Contributions of the Left Intralaminar and Medial Thalamic Nuclei to Memory Comparisons and Report of a Case Mark Mennemeier, PhD; Eileen Fennell, PhD; Edward Valenstein, MD; Kenneth M. Heilman, MD \s=b\ A patient complained of memory disturbance after a small left thalamic infarction. Neuropsychological testing revealed her memory to be normal provided that she was allowed to rehearse or use semantic encoding strategies. When these strategies were prevented, her performance was impaired. Mapping of the lesion demonstrated involvement of the caudal intralaminar nuclei (centre m\l=e'\dianand parafascicular nuclei), and portions of the medial nuclei (medioventral [reuniens], centromedial, and the most inferior aspect of the mediodorsal nucleus). The majority of mediodorsal nucleus, the mammillary bodies, the mammillothalamic tract, and the anterior thalamic nuclei, were spared. A comparison among our patient's performances and those of alcoholic Korsakoff patients, patient NA, and amnestic patients with circumscribed diencephalic lesions suggests that there are two distinct behavioral and anatomic types of memory impairment associated with diencephalic lesions. The severe amnesia associated with damage to the mammillary bodies, midline nuclei, mammillothalamic tract, and/or dorsomedial nucleus of the thalamus (eg, Korsakoff and NA) is characterized by encoding deficits that never approximate normal performance. The memory disturbance associated with damage to the intralaminar and medial nuclei of the thalamus is milder and is characterized by severe distractibility. (Arch Neurol. 1992;49:1050-1058) lesions of the thalamus Discrete lasting Although remains critical for which thalamic can cause severe and amnesia. it uncertain memory, evi¬ dence from human and animal research suggests that one or more of the following structures are important: the an¬ terior nuclei,1 the midline nuclei,2-3 the mammillothalamic and amygdalofugal tracts,3"5 and the mediodorsal nu¬ cleus.6-7 It has also been suggested on anatomic grounds that the contribution of smaller nuclei (medioventral [reuniens], paracentral, and paraventricular) cannot be ex¬ cluded.8 It has been difficult to ascribe specific importance to any single thalamic structure because thalamic lesions, both in animals and in humans, almost invariably affect more than one thalamic structure and because the neustructures are Accepted for publication June 10, 1992. From the Department of Veterans Affairs Medical Center (Drs Mennemeier, Valenstein, and Heilman); Department of Neurology, Center for Neuropsychological Studies (Drs Mennemeier, Fennell, Valenstein, and Heilman); and Department of Clinical and Health Psychology (Dr Fennell), University of Florida College of Medicine, Gainesville. Reprint requests to Department of Neurology, University of Florida, Box J-236, Gainesville, FL 32610 (Dr Mennemeier). ropsychological evaluation of patients in the literature varies considerably from case to case. In fact, the patients whose behavioral deficits have been studied most exten¬ sively, alcoholic Korsakoff's and patient NA (who became amnestic after a fencing foil penetrated his brain), have all had extrathalamic damage as well as damage to several areas within the thalamus. When we encountered a patient with a discrete thalamic lesion who complained of mem¬ ory dysfunction, therefore, we studied her extensively to characterize the nature of her deficits. We found that her deficits differed in important respects from those of the usual "diencephalic" amnesic, and that the locus of her le¬ sion also differed from that of most patients reported with thalamic amnesia. We suggest that the localization of her lesion to the caudal intralaminar thalamic nuclei probably accounts for the nature of her deficits. REPORT OF A CASE and History Neurological Examination A 44-year-old, left-handed woman with 12 years of education and consistently good work history, including managerial positions at retail stores, presented to us. There was no history of focal neuro¬ logic symptoms and there was no history of diabetes, hypertension, or migraine. She was taking no medication. On May 21,1988, she was admitted to the hospital with lightheadedness, dizziness, and transient loss of consciousness. On awakening, she was alert and oriented but had right arm weakness, slurred speech, and diplopia. On examination there was right superior rectus muscle weakness, reduced fine motor control in the right hand, and decreased pain sensation in the right hand. Magnetic resonance imaging (Tr and T2-weighted images) 8 days after the stroke showed a nonhemorrhagic, 1-cm lesion in the medial thalamus. An electroencephalo¬ gram performed 2 days after admission was slightly slow on the left side. Over the next 3 months her symptoms largely resolved. A sec¬ ond electroencephalogram was read as normal. On August 23,1988, she was readmitted to the hospital with slurred speech, occipital headache, and abnormal sensations on the right side, all of which a subsided in less than 24 hours. Since then she has been followed up regularly and has had no new neurologic symptoms. Laboratory studies included a complete blood cell count, erythrocyte sedimen¬ tation rate, antinuclear antibodies, rheumatoid factor, VDRL, hemagglutination treponemal test for syphilis, lipid profile, antiphospholipid antibodies, and cerebrospinal fluid cell count, protein, glu¬ cose, IgG, myelin basic protein, and oligoclonal bands—all showing normal results. Four months following her stroke, the patient was referred for evaluation with continuing complaints of memory and concentra¬ tion problems. Specifically, she described difficulty remembering dates, conversations, and material she had read. She noticed an in¬ ability to perform simultaneous activities that she was previously able to accomplish. For example, she volunteered to cook for a com¬ munity organization but found that she could not talk with other Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/03/2015 Fig 1 .