Department of Pharmacy, Massachusetts General Hospital, Boston, MA, USA; Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital, Boston, MA, USA.
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
Neurotherapeutics. 2024 Jul;21(4):e00374. doi: 10.1016/j.neurot.2024.e00374. Epub 2024 Jul 17.
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.
严重脑损伤通过破坏广泛的神经递质系统来损害意识。新出现的证据表明，对特定神经递质系统（如多巴胺）的药理学调节可促进意识的恢复。临床指南现在基于 1 级证据，支持在创伤性意识障碍（DOC）患者中使用金刚烷胺，并在临床实践中使用多种神经刺激剂进行非标签使用，包括哌甲酯、莫达非尼、溴隐亭、左旋多巴和唑吡坦。然而，单胺能、谷氨酸能、胆碱能、GABA 能和食欲素能神经递质系统对严重脑损伤后意识恢复的相对贡献尚不清楚，个性化的靶向治疗方法尚未开发。这篇综述总结了参与意识行为的神经递质系统的神经化学和神经生物学的最新科学进展，随后讨论了如何使用药物治疗来调节这些神经递质系统并促进意识的恢复。我们考虑了突触、回路和网络水平的意识药理学调节，重点讨论了中回路模型，该模型被提出用于解释各种单胺能、谷氨酸能和矛盾的 GABA 能治疗方法对意识的促进作用。尽管关于神经递质机制、药物靶点的结合以及个体患者的最佳治疗选择仍存在基本问题，但我们提出药物治疗具有很大的潜力，可以促进严重脑损伤患者的恢复并提高其生活质量。
