Transcutaneous vagal nerve stimulation to treat disorders of consciousness: Protocol for a double-blind randomized controlled trial

Abstract

Background: Patients with disorders of consciousness (DoC) are a challenging population prone to misdiagnosis with limited effective treatment options. Among neuromodulation techniques, transcutaneous auricular vagal nerve stimulation (taVNS) may act through a bottom-up manner to modulate thalamo-cortical connectivity and promote patients' recovery. In this clinical trial, we aim to (1) assess the therapeutic clinical effects of taVNS in patients with DoC; (2) investigate the neural mechanisms underlying the effects of its action; (3) assess the feasibility and safety of the procedure in this challenging population; (4) define the phenotype of clinical responders; and (5) assess the long-term efficacy of taVNS in terms of functional outcomes.

Methods: We will conduct a prospective parallel randomized controlled double-blind clinical trial investigating the effects of taVNS as a treatment in DoC patients. Forty-four patients in the early period post-injury (7 to 90 days following the injury) will randomly receive 5 days of either active bilateral vagal stimulation (45 min duration with 30s alternative episodes of active/rest periods; 3mA; 200-300μs current width, 25Hz.) or sham stimulation. Behavioural (i.e., Coma Recovery Scale-Revised, CRS-R) and neurophysiological (i.e., high-density electroencephalography, hd-EEG) measures will be collected at baseline and at the end of the 5-day treatment. Analyses will seek for changes in the CRS-R and the EEG metrics (e.g., alpha band power spectrum, functional connectivity) at the group and individual (i.e., responders) levels.

Discussion: These results will allow us to investigate the vagal afferent network and will contribute towards a definition of the role of taVNS for the treatment of patients with DoC. We aim to identify the neural correlates of its action and pave the way to novel targeted therapeutic strategies.

Clinical trial registration: Clinicaltrials.gov n° NCT04065386.

Keywords: Behavior; Coma; Disorders of consciousness; Electroencephalography; Minimally conscious state; Randomized clinical trial; Treatment; Unresponsive wakefulness syndrome; Vagal nerve stimulation; Vegetative state.

Figure 1

Postulated bottom-up effect influence of transcutaneous auricular vagal nerve stimulation on the mesocircuit in a severely damaged brain. The model suggests that the reduction of thalamocortical and thalamostriatal outflow following deafferentation and loss of neurons from the central thalamus withdraws important afferent drive to the medium spiny neurons of the striatum (green lines). Loss of active inhibition from the striatum (dashed red line) allows neurons of the globus pallidus interna (GPi) to tonically fire and provide active inhibition (red line) to their synaptic targets, including relay neurons of the already understimulated central thalamus, thus reducing thalamic activity and consequent thalamo-cortical connectivity. taVNS may hypothetically supply for the missing thalamic excitatory inputs by stimulating the lower and upper brainstem nuclei and thus promote the reinstatement of the thalamo-cortical connectivity. Adapted fromGiacino et al., 2014.

Figure 2

Study protocol's timeline of first and last day of treatment. taVNS: transcutaneous auricular vagal nerve stimulation; CRS-R: Coma Recovery Scale-Revised; EEG: electroencephalography; EKG: electrocardiogram; NCS-R: Nociception Coma Scale-Revised.