Contribution of the cerebellum to neuropsychological functioning: Evidence from a case of cerebellar degenerative disorder

Neuropsyeholopm, Vol . 30, No . 4, pp . 315-328, 1992 . Printed m Great Britain .

002B-3932,92 $5 .00+0 .00 C 1992 Pergamon Press Ltd

CONTRIBUTION OF THE CEREBELLUM TO NEUROPSYCHOLOGICAL FUNCTIONING : EVIDENCE FROM A CASE OF CEREBELLAR DEGENERATIVE DISORDER NATACHA

A.

AKSHOOMOPF, * t§ ERIC COURCHESNE,*4 GARY

A.

PRE55II

and

VICENTEIRAGUIt *Nnuropsychology Research Laboratory, Children's Hospital Research Center, San Diego ; tDepartment of Psychiatry and ;Department of Neurosciences, University of California, San Diego ; §Department of Psychology, San Diego State University ; and IIDepartment of Radiology, Kaiser Permanents Hospital, San Diego, CA, U .S .A .

(Received

I

December 1989 ;

accepted

13

November

1991)

Abstract-A detailed neuropsychological evaluation was performed on a patient with an idiopathic cerebellar degenerative disorder . Significant deficits were found in Verbal and nonverbal intelligence, verbal associative learning, and visuospatial skills . These deficits were not readily explained by motor control difficulties . In contrast to the patient's moderately impaired language abilities, be was severely impaired on a test of verbal fluency and demonstrated mild naming deficits . Severe cerebellar parenchyma) volume loss was demonstrated by magnetic resonance examination . Supratentorial structures showed only minimal posterior parietal and occipital sulcal prominence . On neurological examination, this patient had signs of severe involvement of the cerebellar systems and mild-tomoderate dysfunction of the corticospinal tract . As is characteristic of patients with cerebellar degeneration, there was neurophysiological evidence of subclinical involvement of auditory and somatosensory pathways at the level of the brain stem . Since relatively little cerebral cortical atrophy was noted in this patient, these findings suggest that an intact cerebellum is important for normal cognitive functions .

studies of patients with diseases of the cerebellum should provide insights into the putative cerebellar contribution to cognitive processes [8, 10, 20, 34, 45] . Because patients with cerebellar lesions often have prominent motor deficits that could interfere with task performance, it is important to demonstrate that any cognitive deficits found are independent of motor abnormalities . In one study of patients afflicted with dominantly inherited olivopontocerebellar atrophy (OPCA), deficits in verbal and nonverbal intelligence, memory, and frontal system function were found on neuropsychological tests minimally reliant on motor skills [32] . These patients had only mild functional deterioration . OPCA patients have associated loss of frontal, temporal, and occipital cortical cholinergic innervation similar to that seen in Alzheimer's disease [31] ; however, their neuropsychological performance resembles that of patients with subcortical or frontal-subcortical dementia rather than Alzheimer's disease . With the exception of this loss of cholinergic innervation, the neuropathological changes in OPCA are generally believed to be restricted to the cerebellum, lower brainstem, and spinal NEUROPSYCHOLOGICAL

`Address for correspondence : Neuropsychology Research Laboratory, Children's Hospital, 8001 Frost St, San Diego, CA 92123, U .S .A . 315



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cord [31] . The pons and the olive are predominantly affected, although some patients have diffuse atrophy of Purkinje and granule cells in the cerebellar cortex, with sparing of the anterior vermis and little loss in the pons and the olive [44] . Neuropsychological studies of patients with Friedreich's ataxia, a hereditary spinocerebellar degenerative disorder with onset in childhood or adolescence, reveal that their neuropsychological deficits are more restricted to motor functioning [20, 23] . While verbal abilities are usually preserved, these patients show deficits on tests of visuoconstructive abilities and sequential organization [20] . It is important to note that Friedreich's ataxia is primarily a disease of the posterior columns and the dorsal and ventral spinocerebellar tracts, while parenchyma) damage in the cerebellum or involvement of the pontine nuclei and the inferior olives are rare [44] . In order to study the neuropsychological consequences of cerebellar damage, evaluation of patients with damage principally or exclusively limited to white matter, gray matter, or deep nuclear structures of the cerebellum (efferent systems) is optimal . Since the affected functional circuits differ in degenerative disorders of the cerebellum, there will likely be differences in functional consequences . A case of cerebellar degeneration predominantly affecting intrinsic cerebellar structures, with relative sparing of the pons and little cerebral cortical abnormality, is presented . A complete neuropsychological assessment was performed to identify the cognitive deficits associated with diffuse damage to the cerebellum . In order to determine the extent of cerebellar and brain stem involvement, magnetic resonance (MR) scans were quantitatively analyzed and an extensive neurological examination was conducted .

