thionin, problems were noted in the fixation. Specifically, numerous small areas were stained more poorly with thionin than the surrounding tissue. This problem did not appear to be related to the staining procedure because adjacent sections showed the same pattern of blotchy staining. The remaining blocks were therefore thawed and placed in 4% paraformaldehyde, 20% glycerol, and 2% dimethylsulfoxide in 0.1 M phosphate buffer to fix for an additional 3 months. The blocks were then refrozen until they were sectioned. No problems with staining were noted after the additional fixation.
Patient WH Case history. Patient WH has been described previously (Salmon et al., 1988WH developed severe memory impairment during March 25-30, 1986, at the age of 63. His wife reported that on the evening of March 25, 1986, he appeared tired and withdrawn. Although he seemed strained and looked ashen, he nevertheless went to work the next day. That evening he admitted to his wife that he was having memory problems. He could not recollect the appearance of his desk at work or his employer's face. He remained at home for the next 3 d during which time he was quiet and passive, often repeated himself, and forgot what he was doing after brief distractions. His wife reported that his memory problems became more severe on March 30. After admission to the hospital, a neurological examination on April 2 revealed him to be alert and normally attentive. He was uncertain of the month and day (believing it was February on two of three occasions), was uncertain about who was President, and did not know who was the governor of his state or the current mayor of his city. He recalled his address and home telephone number, but could not recall his work number. He was able to do simple tests of calculation, but could not recall the names of four objects that had been given 1 min before. His speech was clear and lucid, and his remote memory was reported as intact. Although the cause of his memory impairment was not determined with certainty, it has been suggested that it was attributable to cerebral ischemia, i.e., a period of relative hypotension, the effects of which could have been exacerbated by preexisting subclinical damage to the medial temporal lobe (Kritchevsky and Squire, 1993
After his episode in 1986, WH was admitted to the hospital several times for episodes of shortness of breath and cardiac insufficiency. In addition, an ataxia developed in 1987, which was reported to have been resolved in 1989. In February 1988, he was admitted to the hospital after an episode of shortness of breath and chest pain. During this hospitalization, he suffered one tonic clonic seizure associated with his compromised pulmonary status and secondary to treatment with theophylline. On June 5, 1992, he was admitted to the hospital after three separate episodes of anomic aphasia and was diagnosed as having sustained three transient ischemic attacks.
Except during the transient episodes just noted, WH never exhibited signs of intellectual or cognitive deficits other than memory impairment. After the episode in 1986, his memory impairment remained stable for 7.5 years, during which time he was given a variety of neuropsychological tests (described below). He died in December 1993 from end-stage emphysema at the age of 71.
Acquisition and preparation of tissue. WH's brain was removed at autopsy ~2.5 hr after death and placed in cold 4% paraformaldehyde with 0.02% picric acid. The carotid arteries were cannulated, and the brain was perfused with fresh 4% paraformaldehyde in 0.1 M phosphate buffer for 3 hr. The brain was then placed in fresh 4% paraformaldehyde in 0.1 M phosphate buffer for ~19 hr, at which time photographs of the whole brain surfaces were taken. The brain was then cut into coronal blocks ~1 cm thick, and the blocks were stored in cold 4% paraformaldehyde in 0.1 M phosphate buffer for 48 hr. The brain was then cryoprotected in 10% glycerol with 2% dimethylsulfoxide in 0.1 M phosphate buffer for 2 d, then in 20% glycerol with 2% dimethylsulfoxide in 0.1 M phosphate buffer for 2 d, and frozen as described for patient GD.
Processing of brain tissue. Beginning when the brains were frozen, all three were processed in the same way. Continuous 50 µm sections were cut through each frozen block using a large freezing microtome designed specifically for cutting whole human brain tissue (Tetrander I). Every tenth section was mounted on gelatin-coated slides and stained with 0.25% thionin. The unmounted sections were stored in a cryoprotectant solution of 30% ethylene glycol and 25% glycerol in 0.1 M phosphate buffer at
Evaluation of brain tissue. Sections were analyzed with a Leitz Wild stereomicroscope. Thionin-stained sections through the brains of GD, LM, and WH were examined together with comparable sections from two normal control brains. Each of the two control brains were obtained within 3.5 hr of death, and they were processed using the procedures described for the patient brains. One control brain came from an 85-year-old male who died from pneumonia, and the other from a 54-year-old male who died from esophageal carcinoma. Adjacent sections of selected levels throughout the hippocampal formation of GD and LM were stained using a modified Heidenhain procedure (Hutchins and Weber, 1983
RESULTS
Neuropsychological data from the patients will be described first, followed by the postmortem neuropathological findings. As mentioned above, all three patients were tested on multiple occasions beginning shortly after the onset of amnesia until their deaths. GD was tested for 9.5 years, LM for 6.0 years, and WH for 7.5 years. In the case of tests given on more than one occasion, scores presented here are from the latest administration of the test. No significant changes in memory or cognitive abilities were noted in any patient during the years they were studied.Neuropsychological findings
Data for patients GD, LM, and WH will be presented together with comparable data for patient RB and two other groups of amnesic patients. (1) RB became amnesic in 1978 after an ischemic episode (Zola-Morgan et al., 1986Table 1 shows the full-scale Wechsler Adult Intelligence Scale-Revised (WAIS-R) and Wechsler Memory Scale-Revised (WMS-R) for patients GD, LM, WH, RB, and the MTL and KOR groups. The Vocabulary and Information subscale scores of the WAIS-R are listed separately, as they are relatively resistant to impairment after focal brain injury (Goodglass and Kaplan, 1979). The patients also were given the original versions of both the Wechsler Adult Intelligence Scale (WAIS) and the Wechsler Memory Scale (WMS). A difference of more than 15 points between the WAIS and the WMS suggests a significant memory impairment. Patient RB had a difference score of 20 points (WAIS = 111, WMS = 91). Patients GD and LM had difference scores of 28 and 18, respectively (GD: WAIS = 104, WMS = 76; LM: WAIS = 123, WMS = 105). Patient WH obtained a difference score of 31 in January 1987 and a difference score of 44 in July 1987 (WAIS = 120 and 127, respectively; WMS = 89 and 83, respectively).
