(OPCA) (Kish, El-Awar, Leach, Oscar-Berman, Schut, & Freedman,. 1988a). This disorder is characterized clinically by gait ataxia, dysarthria, and bulbar palsy ...
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Selective Delayed Alternation Deficits in Dominantly Inherited Olivopontocerebellar Atrophy MUNIR EL-AwAR,~,~,~ STEPHENKISH,‘~~ MARLENE OSCAR-BERMAN,~YVES ROBITAILLE,’ LAWRENCESCHUT,’ AND MORRIS FREEDMAN”‘.~.* ‘Rotman Research Institute of Baycrest Centre for Geriatric Care, Toronto, Ontario, Canada; 2Department of Medicine (Behavioural Neurology), Baycrest Centre for Geriatric Care, Toronto, Ontario, Canada; 3Department of Medicine (Division of Neurology), University of Toronto, Ontario, Canada; 4Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; ‘Mount Sinai Hospital Research Institute, Toronto, Ontario, Canada; ‘Boston Veterans Administration Medicat Center; and Department of Neurology and Division of Psychiatry, Boston University School of Medicine, Boston, Massachusetts; ‘Department of Neuropathology, McGill University, Montreal, Quebec, Canada; and ‘Department of Neurology, University of Minnesota, and Veterans Administration Medical Center, Minneapolis, Minnesota
In order to characterize more completely the nature of the frontal lobe-type cognitive changes in patients with dominantly inherited olivopontocerebellar atrophy (OPCA) we administered two tasks sensitive to frontal system dysfunction, delayed alternation (DA) and delayed response (DR), to 12 patients from one OPCA family. Affected members from this family have previously been shown to have a marked and widespread cerebral (including frontal) cortical cholinergic reduction as severe as that observed in Alzheimer’s disease. Performance on DA, but not on DR, was significantly impaired in the OPCA patients compared to that in the controls. We suggest that the DA deficits in OPCA could be a consequence of a loss of cholinergic innervation to orbitofrontal or possibly temporal This study was supported in part by the Medical Research Council of Canada (Dr. Freedman, MA 8908; Dr. Kish, MA9970), the U.S. National Institute of Health (NEUA l-ROl-NS26034, Dr. Kish), a Career Scientist Award from the Ontario Ministry of Health (Dr. Freedman and Dr. Kish), and the U.S. Veterans Administration and U.S. DHHSNIAAA Grant AA07112 to Boston University (Dr. Oscar-Berman). We gratefully acknowledge Celia Greenwood, M. Math, of the Division of Clinical Epidemiology, Mount Sinai Hospital Research Institute, for statistical advice; Reesa Hotz-Sud and Stephanie Bernstein for assistance in data collection and analysis; Ron Ellis for his help, and Vicki Giardino for secretarial assistance. Presented in part at the 40th Annual Meeting of the American Academy of Neurology, Cincinnati, OH 1988. Address requests for reprints to Dr. M. Freeman, Baycrest Hospital, Room 4W36, 3560 Bathurst Street, Toronto, Ontario, Canada M6A 2E1. 121 0278-2626191$3.00
Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
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INTRODUCTION We have previously reported some cognitive deficits in patients from one family with dominantly inherited olivopontocerebellar atrophy (OPCA) (Kish, El-Awar, Leach, Oscar-Berman, Schut, & Freedman, 1988a). This disorder is characterized clinically by gait ataxia, dysarthria, and bulbar palsy (Schut, 1950) and histologically by severe neuronal loss in the cerebellum, pons, and inferior olives. In order to characterize more fully the nature of these frontal lobetype changes in OPCA, we have administered experimental tasks which are sensitive to separate aspects of bilateral frontal lobe damage in nonhuman primates (Warren and Akert, 1964), and which have been validated in humans with bilateral frontal lobe lesions (Freedman and Oscar-Berman, 1986a). The tasks used were delayed alternation (DA) and delayed response (DR). METHODS Subjects. Twelve patients of the Schut pedigree (Schut, 1950) with dominantly inherited OPCA were assessed.Informed consent was obtained from all subjects. Their performance was compared to that of 11 normal controls, equated for age and education. The severity of the patients’ disease was assessedusing the Ataxia Clinical Rating Scale (Pourcher and Barbeau, 1980). Overall cognitive function (see Table 1) was assessedwith the Mini-Mental State Examination (Folstein, Folstein, & McHugh, 1975). Apparatus and procedure. The DA and DR tasks were administered in a modified version of the Wisconsin General Test Apparatus adapted for human use (Oscar-Berman and ZolaMorgan, 1980). The investigator and the patient faced each other across a table, separated by a wood frame approximately 61 cm wide and 53 cm high. A curtain was attached to the top of the frame so that it could be raised to reveal a stimulus board (53 x 28 cm) containing two reinforcement wells. The wells were 24 cm apart from center to center and were covered by identical black square stimulus lids (7.6 x 7.6 x 0.5 cm). When the curtain was lowered neither the investigator nor the stimuli could be seen by the patient. With the curtain raised for each trial, the patient could see the stimuli but not the face of the investigator. DA and DR were carried out as previously described (Freedman and Oscar-Berman, 1986a; Oscar-Berman, Zola-Morgan, Oberg, & Bonner, 1982). Briefly, the investigator explained to the patient in general terms: “Mr. J., I’m going to show you two black lids. Underneath one of them is a penny. I want you to try to get the penny every time the curtain goes up. When you find a penny, put it in the box next to you, and at the end of the session you may keep all the money you’ve made. If you want to stop at any time, we can. All right? Remember, your task is to try to get the penny every time the curtain goes up. There will always be a penny under one of these black lids. Any questions?” For the four patients with OPCA that had ataxia severe enough to interfere with their ability to reach and raise the lid, the procedure was modified so that the patient pointed to the lid and the investigator would then raise the designated lid, take out the penny if present, and place it by the patient. The instructions were modified accordingly. The first trial was initiated by raising the curtain while the investigator reminded the patient again: “Remember, you want to get a penny every time.” On the first trial of the DA problem, both lids were baited with pennies. For the second
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FIG. 1. Performance by groups on the delayed alternation (left) and delayed response (right) tasks. trial, the penny was put under the side not previously chosen. The penny remained on one side until the patient made a correct response. There was a 5-set intertrial interval, and learning criterion was 12 consecutive correct responses. Failure criterion was 45 trials. There were four DR problems with 0-, lo-, 30-, and 60-set delays, respectively. The same black lids used for DA were used. With the two lids covering the wells and the curtain raised, the investigator explained that a penny was going to be placed underneath one of the lids, and the curtain would be immediately lowered. The investigator stated that after the curtain was raised again, the patient could move the lid and take the penny. The lids were baited, in full view of the patient, according to a modified random schedule (Gellermann, 1933). Learning criterion on each DR problem was nine correct responses in a block of 10 trials. For the 0-set delay, the curtain was lowered for a brief instant and then quickly raised again. Just prior to the lo-set delay trial the investigator explained that from now on the patient would have to wait a bit before taking the penny.
