@article{39d68e7b38904fd99d1a922f1437aedb,
title = "Therapies to Restore Consciousness in Patients with Severe Brain Injuries: A Gap Analysis and Future Directions",
abstract = "Background/Objective: For patients with disorders of consciousness (DoC) and their families, the search for new therapies has been a source of hope and frustration. Almost all clinical trials in patients with DoC have been limited by small sample sizes, lack of placebo groups, and use of heterogeneous outcome measures. As a result, few therapies have strong evidence to support their use; amantadine is the only therapy recommended by current clinical guidelines, specifically for patients with DoC caused by severe traumatic brain injury. To foster and advance development of consciousness-promoting therapies for patients with DoC, the Curing Coma Campaign convened a Coma Science Work Group to perform a gap analysis. Methods: We consider five classes of therapies: (1) pharmacologic; (2) electromagnetic; (3) mechanical; (4) sensory; and (5) regenerative. For each class of therapy, we summarize the state of the science, identify gaps in knowledge, and suggest future directions for therapy development. Results: Knowledge gaps in all five therapeutic classes can be attributed to the lack of: (1) a unifying conceptual framework for evaluating therapeutic mechanisms of action; (2) large-scale randomized controlled trials; and (3) pharmacodynamic biomarkers that measure subclinical therapeutic effects in early-phase trials. To address these gaps, we propose a precision medicine approach in which clinical trials selectively enroll patients based upon their physiological receptivity to targeted therapies, and therapeutic effects are measured by complementary behavioral, neuroimaging, and electrophysiologic endpoints. Conclusions: This personalized approach can be realized through rigorous clinical trial design and international collaboration, both of which will be essential for advancing the development of new therapies and ultimately improving the lives of patients with DoC.",
keywords = "Coma, Consciousness, Disorders of consciousness, Gap analysis, Precision medicine",
author = "{the Curing Coma Campaign and its contributing members} and Edlow, {Brian L.} and Sanz, {Leandro R.D.} and Len Polizzotto and Nader Pouratian and Rolston, {John D.} and Snider, {Samuel B.} and Aurore Thibaut and Stevens, {Robert D.} and Olivia Gosseries and Yama Akbari and Bleck, {Thomas P.} and Diringer, {Michael N.} and Brandon Foreman and Hartings, {Jed A.} and Raimund Helbok and Hemphill, {J. Claude} and Ling, {Geoffrey S.F.} and Mayer, {Stephan A.} and Molly McNett and Monti, {Martin M.} and Olson, {Dai Wai M.} and Owen, {Adrian M.} and Soojin Park and Provencio, {J. Javier} and Louis Puybasset and Paul Vespa and Amy Wagner and John Whyte and Wendy Ziai",
note = "Funding Information: This work was supported by the Neurocritical Care Society, the National Institutes of Health National Institute of Neurological Disorders and Stroke (R21NS109627, RF1NS115268, K23NS114178), the National Institutes of Health Director{\textquoteright}s Office (DP2HD101400), the National Institutes of Health Institute of General Medical Sciences (R01GM135420), the University of Li{\`e}ge and University Hospital of Li{\`e}ge, the Belgian National Fund for Scientific Research (research fellow grant to LRDS and research associate mandate to OG), the Generet Fund of the King Baudouin Foundation, the Marie Sklodowska-Curie Actions (H2020-MSCA-IF-2016-ADOC-752686), the European Union{\textquoteright}s Horizon 2020 Framework Program for Research and Innovation under Specific Grant Agreement No. 945539 (Human Brain Project SGA3), the James S. McDonnell Foundation, the Tiny Blue Dot Foundation, the Mind Science Foundation, the BIAL Foundation, and the AstraZeneca Foundation. Funding Information: The members of the Curing Coma Campaign who contributed to this article are as follows: Yama Akbari, MD, PhD; Thomas P. Bleck, MD; Michael N. Diringer, MD; Brandon Foreman, MD; Jed A. Hartings, PhD; Raimund Helbok, MD; J. Claude Hemphill, MD; Geoffrey S. F. Ling, MD, PhD; Stephan A. Mayer, MD; Molly McNett, PhD; Martin M. Monti, PhD; DaiWai M. Olson, PhD; Adrian M. Owen, PhD; Soojin Park, MD; J. Javier Provencio, MD; Louis Puybasset, MD, PhD; Paul Vespa, MD; Amy Wagner, MD; John Whyte, MD, PhD; and Wendy Ziai, MD, MPH. The authors also wish to acknowledge the Curing Coma Campaign collaborators participating in the overall program, as listed in Supplementary Table 1. Funding Information: BLE reports grants from the National Institutes of Health Director's Office, the James S. McDonnell Foundation, the National Institute of Neurological Disorders and Stroke, and Tiny Blue Dot Foundation during the conduct of the study. NP reports personal fees from Abbott and Boston Scientific, outside the submitted work. The other authors declare no conflicts of interest. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = jul,
doi = "10.1007/s12028-021-01227-y",
language = "English (US)",
volume = "35",
pages = "68--85",
journal = "Neurocritical Care",
issn = "1541-6933",
publisher = "Humana Press",
}