Neural Circuit Mechanisms of Disorders of Consciousness and Potential Therapeutic Targets of Brain Stimulation

Disorders of consciousness (DoC) lack an integrated framework to guide neuromodulation. This review updates three hierarchical frameworks-ARAS, mesocircuit, and ICNs-and maps therapeutic targets within each.

We synthesized recent neuroanatomical, optogenetic, neuroimaging, and clinical trial evidence, reevaluating classic frameworks and proposing a hierarchical integration to inform multi-target strategies.

Three major updates are identified. In ARAS, glutamatergic neurons in PPN/LDT and parabrachial nucleus, rather than cholinergic neurons, are the primary arousal drivers; clinical translation relies on peripheral nerve stimulations with variable efficacy. The mesocircuit is expanded from a unidirectional GPi-mediated pathway to a bidirectional GPi-GPe balance modulated by dopamine and adenosine; DBS targeting CM-Pf/CL shows ~44.7% response rate (38/85) but lacks RCTs, whereas amantadine remains the sole Level 1 evidence. Within ICNs, the executive control network has the strongest RCT support, though efficacy depends on etiology and consciousness level; salience network stimulation is untested. These frameworks are hierarchically integrated: ARAS sustains wakefulness, mesocircuit enables cortical activation, and ICNs support conscious content.

Future strategies should adopt multi-target, multi-level approaches grounded in individualized network profiling. Priorities include large-scale RCTs for DBS and stratified protocols based on etiology and consciousness level.