Multi-modal network modulation in Parkinson’s disease

• Applicant: Dr. Bettina Schwab
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Experimental and Theoretical Network Neuroscience ; Human Cognitive and Systems Neuroscience
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 465712062

Parkinson's disease is considered a network disease, affecting connections within the basal ganglia, but also in the whole network of basal ganglia, thalamus, and cortex. Nevertheless, evidence for this view is mainly based on correlative studies, demonstrating increased beta coupling to be associated with several motor symptoms. Direct causal evidence, for example by modulating specific network connections, is missing so far. Simultaneous stimulation of two nodes in the network — nodes may for example be basal ganglia nuclei or cortex — at varying phase lags is thus of special interest to probe the functional relevance of connectivity between these nodes. Here, I propose that the combination of noninvasive electric brain stimulation such as transcranial alternating current stimulation (tACS) with deep brain stimulation (DBS) offers the special possibility of selectively stimulating the network between basal ganglia and different cortical areas in humans. The aim of this project is twofold: to test common assumptions on the basics of tACS in order to get a thorough understanding of this technique, and to then apply the obtained knowledge on the functional connection between motor cortex and basal ganglia by combining tACS and DBS.The interplay between systems and clinical neuroscience is crucial to this project. It takes advantage of both elaborate technical setups and advanced data analysis. First, effects of tACS on human neural spiking will be investigated. This requires single unit recordings in humans during application of tACS (Task A), which is only possible in very special clinical situations. During the surgical implantation of DBS electrodes, neurons may be recorded for several minutes, during which noninvasive tACS can be applied. Such a setup allows to test if spikes actually lock to the applied tACS. Second, I seek a clear demonstration of connectivity modulation during bifocal stimulation. Task B will therefore combine tACS at two different cortical sites with functional magnetic resonance imaging and behavioral testing. As only noninvasive techniques are used in this task, healthy control participants are an appropriate population that allow the implementation of complex movement tasks. Finally, the project will bring together knowledge from the first two tasks and test if functional connectivity between cortex and basal ganglia is causally relevant for the expression of motor symptoms (Task C). In a double blinded study, motor impairment will be quantified depending on the phase lag between simultaneously applied tACS, targeting the motor cortex, and DBS, with surgical targets in the basal ganglia. In sum, the project intends to clarify the physiological mechanism of tACS in humans, and to deepen our understanding of the pathophysiology of Parkinson's disease.

• DFG Programme: Research Grants