Funded Grants

Reanimation and Cognitive Recovery from General Anesthesia

General anesthesia is necessary for the humane practice of surgery. By the time we reach the age of 70, almost all of us will experience general anesthesia at least once. Although general anesthesia is reversible, there is accumulating evidence that it causes post-operative cognitive dysfunction in elderly patients that can persist for months, or even years. As our population gets older, the number of elderly patients requiring surgery will continue to increase. Therefore post-operative cognitive dysfunction is fast becoming a major public health problem with no available treatment.

In clinical practice, general anesthesia is rapidly induced and maintained by the active administration of intravenous or inhalational drugs. In contrast, emergence from general anesthesia is a slow process dictated by the pharmacokinetics of anesthetic drug clearance, a process we term "passive emergence." Passive emergence from general anesthesia is hazardous because at low doses, general anesthetics cause paradoxical excitation of the central nervous system leading to complications such as laryngospasm, hemodynamic instability, and delirium.

My laboratory studies the neural mechanisms of emergence and cognitive recovery from general anesthesia, and we discovered that methylphenidate (Ritalin) induces active emergence from continuous general anesthesia in rodents. We term this active emergence process "reanimation" to distinguish it from the passive emergence process currently employed in clinical practice. Our most recent work demonstrates that stimulation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia, suggesting that methylphenidate and dopamine agonists induce reanimation by activating a dopaminergic arousal pathway projecting from this area of the midbrain. In addition to brainstem activation, methylphenidate also induces evidence of cortical activation and cognitive recovery.

Over the next four years, I will establish a clinical research program at Massachusetts General Hospital that tests the efficacy of methylphenidate for reanimation and cognitive recovery in anesthetized humans. Emergence from general anesthesia provides a unique window into the process of recovery from a comatose state to a conscious state, and our work will provide fundamental insights into how human cognition is restored after general anesthesia. Considering that almost all of us will have general anesthesia at some point in our lives, cognitive recovery from general anesthesia is an important research topic that needs to be investigated. Understanding the neural mechanisms that drive this process will lead us to new treatments for clinical problems with no available therapy, such as post-operative delirium and cognitive dysfunction. In addition, our work may also lead to new treatments for disorders of consciousness and cognition due to brain injuries and neurodegenerative diseases.