—Left, Axial (TR: 2000, TE: 80 2/2); center, coronal (TR: 2400, TE: 80 2/2); and right sagittal (TR: 600, TE: 20 7/7) sections showing our patient's lesion. volunteers and work at the same time. She started bringing work home to save herself embarrassment. In daily activities, she was devastated by her stroke. She was no longer able to work as she could not keep up with the cognitive demands and fatigued quickly. Her social activities changed. She stated that she now socialized with retired persons partly due to living circumstances and partly due to the pace of conversations and activities. This represented a marked change in functioning from premorbid levels. Last, the pa¬ tient had complaints of word-finding problems. On examination, she was normotensive with normal pulses and no carotid or cranial bruits. Other than a 2/6 systolic ejection mur¬ mur, her general physical examination was normal. On neurologic examination, she was alert and oriented. Her digit span was 7 num¬ bers forward, and she recalled two of three words after distraction. She was able to name nine words that started with the letter s in 1 minute. When speaking, she sometimes hesitated as if to find a word. However, her repetition, comprehension, and naming were normal. There was no right-left confusion or finger agnosia, but she had difficulty with serial 7s. She could copy a cube, and there was no evidence of neglect. Except for a slight subjective decrease of touch and pain sensation on the right side the remainder of the neu¬ rological examination was normal. Results of routine laboratory studies were normal, as were sed¬ imentation rate, antinuclear antibody, lupus anticoagulant, antiphospholipid and anticardiolipin antibodies, and a threedimensional echocardiogram. Lesion Localization A magnetic resonance imaging scan was performed on a 1,5-Tesla approximately 9 months after her stroke. Axial, coronal, and sagittal sections the lesion are shown in Fig 1. The an¬ terior and posterior commissures were identified on the midsagittal section (not shown), and the ratio of the anterior-posterior commis¬ sures distance on the scan to that of the atlas of Schaltenbrand and Bailey9 was used to map the anteroposterior extent of the lesion on the midsagittal section of the atlas. Coronal sections from the atlas that traversed the lesion were used for mapping (Fig 2). The lateral extent of the lesion was estimated, again comparing landmarks (in¬ cluding the midline of the third ventricle, the lateral margin of the putamen, and the insular cortical surface) on the axial and coronal magnetic resonance imaging sections with similar measurements in the atlas. Because of differences in the plane of the section, it was more difficult to map the vertical extent of the lesion directly from magnetic resonance imaging to the atlas, but estimates were made based on measurements in the other two planes and adjusting for differences in the plane of the section. We judged that errors caused scanner through by tilt of the sections (ie, right up, left down on axial sections, or right forward, left back on coronal sections) would be small since the le¬ sion was close to the midline. The lesion was confined to the left thalamus and mesencephalic gray matter. It was oval, about 1 cm in its longest anteroposterior dimension, 0.8 cm at its widest, and 0.8 cm high. It involved almost the entirety of the parafascicular nucleus, a large portion of the cen¬ tre médian, and portions of the reuniens or medioventral and centromedial nuclei. The rostral border of the lesion was in the inferior portion of the mediodorsal nucleus, and the caudal border was just superior to the red nucleus, in the central mesencephalic gray mat¬ ter. The mammillary bodies, mammillothalamic tract, anterior tha¬ lamic nuclei, and the vast majority of mediodorsal nuclei appeared normal. No other lesions were apparent on the magnetic resonance imaging scan. Neuropsychological Assessment During testing the examiners noted a disinclination to use the right hand, although no other signs of neglect were detected. Our patient demonstrated a full range of emotions with normal inten¬ sity. Her conversational speech was within normal limits, as tone, quality, and speed were unaltered. She underwent neuropsycho¬ logical testing at approximately 4 and 11 months after her stroke. She was taking no medication other than aspirin at the time of these assessments. No appreciable change occurred on any of the re¬ peated measures; therefore, only the most recent test scores are dis¬ cussed. Table 1 summarizes these test results. Intellectual functions were well within the average range (verbal IQ, 102; performance IQ, 107; and full-scale IQ, 104), with subtest scores ranging from 9 to 13. Digit symbol (a scaled score of 6) was the only abnormal subtest score, owing largely to slow perfor¬ mance. Tests of executive and motor functions provided mixed re¬ sults. The patient's pointing span on the Wechsler Memory ScaleRevised10 was below expectations. The Wisconsin Card Sorting Test11 was within normal limits but Trails of the Trail Making Test12 was slow (116 seconds) with one error (normative data from Heaton13). Finger tapping was slow bilaterally (second percentile from Trahan et al14) but more pronounced on her nondominant right hand. Speech and language testing was largely within normal limits but exceptions were noted in the Controlled Oral Word Association Test (33rd percentile from Benton and Hamsher15) and reading com¬ prehension, indicating problems with seventh-grade material.16 No comprehension, repetition, or naming (ie, Western Apha¬ sia Battery17 and Boston Naming Test18) were evident. A sensory perceptual examination (from the Halstead-Reitan Battery19) indi¬ cated three of four auditory extinctions on the right side with no errors in Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/03/2015 Table 1.