Abstract
Essential tremor is effectively treated with deep brain stimulation (DBS), but the neural mechanisms underlying the treatment effect are poorly understood. Essential tremor is driven by a dysfunctional cerebello-thalamo-cerebral circuit resulting in pathological tremor oscillations. DBS is hypothesised to interfere with these oscillations at the stimulated target level, but it is unknown whether the stimulation modulates the activity of the cerebello-thalamo-cerebral circuit during different task states (with and without tremor) in awake essential tremor patients. To address this issue, we used functional MRI in 16 essential tremor patients chronically implanted with DBS in the caudal zona incerta. During scanning, the patients performed unilateral tremor-inducing postural holding and pointing tasks as well as rest, with contralateral stimulation turned On and Off.We show that DBS exerts both task-dependent as well as task-independent modulation of the sensorimotor cerebello-cerebral regions (p ≤ 0.05, FWE cluster-corrected for multiple comparisons). Task-dependent modulation (DBS × task interaction) resulted in two patterns of stimulation effects. Firstly, activity decreases (blood oxygen level-dependent signal) during tremor-inducing postural holding in the primary sensorimotor cortex and cerebellar lobule VIII, and activity increases in the supplementary motor area and cerebellar lobule V during rest (p ≤ 0.05, post hoc two-tailed t-test). These effects represent differences at the effector level and may reflect DBS-induced tremor reduction since the primary sensorimotor cortex, cerebellum and supplementary motor area exhibit less motor task-activity as compared to the resting condition during On stimulation. Secondly, task-independent modulation (main effect of DBS) was observed as activity increase in the lateral premotor cortex during all motor tasks, and also during rest (p ≤ 0.05, post hoc two-tailed t-test). This task-independent effect may mediate the therapeutic effects of DBS through the facilitation of the premotor control over the sensorimotor circuit, making it less susceptible to tremor entrainment.Our findings support the notion that DBS in essential tremor is modulating the sensorimotor cerebello-cerebral circuit, distant to the stimulated target, and illustrate the complexity of stimulation mechanisms by demonstrating task-dependent as well as task-independent actions in cerebello-cerebral regions.
Highlights
Essential tremor, the most common movement disorder, can be disabling to the degree of necessitating deep brain stimulation (DBS)
DBS resulted in contralateral reductions in postural tremor measured by the accelerometer in 13 patients during the functional MRI (fMRI), p < 0.05
The main tremor frequencies observed during Off stimulation covered 3–8 Hz according to a Fast Fourier Transform
Summary
The most common movement disorder, can be disabling to the degree of necessitating deep brain stimulation (DBS). The abnormally oscillating circuit includes the cerebellum, brainstem, thalamus and the sensorimotor cortex (Raethjen and Deuschl, 2012), the activity of which is coherent with tremor frequency during motor tasks (Schnitzler et al, 2009). Regions within this circuit exhibit dysfunctional activity during active motor tasks and during rest (Bhalsing et al, 2013; Sharifi et al, 2014). How the disease-related activity is influenced by DBS has not yet been clarified
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