712 - Paradoxical Neurostimulation with Zolpidem Outside of Disorders of Consciousness

Friday, February 20, 2026

5:00 PM - 6:30 PM AST

Presenting Author(s)

RP

Rebecca L. Perron, MD

Resident
University of New Mexico
Albuquerque, New Mexico, United States

Co-Author(s)

AD

Austin Davis, MD

Attending Physician
University of New Mexico
Albuquerque, New Mexico, United States

Submitter(s)

RP

Rebecca L. Perron, MD

University of New Mexico
Albuquerque, New Mexico, United States

Case Diagnosis: Paradoxical Neurostimulation with Zolpidem Outside of Disorders of Consciousness

Case Description:
A 16-year-old girl with severe traumatic and hypoxic ischemic brain injury secondary to remote car crash with cardiac arrest presented after plateauing in therapies. She was in a minimally conscious state for 1.5 years before emerging. She is now able to walk short distances with a walker and communicate using an assistive communication device. More recently, improvements in therapy have slowed secondary to difficulty with sustained attention and engagement. 

Family noted that the patient demonstrated improved arousal and eye control after receiving midazolam for a procedure in the past. Given the receptor overlap, zolpidem 5mg thirty minutes prior to therapy was initiated with resulting improved attention and engagement during speech therapy.

Discussions: Although paradoxical awakening with zolpidem has been observed in about 5% of individuals with severe acquired brain injury, all reported cases of benefit to our knowledge involve individuals who remain in a disorder of consciousness (DoC) at the time of zolpidem administration. One proposed mechanism of DoC is “mesocircuit” (cortical – basal ganglia – thalamus - cortical loop) dysfunction due to unchecked inhibition of the thalamus by the globus pallidus internus (GPi). Zolpidem has selective binding with GABA(A) alpha 1 receptors which are found in high concentrations in the GPi; zolpidem’s hypothesized action on the GPi thus inhibits the inhibitor, re-establishing the “mesocircuit” and improving arousal.

Conclusions: This case is unique because the patient demonstrated paradoxical cognitive improvement from zolpidem after she had emerged from DoC. Given that zolpidem’s hypothesized mechanism involves resumption of mesocircuit function, one might expect limited if any benefit from zolpidem after emergence from DoC. Future work should continue to critically evaluate zolpidem’s proposed mechanism of action and examine to what degree, if any, there is a role for zolpidem as a neurostimulant after emergence from DoC.