—Summary of Neuropsychological Testing: 1-Year Follow-up* Intellectual Functions (VIQ=102, PIQ=107, and FSIQ=104) Verbal Scale Performance Scale Information 11 Picture completion 10 Digit span 9 Picture arrangement 9 Vocabulary 9 9 Comprehension 10 Block design Object assembly Digit symbol 10 Arithmetic Similarities 13 12 6 Memory Functions (WMS-R Ml=100) Verbal Memory Digit span, 8 forward, 6 back Nonverbal Memory Pointing span, 4 forward, 4 back WMS visual retention Immediate, 9 Delay, 9 Retention, 100% WMS stories Immediate, 9.5 Delay, 8 Retention, 84% Continuous Visual Memory Test Hits, 38 False alarms, 18 d-Prime, 2.32 Correct, 84 California Verbal Learning Test Monday list, 5, 10, 13, 8, 13 Tuesday list, 5 Monday immediate, 11 Delay, 12 Recognition, 16 Selective Reminding Test Rey-Osterrieth Complex Figure Copy, 34 Recall, 5, 7, 7, 9, 8, 9, 10, 10, 11, 10, 12 Immediate, 23 Delay, 22 LTS, 84 LTR, 81 CLTR, 56 STR, 20 Retention, 96% Milner Facial Recognition 9/12 Levels of processing, No. (%) Semantic, 11/12 (92 correct) Phonemic, 8/12 (67 correct) Orthographic, 4/12 (33 correctif Rates of forgetting verbal, No. (%) Rates of forgetting nonverbal, No. (%) 5 min, 28/30 (93) 1 h, 27/30 (90) 24 h, 24/30 (80) 30 min, 10/12 (83 retention) 8 h, 10/12 (83 retention) 24 h, 10/12 (83 retention) 48h, 24/30 (80) Release from proactive interference, No. (%) 12/15 (80), 10/15 (66), 10/15 (66) 5/15 (33), shift, 10/15 (66) Other Findings Verbal fluency, 27 (30%-33%ile) Boston Naming, 63/64 Spache Reading, 5/8 at 7th-grade levelt Trails A, 30 s Trails B, 116 st Wisconsin Card Sorting, 6/6 categories in 128 sorts Praxis WAB, no errors Finger tapping Sequential commands WAB, no errors Repetition WAB, no errors Naming WAB, no errors RH=33t LH=40 Sensory perceptual examination 3/4 Right ear extinctionst *VIQ indicates verbal IQ; PIQ, performance IQ; FSIQ, full-scale IQ; WMS-R, Wechsler Memory Scale-Revised; Ml, memory index, WMS, Wechsler Memory Scale; LTS, long-term storage; LTR, long-term retrieval; CLTR, consistent long-term retrieval; STR, short-term retrieval; WAB, Western Apha¬ sia Battery; RH, right hand; and LH, left hand. tOutside the range of normal. other apparent deficits. No problems in visuoanalytic or visuospatial constructional abilities were evident on the Rey-Osterrieth Complex Figure20— copy, immediate, or delayed recall (normative data from Lezak21). Memory Tests Mild problems were evident on tests of verbal memory and list learning. Although she showed eventual learning and good reten¬ tion on the logical stories of the Wechsler Memory Scale-Revised10 and the California Verbal Learning Test (CVLT),22 the rate at which the patient acquired verbal information was slow (ie, two standard scores below normal on the first trial of the CVLT). She also tended to recall only the first and last parts of the Wechsler stories. She did demonstrate semantic clustering on the CVLT, however, and was able to recall and recognize items after delays. She was also able to retain information over extended delays as she demonstrated nor¬ mal rates of forgetting for both verbal and nonverbal23-24 material after delays of 5 minutes and 1, 24, and 48 hours. Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/03/2015 Fig 2.—Lesion plotted on corresponding sections of a stereotaxic atlas (details of sections in the coronal plane). Dark lines in plates A through C cor¬ respond to Y (horizontal grid) and axes (vertical grid). Dark lines in brain illustration represent X (horizontal) and (vertical) axes. Speckled area represents lesion. CG indicates central gray; CL, central lateral nucleus; CM, centre médian nucleus; CeM, central medial nucleus; MD, mediodorsal nucleus; O, oralis (principal ventral medial nucleus); Pf, parafascicular nucleus; Re, reuniens (medioventral nucleus); RN, red nucleus; VM, ventral medial; and ZI, zona incerta. Plates redrawn and modified from Schaltenbrand and Bailey.'' Measurements in millimeters under plate numbers in¬ dicate distance of the plane of section posterior to the point midway between the anterior and posterior commissures. The patient's neuropsychological evaluation suggested specific verbal memory and cognitive problems. She could retain informa¬ tion once acquired but had difficulty incorporating new items into long-term memory. She also appeared compromised in her ability to attend to and process multiple bits of information simulta¬ neously. Given several tasks to coordinate at once, her cognitive problems became more pronounced. She appeared to be suffering from specific deficits that were severely impairing her daily functioning. To define the factors underlying her memory problem, several sample of tests were selected and administered to the patient and a age- and education-matched control subjects. These tests examined her ability to encode information in short-term memory, hold in¬ formation over time without rehearsal, and to enter, consolidate, and retrieve information from long-term memory. Control Subjects Four healthy female (mean age, 43 years; SD, 4 years) volunteers provided direct matches on age and geographic region. All were employees of the Department of Veterans Affairs Medical Center, Gainesville, Fla, engaged