Cognitive load amplifies Parkinson's tremor through excitatory network influences onto the thalamus.

Parkinson's tremor is related to cerebral activity in both the basal ganglia and a cerebello-thalamo-cortical circuit. It is a common clinical observation that tremor markedly increases during cognitive load (such as mental arithmetic), leading to serious disability. Previous research has shown that this tremor amplification is associated with reduced efficacy of dopaminergic treatment. Understanding the mechanisms of tremor amplification and its relation to catecholamines might help to better control this symptom with a targeted therapy. We reasoned that, during cognitive load, tremor amplification might result from modulatory influences onto the cerebello-thalamo-cortical circuit controlling tremor amplitude, from the ascending arousal system (bottom-up), a cognitive control network (top-down), or their combination. We have tested these hypotheses by measuring concurrent EMG and functional MRI in 33 patients with tremulous Parkinson's disease, OFF medication, during alternating periods of rest and cognitive load (mental arithmetic). Simultaneous heart rate and pupil diameter recordings indexed activity of the arousal system (which includes noradrenergic afferences). As expected, tremor amplitude correlated with activity in a cerebello-thalamo-cortical circuit; and cognitive load increased tremor amplitude, pupil diameter, heart rate, and cerebral activity in a cognitive control network distributed over fronto-parietal cortex, insula, thalamus and anterior cingulate cortex. The novel finding, obtained through network analyses, indicates that cognitive load influences tremor by increasing activity in the cerebello-thalamo-cortical circuit in two different ways: by stimulating thalamic activity, likely through the ascending arousal system (given that this modulation correlated with changes in pupil diameter), and by strengthening connectivity between the cognitive control network and the cerebello-thalamo-cortical circuit. We conclude that both the bottom-up arousal system and a top-down cognitive control network amplify tremor when a Parkinson's patient experiences cognitive load. Interventions aimed at attenuating noradrenergic activity or cognitive demands may help to reduce Parkinson's tremor.