Table 1. Characteristics of amnesic patients
Patient/group Age WAIS-R WMS-R Full-scale Vocabulary Information Attention Verbal Visual General Delay GD 43 92 39 16 109 86 88 85 60 LM 54 109 55 25 124 94 82 89 62 WH 64 113 64 27 88 72 82 67 <50 RB 52 103 50 18 
MTL (3) 59.0 105.7 56.0 22.6 103.0 70.6 71.7 64.3 52.3 [54-69] [98-115] [50-65] [17-27] [87-117] [62-83] [60-83] [54-70] [<50-57] KOR (8) 58.1 97.4 49.1 18.4 89.8 71.1 73.1 64.8 56.8 [47-73] [88-106] [30-63] [12 -24] [62-115] [55-80] [60-97] [50-80] [<50-72] WAIS-R, Wechsler Adult Intelligence Scale-Revised; WMS-R, Wechsler Memory Scale-Revised. The full-scale WAIS-R and each of the five indices of the WMS-R yield a mean score of 100 in the normal population with an SD of 15. The WMS-R does not provide numerical scores for subjects who score below 50. Therefore, values below 50 were scored as 50 for computing means. Raw scores are shown for two of the WAIS-R subtests, Vocabulary and Information. RB (Zola-Morgan et al., 1986
Table 2. Memory test performance
Patient/group Diagram recall Paired associates Word recall Word recognition 50 words 50 faces GD 7 2-1-2 40 83 25 28 LM 6 1-1-3 47 97 32 33 WH 1 0-0-0 40 84 29 24 RB 3 0-0-1 MTL (3) 3.3 0.3-0.3-1.0 33.3 86.5 33.6 32.0 KOR (8) 3.6 0.4-0.1-1.4 27.8 80.7 29.6 31.6 CON (8) 20.6 5.6-7.6-8.8 71.0 97.7 41.1 38.1 [11-28] [52-93] [96-99] [33-45] [33-45] The diagram recall score is based on delayed (10-15 min) reproduction of the Rey-Osterrieth figure (Osterrieth, 1944 
Fig. 1. The Rey-Osterrieth figure. Patients were first asked to copy the figure illustrated in the small box to the left, then asked to reproduce the figure from memory 10-15 min later. The copy (top) and the reproduction (bottom) are shown from left to right for GD, LM, WH, and for a control subject (CON) matched to the three patients with respect to age, education, and WAIS-R Vocabulary and Information subscale scores.
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WH's scores are lower than LM's scores on all six tests and lower than or equal to GD's scores on four of the six tests. WH also had lower scores than either GD or LM on the WMS-R (Table 1) and had the largest WAIS-WMS difference score. Thus, WH had more severe anterograde amnesia than GD or LM. No difference in severity of anterograde amnesia was apparent for GD and LM. However, GD's lower IQ (17 points below LM) raises the possibility that GD was in fact less amnesic than LM but performed poorly in part because of his general testing ability (see Retrograde memory, below). Finally, RB was given two of the same tests of anterograde memory as GD, LM, and WH: diagram recall test (score = 3) and paired associates test (total score for 3 trials = 1). RB's performance on these two tests and his WAIS-WMS difference score (20) suggest that the severity of RB's anterograde amnesia was similar to that of GD and LM and less severe than that of WH.
Retrograde memory Patients GD, LM, and WH also were tested for their memory of events that had occurred before the onset of amnesia (retrograde memory). Descriptions of the tests of retrograde memory and data for these three patients, as well as other amnesic patients, have been published previously (Beatty et al., 1987a
Fig. 2. Individual scores for GD, LM, and WH on recall tests involving public events and famous faces. For comparison, the mean scores for control subjects (n = 8) are shown in open squares in each panel. In the public events test, SEs for the control subjects ranged from 3.9 to 7.1%. For the famous faces test, SEs for the control subjects ranged from 4.4 to 5.5%. The patients were tested in 1987; GD became amnesic in 1983, LM in 1984, and WH in 1986. Note that GD was born in 1940, so the personalities in the famous faces test for the 1940s came into prominence when he was younger than 10 years old. LM and WH had temporally graded retrograde amnesia (see Results). Also, see Results for discussion of the difficulty of interpreting GD's scores for these tests.