in either retail sales, secretarial, or clerical positions. Their mean education level was equivalent to the pa¬ tient's (mean, 13.5 years). All control subjects were right-handed and none had a history of neurologic disease or insult. Published normative data were also used for comparisons. MATERIALS AND PROCEDURES Four tests of memory formed the basis for this comparison. All subjects received the tests in a random order. The first task involved the Level of Processing Paradigm of Craik and Tulving.25 Subjects were shown 36 words printed separately on index cards. After ex¬ amining each word for 5 seconds, subjects answered whether the: (1) word was printed in upper (or lower) case letters, (2) word rhymed with a given word, or (3) word was a member of a given semantic category. Items were balanced for the number of positive (yes) and negative (no) responses. Recall was tested in a recognition format after a 20-minute delay with intervening motor tasks (ie, tri¬ als of finger tapping). The subject was shown four words printed on an index card and asked to select the previously seen word from among three words not previously seen. Percentage correct recog¬ nition was calculated for each of the three conditions (ie, ortho¬ graphic, phonologic, and semantic) by dividing the number of cor- Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/03/2015 possible for that condition. rect responses obtained by the total The second test involved the Release From Proactive Inhibition 100 technique.26 On each trial, a subject's memory for three words from the same semantic category was tested. Following presentation of the three words, the subject was required to engage in a 15-second distractor task (eg, counting backward from a target number by three). The distractor was given immediately after the words to pre¬ vent rehearsal in short-term memory. Subjects were then required to recall the three words. Subjects were tested in six blocks of five trials. In half of the blocks, the first four trials of words were mem¬ bers of the same semantic category (eg, items of furniture), but on the fifth trial the category shifted (eg, body parts). The category does not shift on the fifth trial for the remaining blocks; rather, words in the fifth trial of these blocks belong to the same category as the pre¬ vious four trials (no shift condition). Percentage correct recall across trials for both shift blocks was calculated by dividing the total words obtained by the total words possible. The distraction technique of Brown27 and Peterson and Peterson28 constituted the third task. Subjects were required to recall three con¬ sonant trigrams after either 3, 9, or 18 seconds of interference (ie, counting backward by three from a given number). There were five trials counterbalanced for each of the delay conditions. Percentage correct recall for consonants across the 3-, 9- or 18-second delay con¬ ditions was obtained by the total possible. Buschke's29 Selective Reminding Memory Test was the fourth test of memory. The words used in this task correspond to the Hannay and Levin30 Form 2. The task consisted of recalling 12 unrelated words on successive trials. On the first trial all 12 items were read aloud at a rate of two words per second. After the first trial, only those items that were not recalled were presented again before the next recall. Repetitions of the list proceeded in this fashion until the subject obtained all the words on the list two times or until 12 trials had been given. The test provides measures of short-term recall, long-term storage, long-term recall, consistent long-term retrieval, and random long-term retrieval (see references 29 and 30 for scoring Phonologic Orthographic Encoding Level Fig 3.—Levels of processing task. Comparison of our patient with con¬ trol subjects. Solid squares indicate our patient; open circles, control subjects. Asterisk indicates a score outside the range of normal. Semantic procedures). RESULTS Data obtained in experiment one were analyzed using measures of central tendency and percentage correct re¬ sponses. Comparisons between our patient's performances and those of the control subjects were evaluated by estab¬ lishing 95% confidence limits for the control subjects' scores using conservative estimates of the variance.31 Limits corre¬ sponded to the 0.05 level of significance for one- and twotailed tests. The patient performed similarly to control subjects on only one test, the release from proactive interference test. The av¬ erage percent correct recall for the control subjects on trials 1 through 5 in the shift condition indicated a build- up and release from proactive interference (86.25%, 80.25%, 48.25%, 60.55%, and 91.75%, respectively). The patient's scores (80%, 66%, 66%, 33%, and 66%) similarly indicate build-up and re¬ lease from proactive interference. She was significantly different from the control subjects on the levels of processing, Peterson-Peterson, and selective re¬ minding tests. Results from the levels of processing task are given in Fig 3. Her ability to recognize words encoded at deeper levels, both semantic and phonologic, was within the range of the control subjects. However, she was markedly impaired when words were processed orthographically (confidence range for control subjects, 12-6.5; patient's score, 4). The patient's deficits were pronounced on the PetersonPeterson paradigm. Figure 4 includes results obtained from the patient, control subjects, and, for comparison, a group of Korsakoff patients.32 Distraction significantly affected her recall at 9- and 18-second delays relative to normal subjects. Fig 4.