Increased brain metabolism and EEG connectivity after apomorphine therapy in patients with chronic disorders of consciousness

Objectives:
Few therapies to improve the prognosis of patients with disorders of consciousness (DoC) have reliable evidence to support their efficacy and outcome measures used in clinical trials rarely include neuroimaging biomarkers of recovery. Apomorphine is a dopaminergic agent which has demonstrated preliminary behavioral results in DoC. Its consciousness-promoting action is thought to rely on the restoration of dopaminergic striato-pallido-thalamo-cortical feedback loops in the mesocircuit. This open-label study uses clinical and neuroimaging outcome measures to investigate changes after apomorphine therapy, to confirm its efficacy and identify surrogate biomarkers of responsiveness.

Methods:
6 patients with chronic DoC following severe brain injury (4 male; 4 traumatic; 1 unresponsive, 3 minimally conscious “minus”, 2 minimally conscious “plus”; 38-year-old average; 99 days post-onset average) received daily subcutaneous apomorphine for 30 days. Multimodal outcome measures were recorded 30 days before, during therapy and 30 days after treatment withdrawal. Weekly behavioral assessments included the Coma Recovery Scale–Revised (CRS-R) and rehabilitation scales. Surveys on subjective feeling about the patient’s clinical status were filled out by families and healthcare staff before and after therapy. High-density electroencephalography (hdEEG) and fluorodeoxyglucose positron emission tomography (FDG-PET) were acquired before and after treatment.

Results:
Compared to the 30-day baseline period, 3 patients improved their CRS-R behavioral diagnosis during therapy, 2 additional patients improved during the 12-month follow-up and the last patient spontaneously emerged before treatment but improved on all rehabilitation scales during therapy. All patients maintained their improvements at the latest available follow-up. Mean CRS-R scores were higher during therapy (+2.1 points) and 30-day washout (+4.3 points) periods, compared to the 30-day baseline.
All items evaluated in the clinical survey were rated higher after treatment than before treatment, both by the family (+30.9% mean difference) and the healthcare staff (+20.5%). The family and the staff observed the most important improvements in the patients’ communication abilities and spontaneous motricity, respectively.
4/6 patients demonstrated increased alpha-band hdEEG functional connectivity measured by network centrality after therapy, while the two patients who had already emerged during treatment did not improve (+23.1% average increase in connectivity when considering only the four “responders"). Wholebrain metabolism measured by FDG-PET increased in the same four patients and decreased in the two remaining (+20.1% on average after treatment, when considering only the four “responders”).

Conclusion:
Long-lasting behavioral improvements were observed in these patients with chronic DoC who received 30-day apomorphine therapy. Multimodal neuroimaging measures such as hdEEG connectivity and FDG-PET metabolism may help tracking responsiveness to therapy and identifying potential responders. However, the clinical profile of patients (e.g., those who already emerged) may influence the dynamics of specific neuroimaging biomarkers. Future studies should confirm these preliminary results and guide the selection of adequate multimodal outcome measures following a precision medicine approach.