Motor cortex plasticity induction by pairing subthalamic nucleus deep brain stimulation and dorsal premotor cortical transcranial magnetic stimulation in Parkinsons disease

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The human brain is capable of shaping the excitability and interaction in neuronal assemblies as an adaptation to changing external influences. Such plasticity of different cortical regions, e.g. motor networks, represents a fundamental requirement of human brain functions. Plasticity is altered in Parkinsons disease (PD) predominantly because of neurodegeneration of dopaminergic cells. Due to the defined cellular loss and neurotransmitter deficits in PD, this disease can serve as a model disease of how dopamine deficiency, initially predominantly in the basal ganglia and later expanding to other brain regions, produces disease-related changes in cortical motor networks, but also how the motor system adapts to these alterations. Cortical plasticity in PD was first tested by pairing sensory stimulation of the median nerve with transcranial magnetic stimulus (TMS) over the primary motor cortex (M1). Recent innovative paired associative stimulation (PAS) protocols modified this approach in healthy subjects by repeatedly pairing TMS pulses given over M1 with those applied to secondary motor areas to analyze the modifiability of cortico-cortical motor networks. Applying these protocols in PD patients is of special interest due to the fact that previous functional magnetic resonance imaging (fMRI) studies have repeatedly shown altered cortical connectivity patterns in PD. These patterns are characterized by a loss of activity within basal ganglia-fronto-mesial cortical loops and probably compensatory hyperactive basal ganglia-dorsal PM (PMd) connections after a dopaminergic drug withdrawal (OFF state) and normalisation after L-Dopa administration (On state). These findings were corroborated by neurophysiological studies, e.g. TMS studies showing altered PMd-M1 interactions that were reversed by L-dopa administration and repetitive TMS of the PMd. Deep brain stimulation (DBS) of the subthalamic nucleus has become an established treatment option in PD in addition to oral dopaminergic replacement therapy and can complement PAS protocols. Against this background, we now propose to explore alterations in basal ganglia-PMd-M1 plasticity in PD using a novel PAS protocol where STN-DBS is coupled with PMd-M1-TMS applied in DBS stimulated PD patients in the OFF and On state. Demonstrating these cortical-subcortical associative plasticity circuits in PD can help understanding the underlying mechanisms of cortical plasticity, as well as motor network alterations in PD and may deepen our understanding of the therapeutic effects of DBS in these patients. Such information are essential for further developing strategies to foster plasticity functions in these patients and other neurodegenerative disorders.