—Comparison of our patient with control subjects and alcoholic Korsakoff patients on the Peterson-Peterson task. Triangles indicate al¬ coholic Korsakoff patients; circles, control subjects; and squares, our patient. Data on alcoholic Korsakoff patients from Butters andCermak.32 Her performance was also below the alcoholic Korsakoff pa¬ tients at 9- and 18-second delay recall periods. Scores from both control subjects and a comparison group of nonforgetful seniors33 were used to evaluate our patient's performance on the selective reminding test. Table 2 lists these results. Her scores differed most from control subjects on measures of long-term retrieval, long-term store, and ran¬ dom long-term retrieval. She also showed an overreliance on short-term memory and a lack of consistency in retrieval from long-term memory. The scores of the comparison group fell in between those of the patient and the agematched control subjects and were not significantly different from either. Even so, our patient's scores on the three indexes were below those obtained by subjects 20 years older. Thus, in spite of a relatively normal neurologic examination, her cognitive complaints were verified by detailed neuropsy¬ chological tests. COMMENT Comparative Neuropsychology of Memory Impairment This patient was able to semantically encode information. Evidence for spared semantic encoding comes from her nor¬ mal performance on the release from Proactive Interference Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/03/2015 Table 2.—Comparison of Our Patient With Control Subjects on the Selective Reminding Test* Control SRMT Subjects, Indexes Mean (SD) Recall LTR 124(15) 122 (14) STR 7 (5.9) LTS 122(16) 112 (26) 7 (7.4) Nonforgetful Seniorst (n=78) Mean (SD) Patient Mean (SD) 101 (2.3) 81 (2.9)* 20(1.0)§ 97.2(19.6) 84(3.1)|| CLTR 68.3 (30) 56 (2.8)§ RLTR 21.3 (12.3) 36 (2.6) *LTR indicates long-term retrieval; STR, short-term retrieval; LTS; long-term storage; CLTR, consistent long-term retrieval; and RLTR, randorn long-term retrieval. tFrom Larrabee et al.33 <.01. §P<.05 (two tailed). ||P<.02. test and her improvement on the levels of processing par¬ adigm. Normal subjects typically show a release effect on the release from the Proactive Interference paradigm. They re¬ gain proficiency at remembering the three words after a shift in semantic category.26 Build-up of proactive interference is interpreted as an ability to differentiate words in short-term memory according to semantic features. Since the patient also demonstrates this phenomenon, she apparently has the ability to make semantic distinctions in short-term memory. She showed good recognition of words that were initially processed according to semantic rather than physical fea¬ tures. Craik and Lockhart34 and later Craik and Tulving25 proposed that the strength of a memory trace was related to the level at which it was initially processed. A semantic anal¬ ysis of words is assumed to involve deeper levels of process¬ ing than phonemic or physical (orthographic) analysis. Al¬ ternative explanations of the levels of processing effect have been proposed35 but regardless of disagreement the levels ef¬ fect is unquestionably robust, occurring in amnestic pa¬ tients36 as well as in normal subjects.37 We view this patient's performance on the Levels of Processing test as a preserved ability to retain words processed semantically but a subnor¬ mal ability to identify words when forced to encode them by less robust means. Both the release from Proactive Interference and Levels of Processing tests manipulate encoding externally. They do not provide an indication of her spontaneous strategy for en¬ coding information. To evaluate this ability we examined how well she clustered items according to semantic category on the CVLT. Her performance on this test indicated a good spontaneous use of semantic clusters. She averaged six clus¬ ters per learning trial (ranging from 1 to 9) and used clus¬ tering effectively during both immediate (seven clusters) and delayed (nine clusters) recall, which is above the average clustering score for normal females of similar age.22 Thus, she spontaneously adopted a semantic clustering strategy that led to normal rates of encoding and recall. Since this strategy was not overtly encouraged, it appears that her preferred mode of processing is semantic, a strategy shown to produce the best rate of recall on list learning tasks in normal sub¬ jects.38 This finding is consistent with our interpretation of our patient's normal ability to encode material semantically. Buschke29 designed the Selective Reminding Test to exam¬ ine how memory items move from short- to long-term stores. He distinguished between items placed in long- and shortterm storage by controlling the times at which they were re¬ peated to the subject during learning trials. This test was par¬ ticularly useful for examining our patient because it demon¬ strated the difficulty she had consolidating information into long-term storage. Her problems reflect consolidation def¬ icits more than retrieval problems because her delayed recall was excellent. Our patient performed much worse on the Selective Re¬ minding Test than on the CVLT. The Selective Reminding Test appears different from the CVLT in at least two ways. First, the semantic associations between items are not obvi¬ ous on the Selective Reminding Test. Ruff et al38 found that only 40% of normal subjects used clusters efficiently in the Selective Reminding Test. Second, list items are only re¬ peated on the Selective Reminding Test if the subject cannot recall them from a previous trial. Thus, maintenance re¬ hearsal through repetition is not an inherent strategy of the Selective Reminding Test. Her relatively poorer