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For LM and WH, corroborative information about their retrograde amnesia comes from earlier, independent assessments using tests of public events and famous faces very similar to the ones used here (Beatty et al., 1987a
WH was also given tests of public events and famous faces before our own assessment (Salmon et al., 1988
GD's performance on the tests of public events and famous faces is more difficult to interpret (Fig. 2). He performed poorly on the tests, but he was also less well educated than the other subjects, he had a lower IQ (92), and he often seemed poorly motivated. The slope analysis did not suggest temporally graded retrograde amnesia in the case of the famous faces test (slope = 1.68). For the public events test, the slope was 9.00, but it was determined by a single point (the 1950s). Thus, it was difficult to determine from these two tests whether GD had extensive retrograde amnesia, or whether his scores were simply low because of his lower motivation and intellectual abilities.
Figure 3 shows the distribution of autobiographical memories produced in response to 75 single-word cues (additional data for GD, LM, and WH were published previously) (MacKinnon and Squire, 1989
Fig. 3. Time periods from which subjects drew their autobiographical memories in response to 75 single-word cues. The temporal distribution of recollections is shown for patients GD, LM, WH, and for a group of five normal control subjects (CON). Of 75 possible recollections, GD had 46, LM had 56, and WH had 45. Control subjects had a mean of 65.2 responses (range, 51-71). Note that GD was born in 1940, so the Before 1950 time point represents episodes that occurred when he was younger than 10 years old.
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Finally, for LM, an additional measure of retrograde amnesia for personal memories comes from an earlier independent assessment with a test that asked him to draw floor plans of homes he had lived in throughout his life (Beatty et al., 1987a
Performance on other cognitive tests The memory impairment of these three amnesic patients occurred in isolation from other cognitive deficits. First, the patients obtained scores in the normal range on the WAIS-R (Table 1). In addition, they were tested on the Dementia Rating Scale (Mattis, 1976The amnesic patients were also given the Boston Naming Test (Kaplan et al., 1983
The Verbal Fluency Test is considered sensitive to frontal lobe dysfunction and requires subjects to provide as many words as possible in 1 min beginning with the letter F (and then A and S). Patients LM and WH performed as well as control subjects (LM = 34, WH = 57, mean of 6 control subjects = 37.5; Squire et al., 1990
Finally, as with other amnesic patients, GD, LM, and WH performed normally on many tests of implicit (nondeclarative) memory. GD participated in four studies of implicit memory, including tests of word priming (Squire et al., 1987
To summarize (Table 3), patient GD had moderately severe anterograde amnesia. Although his retrograde memory performance was mixed, it seems unlikely that he had extensive temporally graded retrograde amnesia. Thus, his memory impairment appeared similar to that of RB (Zola-Morgan et al., 1986
Table 3. Summary of neuropsychological and neuropathological findings from four patients with bilateral damage to the hippocampal formation
Anterograde amnesia Retrograde amnesia Damage to the hippocampal formation RB Moderate Minimal CA1 field GD Moderate Minimal (?) CA1 field LM Moderate Extensive CA1, CA2, CA3 fields, dentate gyrus, entorhinal cortex WH Severe Extensive CA1, CA2, CA3 fields, dentate gyrus, subiculum, entorhinal cortex GD and RB had damage restricted primarily to the CA1 field of the hippocampus bilaterally. GD and RB additionally had cell loss in the region of the CA1/subiculum border. LM, in addition to substantial cell loss in the dentate gyrus and all cell fields of the hippocampus, evidenced some loss of cells in layers II and III of entorhinal cortex. WH sustained more distributed damage to the hippocampal region overall than the other patients, including considerable loss of cells in the subiculum, complete loss of polymorphic cells in the dentate gyrus, and dispersion of the granule cell layer in the dentate gyrus. In addition, WH sustained cell loss in layers III, V, and VI of entorhinal cortex (slight cell loss also occurred in layer II of entorhinal cortex). The severity of memory impairment correlated with the extent of damage to the hippocampal formation. Thus, RB and GD had moderate anterograde amnesia and minimal retrograde amnesia. (The question mark for GD indicates that some uncertainty remains about the interpretation of his performance on remote memory tests.) LM had moderate anterograde amnesia, together with extensive, temporally graded retrograde amnesia covering at least 15 years. WH had severe anterograde amnesia together with extensive, temporally graded retrograde amnesia that was probably more severe than in LM and involved as much as 25 years. Neuropathological findings
Gross appearance of the brains The surfaces of all three brains were examined before further histological processing. No infarcts or general cortical atrophy were apparent. In the brains of LM and WH, who died at the ages of 60 and 71, respectively, there appeared to be some slight widening of sulci, which is frequently observed with aging (Tomlinson et al., 1968Normal appearance of the human hippocampal formation. The hippocampal formation includes the dentate gyrus, the hippocampus proper, the subicular complex, and the entorhinal cortex (Fig. 4). The human dentate gyrus has three layers: the granule cell layer, the molecular layer, and the polymorphic layer, or the hilus. In Nissl-stained tissue, the polymorphic cells are difficult to distinguish from pyramidal cells of the hippocampus, but in other preparations (i.e., Timm's stain or acetylcholinesterase stain) this region shows a distinct pattern of labeling. The hippocampus can be divided into three distinct fields, designated CA1, CA2, and CA3 according to the nomenclature of Lorente de Nó (1934)
Fig. 4. Coronal section from a normal brain through the right rostral hippocampal formation stained with thionin. Arrows mark the borders between regions. CA1 and CA2/3 refer to the CA fields of the hippocampus. DG, Dentate gyrus; ml, molecular layer of the dentate gyrus; gl, granule cell layer; pl, polymorphic layer; S, subiculum; PrS, presubiculum; PaS, parasubiculum; EC, entorhinal cortex; cs, collateral sulcus; PRC, perirhinal cortex. Scale bar, 1 mm.
