Reconnecting the disconnected forebrain: multimodal resting-state bold dynamics underlying zolpidem-induced arousal in incomplete Locked-in syndrome

Primary objective Zolpidem paradoxically restores behavioral responsiveness and communication in select patients with severe disorders of consciousness and profound motor deafferentation. While the anterior forebrain mesocircuit hypothesis attributes this awakening to central thalamic disinhibition, macroscopic network dynamics and lower brainstem gating remain under-characterized in locked-in syndrome (LIS).Methods and procedures A 45-year-old male with ventral pontine necrosis initially misdiagnosed as vegetative state/unresponsive wakefulness syndrome (VS/UWS) was formally identified with incomplete LIS through systematic ocular testing. Multimodal high-resolution MRI, deterministic diffusion tensor imaging (DTI) tractography, resting-state fMRI (before vs. after 10 mg oral zolpidem), dynamic sliding-window graph theory (45 s), infraslow BOLD spectral analysis (Slow-5: 0.010–0.027 Hz; Slow-4: 0.027–0.073 Hz), and seed-based thalamocortical coupling were acquired.Main outcomes and results DTI confirmed focal basis pontis transection with extensive preservation of supratentorial projection architecture. Baseline fMRI exhibited aberrant, unsegregated cross-network hyperconnectivity. Zolpidem restored canonical modular boundaries, pruned noisy long-range edges, induced focal BOLD reactivation in primary motor (M1) and precuneal cores, shifted power into the infraslow Slow-5 domain, and markedly augmented thalamocortical coupling (thalamo-precuneus: r = 0.18 to 0.61; striato-thalamus: r = 0.33 to 0.75).Conclusions Paradoxical awakening in incomplete LIS is underpinned by structural preservation of the supratentorial mantle. Beyond classical mesocircuit release, zolpidem engages brainstem gating structures, restoring modular segregation, infraslow frequency tuning, and cognitive-motor coupling.