METHOD Case history C .Z. is a 21-year-old right-handed male with progressive cerebellar degeneration of unknown etiology . His birth and developmental history were unremarkable and there is no family history of neurological disorders . C .Z . was an honors student in high school, and was also talented in art and sports . Symptoms of ataxia began when he was approx. 16 years old . In his last year of high school, C .Z . noticed progressive gait unsteadiness and began walking with a cane, but continued to perform well in academic pursuits . Neurological examination at age 18 revealed appendicular ataxia without weakness. Truncal ataxia, autonomic disturbance, and nystagmus were absent . Four months later he was noted to also have broken saccades and dysarthric speech . During his freshman year of college as an engineering major, he began having difficulty in his coursework . His physical deficits gradually progressed, he choked on liquids, and he fell frequently_ At the time of the neuropsychological evaluation in our laboratory, C .Z . was 20 years old and was confined to a wheelchair . He was no longer able to successfully attend college, primarily due to concentration and memory problems, and was living at home with his parents . His parents reported that he had difficulty remembering things and in choosing the correct names of common objects . He had no history of depression or other psychiatric disturbance . Laboratory tests, including complete blood counts, standard serum chemistry panels, thyroid function tests, B12, VDRL, lysosomal enzyme screening, and quantitative amino acid determinations, were normal . CSF examination was also normal . A blood test for anti-Purkinje cell antibodies was negative . Electromyography demonstrated signs of chronic denervation . Sensory and motor nerve conduction studies were normal . Muscle biopsy showed neurogenic changes characteristic of recent denervation, but no other abnormalities were found . Neurological and neurophysiological examination Brain stem auditory evoked responses (BERs) and pattern reversal visual evoked responses (V ERs) were recorded in our laboratory when C .Z . was 20 years old . One year later, a neurological examination was conducted in our laboratory . BERs and VERB were repeated for comparison with the previous results, as well as median nerve and tibia) nerve somatosensory evoked potentials (SEPs), following the guidelines of the American EEC Society [19] . A clinical EEC was also recorded with a 20 channel polygraph following the guidelines of the American EEC Society .



NEUROPSYCHOLOGICAL FUNCTIONING AND THE CEREBELLUM Magnetic

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resonance procedures

Magnetic resonance images in three orthogonal planes were obtained on two separate occasions using a 1 .5-T superconducting magnet (Signs ; General Electric, Milwaukee) and standard head coil . Slice thickness was 5 mm with an interslice gap of either 2 .5 or 3 mm in all sequences . The initial MR examination began with a 28-sec TI W scout sequence [200/20/I (TR/TE/excitations) ; held of view (FOV) 24 ; matrix 256 x 128] in the axial and sagittal plane and was utilized to verify precise subject positioning . Subsequently, T1W (600/20/4 ; FOV 16) high-resolution sequences of cerebellum and posterior fossa were performed in the sagittal and corona) planes . The sagittal sequence was carefully planned to provide a truly midline image of the vermin and multiple paramedian images of the left cerebellar hemisphere only . The corona) sequence included the entire cerebellum . A follow-up MR examination performed 15 days later included two long Ta sequences . Axial T2- and PDW (3000/30, 80/1 ; FOV 20; matrix 256 x 256) images of the entire brain were obtained initially . A cardiac-gated long TR sequence (3600/20, 70/4 ; FOV 16) subsequently provided a median sagittal image of the vermin and multiple paramedian saggital images of the left cerebellar hemisphere . Our examinations were qualitatively compared with four MR studies performed 6-24 months previously at outside facilities . The MR images performed by our group were measured independently by two investigators with computerassisted planimetry . The measurement methods used were the same as in previous studies o£ the midsagittal area of the vermin [13], cumulative slice area values of the left cerebellar hemisphere [38], lateral cerebellar width [38], midsagitlal area of the ventral pons [27], and the width of the middle and superior cerebellar peduncles and olivary nucleus (CooacHESNE et al ., in preparation (a)) . The anatomical landmarks utilized are more fully described in CoURCHESNE et aI . [12] and PRESS et a1 . [42, 43] . Measurements of this patient were compared with mean measurements of the cerebellar vermin in 22 normal volunteers and eight patients* between the ages of 13 and 39, the left cerebellar hemisphere and the widith of the lateral cerebellum in three normal volunteers and five patients between the ages of 19 and 37 ; the pons in 20 normal volunteers and eight patients" between the ages of 13 and 39 ; and the middle and superior cerebellar peduncles ; and olivary nucleus in six normal volunteers between the ages of 20 and 37 .

Neuropsychological

assessment

Neuropsychological tests were administered during three testing sessions spanning a 5-month period when the patient was 20 years old . Since the patient's tremor interfered with his writing abilities, few tests involving graphomotor speed or performance were administered . Intellectual functions were assessed with the Wechsler Adult Intelligence Scale-Revised (WAIS-R) [47] . The calculation of the Performance IQ was based on four subtests : Picture Completion, Picture Arrangement, Block Design and Object Assembly . Language skills were assessed using the Auditory Comprehension, Oral Reading, Repetition and Reading Comprehension subtests of the Boston Diagnostic Aphasia Examination (BDAE) [24] . Although a test of confrontation naming is included in this battery, more complex figures of increasing difficulty are included in the Boston Naming Test [24] and therefore this test was given as well . Verbal ability was also assessed using the Peabody Picture Vocabulary Test [18] . Verbal fluency was assessed using the controlled word association test for the letters F, A and S (number of words generated for each letter, 1 min each) [5] . Verbal memory was assessed using the Logical Memory and Paired Associate Learning subtests of the Wechsler Memory Scale-Revised [48], and the California Verbal Learning Test [15] . The Wisconsin Card Sorting Test [26] was used to assess concept formation and ability to shift sets . Visuoperceptual skills were assessed using the Judgement of Line Orientation and Facial Recognition Tests [6] . C .Z. was given the Mini-Mental State Examination [21] which provides a brief general assessment of attention, memory, orientation, and visuospatial abilities . The Information and Orientation and Mental Control subtests of the Wechsler Memory Scale-Revised [48] were administered to assess orientation and attention .