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The entorhinal cortex is multilaminate and is considered to comprise six layers [modification of the nomenclature of Ramon y Cajal (1901-1902)
Patient GD Medial temporal lobe. GD had a bilateral lesion of the hippocampal region involving most of the CA1 field throughout its rostrocaudal extent (Figs. 5, 6, 13, 14). Extensive bilateral loss of CA1 pyramidal cells was observed, and the area of the CA1 field was reduced. Some proximally situated CA1 pyramidal cells remained bilaterally at midrostrocaudal and caudal levels of the hippocampus. An increase in the density of glial cells was evident throughout CA1, especially in the stratum oriens and stratum radiatum, the regions above and below the region usually occupied by the pyramidal cells (see Fig. 6). Increased vascularization, particularly adjacent to the hippocampal fissure, was apparent in occasional sections throughout the rostrocaudal extent of the hippocampus (for example, see Fig. 6A). No cell loss was observed in the CA2 or CA3 fields at any level of the hippocampus.
Fig. 5. Coronal section through GD's right rostral hippocampal formation stained with thionin. Region of total pyramidal cell loss in the CA1 field is marked with arrowheads. No cell loss is evident in the CA2 or CA3 fields, the dentate gyrus, or entorhinal cortex. Star indicates an area of slight cell loss in proximal subiculum. An arrow indicates the border between the entorhinal and perirhinal cortex. Abbreviations as in Figure 4. Scale bar, 1 mm.
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Fig. 6. Coronal sections through the left and right sides of GD's hippocampal formation at rostral (A, B), mid (C, D), and caudal (E, F) levels. Region of pyramidal cell loss is marked with arrowheads at each level. The lesion includes most of CA1 and proximal subiculum, with more subiculum damage on the left side. Note the sparing of proximal CA1, particularly in the caudal hippocampal region (small arrows in C-F). At these caudal levels, more of the proximal subiculum is damaged. Scale bar, 1 mm.
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Fig. 13. Photomicrographs taken at a higher magnification of the CA1 field (top row) and the CA3 field (bottom row) of the hippocampal region of a normal brain (A and E), patient GD (B and F), patient LM (C and G), and patient WH (D and H). In the CA1 field, note the complete loss of CA1 pyramidal cells in GD (B) and LM (C), and patchy loss in WH (D). In the CA3 field, no pyramidal cell loss is evident in GD (F). However, there was extensive loss of CA3 pyramidal cells in LM (G) and in WH (H). Scale bar, 0.5 mm.
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Fig. 14. Photomicrographs taken at a higher magnification of the dentate gyrus (A-D), subiculum (E-H), and entorhinal cortex (I-L) in, from left to right, a normal brain (NORMAL), GD, LM, and WH. In the dentate gyrus, granule polymorphic cell loss is visible in LM (C). Dispersion of the granule cell layer is apparent in WH (D). Patchy cell loss is evident in the subiculum in WH (H). WH also had cell loss in the entorhinal cortex (L). Scale bars, 0.5 mm.
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There was also some subicular cell loss bilaterally in the area of the subiculum/CA1 border, with more loss evident on the left side (Fig. 6C-F). This cell loss was more pronounced caudally. No damage was observed in any of the layers of the dentate gyrus.
Sections stained with a modified Heidenhain fiber procedure demonstrated that the alveus, which runs below the pyramidal cell layer of CA1, was apparently intact. Fibers of the perforant path, which originates in the entorhinal cortex, could be seen passing through the CA1 field to terminate in the dentate gyrus and CA3 field. The fimbria appeared to be slightly shrunken on the left side, although no gliosis was observed in the sections stained with thionin.
The entorhinal cortex receives approximately two-thirds of its cortical input from the adjacent perirhinal and parahippocampal cortices (Insausti et al., 1987
Diencephalon. Damage to medial diencephalic structures, including the anterior nucleus, internal medullary lamina, mediodorsal nucleus, and other midline nuclei of the thalamus, as well as the mammillary nuclei, has been associated with memory impairment (Markowitsch, 1988
Other areas. Sections were examined from all major cortical areas. A few small acellular foci were observed in the neocortex, including one in the polar cortex of the left temporal lobe, a few bilaterally in anterior lateral temporal cortex, and three in the occipital lobe. Otherwise, the cortex had a normal appearance. All cortical layers were present throughout cortex, with no apparent decrease in cell density in any area other than those mentioned above.