RESULTS
The performance scores on DA and on DR were the total number of errors made, i.e., raising a lid with no penny under it (Fig. 1). On DA, the patients with OPCA were significantly impaired compared to the normal controls (422) = 3.02; p < 0.01) (OPCA error score: 9.8 + 2.5 [SE]; controls 2.5 f 0.6). On DR, the distribution of scores necessitated the use of the Mann-Whitney U test, a nonparametric statistic. The performance of the OPCA patients on DR was not significantly different from that of the normal controls (p < 0.3, two-tailed) (OPCA error score: 0.1 + 0.1; controls 0 & 0). DISCUSSION
Results of the present study showed that patients with OPCA were impaired on DA but not on DR tasks. Although caution should be exercised when making anatomical interpretations based upon behavioral data, the marked deficits we observed in OPCA patients on DA, in the
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setting of their good performance on DR, suggests that: (1) impairments may be more closely tied to abnormal perseverative responding than to deficits in spatial memory, and (2) damage to orbitofrontal cortex, or its related projection systems, is more pervasive in this disorder than damage to dorsolateral prefrontal systems. It is generally agreed that DA and DR tasks are sensitive to prefrontal pathology, and measure certain functions in common. Nonetheless, the tasks require somewhat different skills for successful performance and have been shown to be sensitive to damage in different frontal subsystems of the brain (Fuster, 1989; Oscar-Berman, McNamara, & Freedman, 1991). Thus, while deficits on both tasks have been observed following damage to dorsolateral as well as to orbitofrontal cortex in monkeys, damage to the former system leads to the most impaired DR performance (Oscar-Berman, 1975). Likewise, while both tasks measure spatial mnemonic factors and abnormal perseveration (i.e., the tendency to repeat a response just made), DR performance is more closely tied to spatial memory ability, and DA is associated with normal inhibitory functions (Butters and Rosvold, 1968; Goldman and Rosvold, 1970; Mishkin, 1964; Warren and Akert, 1964). Finally, abnormal perseverative responding on alternation tasks has been associated more with damage to the orbitofrontal than to the dorsolateral system (Mishkin, 1964). Initially then, the poor performance of the OPCA patients on DA might be ascribed to abnormal perseverative responding consequent to orbitofrontal pathology. DA is a more demanding task than DR, thus raising the possibility that the spared performance of patients with OPCA on DR may have been due to a ceiling effect obscuring a mild deficit in spatial memory. If so, the pattern of performance by our OPCA patients would be reflecting the presence of combined damage to the dorsolateral frontal system (spatial memory deficits) and the orbitofrontal system (perseveration). In support of this notion are the observations by Kish and his colleagues (Kish, El-Awar, Leach, Oscar-Berman, Schut, & Freedman, 1988a) that OPCA patients display deficits on the Wisconsin Card Sorting Test (WCST), similar to those observed in patients with widespread frontal damage. In humans, abnormal perseveration typically has been measured by the WCST, a standard clinical and laboratory test of frontal pathology thought to reflect dorsolateral damage (e.g., Lezak, 1983; Milner, 1964). Perseveration can take several forms. For example, one form is stuck-in-set perseveration in which a patient inappropriately maintains a current category or framework. Another type is continuous perseveration in which a patient inappropriately repeats a current behavior (Sandson and Albert, 1984). It is likely that the type of perseveration measured by DA is different from that tapped by the WCST. On DA, subjects are required to establish the set of alternating from one side to the other (i.e., spatial
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alternation from left to right); after establishing this set, subjects are not required to shift from alternating spatially to responding according to some other strategy. By contrast, on the WCST, subjects are not only required to establish and maintain the set of responding to a stimulus dimension such as color, form, or number, but they are also subsequently required to relinquish the initial set and then to shift their response strategy to one of the other two alternative stimulus parameters. In other words, tasks such as DA, DR, and the WCST are sensitive to an array of functions--perhaps overlapping-and controlled by different prefrontal systems (likely overlapping). Therefore, any apparent discrepancies between neuroanatomical correlates of function, such as perseveration on alternation tasks and perseveration on the WCST, can be explained by differences inherent in the tests themselves (Freedman, 1990). It should be noted, however, that damage to intrinsic cerebral cortical neurons in frontal cortex is unlikely to explain the DA deficits we observed, since patients from this OPCA family have been found, at autopsy, to have little or no cerebral cortical atrophy (Robitaille