Cerebellar Transcranial Alternating Current Stimulation in Essential Tremor Patients with Thalamic Stimulation: A Proof-of-Concept Study

Abstract

Essential tremor (ET) is a disabling condition resulting from a dysfunction of cerebello-thalamo-cortical circuitry. Deep brain stimulation (DBS) or lesion of the ventral-intermediate thalamic nucleus (VIM) is an effective treatment for severe ET. Transcranial cerebellar brain stimulation has recently emerged as a non-invasive potential therapeutic option. Here, we aim to investigate the effects of high-frequency non-invasive cerebellar transcranial alternating current stimulation (tACS) in severe ET patients already operated for VIM-DBS. Eleven ET patients with VIM-DBS, and 10 ET patients without VIM-DBS and matched for tremor severity, were included in this double-blind proof-of-concept controlled study. All patients received unilateral cerebellar sham-tACS and active-tACS for 10 min. Tremor severity was blindly assessed at baseline, without VIM-DBS, during sham-tACS, during and at 0, 20, 40 min after active-tACS, using kinetic recordings during holding posture and action ('nose-to-target') task and videorecorded Fahn-Tolosa-Marin (FTM) clinical scales. In the VIM-DBS group, active-tACS significantly improved both postural and action tremor amplitude and clinical (FTM scales) severity, relative to baseline, whereas sham-tACS did not, with a predominant effect for the ipsilateral arm. Tremor amplitude and clinical severity were also not significantly different between ON VIM-DBS and active-tACS conditions. In the non-VIM-DBS group, we also observed significant improvements in ipsilateral action tremor amplitude, and clinical severity after cerebellar active-tACS, with a trend for improved postural tremor amplitude. In non-VIM-DBS group, sham- active-tACS also decreased clinical scores. These data support the safety and potential efficacy of high-frequency cerebellar-tACS to reduce ET amplitude and severity.

Keywords: Cerebellum; Deep brain stimulation; Essential tremor; Motion capture; Transcranial alternating current stimulation.

Fig. 1

Study design. For VIM-DBS patients (upper panel, left part), assessments were performed first ON-VIM DBS, then after ceasing VIM-DBS for 3 h (OFF DBS/baseline). In the OFF-DBS condition, sham-tACS was applied for 10 min followed by active-cerebellar tACS for 10 min. Patients were assessed during sham-tACS, during active-tACS and at 0, 20 and 40 min following current offset. The same protocol was applied for the patients not previously operated for VIM-DBS, i.e. No-DBS Group (lower panel, left part). We measured tremor amplitude using kinematic arm recordings using the VICON® 3D motion capture system with 29 reflective markers positioned bilaterally on the arms, head and trunk during posture holding and action with the 'nose-to-target' task (right part, lower and upper panels, respectively)

Fig. 2

Effects of active- and sham-tACS at high-frequency on postural tremor. Box plots for postural tremor amplitude as measured by the sum of the displacements of the two arm markers (left panels) during posture holding in ET patients with VIM-DBS (upper panels), and No-DBS patient group (lower panels). Postural tremor amplitude for the contralateral (middle panels) and ipsilateral (right panels) arms. *P < 0.05 relative to baseline condition; †P < 0.05 relative to sham-tACS

Fig. 3

Effects of active- and sham-tACS at high-frequency on action tremor. Box plots for action tremor amplitude as measured by the sum of the displacements of the finger in the 2cm2 area around the target, for the two arms (left graphs), the contralateral (middle panels) and ipsilateral (right panels) arms, during the 'nose-to-target' task in ET patients with VIM-DBS (upper panel), and No-DBS patient group (lower panel ). *P < 0.05 relative to baseline condition; †P < 0.05 relative to sham-tACS

Fig. 4

Effects of active- and sham-tACS at high frequency on clinical tremor severity. Box plots for the severity of tremor as measured by the FTM total and by the FTM subscore A in ET patients with VIM-DBS (upper panels) and No-DBS patient group (lower panels). *P < 0.05 relative to baseline condition; †P < 0.05 relative to sham-tACS