Parkinson's resting tremor has been linked to pathophysiological changes both in the basal ganglia and in a cerebello-thalamo-cortical motor loop, but the role of those circuits in initiating and maintaining tremor remains unclear. Here, we test whether and how the cerebello-thalamo-cortical loop is driven into a tremor-related state by virtue of its connectivity with the basal ganglia. An internal replication design on two independent cohorts of tremor-dominant Parkinson patients sampled brain activity and tremor with concurrent EMG-fMRI. Using dynamic causal modeling, we tested: (1) whether activity at the onset of tremor episodes drives tremulous network activity through the basal ganglia or the cerebello-thalamo-cortical loop and (2) whether the basal ganglia influence the cerebello-thalamo-cortical loop through connectivity with the cerebellum or motor cortex. We compared five physiologically plausible circuits, model families in which transient activity at the onset of tremor episodes (assessed using EMG) drove network activity through the internal globus pallidus (GPi), external globus pallidus, motor cortex, thalamus, or cerebellum. In each family, we compared two models in which the basal ganglia and cerebello-thalamo-cortical loop were connected through the cerebellum or motor cortex. In both cohorts, cerebral activity associated with changes in tremor amplitude (using peripheral EMG measures as a proxy for tremor-related neuronal activity) drove network activity through the GPi, which effectively influenced the cerebello-thalamo-cortical loop through the motor cortex. We conclude that cerebral activity related to Parkinson's tremor first arises in the GPi and is then propagated to the cerebello-thalamo-cortical circuit.
Significance statement: Parkinson's resting tremor has been linked to pathophysiological changes both in the basal ganglia and in a cerebello-thalamo-cortical motor loop, but the role of those circuits in initiating and maintaining tremor remains unclear. Using dynamic causal modeling of concurrently collected EMG-fMRI data in two cohorts of Parkinson's patients, we showed that cerebral activity associated with changes in tremor amplitude drives network activity through the basal ganglia. Furthermore, the basal ganglia effectively influenced the cerebello-thalamo-cortical circuit through the motor cortex (but not the cerebellum). Out findings suggest that Parkinson's tremor-related activity first arises in the basal ganglia and is then propagated to the cerebello-thalamo-cortical circuit.
Keywords: Parkinson's; cerebellum; effective connectivity; frontostriatal circuits; functional magnetic resonance imaging.
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