RESULTS Neurological and neurophysiological examination Neurological examination by our group when C .Z . was 21 years of age revealed horizontal and vertical nystagmus, poor smooth pursuit eye movements, head titubation, moderate "These eight patients had undergone MR scanning at the University of California, San Diego/AM! Magnetic Resonance Institute . The entire file of scans was searched for brain scans that included axial and sagittal images ; 90 such scans were found . From the patients represented by these scans, these normal controls were selected by using the following criteria : age between 6 and 36 years, no symptoms of cerebellar dysfunction, and no evidence of central nervous system abnormalities on the scan, as reviewed independently by two neuroradiologists . Among the reasons for referral were head and neck pain, depression, headaches and neurogenic bladder .

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dysarthria, ocular and appendicular dysmetria, mild truncal ataxia, marked gait ataxia, dysdiadochokinesia, intention tremor, diffuse hyperrefiexia, spastic tone and bilateral Babinski signs . There were no signs of weakness or sensory dysfunction . Visual acuity was 20/20 . The EEG demonstrated diffuse slowing in the theta frequency range . There were no focal abnormalities or epileptiform discharges . BER results suggested significantly abnormal auditory brainstem neural transmission bilaterally [Fig . 1(a)] . These findings are based on unusual waveform morphology, the absence of the more rostral brainstem generators, abnormal interwave intervals and abnormal amplitude ratios . Wave I was normal bilaterally . Wave III had normal amplitude but prolonged latency with left ear stimulation and was absent with right ear stimulation . With left ear stimulation, the I-III interval was abnormally prolonged . Wave V was absent bilaterally which indicates bilateral dysfunction at the midbrain level [Fig . 1(a)] . With condensation clicks on the first testing session, a response that appeared to be wave V was detected on both the left and right sides . VERB showed P100 potentials of normal amplitude but slightly prolonged peak latency (left eye : 123 .5 msec ; right eye : 122 .0 msec) suggesting mild bilateral visual system dysfunction [Fig . 1(b)] . These results are comparable to those obtained in the previous year . Median nerve SEPs showed normal brachial plexus potentials (Eros present) on both sides . However, left median nerve stimulation elicited a cervical N14 potential of normal latency (14.6 msec) but very low amplitude, and a broad scalp N19 potential with abnormally prolonged peak latency of 24 .7 msec [Fig . 1(c)] . With right median nerve stimulation, the cervical N14 potential had normal latency and amplitude but the N19 potential was absent . These findings indicate bilateral dysfunction in the somatosensory system at the brainstem . Tibial nerve SEPs showed normal popliteal and lumbar potentials, but the NI9 potentials were absent to stimulation of either side, suggesting bilateral central nervous system somatosensory dysfunction .

Magnetic resonance

Although the lobar and lobular morphology of the vermis and cerebellar hemispheres in coronal, sagittal and axial planes was normal, extensive increased sulcal widening and volume loss were present throughout the cerebellum . Figure 2 shows the sagittal and coronal MR images of this patient compared with a normal subject . The volume loss in the cerebellar vermis and hemispheres was associated with deepening of the surface sulci and major fissures, suggesting a diagnosis of atrophy, rather than hypoplasia which would likely be associated with a smooth cerebellar surface . The fourth ventricle was dilated greatly in this patient . The volume loss appeared to involve the anterior, posterior and fiocculonodular lobes without regional sparing . The tonsils were particularly diminutive . The cerebellar cortical gray matter appeared to be severely involved ; loss was also present in the corpus medullare and white matter tracts . The middle cerebellar pcdunclcs appeared smaller than normal (Fig . 3) . However, relative preservation of the brain stem was evident . Axial sections revealed that the medulla had lateral olivary prominences . Although the outside MR examinations were performed at several different sites using different field strengths and pulse sequences, relatively T2-, PD- and TIW images were available for comparison with the current examination . No change was noted in the



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NEUROPSYCHOLOGICAL FUNCTIONING AND THE CEREBELLUM

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4 meet Fig . 1 . (A) Brain stem auditory evoked responses from the first testing session . Average ipsilateral waveforms with left and right ear stimulation, monaural rarefaction clicks at 17 .1/sec, 80 dB HL . Stimulus artifact eliminated from tracing . (B) Pattern reversal visual evoked responses from the second testing session (rate =l .9/sec) with replications superimposed . (C) Left median nerve somatosensory evoked potentials with replications superimposed . C4+ is scalp overlying the sensoriparietal cortex (2 cm behind the 10-20 system C4 position) . Erb L is Erbs point on the left leg . C4 is the middle back of the neck over the C4 cervical vertebra .

decreased volume of the cerebellum when our MR examination was compared visually with the earlier studies. Table 1 shows the measurements from sagittal and axial MR scans in this patient and measurements obtained from normal subjects by our laboratory . The midsagittal area of the ante for vermal lobules I-V in this patient was only 27 .7% of normal (7 .83 SD below the norlhal mean) . Vermal lobules V I and VII (neocerebellar vermis) were 23 .2% of normal (6 .87 SD below the normal mean) . The average cumulative sagittal slice area measure of the left



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cerebellar hemisphere in this patient was 57 .6% of normal (5 .63 SD below the normal mean) . In contrast, the midsagittal area of the ventral pons (i .e . pontine nuclei and transverse pontine fibers) was 86.9% of normal (1 .13 SD below the normal mean) . Table 1 . Measurements from sagittal and axial MR scans

Vermal lobules r-V (midsagittal area in mm') Vermal lobules VI-VII (midsagittal area in mm') Left cerebellar hemisphere (cumulative slice area in mm') Lateral cerebellum (width in mm) Ventral pons (midsagittal area in mmr) Middle oerebellar peduncle (width in mm) Left Right Superior cerebellar peduncle (width in mm) Left Right Olivary nucleus (width in mm) Left Right

Patient C .Z .