perfor¬ mance on the Selective Reminding Test may reflect an inabil¬ ity to process memory items without the use of direct encod¬ ing strategies. Consistent with this interpretation, she did not cluster items on recall trials of the Selective Reminding Test. The patient shows a dramatic susceptibility to the effects of interfering tasks on the Peterson-Peterson paradigm. When rehearsal was prevented by use of a dis tractor task, she demonstrated a significant loss of information at 9- and 18second delay intervals. She even performed below the level reported for Korsakoff patients on this task.32 Although the psychometric qualities of the Peterson-Peterson task have not been described,39 forgetting is assumed to reflect either trace decay and /or susceptibility to interference.35 The ef¬ fects of trace decay are short lived, occurring within 5 sec¬ onds.40 Her performance at 3-second delay intervals re¬ mained within the range of normal subjects, suggesting that trace decay was not a significant factor leading to poorer re¬ tention on longer delay periods. Rather, her errors on longer delay trials reflect an inability to distinguish new items from those presented on previous trials. Baddeley35 has suggested that distinguishing old from new items in the PetersonPeterson paradigm is the primary task component account¬ ing for the performance of normal subjects. Thus, she ap¬ pears extremely susceptible to the effects of a simultaneous task that competes for her processing resources. To learn whether the caudal intralaminar nuclei have a unique contribution to memory processes, we compared our patient's test scores with those of other patients who dem¬ onstrated memory disturbances following diencephalic le¬ sions. Specifically, we reviewed test performances of Korsa¬ koff patients and patient NA41 and other cases with lesions involving either the mammillary bodies and midline nuclei2 or the dorsomedial nucleus of the thalamus.42 The pathology of the Korsakoff syndrome is certainly more widespread than that observed in our case. Whereas our patient's lesion is largely confined to a small region in¬ volving and immediately surrounding the left caudal in¬ tralaminar nuclei, the changes in Korsakoff syn¬ drome may include this area (up to 50% of cases) in addition to many other thalamic (mediodorsal nuclei, 88.4% and me¬ dial Pulvinar, 95%) and hypothalamic nuclei (medial mam¬ millary, 100%), as well as structures outside the diencephalon (eg, cerebral cortex, 56.9%).7 Korsakoff patients exhibit a profound anterograde amnesia with differences between their Wechsler Memory Scale memory quotient and verbal IQ of approximately -15 points.32 Our patient clearly does Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/03/2015 pathological not demonstrate a profound amnesia (ie, memory quotient, 100; verbal IQ, 102; difference, -2); although her scores on specific verbal memory tests, including certain subtests of the Wechsler Memory Scale, do demonstrate memory im¬ pairment that is out of proportion to other neuropsycholog¬ ical findings such as intelligence. The first distinction, then, between our patient and Korsakoff patients is at the level of global memory impairment. Korsakoff patients cannot use semantic information to fa¬ cilitate memory in the same manner as our patient. Korsakoff patients show a normal decline in recall due to a build-up of proactive interference when learning successive groups of words from the same semantic category.43 However, these patients fail to improve when semantic categories are shifted (ie, release from proactive interference). She demonstrates a normal build-up and subsequent release from proactive in¬ terference. Additionally, it is questionable whether Korsa¬ koff patients benefit from procedures designed to control the level at which verbal memory items are processed. Origi¬ nally, Cermak and Reale44 and later Wetzel and Squire45 found that Korsakoff patients did not improve on the Levels of Processing paradigm. Mayes and Meudell,36 however, showed that if subjects are equated on the strength of their memory for items, Korsakoff patients improve as much as normal subjects on similar paradigms, although their perfor¬ mances always remain below the level of normal subjects. Our patient clearly shows successive improvement in rec¬ ognition when words are encoded according to ortho¬ graphic, phonologic, or semantic features during the initial presentation phase. Her recognition rates were excellent for semantic (92%), low for phonologic (67%), and significantly impaired for orthographically encoded words (33%) relative to normal control subjects. These data suggest fundamental differences in the abilities of Korsakoff patients and our pa¬ tient to use semantic information. Whereas our patient uses these strategies to retain information at normal levels, Kor¬ sakoff patients may improve with them but are not able to reach the level of normal subjects. Our patient does demonstrate some similarities to Korsa¬ koff patients. Korsakoff patients and our patient alike show normal rates of forgetting.23-24-46 They are different, however, in the rate at which they can acquire information. A compar¬ ison of our patient's performance with Korsakoff patients on similar tasks used to assess nonverbal rates of forgetting23-24 indicated normal retention abilities for both over extended delays. However, Korsakoff patients required longer expo¬ sure periods (ie, four to eight times longer) to acquire the in¬ formation than our patient. Thus, their rate of initial acqui¬ sition, at least for nonverbal information, appears much slower. This could be due in part to the laterality of our pa¬ tient's lesion. We have no