Throughout the white matter, there were small holes, which appeared to be enlargements of the perivascular space, i.e., Virchow-Robin space (Braffman et al., 1988
An infarct was observed in the lateral segment of the right globus pallidus that appeared to extend ~7 mm rostrocaudally and ~2 mm in width at its widest point. The lesion consisted of a region of cell loss and degeneration surrounded by a dense band of gliosis. The cerebellum showed no evidence of damage other than a small area of ischemic cell loss in the vermis. Damage to the basal forebrain has been implicated in some cases of amnesia (Alexander and Freedman, 1984
Patient LM Medial temporal lobe. The primary finding in LM's brain was an extensive bilateral lesion of the hippocampal region (Figs. 7, 8, 13, 14) with somewhat more severe damage on the left side than on the right. There was nearly complete bilateral loss of the CA1 pyramidal cells, with only a small portion of the distal part of the field remaining intact through the rostrocaudal extent of this field (Fig. 8). Throughout CA1, there was an increase in the density of glial cells. Increased vascularization, particularly associated with the hippocampal fissure, was apparent in occasional sections throughout the rostrocaudal extent of the hippocampal region (Fig. 8C).
Fig. 7. Coronal section through LM's right rostral hippocampal formation. Note the complete loss of CA1 pyramidal cells and the extensive loss of CA3 pyramidal cells (some CA3 cells remain distally). The CA2 field is partially intact. Extensive loss of polymorphic cells is evident in the hilus of the dentate gyrus (indicated by arrow). The subiculum and entorhinal cortex do not show any cell loss at this level. Abbreviations as in Figure 4. Asterisk indicates regions of faint staining, which are artifactual and are not areas of cell loss. Scale bar, 1 mm.
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Fig. 8. Coronal sections through the left and right sides of LM's hippocampal formation at rostral (A, B), mid (C, D), and caudal (E, F) levels. Arrowheads mark borders between areas of preserved neurons and areas of pyramidal cell loss. The lesion includes the CA3 pyramidal cells and most of the CA1 field, sparing some distal CA1. Regions of extensive loss of polymorphic cells in the hilus are indicated with long arrows. Cell loss also is evident in some portions of the granule cell layer (see especially A and C). Star indicates artifact attributable to cutting or staining of tissue. Scale bar, 1 mm.
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The CA2 field also sustained damage, but there appeared to be some remnant of CA2 at most rostrocaudal levels of the hippocampus, bilaterally. There also was extensive loss of the pyramidal cells in the CA3 field bilaterally. Essentially complete bilateral CA3 pyramidal cell loss was observed through the rostral half of the hippocampal region. At progressively more caudal levels, there was a progressive increase in the length of CA3 with at least some pyramidal cells intact (Fig. 8). In both the CA2 and CA3 fields, the damage was more extensive in anterior than posterior hippocampus.
Patches of granule cell layer thinning were apparent in the dentate gyrus. Dentate granule cell loss was particularly notable on the left side (see Fig. 8E). Only the most caudal sections on both sides (not shown) appeared to have a completely normal complement of dentate granule cells. The molecular layer of the dentate gyrus also appeared to be somewhat thinner than normal. In addition, almost total cell loss was observed in the hilar region. Again, the loss of polymorphic cells was more extensive rostrally than caudally (note the loss of hilar cells in Fig. 7). The subiculum had a generally normal appearance at most levels through the hippocampal region, although there were patches of cell loss in its proximal portion (particularly evident in Fig. 8E,F). The thinning of the subiculum was more apparent on the right side than on the left.
Sections stained for myelinated axons demonstrated that the alveus was not affected by the pathology. Moreover, the perforant path was visible bilaterally at all rostrocaudal levels of the hippocampal region. Fibers of the perforant path could be seen to travel through CA1 to reach their normal termination in the dentate gyrus and the CA3 field of the hippocampus. The fimbria appeared slightly shrunken, but with little evidence of gliosis.
All layers of the entorhinal cortex were evident, but layers II and III appeared to have some cell loss bilaterally (Fig. 8A,B). The paucity of cells was particularly evident in the deep half of layer III. No obvious damage was detected in other medial temporal lobe cortical areas, including the perirhinal and parahippocampal cortices. The amygdaloid complex showed no evidence of cell loss. Overall, the lesion observed in LM's hippocampal formation was fairly symmetrical, although there was somewhat more damage to the left than to the right side.
Diencephalon. In LM, neither the mammillary nuclei nor the medial thalamic nuclei showed any signs of damage. The mammillary nuclei were normal in size and shape, and microscopically had a normal cell density. Volume measurements of LM's mammillary nuclei in a previous MRI study were in the range of normal subjects (Squire et al., 1989
Other regions. Sections were examined from all major cortical areas. The only significant area of cortical damage was an infarct in the right lateral occipitotemporal cortex (area 19 of Brodmann), extending ~2 cm rostrocaudally and as wide as 2.5 cm mediolaterally. Damage in this area involved all layers of the cortex and the underlying white matter. A second, much smaller infarct was observed in the anterior left middle temporal sulcus and extended ~8 mm rostrocaudally through all cortical layers. This infarct appeared quite narrow (<1 mm wide) and involved a small area of white matter directly below it. Much less white matter damage was associated with the infarct in the left medial temporal sulcus than in occipitotemporal cortex.
