The Daily Dose • Sunday, May 19

Anesthesia and Consciousness: How Investigations of the Anesthetized State Shape Current Concepts of Consciousness

By Christian S. Guay, MD, from the IARS, AUA and SOCCA 2019 Annual Meetings*

Every induction, maintenance and emergence from an anesthetic state is fundamentally an experiment in the field of consciousness studies. In this way, anesthesiologists are uniquely positioned to investigate the basic principles of conscious states and how we transition between them. The diverse backgrounds of the speakers at AUA Symposium: Anesthesia and Consciousness: How Investigations of the Anesthetized State Shape Current Concepts of Consciousness provided attendees with a multidisciplinary view of consciousness, connectedness, responsiveness, and emergence from oblivion.

Moderated by Ines P. Koerner, MD, PhD, Oregon Health & Science University, the session included experts Robert Sanders, MBBS, PhD, FRCA, University of Wisconsin School of Medicine and Public Health, Ken Solt, MD, Harvard Medical School and Massachusetts General Hospital, George A. Mashour, MD, PhD, University of Michigan, and Stefanie Blain-Moraes, PhD, McGill University.

Dr. Mashour began the symposium with a discussion of the neural correlates of consciousness. His talk focused on the functional connectivity between frontal and parietal brain regions. Fronto-parietal connectivity tends to break down during general anesthesia induced by different agents, including ketamine, propofol and sevoflurane. To investigate this phenomenon further, Dr. Mashour’s group performed a series of experiments using rats fitted with intracranial electrodes and microdialysis catheters positioned in the frontal and parietal cortexes.

During the experiments, rats were anesthetized with sevoflurane, maintained at a level of 1 MAC. Once stable sevoflurane levels were achieved, carbachol (muscarinic agonist) was injected into either the prefrontal or posterior parietal catheters. Although the EEG of both groups showed increased activation (lower amplitude, higher frequency), only the prefrontal group became sufficiently aroused to recover their righting reflex. Interestingly, cerebral acetylcholine levels were also selectively increased in the prefrontal group, likely driven by prefrontal projections to the basal forebrain. A follow-up experiment found that although adding ketamine to sevoflurane induced a higher burst suppression ratio, it also decreased emergence time in concert with increasing prefrontal cholinergic tone. Together, these findings shed light on the molecular mechanisms driving fronto-parietal connectivity and their relationship to conscious state transitions.

The next speaker, Dr. Sanders, started his presentation by defining three distinct brain states: conscious (i.e., any form of subjective experience), connected (i.e., sensory perception contributes to the subjective experience) and responsiveness (i.e., interaction of an organism with its environment based on its perceptions and subjective experience). Although we oft assume that a patient is unconscious if they do not respond to commands or noxious stimuli, they may in fact be in a state of disconnected consciousness. We are all familiar with these states of disconnected consciousness in the form of dreams. In fact, Dr. Sanders posits that a dreaming state is an acceptable anesthetic state, and that it may be more prevalent than expected. In fact, a recent study during which subjects were roused from states of sedation with propofol or dexmedetomidine (Dex) found that 90% of subjects in the Dex group and 74% in the propofol reported subjective but disconnected experiences immediately preceding the arousal, consistent with a dream state. Therefore, a brain monitor that is perfectly sensitive for conscious experience will likely identify a larger proportion of patients who are dreaming than those who are conscious and connected to their environments. These findings have led Dr. Sanders and his colleagues to design methods to identify sensory connection and disconnection. A promising approach uses transcranial magnetic stimulation to describe brain states in how they respond to magnetic stimulation. Preliminary data suggests that evoked alpha oscillatory activity may be a good marker for connected consciousness (lost in states of REM and ketamine dissociation), whereas higher frequency oscillations in the beta and gamma frequency are specific for any conscious experience (lost in propofol anesthesia and NREM sleep).

Dr. Solt then shifted gears to focus on mechanisms of emergence from anesthesia, and on methods to accelerate the process. The first part of the presentation provided a clear overview of various arousal promoting pathways, including those based on acetylcholine, norepinephrine, dopamine, histamine, serotonin and orexin. This foundational knowledge then allowed Dr. Solt to guide attendees through a series of preclinical experiments that leverage these arousal pathways to induce emergence from anesthesia. In particular, he discussed caffeine, an adenosine antagonist, carbachol, a cholinergic agonist, and methylphenidate, a mixed dopamine/norepinephrine re-uptake inhibitor. Dr. Solt also presented the unpublished results from a recent phase 2 clinical trial investigating intravenous methylphenidate as a method to induce emergence from general anesthesia in human patients. Despite the clear preclinical evidence and biological plausibility of their hypothesis, the trial did not show any significant difference in time to extubation between patients who received placebo compared to those who received methylphenidate immediately preceding sevoflurane discontinuation. Possible explanations include the timing of drug administration, insufficient dosing, and perioperative polypharmacy. Dr. Solt’s group is now investigating D-amphetamine, a more potent enhancer of dopaminergic and adrenergic tone. 

Dr. Blain-Moraes concluded the symposium with a discussion on how anesthesia can be used to study disorders of consciousness (DOC). Patients who suffer from a DOC such as minimally conscious state (MCS) or unresponsive wakefulness syndrome (UWS) are notoriously difficult to compare to healthy controls due to their altered baseline neurophysiology. Furthermore, recent evidence suggests that up to 40% of patients with MCS are misdiagnosed with UWS. Therefore, Dr. Blain-Moraes developed a within-subject, high density EEG study protocol that uses induction and emergence from anesthetic states to distinguish patients who have retained features of conscious state transitions and possibly prognosticate recovery. Specifically, she uses measures of functional connectivity and graph theory in addition to traditional spectral analysis to characterize brain states. She highlighted the example of a patient recruited in her ongoing study who was unresponsive (UWS), but exhibited features of conscious state transitions during induction and emergence from propofol anesthesia. Several weeks later, the patient began interacting with their environment, emerging from oblivion.

*Coverage from AUA Symposium: Anesthesia and Consciousness: How Investigations of the Anesthetized State Shape Current Concepts of Consciousness, moderated by Ines P. Koerner, MD, PhD, and presented by Robert Sanders, MBBS, PhD, Ken Solt, MD, George Mashour, MD, PhD, and Stefanie Blain-Moraes, PhD, during the IARS 2019 Annual Meeting