Normal group mean (SD)

117 .20 66 .20 3490 .05 99 .65 303 .08 12 .22 13.05 2 .50 2 .50 7 .30 7 .50

423.56 (39 .12)" 284 .80 (3L81)" 6059 .50 (456 .00)t 104.20 (3 .60)t 349.11 (40.77)] 16.38 (0.88)§ (6 .73 (1 .48)§ 2.60 (0.46)§ 2.78 (0 .30)§ 7 .38 (0.93)§ 7.83 (0.86)§

"Normal means from CUURCHESNE et a! . (in preparation (b)), n=30 . tNormal means from MtJRAKAMI et al. (1989), n=8 . *Normal means from Hsu et a! . (1991), n=28 . §Normal means from COURCHESNE et al. (in preparation (a)), n=6 .

The width of the left and right middle cerebellar peduncles was 74.6% and 78 .0% of normal, respectively . Although the left and right superior cerebellar peduncles appeared somewhat small on visual inspection, this was not confirmed when compared with the measurements of six normal adults . Symmetric mild dilatation of the occipital horns and abnormally prominent sulci of the parietal and occipital lobes suggested focal atrophy (see Fig . 3) . The frontal and anterior temporal lobes appeared normal . No regions of abnormal signal intensity within the parenchyma were noted on T2-, PD- or TI W images . J'Teuropsychological testing

Intelligence. Although there are no premorbid objective test results for comparison, C .Z .'s intellectual functioning, as measured by the WAIS-R (Table 2), has presumably declined significantly from his previous high level of functioning, given his prior academic achievements . Both his verbal IQ (81) and performance IQ (63) are currently below average normal levels . On the Information subtest, in which the patient gave his best verbal performance, he answered a few of the more difficult items, such as the name associated with the theory of relativity, yet could not say how many weeks there are in a year and could name only three presidents since Eisenhower . On the Vocabulary subtest, his responses were sometimes short and unelaborated and he occasionally used the test word as part of the definition . He also gave concrete responses on the Picture Completion, Comprehension and Similarities subtests . C .Z . was permitted to continue working on all timed tests until he was completely finished in order to assess potential performance independent of motor speed and skill . He made no broken configuration errors on the Block Design test . Although his speed and motor coordination were poor, his low scores on the Block Design, Object Assembly and Picture Arrangement WAIS-R subtests were due to failures in perceptual capacity . That is, even

NEUNOISYCHOLOOICAL FUNCTIONING AND THE CEREBELLUM

Fig . 2 . T1 W corona) (A) and sagittal (B) images of a normal volunteer . T1W corona) (C) and sagittal (D) images of patient C .Z. Severe volume loss of cerebellar vermin and hemispheres in C .Z . is associated with marked dilatation of overlying sold and fourth ventricle (4) . The tonsils (T) are 'particularly decreased in size (P=ventral pons, 1-V=vernal lobules I-V, VI-VI =vernal lobules VI-VII, Cm=corpus medullare) . .

321

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et a! .

Fig . 3 . Axial T2 W image (A) demonstrates small middle cerebellar peduncle (mcp), and dilated fourth ventricle (4) and oerebellar sold . Higher section (B) shows suchl overlying oocipital lobe (arrows) are more prominent than those in the temporal (Te) and frontal (F) regions . There is also mild dilatation of the occipital horns (O) .



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Table 2 . C .Z .'s neuropsychological test performance Intelligence WAIS-R Information Digit Span Vocabulary Arithmetic Comprehension Similarities Verbal IQ : 81

10 5 (4 FWD, 3 BWD) 6 5 6 6 Performance lQ : 63

Language assessment Peabody Picture Vocabulary Test Boston Naming Test Verbal Fluency : "F" :2 "A" :1 "S" :1

97 51/60 Total=4

Picture Completion Picture Arrangement Block Design Object Assembly

5 4 5 1

Full Scale IQ : 72

(Norm : 100±15) (Norm : 55 .9±2.9) (Norm : 37.5±10.0)

Memory functions Wechsler Memory Scale-Revised Logical Memory : Immediate 19/50 (Norm : 25 .7±7 .3) Delayed 13/50 (Norm : 22 .1 ±7 .6) Paired Associate Learning : Learning Trial 1 2 3 Easy (4) 3 3 4 0 2 4 Hard (4) Total : 16 (Norm : 21 .8± 1 .8) Delay : 8 (Norm : 7 .7±0 .6) California Verbal Learning Test (16 words) List A Trial 1 4 (-2 SD) Trial S 12 (-2 SD) List B 4(-25D) Short Delay Free Recall 10 (-2 SD) Short Delay Cued Recall 12 (-1 SD) Long Delay Free Recall 10 (-2 SD) Long Delay Cued Recall 12 (-1 SD) Recognition 15 (-1 SD) Visuoperceptual functions

Benton Facial Recognition Benton Line Orientation Conceptualfunctions Wisconsin Card Sorting Test Categories Total Errors Perseverative Errors

43/54 (Normal range : 41-54) 15/30 (Normal range : 19-30)