information on Korsakoff patients' rates of forgetting for verbal material that would be directly comparable with that obtained on this patient. Our patient performed nearly identically to Korsakoff pa¬ tients on the trigram test of Brown27 and Peterson and Peter¬ son.28 Her performance fell rapidly (from 100% correct to 50%) after only 3 seconds of interference and, like Korsakoff patients, continued to become worse (33%) after 9 and 18 sec¬ onds. Neither our patient nor Korsakoff patients appear able to retain information if they are distracted by an interfering task. Since our patient clearly can use semantic encoding strat¬ egies to retain information at normal levels, the difference between her and Korsakoff patients is in their poor ability to encode material by use of any strategy. This view is consis- tent with data suggesting that Korsakoff patients require Also, since repetitions to place items into both our patient and Korsakoff patients show normal rates more memory,23-24-46 of forgetting for material once learned,47 it is again apparent that their primary difficulties are in encoding information rather than retention. The pervasiveness of encoding deficits in Korsakoff syndrome37 may be grounded in the fact that multiple structures are involved. The memory problems demonstrated by our patient clearly show that damage to the intralaminar nuclei, which may occur in up to 50% of Kor¬ sakoff patients, can contribute to their amnesia, but is not suf¬ ficient to produce it. Patient NA41 is a purer example of diencephalic amnesia than Korsakoff patients because his lesion was largely con¬ fined to the thalamus and hypothalamus.48 His lesion was more extensive than our patient's lesion, involving white matter tracts and the mammillary bodies bilaterally41; how¬ ever, both patients had lesions involving the left centre médian-parafascicular complex and possibly the ventral mediodorsal nucleus and the reuniens nucleus. The largest dif¬ ference between NA41 and our patient in terms of neuropsy¬ chological performance is the severity of memory impair¬ ment. NA41 memory quotient was 27 points below his fullscale IQ.48 Both NA 41 and ours performed worse on verbal than nonverbal memory tests but NA's performance on ver¬ bal tests was markedly worse than that of our patient.48 An¬ other difference between NA and ours is that although NA showed semantic encoding abilities on the release from Pro¬ active Interference and Levels of Processing paradigms, his performances on these tasks never reached the level of nor¬ mal subjects. Thus, while our patient and NA both demon¬ strate similar levels of impairment for words that are not pro¬ cessed semantically, our patient could use semantic encod¬ ing to achieve the performance levels of normal subjects, something NA and other amnestic patients are unable to do.37 NA also performed poorly after only 3 seconds of inter¬ ference on the Peterson-Peterson paradigm.49 That Korsakoff patients, NA, and our patient share a common site of pathol¬ ogy, left intralaminar and medial thalamic nuclei, and a com¬ mon processing deficit on the Peterson-Peterson test raises an interesting possibility that these anatomic areas are im¬ portant in preventing information loss due to distraction. However, to support this theory it must be shown that iso¬ lated damage to other structures damaged in Korsakoff syn¬ drome or in patient NA, such as the mediodorsal nucleus, mammillary bodies, or midline nuclei does not result in sim¬ ilar deficits on the Peterson-Peterson paradigm. Comparative Neuroanatomy of Memory Impairment Several recent case reports of left thalamic infarcts,6-50 he¬ matoma,42 and tumor51 with radiologie confirmation of the lesion and detailed neuropsychological testing are available. Of these, Speedie and Heilman6 and Brown et al42 reported results for the Peterson-Peterson task. Both cases had dam¬ age to the left thalamus (ie, region of the mediodorsal nu¬ cleus6; the mediodorsal nucleus, anterior nucleus Pulvinar, and most probably white matter tracts42) and both patients displayed low memory quotients relative to their verbal IQs and deficits on list-learning tasks. However, only Speedie and Heilman's6 patient showed deficits on the PetersonPeterson paradigm. It is not possible to determine whether their patient also suffered damage to nuclei ventral to the mediodorsal nucleus. The patient of Brown et al,42 however, per¬ formed better than control subjects on the interference task Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/03/2015 Table 3.—Comparison of Patients With Diencephalic Lesions* Peterson-Peterson Full Scale Source, y Brown et al,42 1989 Mairet al,2 1979 Patient Lesion Site 18' IQ MI+ 1 95 86 87 87 2 3 106 106 60 60 90 80 93 90 95 70 104 100 53 33 33 Left, dorsomedial anterior and pulvinar Bilateral, mammillary bodies and midline nuclei Bilateral, mammillary bodies and midline nuclei Present case 4 Left, intralaminar »Boldfaced scores indicate impairment. tMemory index (Ml) (X, 100; SD, 15). and clearly demonstrated thalamic damage anterior and su¬ perior to that of our patient (Table 3). This case suggests that damage to the mediodorsal nucleus and anterior nucleus is not sufficient to produce deficits on the Peterson-Peterson paradigm. Regarding damage to the mammillary bodies and midline nuclei, Mair et al2 examined two Korsakoff patients using the Peterson-Peterson interference procedure. Pathological study confirmed that both patients had extensive cell loss in the mammillary bodies and a thin band of gliosis lying me¬ dial to, but not involving, the mediodorsal nuclei. In spite of their severe amnesias, both patients' performances on the in¬ terference task either