Primary dystonia / pathophysiology

TP9 Team

SP9: Genetic fingerprints of oscillatory network activity in dystonia

Principle Investigator: Andrea Kühn

The pathophysiology of dystonia is not fully understood, and pathological findings are evident at the cortical, brainstem and BG levels of the motor and sensory network. At the level of the BG, increasing evidence suggests that neuronal activity is characterized by enhanced synchronized oscillations in the low frequency band (4 - 12 Hz).

Recent findings suggest that cortex-basal ganglia-cortical but also cerebellar-thalamo-cortical circuits are abnormal in dystonia. Modulation of network activity by deep brain stimulation (DBS) of the internal pallidum (GPi) has been shown to be of therapeutic benefit in patients with primary dystonia. However, the mechanism of DBS in dystonia is still not fully understood. One proposed hypothesis is that DBS interferes with ongoing oscillatory network activity in the cortex-basal ganglia loops. Hence, DBS in the GPi would lead to network alterations of functional oscillatory connectivity in these loops. Using novel techniques of parallel local field potential recordings from DBS electrodes, electromyography from dystonic muscles and whole head magnetoencephalographic recordings, it is our aim to characterize the interplay between cortico-pallidal rhythm generation to dystonic muscle activity in functionally distinct oscillatory networks. Genetic fingerprints and the translation from functional to structural connectivity networks in non-manifesting and manifesting DYT1 and DYT6 gene carriers will be obtained by the combination of diffusion tensor imaging and combined EMG-MEG recordings.

This approach will shed new light on the pathophysiology of dystonia with respect to the genetically  determined subtype. It will open up new avenues for optimized patient selection for DBS on the basis of neuronal response patterns and evaluate potential target areas for future non-invasive stimulation strategies in dystonia.

The objectives are:

A) To characterize pathological cortico-subcortical network activity in patients with primary dystonia using advanced imaging techniques with simultaneous deep brain recordings from the basal ganglia and magnetoencephalography; i.e. 1) can we identify pathophysiological signatures of the cortico-basal ganglia motor network in genetically determined dystonia (DYT1, DYT6); 2) is there a final common pathway in patients with different types of dystonia leading to involuntary movements?

B) To identify patterns of pathological motor activation during simple movement tasks, i.e. what is the basal ganglia vs cerebellar vs motor cortical influence during abnormal movements?

C) To characterize functional and structural networks in dystonia by combining MEG and diffusion tensor imaging based fiber tracking methods in a cohort of genetically determined manifesting and non-manifesting DYT1 and DYT6 gene carriers; i.e. 1) what are the specific neurophysiological signatures for subtypes of dystonia? 2) can we identify compensatory/protective mechanisms in non-manifesting gene carriers? We expect to find a disease-specific cortico-subcortical network with increased low frequency (4-12 Hz) oscillatory activity in dystonia patients that relates to the severity of motor symptoms. Frequency-specific cerebello-BG-cortical network connectivity is hypothesized to differentiate between genetically different types of dystonia as well as cortical connectivity patterns may differentiate between manifesting and non-manifesting gene carriers.