Small foci of cell loss, similar to but fewer in number than those described in patient RB (Zola-Morgan et al., 1986
Also found distributed throughout cortex were small hypercellular regions presumed to be metastases, secondary to LM's lung carcinoma. Multiple brain metastases are frequently observed with small-cell lung carcinoma (Hirsch et al., 1982
Overall, the cortex had a normal appearance. The layers of all cortical areas were evident, and there was no laminar necrosis as has been observed in cases of prolonged ischemia (Garcia and Conger, 1981
Substantial cell loss was noted in the medial septal nuclei of the basal forebrain, but no damage was detected in other basal forebrain areas, including the nucleus accumbens, substantia innominata, nucleus of the diagonal band, and nucleus basalis of Meynert. The striatum had a normal appearance. As frequently seen in cases of ischemia and anoxia, there was patchy loss of cerebellar Purkinje cells in the vermis. In addition, the right and left lobules of the cerebellum were mildly atrophic.
Patient WH Medial temporal lobe. WH had an extensive bilateral lesion of the hippocampal formation (Figs. 10, 11, 13, 14) with somewhat more severe damage on the left side than on the right. Bilateral loss of CA1 pyramidal cells was observed, but more CA1 pyramidal cells were spared in WH than in RB, GD, or LM. The spared CA1 pyramidal cells were observed throughout the full transverse extent of the field; the preserved cells appeared to be those normally residing in the superficial portion of the layer (Fig. 11C). There was cell loss also in the CA2 field but less than in the CA1 and CA3 fields. Some pyramidal cells were present, bilaterally, at all rostrocaudal levels of the CA2 field. There was nearly complete loss of pyramidal cells in the CA3 field, bilaterally (Fig. 11). On the right side, some CA3 pyramidal cells remained in the most caudal levels of the hippocampus. Damage to the CA2 and CA3 fields was more extensive rostrally than caudally in the hippocampus. Holes were present in the CA3 and CA1 fields that were also visible in WH's MR images (Fig. 12).
Fig. 10. Coronal section through WH's right rostral hippocampal formation showing pronounced neuropathology. Extensive pyramidal cell loss is apparent in the CA1 and CA3 fields, and less substantial loss of CA2 pyramidal cells. The dentate gyrus appears very abnormal, with dispersion of the granule cell layer (small arrow) and complete loss of polymorphic cells. A star indicates a hole in the hilar region that is apparent at many rostrocaudal levels of the hippocampal formation; it does not appear to be histological artifact. Patchy cell loss is evident in the subiculum and the entorhinal cortex (layers III, V, and VI). A large arrow indicates the border between the entorhinal cortex and the perirhinal cortex. Abbreviations as in Figure 4. Scale bar, 1 mm.
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Fig. 11. Coronal sections through the left and right sides of WH's hippocampal formation at rostral (A, B), mid (C, D), and caudal (E, F) levels. In rostral hippocampus, more CA pyramidal cell loss is apparent on the left side (A) than on the right (B). Note the increased vascularization and the hole in the hilar region (indicated in each section on the right with a star). On the left side (A), substantial loss of neurons is apparent in the subiculum and entorhinal cortex. In a midrostrocaudal level of the hippocampus, a hole is evident in the hilar region bilaterally (stars), and increased vascularization is evident on both sides (C, D). In addition, damage is apparent in the hippocampal pyramidal cell fields and the dentate gyrus, including extensive pyramidal cell loss in the CA1 and CA3 fields, dispersion of the granule cell layer, and complete loss of polymorphic cells. Note the sparing of the superficial portion of the CA1 pyramidal cell layer on the left (arrow in C). Patchy cell loss is evident in layers III, V, and VI of the entorhinal cortex. The general pattern of damage continues through the caudal hippocampus, with increasing cell loss in the subiculum (E, F). Some preservation of CA1 and CA2 pyramidal cells is visible on the right side (F). Scale bar, 1 mm.
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Fig. 12. Comparison of a T1-weighted MRI (top) and a Nissl-stained histological section (bottom) from the brain of patient WH at a level just rostral to the lateral geniculate nucleus. Note the enlarged ventricle (V) adjacent to the hippocampus (H). Note also the cystic defect in the right CA1 region of the hippocampus (), which appears in the Nissl section and in the magnetic resonance image. The fornix (f) is indicated in the Nissl-stained section. The right side of the brain is shown on the right side of the illustrations.