6 (Norm : 5 .4±1 .3) 33 (Norm : 24 .9±19 .4) 12 (Norm : 12 .6±10.2)

given extended time he was not able to successfully complete the more difficult items on these subtests . Language . Despite dysarthria, C.Z . was able to engage in conversation . He was attentive and responded with appropriate latency to questions, although he sometimes had difficulty finding particular words to describe past events in his life . For example, during the first testing session when asked what he had for lunch the previous day, he detailed at length precisely how his mother had made him "fish mixed with mayonnaise and chopped up celery" ; it was apparent that he was trying to say "tuna salad", although he did not describe it as such . His parents reported that he frequently had similar difficulties recalling the names of common objects . C .Z .'s conversational speech was formally assessed during the second testing session using



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the BDAE . His speech was found to be fluent, with long uninterrupted strings of words, and contained normal syntactic and semantic structure . When he was asked specific questions about his family and his plans for the weekend, he did not exhibit the same types of word finding difficulty as during the first testing session . This may be due to the higher degree of structure surrounding these specific questions which required less effort . His description of the "Cookie Theft Picture" was well integrated and rich in details . Compared to the normative sample of 242 aphasic patients, his scores on the Responsive Naming, Confrontation Naming, Auditory Comprehension, Oral Reading, Repetition and Reading Comprehension subtests were all at or above the 90th percentile level [24] . C .Z . demonstrated mild word retrieval difficulties on the Boston Naming test (nearly 2 SD below normal). He obtained six additional names with phonemic cuing . His verbal fluency, as measured by the controlled word association test ("F A S") was very poor (a total of four words in 3 min, < 4th percentile), in marked contrast to his fluency in conversational speech as recorded during the BDAE (an average of 60 words/min) . When asked to name items from a category (Animal Naming) his fluency improved slightly (11 words in 1 min) . Memory . C .Z.'s ability to learn and recall a short story was only slightly below average . However, on the California Verbal Learning Test, his total recall across the five learning trials was approx . 2 SD below the mean for his age and gender. Use of semantic and serial clustering strategies were normal, but consistency of words recalled (64%) was 3 SD below the mean . The number of perseverations (7) and intrusions (2) was within normal limits . Both immediate and delayed free recall were 2 SD below the mean, but categorical cuing brought his performance to 1 SD below the mean . Recognition testing was normal with only one false positive . His learning performance on the Paired Associate Learning test was more than 3 SD below the normal mean, but his delayed recall of the pairs was within normal limits . Visuoperceptual functions . His score on the Facial Recognition test placed him in the 33rd percentile . His performance on the Line Orientation test was below the 4th percentile . Conceptual functions . C .Z : s performance on the Wisconsin Card Sorting Test was essentially within normal limits . Nevertheless, on three occasions he gave five or six correct responses in a row but failed to provide the 10 responses required to complete the category ("failure to maintain set") . Screening measures . C .Z . demonstrated impairment on the Mini-Mental State Examination (24/30 points) . He correctly recalled only two of the three words with one semanticallyrelated intrusion error . He was also unable to count backwards by sevens . He lost one point when asked to name "pencil" and he instead said "pen" . On the Mental Control subtest of the Wechsler Memory Scale-Revised, C .Z . received only three out of six points . He was unable to count forwards by threes and he skipped one number while counting backwards from 20 . He obtained 13 out of 14 points on the Information and Orientation subtest, being unable to name the president before Reagan, but choosing the correct answer when given three choices . On the Beck Depression Inventory [4], he received a score of 13 which is indicative of mild depression . The items he endorsed reflect mild concern over physical symptoms, self-criticism and mild irritability . DISCUSSION This patient demonstrated significant impairment in a number of cognitive domains . These deficits are not readily explained by associated motor impairment because the

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neuropsychological tests employed in this study relied minimally on motor coordination . His poor performance on the tests with time limits did not appear to be due to motor slowing because his performance did not improve when he was given additional time to complete the tests. Atrophy primarily affecting the parenchyma of the cerebellum was confirmed in our patient by high-resolution MR scans . From a neurological standpoint, this patient has signs of severe involvement of the cerebellum and mild-to-moderate dysfunction of the cortidospinal tract . There was also evidence of lower motor neuron involvement in EMG and muscle biopsy . Neurophysiologically there was evidence of subclinical involvement of auditory and somatosensory pathways at the level of the brain stem . In addition, there was mild slowing of conduction in the visual pathways . These sensory findings would not be expedted to significantly influence performance on standard neuropsychological tests . This constellation of clinical and evoked potential findings are quite characteristic of patients with cerebeflar degenerations where there is severe cerebellar dysfunction and mild involvement of other systems [25] . Deficits in learning verbal paired associates were found in this patient . Similar deficits in learning verbal paired associates, as well as in learning arbitrary associations between colors and abstract words, were found in patients with damage to the cerebellum [to] . As with our patient, these patients were also impaired on all IQ measures but were not impaired on the Wisconsin Card Sorting Test, and were not significantly impaired in short-term and delayed verbal memory . Patients with OPCA may also be impaired in verbal paired associate learning, but have been found to have deficits on the Wisconsin Card Sorting Test [32] . This fatted deficit may reflect a greater disruption in frontal lobe function than is present in our patient because of associated cortical cholinergic dysfunction in OPCA [31] . Our patient demonstrated a deficit in verbal fluency that is worse than would be predicted by his moderate language deficits . Deficits in verbal fluency were also reported in a study of OPCA patients who had relatively few deficits on standard neuropsychological tests [7] . This word finding difficulty found in our patient appears to be related to an initiation deficit or a breakdown in semantic associations, rather than motor output problems associated with' dysarthria, because during the testing he reported being unable to think of any additional words . During a semantic association task, the inferior lateral cerebellum was found to be distinctly activated in a positron emission tomography (PET) study of normal subjects [41] . Activation was calculated after pure motor activation was subtracted, arguing for cognitive activation in this region of the cerebellum, rather than sensory or motor . This activation was localized in the right cerebellar hemisphere, which projects to the left cerebral cortex . Our patient had significant visuospatial deficits. Patients with Friedreich's ataxia [20], patients with OPCA [32], as well as patients with cerebellar atrophy due to long-term treatment for epilepsy [8], have all been found to have deficits on visuospatial tests . More specifically, deficits performing cognitive operations in three-dimensional space were found in patients with damage limited to the left neocerebellar cortex [46] . These deficits are consistent with disruption of reciprocal projections of the left cerebellar cortex with the right parietal lobe [45], an area known to be important for spatial operations . It has been suggested that these visuospatial deficits point to the importance of the parietal-cerebellum connections for visuospatial organization [8, 46] . Cm's neuropsychological profile in general is similar to that of patients with noncerehellar, subcortical dementia, such as Huntington's disease, progressive supranuclear