and Kish, unpublished observations). These autopsy studies included three patients who were examined in the present study. In addition to involvement of the orbitofrontal system, three alternative neuropathological mechanisms warrant consideration in discussing the OPCA patients’ selective deficits on DA tasks: damage to the cerebellum; damage to the temporal lobes; and abnormalities in the brain cholinergic neurotransmitter system. Each will be discussed in turn. First, Botez and others (Botez, Gravel, Attig, & Vezina, 1985; Botez, Elie, Botez, & et al., 1987; Botez, Leveille, & Botez, 1989; Leiner, Leiner, & Dow, 1986) have described a variety of cognitive deficits associated with cerebellar damage that are suggestive of frontal system involvement. The hypothesis that impaired performance on DA in OPCA is due to cerebellar involvement affecting the integrity of the cerebellofrontal loops must, therefore, be considered. Second, it may be necessary to consider the possibility that the deficits on DA by the OPCA patients may have been related to involvement of the temporal lobes. This is possible since mild deficits on DA, but not on DR, have been observed following bilateral temporal lobe damage (Mahut & Cordeau, 1963, 1971; Rosvold & Szwarcbart, 1964). Kish and co-workers have recently described a marked deficit in the activities of the cholinergic marker enzymes cholineacetyltransferase (Kish, Currier, Schut, Perry, & Morito, 1987) and acetylcholinesterase (Kish, Scat, Simmons, Gilbert, Chang, & Rebbetoy, 1988b) in cerebral cortex, including orbitofrontal cortex, of all examined patients of the Schut pedigree who have recently come to autopsy (n = 7), including two of the patients reported in this study. Interestingly, the magnitude of this
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cholinergic deficit (60-70%) was similar to that observed in Alzheimer’s disease brains (Perry and Perry, 1980; Rossor, Garret, Johnson, & et al., 1982; Perry, 1986). The performance profile in OPCA on the DA and DR tasks is, however, different from that reported previously in Alzheimer’s disease, where both DA and DR were significantly impaired (Freedman and Oscar-Berman, 1986b). The question may be raised whether impairment on DA, but not on DR, in OPCA is due to a qualitatively similar but less severe dementia than in Alzheimer’s disease. This explanation implies, however, that DA is affected earlier than is DR (the latter being an easier task) and that the patients have simply not progressed enough to show deficits on DR. It is important to stress that this likely is not the explanation, since normal DA performance can occur concurrently with impaired DR performance in Alzheimer’s disease (Freedman and Oscar-Berman, 1986b). In this regard our findings of a severe cerebral cortical cholinergic reduction in both OPCA and Alzheimer’s disease accompanied by DA impairment suggest the possibility that the loss of cholinergic innervation to orbitofrontal cortex may explain the DA (but not DR) cognitive deficits in both disorders. REFERENCES Botez, M. I., Elie, R., Botez, T., & et al. 1987. Cerebellar atrophy in outpatient epileptics: A neurobiological study. Canadian Journal of Neurological Sciences, 14, 251-252. Botez, M. I., Gravel, J., Attig, E., & Vezina, J. L. 1985. Reversible chronic cerebellar ataxia after phenytoin intoxication: Possible role of cerebellum in cognitive thought. Neurology, 35, 1152-1157. Botez, M. I., Leveille, J., & Botez, T. 1989. Role of the cerebellum in cognitive thought: SPECT and neuropsychological findings. In M. Matheson & H. Newman (Eds.), Proceedings of the Thirteenth Annual Brain Impairment Conference. Sydney, Australia: Australian Society for the Study of Brain Impairment. Pp. 179-195. Butters, N., & Rosvold, H. E. 1968. Effect of spetal lesions on resistance to extinction and delayed alternation in monkeys. Journal of Comparative Psychology, 66, 389-395. Folstein, M. F., Folstein, S. E., & McHugh, P. R. 1975. “Mini-Mental State”: A practical method for grading the mental state of patients for the clinician. Journal of Psychiatric Research, l2, 189-198. Freedman, M. 1990. Object alternation and orbitofrontal system dysfunction in Alzheimer’s and Parkinson’s disease. Brain and Cognition, 14, 134-143. Freedman, M., & Oscar-Berman, M. 1986a. Bilateral frontal lobe disease and selective delayed response deficits in humans. Behavioral Neuroscience, 100, 337-342. Freedman, M., & Oscar-Berman, M. 1986b. Selective delayed response deficits in Alzheimer’s and Parkinson’s disease. Archives of Neurology, 43, 886-890. Fuster, J. M. 1989. The prefrontal cortex: Anatomy, physiology and neuropsychology of the frontal lobe. New York: Raven Press. Gellermann, L. W. 1933. Chance order of alternating stimuli in visual discrimination experiments. Journal of Genetic Psychology, 42, 207-208. Goldman, P. S., & Rosvold, H. E. 1970. Localization of function within the dorsolateral prefrontal cortex of the rhesus monkey. Experimental Neurology, 27, 291-304. Kish, S. J., Currier, R. D., Schut, L., Perry, T. L., & Morito, C. L. 1987. Brain choline
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