Phase dependent modulation of tremor amplitude in essential tremor through thalamic stimulation

Abstract

High frequency deep brain stimulation of the thalamus can help ameliorate severe essential tremor. Here we explore how the efficacy, efficiency and selectivity of thalamic deep brain stimulation might be improved in this condition. We started from the hypothesis that the effects of electrical stimulation on essential tremor may be phase dependent, and that, in particular, there are tremor phases at which stimuli preferentially lead to a reduction in the amplitude of tremor. The latter could be exploited to improve deep brain stimulation, particularly if tremor suppression could be reinforced by cumulative effects. Accordingly, we stimulated 10 patients with essential tremor and thalamic electrodes, while recording tremor amplitude and phase. Stimulation near the postural tremor frequency entrained tremor. Tremor amplitude was also modulated depending on the phase at which stimulation pulses were delivered in the tremor cycle. Stimuli in one half of the tremor cycle reduced median tremor amplitude by ∼10%, while those in the opposite half of the tremor cycle increased tremor amplitude by a similar amount. At optimal phase alignment tremor suppression reached 27%. Moreover, tremor amplitude showed a non-linear increase in the degree of suppression with successive stimuli; tremor suppression was increased threefold if a stimulus was preceded by four stimuli with a similar phase relationship with respect to the tremor, suggesting cumulative, possibly plastic, effects. The present results pave the way for a stimulation system that tracks tremor phase to control when deep brain stimulation pulses are delivered to treat essential tremor. This would allow treatment effects to be maximized by focussing stimulation on the optimal phase for suppression and by ensuring that this is repeated over many cycles so as to harness cumulative effects. Such a system might potentially achieve tremor control with far less power demand and greater specificity than current high frequency stimulation approaches, and may lower the risk for tolerance and rebound.

Short pauses in thalamic deep brain stimulation promote tremor and neuronal bursting

“…The effects of DBS are strongly dependent on stimulation frequency; high frequency (> 100 Hz) DBS alleviates postural tremor [Kuncel et al, 2006; Sydow et al, 2003], whereas low frequency DBS is clinically ineffective and may exacerbate tremor [Cagnan et al, 2013; Pedrosa et al, 2013]. Therapeutic efficacy is also sensitive to the temporal pattern of stimulation [Birdno et al, 2007, 2008; Brocker et al, 2013; Dorval et al, 2010; Montgomery et al, 2005] and increasing evidence suggests that long pauses during stimulation (≥50 ms) reduce tremor suppression during Vim thalamic DBS [Birdno et al, 2012; Kuncel et al, 2012].…”

The nature of tremor circuits in parkinsonian and essential tremor

“…We compare the response of parkinsonian rest tremor to stimulation at near tremor frequencies to that observed in essential tremor patients during ventrolateral thalamic stimulation (Cagnan et al , 2013). The findings point to fundamental differences in the nature of the underlying tremor network in the two conditions.…”

Deep brain stimulation for movement disorders: update on recent discoveries and outlook on future developments

“…A similar approach has been made in a study on ET using a peripheral electrophysiological marker namely tremor amplitude and phase [98]. Stimulation near the tremor frequency could both reduce or enhance tremor amplitude depending on when the stimulation impulse was delivered in the phase of the tremor cycle.…”