Efficacy and Mechanisms of Transcutaneous Auricular Vagus Nerve Stimulation for Promoting Recovery of Consciousness After Surgery for Spontaneous Intracerebral Hemorrhage: A Multicenter, Prospective, Double-Blind, Randomized, Sham-Controlled Trial

This study uses a core randomized controlled trial with nested multimodal mechanistic substudies. The primary clinical aim is to determine whether early taVNS improves recovery of consciousness after surgical treatment of spontaneous intracerebral hemorrhage (sICH). The mechanistic aims are to characterize treatment-related changes in residual arousal networks, cerebral perfusion and metabolism, neuroinflammation and neural injury, electrophysiological function, and autonomic regulation; to test whether these changes mediate clinical recovery; and to identify baseline phenotypes associated with treatment response.

Eligible participants will be randomized in a 1:1 ratio using a minimization procedure on postoperative day 5 (±1 day). The active group will receive left-ear taVNS at 25 Hz, a pulse width of 500 microseconds, and an intensity of 0.8-1.5 mA, using alternating 30-second on and 30-second off cycles. Stimulation will continue for 8 hours once daily for 6 weeks. The sham group will wear the same device with the electrode placed at the same left-ear location for 8 hours once daily for 6 weeks, but no current will be delivered. Other standard postoperative and rehabilitation care will be provided according to local clinical practice.

Consciousness will be assessed with the Coma Recovery Scale-Revised (CRS-R) at baseline and on postoperative days 28 and 90. The postoperative day-90 assessment will be performed by an independent blinded assessment team. CRS-R diagnostic categories will be used to classify participants as being in unresponsive wakefulness syndrome/vegetative state (UWS/VS), minimally conscious state minus (MCS-), minimally conscious state plus (MCS+), or emergence from the minimally conscious state (eMCS)/conscious.

Mechanistic assessments will be organized around a common schedule, with modality-specific windows and eligibility criteria. Reference time points are the pre-stimulation baseline on postoperative day 5 (±1 day), an early-treatment window, postoperative day 28, the end of the 6-week treatment period, and postoperative day 90. Not every participant is required to complete every mechanistic modality. Participation depends on clinical stability, contraindications, site capability, sample availability, and separate consent where required.

The neuroimaging platform may include noncontrast computed tomography to quantify hematoma location and volume, perihematomal edema, intraventricular extension, hydrocephalus, midline shift, residual hematoma, and secondary injury; computed tomography angiography when clinically obtained to characterize vascular features; and computed tomography perfusion to measure cerebral blood flow, cerebral blood volume, mean transit time, and time-to-maximum in the central thalamus, brainstem and basal forebrain arousal nodes, and distributed cortical networks. Magnetic resonance imaging may include T1- and T2-weighted imaging, fluid-attenuated inversion recovery, diffusion-weighted imaging, susceptibility-weighted imaging, diffusion tensor imaging, arterial spin labeling, and resting-state functional magnetic resonance imaging. Prespecified imaging features may include structural preservation of arousal-network nodes and pathways, white-matter integrity, regional perfusion, functional connectivity, network segregation and integration, and longitudinal change after treatment.