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

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