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palsy, and Parkinson's disease [14] . He demonstrated mild recall deficits which were ameleriorated by suing, and his recognition score was proportionately better than his recall score . C.Z .'s deficits in verbal fluency with generally intact language skills, are also common in such patients . Naming and spatial perceptual difficulties were also found, deficits that are also sometimes present in patients with subcortical damage . Also consistent with a subcortical profile was the absence of aphasia, apraxia, and agnosia . Why should damage to the cerebellum affect performance on tests known to be sensitive to cerebral cortex damage? Patients with cerebellar atrophy or lesions restricted to the cerebellum can have variable involvement of structures outside the cerebellum, which may account for variability in neuropsychological test performance across patients [7] . It is possible that the cognitive deficits found in our patient are due to damage to structures outside the cerebellum . The EEG findings suggested a mild degree of diffuse slowing, but this finding is nonspecific and therefore does not readily explain the constellation of impaired and spared cognitive functions found in this patient . There was also evidence of minimal posterior parietal and occipital sulcal prominence bilaterally on MR examination . These findings may reflect remote loss due to the loss of functional input from the cerebellum . The cerebellum is known to be involved in the execution of rapid, skilful movements, and it has therefore been hypothesized that the existence of extensive cortical connections may allow the cerebellum to also play a role in the acquisition and execution of skilled mental operations in humans [34, 35] . Of particular interest are the newest cerebellar structures, the lateral or neocerebellum, and their reciprocal connections with the association areas of the cerebral cortex [28, 29, 45] . The ventrolateral newer part of the dentate nucleus accounts for a large portion of the dentate nucleus in humans, and its increase in size has paralleled that of the cerebral cortex and the cerebellar cortex [34] . This part of the dentate nucleus sends projections, via the ventrolateral, ventroanterior, intralaminar, pulvinar, and dorsomedial nuclei of the thalamus, and these in turn project to cortical association areas [28, 29, 39,45] . The neocerebellum in turn receives projections from the cerebral association areas, via the pons . PET and single photon emission computed tomography (SPELT) studies reveal that damage to the cerebellum can lead to reduced metabolic activity in the cerebral cortex . Patients with cerebellar infarctions have been found to have lowered metabolism in the contralateral frontal and parietal regions on SPELT scans [9, 11, 22] . Paraneoplastic cerebellar degeneration can also produce a reduction in the metabolic rate in cerebral cortical and subcortical regions [1] . These metabolic changes suggest that in patients with damage to the cerebellum, subcortical structures and the cerebral cortex are less functionally active, despite the absence of any evidence of structural damage to them . There is also evidence for the functional importance of cerebral cortical input to the cerebellum . Metabolic depression in the cerebellar hemisphere contralateral to a focal cerebral lesion (crossed cerebellar diaschisis) has been described in several studies [3, 36, 37, 40] . These findings may reflect a loss of excitatory afferent input to the cerebellum, particularly from cerebral cortical areas supplied by the deep middle cerebral artery [33, 40] . A PET study of normal subjects provides evidence that the frontal cortex normally exerts a strong modulating influence on the contralateral cerebellum [30] . Similar results have also been reported between sensory-motor cortex and the contralateral cerebellar hemisphere [2] . The findings from the present study suggest that an intact cerebellum is important in several areas of cognitive functioning . Given the limitations in a single case study [49],



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further neuropsychological and imaging studies of patients with degenerative disorders of the cerebellum will be necessary to determine how consistently cognitive deficits are found in these patients . In addition to quantitative analysis of MR data of the cerebellum, it will also be important for future studies to consider the degree of involvement of structures outside the cerebellum and how remote loss to those structures due to cerebellar damage may affect neuropsychological functioning in these patients . A better understanding of the cerebellum's role in specific cognitive operations demands the experimental approach with patients who have specific cerebellar lesions . Acknowledgements-This study was supported by NINDS grant 5-R01-NS-19855 awarded to Eric Courchesne, Ph .D . and a research grant from Children's Hospital awarded to Natacha Akshoomoff and Eric Courchesne . The authors gratefully acknowledge the neurophysiological assistance of Julie Kasanoff, MS ., CCC-A and Rosemary Truesdale, REEGT .