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The appearance of WH's dentate gyrus was very abnormal bilaterally. Prominent holes appeared in the hilus of the dentate gyrus. Whereas some of these appeared to be enlarged blood vessels, others were infarcts or other defects in the hippocampal tissue. Essentially complete loss of hilar cells was noted (Fig. 11). The granule cell layer did not have its normal tightly packed appearance. Rather, there was a radial dispersion of the granule cells that constituted the layer. Dispersion of the granule cells was prominent at most rostrocaudal levels, decreasing slightly at caudal levels. Because of the changes in the density of the granule cell layer caused by the dispersion, it was not clear whether there was actual cell loss. If there were actual cell loss, it would likely have been minimal. In addition to changes in the cell density and thickness of the granule cell layer, the granule cells appeared larger than normal with thickening of proximal dendrites. Similar pathology has been reported in patients with temporal lobe epilepsy (Houser et al., 1990
Patchy cell loss was observed in the subiculum. Cell loss in the subiculum was more pronounced caudally and greater on the left side than on the right (Fig. 11E,F). The fimbria was shrunken and gliotic bilaterally. The entorhinal cortex also appeared abnormal, but its pathology was slightly different than that seen in LM. At rostral levels of WH's entorhinal cortex, the lamina were clearly defined, although the distinctiveness of the layers decreased at more caudal levels. Cell loss in the entorhinal cortex was noted bilaterally in layers III, V, and VI, and slight loss was observed in layer II. The deep portion of layer III had the most apparent loss of neurons. The entorhinal cortex sustained more damage on the left side than the right (Fig. 11C). No damage was detected in the perirhinal and parahippocampal cortices.
Diencephalon. WH's mammillary nuclei were reduced in size, corresponding to findings from magnetic resonance studies performed 5 years before his death (Squire et al., 1990
Fig. 15. Photomicrographs of the medial mammillary nuclei in a normal brain (A) and WH (B). WH's medial mammillary nuclei are small, gliotic, and more densely packed with cells (B). MMN, Medial mammillary nuclei; mtt, mammillothalamic tract. Scale bar, 1 mm.
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Other areas. Overall, the cortex had a normal appearance with clearly defined lamina and no decrease in cell density apparent in any cortical area. Numerous areas of perivascular dilation were noted throughout the white matter of WH's brain. These were substantially more abundant and of larger size than those observed in GD. These lacunae were densely distributed especially in the temporal poles bilaterally, and subcortically in the striatum, claustrum, and the globus pallidus, particularly in its medial segment. The only other damage noted in the brain of WH was an infarct in the pons. The appearance of the cerebellum was normal with the exception of some loss of Purkinje cells in the vermis. No cell loss was noted in the basal forebrain.
Summary of the three brains Patient GD had the least damage of the three patients. The primary lesion in GD's brain involved nearly all the CA1 field of the hippocampus bilaterally, sparing a small portion of proximal CA1, and also included a small region of the subiculum near the CA1 border. No bilateral damage was identified elsewhere in the hippocampal region or in the entorhinal, perirhinal, or parahippocampal cortices. Other than in the medial temporal lobe, there was minimal damage to the left medial mammillary nucleus and the left mediodorsal nucleus of the thalamus. There was no evidence of damage in the basal forebrain. Damage was also detected in the external segment of the right globus pallidus, and enlarged perivascular spaces were noted in a widespread distribution throughout the white matter.Patient LM had more damage to the hippocampal formation than GD. His lesion included most of the CA1 field bilaterally, sparing the most distal portion of the field near the subiculum border. The CA2 field sustained some damage, but there were patches of preserved CA2 throughout the rostrocaudal length of the hippocampus. In addition, there was essentially complete loss of CA3 pyramidal cells bilaterally. Loss of the CA2 and CA3 pyramidal cells was generally more extensive in the rostral than in the caudal hippocampus. In the dentate gyrus, there was extensive loss of cells in the polymorphic layer (the hilar region) as well as patchy loss of granule cells. Although the subiculum was generally intact, there was some slight patchy loss of the most proximal portion of the field. The entorhinal cortex also demonstrated some cell loss. This was most noticeable in layers II and III, particularly deep in layer III. Finally, there was a substantial loss of cells in the medial septum. Other damage included infarcts in the right lateral occipitotemporal cortex and the left medial temporal sulcus. In addition, small metastases were distributed in frontal, parietal, temporal, and occipital cortices, and in the basal ganglia.
Patient WH had the most distributed damage to the hippocampal formation of the three patients, including substantial cell loss in the CA fields, the dentate gyrus, and the subiculum, as well as cell loss in the entorhinal cortex. Unlike GD and LM, cell loss in WH's CA1 spared some of the superficial CA1 pyramidal cells. Also unlike in GD and LM, in WH the most extensive and complete loss of cells occurred in the CA3 field with partial damage to the CA2 and CA1 fields. As observed in LM, damage to the CA fields was more extensive in the rostral than in the caudal hippocampus. Furthermore, WH's dentate gyrus was very abnormal. Essentially complete loss of polymorphic cells was noted in addition to marked dispersion of the granule cell layer. The subiculum had extensive patchy cell loss, especially caudally. Holes and increased vascularization were present in the hippocampal region, particularly in the hilus. The entorhinal cortex of WH was also damaged, including bilateral cell loss in layers III, V, and VI, and minimal loss in layer II. The cell loss in the subiculum and entorhinal cortex was worse on the left than on the right side. No damage was detected in perirhinal or parahippocampal cortices. WH's mammillary nuclei appeared small, gliotic, and had a higher cell density than normal. Other sites of damage in WH included an infarct in the pons and widespread perivascular enlargements in the white matter and striatum, particularly in the medial segment of the globus pallidus and the claustrum.
