Restoring consciousness with pharmacologic therapy: Mechanisms, targets, and future directions.

Barra, ME; Solt, K; Yu, X; Edlow, BL

Restoring consciousness with pharmacologic therapy: Mechanisms, targets, and future directions.

Barra, ME Solt, K Yu, X

Edlow, BL

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Publisher:: ELSEVIER SCIENCE INC
Publication Type:: Journal Article
Citation:: Neurotherapeutics, 2024, 21, (4), pp. e00374
Issue Date:: 2024-07

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Field	Value	Language
dc.contributor.author	Barra, ME
dc.contributor.author	Solt, K
dc.contributor.author	Yu, X https://orcid.org/0000-0002-0269-5649
dc.contributor.author	Edlow, BL
dc.date.accessioned	2024-12-02T00:43:56Z
dc.date.available	2024-05-03
dc.date.available	2024-12-02T00:43:56Z
dc.date.issued	2024-07
dc.identifier.citation	Neurotherapeutics, 2024, 21, (4), pp. e00374
dc.identifier.issn	1933-7213
dc.identifier.issn	1878-7479
dc.identifier.uri	http://hdl.handle.net/10453/182166
dc.description.abstract	Severe brain injury impairs consciousness by disrupting a broad spectrum of neurotransmitter systems. Emerging evidence suggests that pharmacologic modulation of specific neurotransmitter systems, such as dopamine, promotes recovery of consciousness. Clinical guidelines now endorse the use of amantadine in individuals with traumatic disorders of consciousness (DoC) based on level 1 evidence, and multiple neurostimulants are used off-label in clinical practice, including methylphenidate, modafinil, bromocriptine, levodopa, and zolpidem. However, the relative contributions of monoaminergic, glutamatergic, cholinergic, GABAergic, and orexinergic neurotransmitter systems to recovery of consciousness after severe brain injury are unknown, and personalized approaches to targeted therapy have yet to be developed. This review summarizes the state-of-the-science in the neurochemistry and neurobiology of neurotransmitter systems involved in conscious behaviors, followed by a discussion of how pharmacologic therapies may be used to modulate these neurotransmitter systems and promote recovery of consciousness. We consider pharmacologic modulation of consciousness at the synapse, circuit, and network levels, with a focus on the mesocircuit model that has been proposed to explain the consciousness-promoting effects of various monoaminergic, glutamatergic, and paradoxically, GABAergic therapies. Though fundamental questions remain about neurotransmitter mechanisms, target engagement and optimal therapy selection for individual patients, we propose that pharmacologic therapies hold great promise to promote recovery and improve quality of life for patients with severe brain injuries.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	ELSEVIER SCIENCE INC
dc.relation	National Institute of Neurological Disorders and StrokeR01NS122904
dc.relation.ispartof	Neurotherapeutics
dc.relation.isbasedon	10.1016/j.neurot.2024.e00374
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1109 Neurosciences, 1115 Pharmacology and Pharmaceutical Sciences, 1117 Public Health and Health Services
dc.subject.classification	Neurology & Neurosurgery
dc.subject.classification	3209 Neurosciences
dc.subject.classification	3214 Pharmacology and pharmaceutical sciences
dc.subject.classification	5202 Biological psychology
dc.subject.mesh	Humans
dc.subject.mesh	Consciousness Disorders
dc.subject.mesh	Animals
dc.subject.mesh	Brain Injuries
dc.subject.mesh	Consciousness
dc.subject.mesh	Neurotransmitter Agents
dc.subject.mesh	Recovery of Function
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Brain Injuries
dc.subject.mesh	Consciousness Disorders
dc.subject.mesh	Neurotransmitter Agents
dc.subject.mesh	Consciousness
dc.subject.mesh	Recovery of Function
dc.subject.mesh	Humans
dc.subject.mesh	Consciousness Disorders
dc.subject.mesh	Animals
dc.subject.mesh	Brain Injuries
dc.subject.mesh	Consciousness
dc.subject.mesh	Neurotransmitter Agents
dc.subject.mesh	Recovery of Function
dc.title	Restoring consciousness with pharmacologic therapy: Mechanisms, targets, and future directions.
dc.type	Journal Article
utslib.citation.volume	21
utslib.location.activity	United States
utslib.for	1109 Neurosciences
utslib.for	1115 Pharmacology and Pharmaceutical Sciences
utslib.for	1117 Public Health and Health Services
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated	2024-12-02T00:43:51Z
pubs.issue	4
pubs.publication-status	Published
pubs.volume	21
utslib.citation.issue	4

Abstract:

Severe brain injury impairs consciousness by disrupting a broad spectrum of neurotransmitter systems. Emerging evidence suggests that pharmacologic modulation of specific neurotransmitter systems, such as dopamine, promotes recovery of consciousness. Clinical guidelines now endorse the use of amantadine in individuals with traumatic disorders of consciousness (DoC) based on level 1 evidence, and multiple neurostimulants are used off-label in clinical practice, including methylphenidate, modafinil, bromocriptine, levodopa, and zolpidem. However, the relative contributions of monoaminergic, glutamatergic, cholinergic, GABAergic, and orexinergic neurotransmitter systems to recovery of consciousness after severe brain injury are unknown, and personalized approaches to targeted therapy have yet to be developed. This review summarizes the state-of-the-science in the neurochemistry and neurobiology of neurotransmitter systems involved in conscious behaviors, followed by a discussion of how pharmacologic therapies may be used to modulate these neurotransmitter systems and promote recovery of consciousness. We consider pharmacologic modulation of consciousness at the synapse, circuit, and network levels, with a focus on the mesocircuit model that has been proposed to explain the consciousness-promoting effects of various monoaminergic, glutamatergic, and paradoxically, GABAergic therapies. Though fundamental questions remain about neurotransmitter mechanisms, target engagement and optimal therapy selection for individual patients, we propose that pharmacologic therapies hold great promise to promote recovery and improve quality of life for patients with severe brain injuries.

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http://hdl.handle.net/10453/182166