REFERENCES I . ANDERSON, N . E ., PosNER, LB., Sums, J. J ., MoELLER, J . R., STROTHER, S . C ., DHAWAN, V . and ROTrENBERG, D . A . The metabolic anatomy of paraneoplastic cerebellar degeneration . Ann. Neural . 23, 533-540, 1988 . 2. BARKER, W, W., Yosul, F ., LOEWENSTEIN, D . A ., CHANG, J. Y ., APICELLA, A ., PASCAL, S., Boom, T . E., GInsEnto, M . D . and DUARA, R . Cerebrocerebellar relationship during behavioral activation : A PET study . J. cereb . Blood Flow Metal, . 11, 48-54, 1991 . 3 . BARON, J. C., BOUSSER, M . G ., CoMAR, D ., DUQUESNOY, N., SASmE, J . and CASTAIGNE, P . "Crossed cerebellar diaschisis" : a remote functional depression secondary to supratentorial infarction in man . J. cereb . Blood Flow Metal, .!, 5500-5501, 1981 . 4. BECK, A . T ., WARD,C . H ., MENDELBON, M . et al . An inventory formeasuring depression . Arch . gen . Psychiat .4, 561-571,1961 . 5. BENTGN, A . L. and HAMSRER, K. DES . Multilingual Aphasia Examination . University of Iowa, Iowa City, 1976 . 6. BENTON, A . L ., HAMSHER, K. DES ., VARNEY, N. R . and SPREEN, O. Contributions to Neuropsychological Assessment . Oxford University Press, New York, 1983 . 7 . BERENT, S ., GIORDANI, B ., GILMAN, S ., JUNCK, L ., LEHTINEN, S ., MARKEL, D . S ., Bo1VIN, M ., KLUIN, K. l ., PARKS, R. and KOEPPE, R. A . Neuropsychological changes in olivopontocerebellar atrophy. Arch . Neural . 47, 997-1001, 1990 . 8 . Bomz, M . L, norm, T., ELSE, R . and Arrio, E, Role of the cerebellum in complex human behavior . Ital . J . neural . Set . 10, 291-300, 1989 . 9. BOTEZ, M . I ., Bomz, TH ., LEVEILLE, J . and LAMBERT, it. Cerebella-cerebral diaschisis and the role of the cerebellum . Neurology 40 (suppl . 1), 173, 1990 . 10. BRACKE-TOLKMITT, R ., LINDEN, A ., CANAVAN, A. G . M ., ROCKSTROH, B ., SCHOLZ, E ., WRSSEL, K . and DIENER, H .-C. The cerebellum contributes to mental skills . Behuv . Neurosci. 103, 442-446, 1989 . Ii . BRO1cH, K ., HARTMANN, A., BIERSACK, H : J. and HORN, R. Crossed cerebella-cerebral diaschisis in a patient with cerebellar infarction, Neurosci. Lett . 83, 7-12, 1987. 12. COURCHESNE, E ., PRESS, G. A ., MURAKAMI, J . W ., BERTHOTY, D . P ., GRAPE, M ., WILEY, C . A . and HESSELINK, J. The cerebellum in sagittal plane-anatomic-MR correlation : 1 . The vermin . Am . J. Neuroradiol . 10, 659-665, 1989. 13 . COURCHESNE, E ., YEUNG-COURCHESNE, R ., PRESS, G . A ., HESSELINK, J . R . and JERNIGAN, T . L . Hypoplasia of cerebellar vermal lobules VI and VII in infantile autism . N. Engi. J. Med . 318, 1349-1354, 1988 . 14. CUMMINGS, L L . Subeortical dementia : Neuropsychology, neuropsychiatry, and pathophysiology . Br . J . Psychtat . 149, 682-697, 1986 . 15. DELIS, D . C ., KRAMER, J ., KAPLAN, E., OBER, B . A . and FRmWND, A. California Verbal Learning Test, Research edn (CVLT) . Psychological Corporation, San Antonio, TX, 1987 . 16. Dow, R . S. Cerebella- action potentials in response to stimulation of the cerebral cortex in monkeys and cats . J . Neurophysiol . 5, 121-136, 1942 . 17. Dow, R . S. Contributions of electrophysiological studies to cerebellar physiology . J. din . Neurophysiol . 5, 307-323,1988 . 18 . DUNK, L. M . and DUNN, L . M . Manual for the Peabody Picture Vocabulary Test-Revised . American Guidance Services, Circle Pines, MN, 1981 . 19. EEG Society . American EEG Society guidelines for clinical evoked potential studies . J. din. Neurophysiol. 1, 3-53, 1984 . 20. FEHRENBACH, R . A ., WALLESCH, C .-W . and CLAUS, D . Neuropsychologic findings in Friedreich's ataxia . Arch . Neural. 41, 306-308, 1984 .



328

N . A. AKSHOOMOEF et al.

