Transcutaneous Auricular Vagus Nerve Stimulation for Recovery of Consciousness After Surgery for Spontaneous Intracerebral Hemorrhage

This study uses a core randomized controlled trial with nested multimodal mechanisticsubstudies. The primary clinical aim is to determine whether early taVNS improvesrecovery of consciousness after surgical treatment of spontaneous intracerebralhemorrhage (sICH). The mechanistic aims are to characterize treatment‐related changes inresidual arousal networks, cerebral perfusion and metabolism, neuroinflammation andneural injury, electrophysiological function, and autonomic regulation; to test whetherthese changes mediate clinical recovery; and to identify baseline phenotypes associatedwith treatment response.Eligible participants will be randomized in a 1:1 ratio using a minimization procedure onpostoperative day 5 (±1 day). The active group will receive left‐ear taVNS at 25 Hz, apulse width of 500 microseconds, and an intensity of 0.8‐1.5 mA, using alternating30‐second on and 30‐second off cycles. Stimulation will continue for 8 hours once dailyfor 6 weeks. The sham group will wear the same device with the electrode placed at thesame left‐ear location for 8 hours once daily for 6 weeks, but no current will bedelivered. Other standard postoperative and rehabilitation care will be providedaccording to local clinical practice.Consciousness will be assessed with the Coma Recovery Scale‐Revised (CRS‐R) at baselineand on postoperative days 28 and 90. The postoperative day‐90 assessment will beperformed by an independent blinded assessment team. CRS‐R diagnostic categories will beused to classify participants as being in unresponsive wakefulness syndrome/vegetativestate (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, withmodality‐specific windows and eligibility criteria. Reference time points are thepre‐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. Participationdepends on clinical stability, contraindications, site capability, sample availability,and separate consent where required.The neuroimaging platform may include noncontrast computed tomography to quantifyhematoma location and volume, perihematomal edema, intraventricular extension,hydrocephalus, midline shift, residual hematoma, and secondary injury; computedtomography angiography when clinically obtained to characterize vascular features; andcomputed tomography perfusion to measure cerebral blood flow, cerebral blood volume, meantransit time, and time‐to‐maximum in the central thalamus, brainstem and basal forebrainarousal nodes, and distributed cortical networks. Magnetic resonance imaging may includeT1‐ and T2‐weighted imaging, fluid‐attenuated inversion recovery, diffusion‐weightedimaging, susceptibility‐weighted imaging, diffusion tensor imaging, arterial spinlabeling, and resting‐state functional magnetic resonance imaging. Prespecified imagingfeatures may include structural preservation of arousal‐network nodes and pathways,white‐matter integrity, regional perfusion, functional connectivity, network segregationand integration, and longitudinal change after treatment.The electrophysiology and autonomic platform may include routine or high‐densityelectroencephalography, spectral power, background organization, reactivity, complexity,functional connectivity, sleep‐wake organization, and event‐related responses wherefeasible. Electrocardiography‐derived heart‐rate variability, blood‐pressure variability,and other prespecified autonomic indices may be used to assess engagement of vagal andcentral autonomic pathways.The biospecimen platform may include serial blood collection for inflammatory, immune,endothelial, coagulation, metabolic, and neural‐injury biomarker domains. Candidatemeasures may include blood‐cell and routine biochemical indices, C‐reactive protein,cytokines and chemokines, neurofilament light chain, glial fibrillary acidic protein,S100 calcium‐binding protein B, neuron‐specific enolase, and other prespecified markersdocumented in the laboratory analysis plan. Cerebrospinal fluid may be collected onlywhen available from clinically indicated external ventricular drainage, lumbar drainage,or another clinically necessary procedure, unless an additional research‐only procedurehas received specific ethics approval and separate informed consent. Paired blood andcerebrospinal‐fluid analyses may be used to characterize central and systemicinflammatory or neural‐injury responses.Mechanistic analyses will evaluate: (1) the effect of taVNS on longitudinal biomarker andnetwork changes; (2) associations between these changes and CRS‐R improvement oremergence from the minimally conscious state; (3) mediation pathways linking taVNS,target engagement, and recovery of consciousness; and (4) treatment‐effect heterogeneityaccording to baseline structural preservation, perfusion, functional connectivity,electrophysiological patterns, autonomic function, and biomarker profiles. These analysesare exploratory unless otherwise prespecified in the statistical analysis plan.Sample Size Calculation: The sample size was calculated based on the proportion ofparticipants who achieve emergence from the minimally conscious state (eMCS) or regain ahigher level of consciousness by postoperative day 90. Previous cohorts of patients withintracerebral hemorrhage or prolonged disorders of consciousness reported thatapproximately 59%‐67% achieved eMCS during follow‐up. Because the present trial enrolls amore severely affected population with a Glasgow Coma Scale score of 5‐9 on postoperativeday 5, the eMCS rate in the sham‐control group was conservatively assumed to be 55%. Thecorresponding eMCS rate was assumed to be 80% in the active taVNS group, representing anabsolute difference of 25 percentage points. With a two‐sided alpha level of 0.05, 90%statistical power, and a 1:1 allocation ratio, 72 evaluable participants are required pergroup. Allowing for approximately 10% loss to follow‐up, withdrawal, or missing primaryoutcome data, the final planned enrollment is 160 participants, with 80 participants ineach group.One formal interim analysis is planned for March 2027, provided that approximately 80participants, representing 50% of the planned information size, have completed the 90‐dayprimary‐outcome assessment. If this information threshold has not been reached by March2027, only a blinded review of recruitment, protocol adherence, data completeness, and anappropriate safety review will be conducted, and the formal interim efficacy analysiswill be postponed until the prespecified information threshold is reached. The interimanalysis will be performed by an independent statistician and reviewed by an independentData Monitoring Committee. Interim assessments will address efficacy, safety, andfutility. A Lan‐DeMets alpha‐spending function approximating O'Brien‐Fleming boundarieswill be used to preserve the overall two‐sided type I error rate. A stringent stoppingboundary will be applied for overwhelming efficacy, while a non‐binding conditional‐powerboundary will be used for futility. Investigators, outcome assessors, and the sponsor'soperational study team will remain blinded to comparative interim results. Based on theprespecified Data Monitoring Committee charter, the committee may recommend continuation,early termination for overwhelming efficacy or safety concerns, or discontinuation forfutility.