Comparison of findings from MRI with postmortem findings Patients LM and WH had been evaluated with MRI in 1989, approximately 1 and 4 years before their deaths, respectively (Squire et al., 1990
Fig. 9. Comparison of a T1-weighted MRI (top) and a Nissl-stained histological section (bottom) from the brain of patient LM at the level of the mammillary nuclei (MMN). The brain appeared to be somewhat asymmetrical because the amygdaloid complex (A) is seen on the left side, whereas the hippocampus (H) is seen on the right. The asymmetry does not appear to be attributable to oblique coronal sectioning because the mammillary nuclei are apparent bilaterally. Note the enlarged ventricle located dorsal to the hippocampus on the right side and the markedly shrunken appearance of the hippocampus. There is a clear correspondence in the appearance of the hippocampal formation in the MRI and in the histological section. The entorhinal cortex (EC) also is visible bilaterally. The right side of the brain is shown on the right side of the illustrations.
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DISCUSSION
Neuropsychological and neuropathological findings from the three cases of amnesia reported here, patients GD, LM, and WH, together with the previously reported findings from RB (Zola-Morgan et al., 1986The hippocampal formation and anterograde amnesia
For the purpose of this discussion, we consider the hippocampal formation to consist of two components, i.e., the hippocampal region (including the dentate gyrus, the cell fields of the hippocampus proper, and the subicular complex) and the entorhinal cortex. The present findings, as summarized in Table 3, make two important points. First, the findings from patients RB, GD, and LM show that damage limited primarily to the hippocampal region, even when incomplete, is sufficient to produce a clinically significant memory impairment. (Of these three, only LM had damage outside the hippocampal region, involving some loss of cells in entorhinal cortex.) These findings correspond to previous findings in monkeys (Zola-Morgan et al., 1992The second point is that anterograde memory impairment can be exacerbated when more extensive damage occurs to the hippocampal formation. The damage in WH, whose memory was the most severely impaired, involved the whole hippocampal formation, i.e., there was extensive cell loss in the hippocampal region (including the dentate gyrus, all the cell fields of the hippocampus, and the subicular complex), and there was additional cell loss in the entorhinal cortex. The same point can be made for the well studied amnesic patient, HM (Scoville and Milner, 1957
The work described here comes from patients with apparent ischemic or anoxic damage to the hippocampal formation. The question naturally arises whether the cascade of events initiated by ischemia or anoxia might produce neuronal damage sufficient to impair behavioral performance, but not sufficient to progress to cell death and to be detectable in histopathology. This possibility has been referred to as covert damage (Bachevalier and Mishkin, 1989
The hippocampal formation and retrograde amnesia
Damage limited primarily to the CA1 field of the hippocampal region (patients RB and GD) caused minimal retrograde amnesia, involving perhaps 1 or 2 years. Patient GD was previously thought to have extensive, temporally graded retrograde amnesia (MacKinnon and Squire, 1989Early work on retrograde amnesia in amnesic patients, which depended primarily on anecdotal evidence of impaired memory, suggested that retrograde amnesia gradients are rather limited, perhaps a few years or less, even after substantial damage to the medial temporal lobe. One of the most influential early reports was that amnesic patient HM's retrograde amnesia covered only the 2 years preceding his medial temporal lobe surgery (Milner et al., 1968
The report of HM's limited retrograde amnesia at the time was consistent with other reports of apparently brief retrograde amnesia after medial temporal lobe damage or removal. For example, Penfield and Milner (1958)
Some 20 years after the onset of his amnesia, patient HM was given formal tests to assess his memory for past public and personal events (Marslen-Wilson and Teuber, 1975
We also note that HM's ability to recall the names of famous tunes was below the normal range for the 1930s as well as the 1940s (Corkin, 1984
Recent prospective studies in experimental animals have substantiated the idea that medial temporal lobe damage can produce temporally graded retrograde amnesia (Winocur, 1990
Findings of extensive, temporally graded retrograde amnesia led to the idea that, as the years pass after learning, there is gradual reorganization or consolidation within long-term memory storage. The importance of structures in the medial temporal lobe gradually diminishes and more permanent memory storage develops (presumably in neocortex) that is independent of this region (for a recent review, see Squire and Alvarez, 1995
FOOTNOTES
Received March 21, 1996; revised May 30, 1996; accepted June 3, 1996.
This work was supported by the Human Frontiers Science Program, the Medical Research Service of the Department of Veterans Affairs, National Institute of Mental Health Grant MH24600, the McKnight Foundation, the Office of Naval Research, National Institutes of Health Grant NS 16980, and a McDonnell-Pew predoctoral fellowship in cognitive neurosciences (N.R.-C.). We thank Dr. Mark Kritchevsky, Dr. Eliezer Masliah, Cecelia LeClair, Amy Lockwood, and Scott Hanson for their contributions, and we thank the patients and their families for their cooperation and encouragement.
Correspondence should be addressed to Stuart M. Zola, Department of Psychiatry 0603, University of California at San Diego School of Medicine, La Jolla, CA 92093.
Dr. Rempel-Clower's present address: Department of Health Sciences, Boston University, Boston, MA 02215.
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