Alpha tACS for Disorders of Consciousness : a Single Case Experimental Design

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BRIEF SUMMARY \* (Include a statement of the study hypothesis) Avoid all personal pronouns (Limit: 5000 characters) Disorders of consciousness (DoC) following a severe traumatic brain injury represent a major medical challenge, with very limited therapeutic options and many patients remaining in a minimally conscious state or vegetative/unresponsive wakefulness state for months. To date, only two pharmacological treatments (amantadine and zolpidem) have shown partial benefits. Non-invasive neuromodulation techniques such as transcranial direct current stimulation (tDCS) have produced modest but encouraging results. Recent advances in transcranial alternating current stimulation (tACS) have demonstrated its ability to modulate brain oscillations, particularly in the alpha frequency range (8-12 Hz), which plays a central role in large-scale functional connectivity, especially within the default mode network (DMN). Neuroimaging studies suggest alpha activity and DMN connectivity are major correlate of the level of consciousness in DoC. Yet experimental evidence suggests that alpha tACS can enhance alpha power and antero-posterior connectivity in healthy subjects, as well as connectivity within the default mode network (DMN). However, no controlled study has yet evaluated its therapeutic potential in patients with DoC. The present study (SPARC) is a single-center clinical investigation aiming to assess the clinical efficacy of alpha tACS in patients with DoC after traumatic brain injury. The primary hypothesis is that repeated sessions of alpha tACS will improve the level of consciousness, compared to baseline and non-stimulation periods, by reinforcing power and functional connectivity in the alpha band. This trial adopts a Single-Case Experimental Design (SCED), a robust methodology particularly suited to rare and heterogeneous clinical populations such as DoC. Five adult patients (aged 18-70 years) with DoC persisting for 3-12 months post-trauma will be included. Each participant will undergo six consecutive phases over three months: three non-stimulation (baseline/washout) periods and three stimulation periods, each period lasting two weeks, in an A-B-A-B-A-B sequence. This intra-subject design allows each patient to serve as their own control, maximizing sensitivity to individual changes and limiting confounding by clinical heterogeneity. The primary outcome measure is the change in the Simplified Evaluation of Consciousness Disorders (SECONDS) score, a validated clinical scale routinely used in DoC assessment. SECONDS will be measured three times weekly throughout the study. Secondary outcomes include: (1) EEG-based classification of consciousness state using an established machine-learning algorithm, (2) spectral power and functional connectivity changes in the alpha band, and (3) resting-state fMRI measures of DMN connectivity. These multimodal assessments aim both to provide objective evidence of clinical improvement and to explore the underlying neurophysiological mechanisms of tACS. Safety and tolerability are monitored. Previous studies confirm that tACS is safe and well-tolerated, with only minor, transient side effects (tingling, scalp redness, phosphene perception). The study also involves EEG and MRI recordings, both of which are non-invasive and carry only minimal risks. This study, although limited to five patients, is designed to provide rigorous individual-level evidence of efficacy and mechanistic plausibility. If results demonstrate consistent clinical and neurophysiological improvements, they will justify the design of a larger confirmatory trial and contribute to the development of novel therapeutic approaches for this severely disabled population.

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