Abstract
Tremor is a cardinal feature of Parkinson's disease and essential tremor, the two most common movement disorders. Yet, the mechanisms underlying tremor generation remain largely unknown. We hypothesized that driving deep brain stimulation electrodes at a frequency closely matching the patient's own tremor frequency should interact with neural activity responsible for tremor, and that the effect of stimulation on tremor should reveal the role of different deep brain stimulation targets in tremor generation. Moreover, tremor responses to stimulation might reveal pathophysiological differences between parkinsonian and essential tremor circuits. Accordingly, we stimulated 15 patients with Parkinson's disease with either thalamic or subthalamic electrodes (13 male and two female patients, age: 50-77 years) and 10 patients with essential tremor with thalamic electrodes (nine male and one female patients, age: 34-74 years). Stimulation at near-to tremor frequency entrained tremor in all three patient groups (ventrolateral thalamic stimulation in Parkinson's disease, P=0.0078, subthalamic stimulation in Parkinson's disease, P=0.0312; ventrolateral thalamic stimulation in essential tremor, P=0.0137; two-tailed paired Wilcoxon signed-rank tests). However, only ventrolateral thalamic stimulation in essential tremor modulated postural tremor amplitude according to the timing of stimulation pulses with respect to the tremor cycle (e.g. P=0.0002 for tremor amplification, two-tailed Wilcoxon rank sum test). Parkinsonian rest and essential postural tremor severity (i.e. tremor amplitude) differed in their relative tolerance to spontaneous changes in tremor frequency when stimulation was not applied. Specifically, the amplitude of parkinsonian rest tremor remained unchanged despite spontaneous changes in tremor frequency, whereas that of essential postural tremor reduced when tremor frequency departed from median values. Based on these results we conclude that parkinsonian rest tremor is driven by a neural network, which includes the subthalamic nucleus and ventrolateral thalamus and has broad frequency-amplitude tolerance. We propose that it is this tolerance to changes in tremor frequency that dictates that parkinsonian rest tremor may be significantly entrained by low frequency stimulation without stimulation timing-dependent amplitude modulation. In contrast, the circuit influenced by low frequency thalamic stimulation in essential tremor has a narrower frequency-amplitude tolerance so that tremor entrainment through extrinsic driving is necessarily accompanied by amplitude modulation. Such differences in parkinsonian rest and essential tremor will be important in selecting future strategies for closed loop deep brain stimulation for tremor control.
Highlights
Tremor, as most commonly seen in Parkinson’s disease and essential tremor, is associated with brain activity at tremor frequency or double this
Eight patients with Parkinson’s disease who had been implanted with deep brain stimulation (DBS) electrodes into the ventrolateral thalamus, seven patients with Parkinson’s disease who had been implanted with DBS electrodes into the subthalamic nucleus and 10 patients with essential tremor who had been implanted with DBS electrodes into the ventrolateral thalamus were stimulated at the nearest integer frequency of their tremor frequency
While the definitive test of the use of these phase interference techniques in Parkinson’s disease awaits the tracking of tremor phase and the delivery of stimuli at the optimal phase for tremor suppression over more prolonged periods lest this harnesses even weak cumulative effects in Parkinson’s disease, our results suggest that these techniques might be better piloted and refined in essential tremor
Summary
As most commonly seen in Parkinson’s disease and essential tremor, is associated with brain activity at tremor frequency or double this. Tremor entrainment and amplitude modulation can potentially be separated, as suggested in recent imaging studies in patients with Parkinson’s disease (Helmich et al, 2011), or combined (Cagnan et al, 2013). The distinction between these different functions is potentially important, as the involvement of a given structure in a pacemaker circuit opens up the possibility of targeting specific instances in the cycle (i.e. phases) of pathological neural oscillations to more efficiently promote clinically significant tremor control (Tass and Majtanik, 2006; Brittain et al, 2013; Cagnan et al, 2013)
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