Principal Investigator: Jeremy D. Schmahmann
Cognitive Effects of Cerebellar Lesions in Monkeys
It has long been held that the principal role of the cerebellum is confined to motor control. Recent clinical investigations in patients with cerebellar lesions, functional imaging experiments in normal subjects, and behavioral studies in animals have suggested that the role of the cerebellum extends beyond the control of voluntary movement. Our previous tract tracing studies in monkey have led to the suggestion that the connections between cerebral association areas and the cerebellum may be the anatomic substrate that supports this cerebellar contribution to behavior. Further, they have revealed a dichotomy in the cerebrocerebellar system such that the cerebellum is linked with cerebral areas concerned with visual-spatial and executive processing, but not with cerebral areas concerned with feature discrimination and object analysis. There is as yet, however, no animal model in which specific hypotheses have been tested concerning the cerebellar participation in higher order function, or the mechanisms that may be responsible. The overall goal of this research effort is to test the hypothesis that the cerebellum is an integral and necessary component of the distributed neural circuitry subserving cognitive operations. The specific objectives of these studies are to demonstrate that cerebellar lesions in the rhesus monkey adversely affect cognitive functions thought to be subserved by the cerebral association areas that are anatomically interconnected with the cerebellum. Conversely, we aim to demonstrate that functions dependent upon the cerebral cortical regions that are not part of the cerebrocerebellar circuitry are spared. The specific hypotheses to be investigated are as follows.
HYPOTHESIS 1. Lesions of the cerebellar dentate nucleus will produce cognitive deficits in the executive and visual-spatial domains but spare functions related to object discrimination and object based learning.
HYPOTHESIS 2. Dentate nucleus lesions are associated with neuronal hypometabolism (characterized by reversed cerebellar diaschisis) in areas of the cerebral cortex that are anatomically linked with the cerebellum.
The research plan designed to accomplish these objectives is as follows. The coordinates of the dentate nuclei of the cerebellum will be identified by magnetic resonance imaging (MRI) in ten monkeys, five in each of the first two years of the study. Ibotenic acid lesions will then be placed in the dentate nuclei bilaterally (for maximal behavioral effect) in 6 animals. Sham injections will be made in the 4 controls. The monkeys will then be trained on a battery of tests chosen for their previously demonstrated sensitivity to lesions located in prefrontal, posterior parietal, inferotemporal and parahippocampal cortices. The tests employ both a Wisconsin box and a computer generated display to assess different cognitive functions. They include delayed non-matching to sample, delayed spatial or object recognition span, spatial and object reversal, and landmark discrimination tasks. The operated and control groups will be compared with respect to the rate of acquisition of the tasks, and the level of peak performance. At the conclusion of the behavioral testing the animals will be sacrificed and cytochrome oxidase staining of the brain will be performed to evaluate the presence of cerebral neuronal hypometabolism.
In summary, this series of behavioral and anatomical investigations will
determine the presence and nature of any cognitive deficits resulting
from pure cerebellar lesions, and whether reversed cerebellar diaschisis
(neuronal hypometabolism in the cerebral cortex) is correlated with cerebellar
behavioral deficits. These studies will test the hypothesis that the cerebellum
is an integral part of the distributed neural circuitry subserving cognitive
operations, and that the anatomic connections between cerebellum and cerebral
association areas are functionally important.