21 . FoLSTEIN, M . F., Fos.smIN, S. E. and MCHuGH, P . R. "Mini-mental state" . J. psychiat . Res . 12, 189-198,1975 . 22. GILMAN, S ., MARKEL, D . S ., KOEPPE, R. A ., JUNCK, L., KLUIN, K . J., GESARSK[, S . S. and HrcHwA, R . D . cerebellar and brainstem hypometabolism in olivopontocerebellar atrophy detected with positron emission tomography . Ann . Neural. 23, 223-230, 1988 . 23 . GIORDnn, B ., BOIVnt, M ., BERENT, S ., GILMAN, S ., JUNCK, L ., LEIHENEN, S ., MArnca, D. and KLUIN, K . Cognitive and emotional function in Friedreich's ataxia . J. din. exp . Neuropsychol . 11, 53, 1989 . 24. Cro0DGLASS, H . and KAPLAN, E . The Assessment of Aphasia and Related Disorders. Lea & Febiger, Philadelphia, 1983 . 25. HARDING, A . E The Heriditary Ataxias and Related Disorders . Churchill Livingstone, New York, 1984 . 26. HEATON, R . K . Wisconsin Card Sorting Test Manual . Psychological Assessment Resources, Odessa, Florida, 1981 . 27. Hsu, M ., YEUNaCOURCHESNE, R ., CouacRuSNE, F . and PRESS, G . A . Absence of magnetic resonance imaging evidence of pontine abnormality in infantile autism . Arch . Neural . 48, 1160-1163 . 28 . ITO, M . The Cerebellum and Neural Control . Raven, New York, 1984 . 29 . ITCH, K . and MIZUNO, N. A cerebella-pulvinar projection in the cat as visualized by the use of antero-grade transport of horseradish peroxidase . Brain Res . 171,131-134, 1979 . 30. JUNCK, L ., GILMAN, S., RoTHLEv, J . R ., BETLEY, A . T ., KOEPPE, R. A. and HICHWA, R . D . A relationship between metabolism in frontal lobes and cerebellum in normal subjects studied with PET. J. cereb. Blood Flow Metal, . 8, 774-782,1988 . 31 . KISH, S. J ., CURIUER, R . D ., SCHUT, L ., Pt7trtx, T . L. and MORITO, C . L . Brain choline acetyltransferase reduction in dominantly inherited olivopontocerebellar atrophy . Ann . Neural. 22, 272-275, 1987 . 32. KISH, S . J ., EL-AWAR, M ., Scrrui, L ., LEACH, L ., OSCAR-BERMAN, M . and FREEDMAN, M . Cognitive deficits in olivopontocerebellar atrophy : Implications for the cholinergie hypothesis of Alzheimer's dementia . Ann . Neural. 24, 200-206, 1988 . 33 . KURTHEN, M ., REICHMANN, K ., LINKS, D. B ., BIERSACK, H. J ., Rruma, B . M., DURWEN, H . F . and GRUNWALD, F . Crossed cerebellar diaschisis in intracarotid sodium amytal procedures : a SPELT study . Acta neurol. Scand. 81, 416-422, 1990 . 34. LEINER, H . C., LEINER, A. L . and Dow, R . S . Does the cerebellum contribute to mental skills? Behav . Neurosci . 100, 443-454, 1986 . 35 . LEINER, H . C., LEINER, A . L . and Dow, R . S Re-appraising the cerebellum: What does the hindbrain contribute to the forebrain? Behav . Neurosci. 103,998-1008, 1989 . 36. MARTIN, W . R . W . and RAICHLE, M. E. cerebellar blood flow and metabolism in cerebral hemisphere infarction . Ann . Neural. 14, 168-176, 1983 . 37. METTEA, E . J ., KEMPLER, D ., JACKSON, C . A ., HANSON, W . R ., RIEGE, W. H ., CAMRAS, L . R ., MAZZIOTTA, J . C . and PIaPS, M . E . cerebellar glucose metabolism in chronic aphasia . Neurology 37, 1599-1606, 1987 . 38 . MuRAKAMI, J . W ., CotrnermsNe, E., PRESS, G . A., YEUNG-COURCwsNE, R . and HESSELINK, J . R. Reduced cerebellar hemisphere size and its relationship to vernal hypoplasia in autism . Arch . Neural. 46, 689-694,1989 . 39 . NIEUWENUYS, R ., VOOGD, J . and VAN HUUZEN, CHR . The Human Central Nervous System, 3rd edn . SpringerVedag, Berlin, 1988 . 40. PANTANO, P ., BARON, J. C., SAMSON, Y., BOUSSER, M. G ., DEROUESNE, C . and COMAR, D. Crossed cerebellar diaschisis . Brain 109, 677-694, 1986 . 41 . PETERSEN, S- E ., Fox, P . T., P03NER, M.1 ., MINTUN, M . A . and RAICHILE, M . E . Positron emission tomographic studies of the processing of single words . J . cognit. Neurosci. 1, 153-170, 1989 . 42 . PRESS, G . A ., MURAKAMI, J . W., COURCHESNE, E., BERTHOTY, D . P ., GRAS£, M ., WILEY, C. A . and HESSELINK, l . R . The cerebellum in sagittal plane-anatomic-MR correlation : 2 . The cerebellar hemispheres . Am. J. Neuroradiol . 10, 667-676, 1989 . 43 . PRESS, G . A., MURAKAMI, J . W ., COURCHESNE, E., GRAPE, M . and HESSELINK, l . R . The cerebellum : 3 . The coronal plane . Am. J. neural. Res . 11, 41-50, 1990 . 44. RosaSaEao, R . N . Hereditary ataxias . In Merriti's Textbook of Neurology, L . P. ROWLAND (Editor), 8th edn . Lea & Febiger, Philadelphia, 1989 . 45 . SCRMAHMANN, J . and PANDYA, D. N. Anatomical investigation of projections to the basis ponds from posterior parietal association cortices in rhesus monkey . J. comp. Neural. 289, 53-73, 1989 . 46. WALLESCH, C.-W . and HORN, A . Long-term effects of cerebellar pathology on cognitive functions . Brain and Cognition 14, 19 25, 1990 . 47 . WECHSLER, D . WADS--R Manual . Psychological Corporation, New York, 1981 . 48 . WECHSLER, D . Wechsler Memory Scale-Revised. Psychological Corporation, New York, 1987 . 49. ZURIE, E. B ., GARDNER, H . and BROWNELL, H. H . The case against group studies . Brain and Cognition 10, 237-255, 1989 .