Dystonia is a neurological disorder characterized by involuntary twisting movements or abnormal postures caused by excessive activation of specific muscle groups or abnormal co-activation of agonist and antagonist muscles. The neurobiological basis for this disorder is not well understood, and even the neuroanatomical substrates remain uncertain. While clinical studies of affected patients have traditionally associated dystonia with damage or dysfunction of the basal ganglia and its connections, laboratory studies of rodents have more consistently associated the disorder with dysfunction of the cerebellum and its connections. The overall goal of this proposal is to bridge our understanding of the gaps between the basal ganglia and the cerebellum in the expression of dystonia. Our hypothesis is that dystonia is not simply the reflection of dysfunction of a single motor control system, but may result from dysfunction in either the basal ganglia or cerebellum, or abnormal interactions between these two regions.
In Aim 1 we will investigate the contributions of the basal ganglia in two well-characterized mouse models where dystonia is known to be triggered by dysfunction of the cerebellum. These studies will be valuable for demonstrating the involvement of the basal ganglia in these models as well as important interactions between these two motor control systems in the expression of rodent dystonia.
In Aim 2 we will perform manipulations of the cerebellum in rhesus monkeys analogous to those that have been demonstrated to provoke dystonia in rodents. These studies will establish a role for abnormal cerebellar output in the genesis of dystonia in monkeys and have the potential to result in a novel monkey model for dystonia.
Aim 3 is devoted to a careful reassessment of autopsy material from the cerebellum of dystonia patients. These studies will be valuable because prior autopsy studies, which traditionally focused almost entirely on the basal ganglia, have generally failed to disclose any consistent neuropathological changes in most forms of idiopathic dystonia. Overall, the studies described in this proposal have the potential to stimulate a major revision of current concepts concerning the neuroanatomical basis for dystonia. A more complete understanding of the neuroanatomical substrates for dystonia is of elemental importance for any future studies of dystonia addressing relevant pathogenetic changes at the molecular, cellular, and physiological levels. In addition, the studies will have direct relevance for modern neurosurgical approaches to the management of dystonia that involve focal brain stimulation or lesion techniques. ? ?
Showing the most recent 10 out of 41 publications
