Neural signatures of α2-Adrenergic agonist-induced unconsciousness and awakening by antagonist

Abstract

How the brain dynamics change during anesthetic-induced altered states of consciousness is not completely understood. The α2-adrenergic agonists are unique. They generate unconsciousness selectively through α2-adrenergic receptors and related circuits. We studied intracortical neuronal dynamics during transitions of loss of consciousness (LOC) with the α2-adrenergic agonist dexmedetomidine and return of consciousness (ROC) in a functionally interconnecting somatosensory and ventral premotor network in non-human primates. LOC, ROC and full task performance recovery were all associated with distinct neural changes. The early recovery demonstrated characteristic intermediate dynamics distinguished by sustained high spindle activities. Awakening by the α2-adrenergic antagonist completely eliminated this intermediate state and instantaneously restored awake dynamics and the top task performance while the anesthetic was still being infused. The results suggest that instantaneous functional recovery is possible following anesthetic-induced unconsciousness and the intermediate recovery state is not a necessary path for the brain recovery.

Weak Coupling Between Spontaneous Local Cortical Activity State Switches Under Anesthesia Leads to Strongly Correlated Global Cortical States

“…Thus, for instance, the ability to infer the current state of one channel by observing the state of a nearby channel in the cortex is limited. Remarkably, we provide evidence that abrupt transitions between discrete macroscopic cortical activity patterns (Ballesteros et al, 2020;Chander et al, 2014;Hudson et al, 2014;Ishizawa et al, 2016;Lee et al, 2020;Patel et al, 2020) emerge naturally from the multitude of these quasi-independent local fluctuations. We also demonstrate that the strength of the interactions between recording sites depends on the inter-electrode distance and on the cortical layer.…”

“…These data suggest that global brain states comprise regionally distinct oscillation patterns that are weakly coupled with one another. Remarkably, these results show that discrete transitions between global cortical states (Ballesteros et al, 2020;Hudson et al, 2014;Patel et al, 2020) under a fixed anesthetic concentration arise from the multitude of weakly coupled local fluctuations.…”

Dexmedetomidine Preserves Activity of Neurons in Primary Somatosensory Cortex Compared to Propofol and Ketamine

“…It has been suggested that the locus coeruleus–norepinephrine (LC-NE) system plays a key role in sensory signal processing to facilitate information integration such as decision making and motor response [ 25 , 26 ]. Most studies generally claim that LC-NE activation facilitates the representation of sensory signals by inhibiting spontaneous neuronal activity more than sensory-evoked response, effectively enhancing the signal-to-noise ratio (SNR) at the population level [ 27 , 28 ]. In addition, the ventral tegmental area-dopamine (VTA-DA) system has also been reported as an important target involved in dexmedetomidine-induced sedation [ 29 ].…”

Scientific rationale for the use of α2A-adrenoceptor agonists in treating neuroinflammatory cognitive disorders

“…Potential sedative effects through the thalamus α2-AR agonists can produce sedation, which is a side effect when used to treat ADHD, but helpful when used as an anesthetic, e.g., dexmedetomidine [151]. While presynaptic α2A-AR actions appear to contribute to a sleep state [152], they are unlikely the whole story in primates, as the α2A-AR selective agonist, guanfacine, has little sedative actions, while the very sedating dexmedetomidine is a full agonist at the α2B-AR subtype, and only a partial agonist at the α2A-AR and the α2C-AR subtypes (Table 1) [153].…”