Pathophysiology of Basal Ganglia Disorders

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

A major effort in the laboratory has been devoted to understanding dystonia (NCT03223623). Our fundamental view is that there is a deficiency of inhibition in central nervous system mechanisms in dystonia. Specifically, an important type of defective inhibition is surround inhibition, where muscles and movements not desired for the task need to be inhibited. Lack of inhibition leads to motor overflow and action dystonia. We are trying to identify specific inhibitory circuits that contribute to surround inhibition. Studies are first done in normal subjects and then in patients. We have been continuing to investigate a variety of inhibitory mechanisms (NCT03018262). Recent evidence suggests that the final part of the mechanism of surround inhibition actually arises from the connections within the motor cortex itself. We have now also demonstrated the important role of parietal-premotor connections. In this regard, we have also shown that repetitive transcranial magnetic stimulation (rTMS) can modulate these connections in patients bringing the connections closer to normal (NCT03223623). We are also investigating the mechanism of sensory tricks (NCT03223623). Evidence from EEG, TMS and cortico-muscular coherence all suggest an important role for the supplementary motor area in mediating this phenomenon. Studies on the pathophysiology of dystonic tremor are described in another project in the report from our Section. There is also evidence for cholinergic abnormality in dystonia. We have found decrease of cholinergic markers in the pedunculo-pontine region in a pathological study of cervical dystonia and are now doing a PET study with a cholinergic ligand (NCT02689466). The genetic markers in focal dystonia are largely unknown. We are cooperating with the multisite NIH sponsored Dystonia Coalition for work in this area (NCT03223623). In regard to the Dystonia Coalition, we are also participating in studies developing new scales for the diagnosis and severity of blepharospasm. We are also using Dystonia Coalition data to see how talking affects the severity of blepharospasm. Studies of Parkinson disease have largely been shifted to the Parkinson clinic. The Parkinson clinic is an associated unit with a focus on this disease. Studies of Parkinson tremor have been recently completed and others are ongoing. We have shown for example that there are two types of postural tremor in patients, the more common being "re-emergent tremor", and we have explored the role of the cerebral cortex and cerebellum in the genesis of tremor. In the last year, we also published our study on where patients with Parkinson disease look when they are walking. Importantly, they tend to look down rather than at the goal of their walking (NCT01019343).