Pathophysiology of Basal Ganglia Disorders

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

A major effort in the laboratory is 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 investigated a variety of inhibitory mechanisms already, and we are now engaged in understanding the premotor to motor cortex interactions and parietal to motor cortex interactions in focal hand dystonia (NCT03018262). Recent evidence suggests that the final part of the mechanism of surround inhibition actually arises from the connections within the motor cortex itself. Recent studies include the EEG response to TMS and checking its response with surround inhibition. We are also exploring the physiology of motor learning in dystonia. Motor learning seems disturbed and seems to have a principal role in producing focal hand dystonia since long term repetitive activity is certainly an etiological factor. Experiments are ongoing using a technique called corticocortical paired associative conditioning, ccPAS, which can evaluate plasticity in corticocortical circuits (NCT02504905). We are studying the parieto-frontal circuit which we have previously shown to be relevant in task specific dystonia. 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. We have published one study on the pathophysiology of dystonic tremor and are further evaluating this manifestation. 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. We are completing a protocol (NCT04565080) that encompasses a study of our patients evaluating how they are impacted by the pandemic, and this includes patients with Parkinson disease.