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.

GABAergic changes in the thalamocortical circuit in Parkinson's disease.

Parkinson's disease is characterized by bradykinesia, rigidity, and tremor. These symptoms have been related to an increased gamma-aminobutyric acid (GABA)ergic inhibitory drive from globus pallidus onto the thalamus. However, in vivo empirical evidence for the role of GABA in Parkinson's disease is limited. Some discrepancies in the literature may be explained by the presence or absence of tremor. Specifically, recent functional magnetic resonance imaging (fMRI) findings suggest that Parkinson's tremor is associated with reduced, dopamine-dependent thalamic inhibition. Here, we tested the hypothesis that GABA in the thalamocortical motor circuit is increased in Parkinson's disease, and we explored differences between clinical phenotypes. We included 60 Parkinson patients with dopamine-resistant tremor (n = 17), dopamine-responsive tremor (n = 23), or no tremor (n = 20), and healthy controls (n = 22). Using magnetic resonance spectroscopy, we measured GABA-to-total-creatine ratio in motor cortex, thalamus, and a control region (visual cortex) on two separate days (ON and OFF dopaminergic medication). GABA levels were unaltered by Parkinson's disease, clinical phenotype, or medication. However, motor cortex GABA levels were inversely correlated with disease severity, particularly rigidity and tremor, both ON and OFF medication. We conclude that cortical GABA plays a beneficial rather than a detrimental role in Parkinson's disease, and that GABA depletion may contribute to increased motor symptom expression.

Cerebral differences between dopamine-resistant and dopamine-responsive Parkinson's tremor.

Rest tremor in Parkinson's disease is related to cerebral activity in both the basal ganglia and a cerebello-thalamo-cortical circuit. Clinically, there is strong interindividual variation in the therapeutic response of tremor to dopaminergic medication. This observation casts doubt on the idea that Parkinson's tremor has a dopaminergic basis. An interesting alternative explanation is that interindividual differences in the pathophysiology of tremor may underlie this clinical heterogeneity. Previous work showed that dopaminergic medication reduces Parkinson's tremor by inhibiting tremulous activity in the pallidum and thalamus, and this may explain why some tremors are dopamine-responsive. Here we test the hypothesis that dopamine-resistant resting tremor may be explained by increased contributions of non-dopaminergic brain regions, such as the cerebellum. To test this hypothesis, we first performed a levodopa challenge test in 83 tremulous Parkinson's disease patients, and selected 20 patients with a markedly dopamine-responsive tremor (71% reduction) and 14 patients with a markedly dopamine-resistant tremor (6% reduction). The dopamine response of other core motor symptoms was matched between groups. Next, in all 34 patients, we used combined EMG-functional MRI to quantify tremor-related brain activity during two separate sessions (crossover, double-blind, counterbalanced design): after placebo, or after 200/50 mg dispersible levodopa/benserazide. We compared tremor-related brain activity between groups and medication sessions. Both groups showed tremor amplitude-related brain activity in a cerebello-thalamo-cortical circuit. Dopamine-resistant tremor patients showed increased tremor-related activity in non-dopaminergic areas (cerebellum), whereas the dopamine-responsive group showed increased tremor-related activity in the thalamus and secondary somatosensory cortex (across medication sessions). Levodopa inhibited tremor-related thalamic responses in both groups, but this effect was significantly greater in dopamine-responsive patients. These results suggest that dopamine-resistant tremor may be explained by increased cerebellar and reduced somatosensory influences onto the cerebellar thalamus, making this region less susceptible to the inhibitory effects of dopamine.