Ketamine to Treat Patients With Post-comatose Disorders of Consciousness

Complexity-enhancing Drugs to Treat Disorders of Consciousness (DoC): a Ketamine Study

The investigators will run a Randomized Clinical Trial with 30 patients with disorders of consciousness (DoC), with intravenous subanesthetic doses of ketamine. Patients will simultaneously undergo TMS-EEG. The piloting will be done on 3 patients, with EEG only.

The protocol will be organized in three phases: baseline, experimental, and follow-up. In the baseline, patients will receive a multimodal assessment [functional magnetic resonance imaging (fMRI), positron emission tomography (PET), electroencephalogram (EEG)]. The experimental phase is made of 2 sessions spaced 5 days apart: on day 1, patients will receive placebo (or ketamine), on day 5 patients will receive ketamine (or placebo). The order will be randomized and balanced. The investigators will use a targeted-controlled infusion (TCI) system to infuse a continuous subanesthetic dose of ketamine, which is known to have psychedelics effects, or a saline solution. The investigators will periodically assess for new signs of consciousness with the "simplified evaluation of consciousness disorders" (SECONDs) scale. The investigators will use transcranial magnetic stimulation coupled to EEG (TMS-EEG) to measure brain activity and calculate brain complexity. TMS-EEG will be performed from 20 minutes before the beginning of the infusion up to the max duration of the experiment (90 minutes). Another SECONDs will be performed on the following day of each session to control for carry-over effects. The primary outcomes are the emergence of new conscious behaviours and higher brain complexity following ketamine infusion. The secondary outcomes are baseline brain differences in neurophysiological and brain imaging measures between responders (new conscious behaviors or higher brain complexity) and non-responders (no new conscious behaviors or higher brain complexity). In the follow-up phase, patients' health will be evaluated at 1, 6, and 12 months.

Inclusion Criteria:

• Clinically stable
• Diagnosis of UWS or MCS based on repeated "coma recovery scale-revised) (CRS-R) or SECONDs
• More than 28 days post-insult
• Informed consent from the legal representative of the patient

Exclusion Criteria:

• Neurological medications other than anti-spasticity drugs in the last 2 weeks or 4 half-lives
• Previous neurological functional impairment other than related to their DoC
• A history of psychotic disorders
• Contraindication to MRI, EEG, PET or TMS
• Use of nitrates or other vasodilators, central nervous system acting agents such as barbiturates, morphine and related drugs.
• Use of drugs known to interact with ketamine (i.e., CYP3A4, diazepam, ...)
• Coronary insufficiency
• Other sympathomimetic drugs