equaled or exceeded the levels ob¬ tained by their control subjects (Table 3). These cases suggest that bilateral damage of the mammillary bodies or midline nuclei is not sufficient to produce a deficit performance on the Peterson-Peterson task. Deficits on the Peterson-Peterson interference task are thus not an integral part of the amnesic syndrome resulting from diencephalic lesions, but are one part of a double dis¬ sociation (Table 4): the patient of Brown et al42 and those of Mair et al2 summarized above demonstrate severe amnesia without abnormalities on the interference task, and had le¬ sions that spared the region involved in the present case. In our case, only a mild memory problem is evident but severe impairment is noted on the Peterson-Peterson task. Involve¬ ment of the intralaminar nuclei may account for the differ¬ ences in performance between these patients. Involvement of the ventral mediodorsal nucleus, in our case, should be considered. However, it seems unlikely that this lesion could account for our findings since larger lesions of the mediodorsal nucleus have not been shown to produce deficits on the Peterson-Peterson task.28 Additionally, while it is likely that our patient's behavioral problems are related to the involve¬ ment of the mesencephalic gray matter and caudal intralaminar nuclei, consideration must be given to the contribution of the medioventral (reuniens) and centromedial nuclei that were also involved by the lesion. The connections of midline nuclei to the hippocampus have suggested that they may have a role in memory.8-52"54 We do not know how these le¬ sions may have influenced our findings. Diencephalic Memory Disturbances Based on the differences we have discussed, we propose that there are at least two types of memory disturbance as¬ sociated with diencephalic lesions. One is the amnestic syn¬ drome previously described by Lhermitte and Signoret,55 Squire,37-46 and Squire et al,48 which is characterized by weak encoding, regardless of the strategy used, but normal rates of forgetting for acquired information. The second type is a memory defect associated with lesions involving the in¬ tralaminar and medial nuclei of the left thalamus. The latter is characterized by a normal ability to semantically encode Table 4.—Matrix of Memory Function by Distractibility Normal Performance on the Abnormal Performance on the Peterson-Peterson Peterson-Peterson Task Task Normal memory index Normal subjects Our patient Amnestic Patients 1, 2, and 3 Some Korsakoff patients material and good retention of acquired information; how¬ ever, when active semantic processing or rehearsal strategies are interrupted, severe encoding deficits become apparent. It has long been believed that the caudal intralaminar nu¬ clei may be important for normal arousal and/or attention. Stimulation in this region of the thalamus produces the re¬ cruiting response of the cortical electroencephalogram.56,57 There are extensive connections to the centre médianparafascicular nucleus from the brain-stem reticular forma¬ tion,58 including cholinergic innervation from the pedunculopontine and lateral dorsal tegmental nuclei and serotonergic innervation from the dorsal raphé nuclei. Anatomically, the parafascicular nucleus is adjacent to the central mesencephalic gray matter, which was also involved by the lesion. Efferent connections of the intralaminar nuclei include the striatum and neocortex.58-59 The projections of the caudal intralaminar nuclei are heaviest to the putamen. These connections presumably play a role in preparing an organism to move.60 Cortical efferente of the intralaminar nu¬ clei, however, are light and project diffusely to most cortical areas. These diffuse thalamocortical projections appear to be involved in regulating cortical rhythms56 and maintaining cortical tone (reviewed by Jones58). In Luria's conceptualiza¬ tion, the intralaminar nuclei would also be part of a func¬ tional system subserving cortical tone. Interestingly, as Christensen61 points out, memory disturbances resulting from damage to this system are characterized by suscepti¬ bility to distraction. Our observations on neuropsychological tests of memory span, attentional switching, and speeded performance indi¬ cate that our patient has deficits in attention and concentra¬ tion. These appear most pronounced on tasks involving simultaneous cognitive operations and are suggestive of increased distractibility. Heightened distractibility, an atten¬ tional deficit, may not only explain her poor memory per¬ formance on neuropsychological tests but also the problems she encounters in environmental settings where distracting stimuli cannot be controlled. The double dissociation be¬ tween our patient and amnestic patients with circumscribed diencephalic lesions suggests that the intralaminar nuclei are Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/03/2015 they appear part of a functional system important in regulating attention for si¬ multaneous activities, possibly through maintaining ade¬ quate cortical tone. Lesions in this area may give rise to mem¬ ory disturbances through changing levels of distractability. Given the anatomy of the intralaminar nuclei, this case may also speak to the reticular formation's contribution to mem¬ ory processes. This study was supported by the Research Service, Department of Veterans Affairs, Gainesville, Fla. We thank Russell Bauer, PhD, for use of his nonverbal rates of for¬ not memory structures per se. Rather, getting paradigm and Jimmy Franco for illustrations. References 1. Aggleton JP. Memory impairments caused by experimental thalamic lesions in monkeys. 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