The precise neural mechanisms underlying transitions between consciousness and anesthetic-induced unconsciousness remain unclear. Here, we studied intracortical neuronal dynamics leading to propofol-induced unconsciousness by recording single-neuron activity and local field potentials directly in the functionally interconnecting somatosensory (S1) and frontal ventral premotor (PMv) network during a gradual behavioral transition from full alertness to loss of consciousness (LOC) and on through a deeper anesthetic level. Macaque monkeys were trained for a behavioral task designed to determine the trial-by-trial alertness and neuronal response to tactile and auditory stimulation. We show that disruption of coherent beta oscillations between S1 and PMv preceded, but did not coincide with, the LOC. LOC appeared to correspond to pronounced but brief gamma-/high-beta-band oscillations (lasting ∼3 min) in PMv, followed by a gamma peak in S1. We also demonstrate that the slow oscillations appeared after LOC in S1 and then in PMv after a delay, together suggesting that neuronal dynamics are very different across S1 versus PMv during LOC. Finally, neurons in both S1 and PMv transition from responding to bimodal (tactile and auditory) stimulation before LOC to only tactile modality during unconsciousness, consistent with an inhibition of multisensory integration in this network. Our results show that propofol-induced LOC is accompanied by spatiotemporally distinct oscillatory neuronal dynamics across the somatosensory and premotor network and suggest that a transitional state from wakefulness to unconsciousness is not a continuous process, but rather a series of discrete neural changes. SIGNIFICANCE STATEMENT How information is processed by the brain during awake and anesthetized states and, crucially, during the transition is not clearly understood. We demonstrate that neuronal dynamics are very different within an interconnecting cortical network (primary somatosensory and frontal premotor area) during the loss of consciousness (LOC) induced by propofol in nonhuman primates. Coherent beta oscillations between these regions are disrupted before LOC. Pronounced but brief gamma-band oscillations appear to correspond to LOC. In addition, neurons in both of these cortices transition from responding to both tactile and auditory stimulation before LOC to only tactile modality during unconsciousness. We demonstrate that propofol-induced LOC is accompanied by spatiotemporally distinctive neuronal dynamics in this network with concurrent changes in multisensory processing.

Background: Ketamine is a noncompetitive N-methyl-d-aspartate antagonist and is known for unique electrophysiologic profiles in electroencephalography. However, the mechanisms of ketamine-induced unconsciousness are not clearly understood. The authors have investigated neuronal dynamics of ketamine-induced loss and return of consciousness and how multisensory processing is modified in the primate neocortex. Methods: The authors performed intracortical recordings of local field potentials and single unit activity during ketamine-induced altered states of consciousness in a somatosensory and ventral premotor network. The animals were trained to perform a button holding task to indicate alertness. Air puff to face or sound was randomly delivered in each trial regardless of their behavioral response. Ketamine was infused for 60 min. Results: Ketamine-induced loss of consciousness was identified during a gradual evolution of the high beta-gamma oscillations. The slow oscillations appeared to develop at a later stage of ketamine anesthesia. Return of consciousness and return of preanesthetic performance level (performance return) were observed during a gradual drift of the gamma oscillations toward the beta frequency. Ketamine-induced loss of consciousness, return of consciousness, and performance return are all identified during a gradual change of the dynamics, distinctive from the abrupt neural changes at propofol-induced loss of consciousness and return of consciousness. Multisensory responses indicate that puff evoked potentials and single-unit firing responses to puff were both preserved during ketamine anesthesia, but sound responses were selectively diminished. Units with suppressed responses and those with bimodal responses appeared to be inhibited under ketamine and delayed in recovery. Conclusions: Ketamine generates unique intracortical dynamics during its altered states of consciousness, suggesting fundamentally different neuronal processes from propofol. The gradually shifting dynamics suggest a continuously conscious or dreaming state while unresponsive under ketamine until its deeper stage with the slow-delta oscillations. Somatosensory processing is preserved during ketamine anesthesia, but multisensory processing appears to be diminished under ketamine and through recovery. Editor’s Perspective: What We Already Know about This Topic: What This Article Tells Us That Is New:

Both the global neuronal workspace (GNW) and integrated information theory (IIT) posit that highly complex and interconnected networks engender perceptual awareness. GNW specifies that activity recruiting frontoparietal networks will elicit a subjective experience, whereas IIT is more concerned with the functional architecture of networks than with activity within it. Here, we argue that according to IIT mathematics, circuits converging on integrative versus convergent yet non-integrative neurons should support a greater degree of consciousness. We test this hypothesis by analyzing a dataset of neuronal responses collected simultaneously from primary somatosensory cortex (S1) and ventral premotor cortex (vPM) in nonhuman primates presented with auditory, tactile, and audio-tactile stimuli as they are progressively anesthetized with propofol. We first describe the multisensory (audio-tactile) characteristics of S1 and vPM neurons (mean and dispersion tendencies, as well as noise-correlations), and functionally label these neurons as convergent or integrative according to their spiking responses. Then, we characterize how these different pools of neurons behave as a function of consciousness. At odds with the IIT mathematics, results suggest that convergent neurons more readily exhibit properties of consciousness (neural complexity and noise correlation) and are more impacted during the loss of consciousness than integrative neurons. Last, we provide support for the GNW by showing that neural ignition (i.e., same trial coactivation of S1 and vPM) was more frequent in conscious than unconscious states. Overall, we contrast GNW and IIT within the same single-unit activity dataset, and support the GNW. SIGNIFICANCE STATEMENT A number of prominent theories of consciousness exist, and a number of these share strong commonalities, such as the central role they ascribe to integration. Despite the important and far reaching consequences developing a better understanding of consciousness promises to bring, for instance in diagnosing disorders of consciousness (e.g., coma, vegetative-state, locked-in syndrome), these theories are seldom tested via invasive techniques (with high signal-to-noise ratios), and never directly confronted within a single dataset. Here, we first derive concrete and testable predictions from the global neuronal workspace and integrated information theory of consciousness. Then, we put these to the test by functionally labeling specific neurons as either convergent or integrative nodes, and examining the response of these neurons during anesthetic-induced loss of consciousness.

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.

How the brain recovers from general anaesthesia is poorly understood. Neurocognitive problems during anaesthesia recovery are associated with an increase in morbidity and mortality in patients. We studied intracortical neuronal dynamics during transitions from propofol-induced unconsciousness into consciousness by directly recording local field potentials and single neuron activity in a functionally and anatomically interconnecting somatosensory (S1, S2) and ventral premotor (PMv) network in primates. Macaque monkeys were trained for a behavioural task designed to determine trial-by-trial alertness and neuronal response to tactile and auditory stimulation. We found that neuronal dynamics were dissociated between S1 and higher-order PMv prior to return of consciousness. The return of consciousness was distinguishable by a distinctive return of interregionally coherent beta oscillations and disruption of the slow-delta oscillations. Clustering analysis demonstrated that these state transitions between wakefulness and unconsciousness were rapid and unstable. In contrast, return of pre-anaesthetic task performance was observed with a gradual increase in the coherent beta oscillations. We also found that recovery end points significantly varied intra-individually across sessions, as compared to a rather consistent loss of consciousness time. Recovery of single neuron multisensory responses appeared to be associated with the time of full performance recovery rather than the length of recovery time. Similar to loss of consciousness, return of consciousness was identified with an abrupt shift of dynamics and the regions were dissociated temporarily during the transition. However, the actual dynamics change during return of consciousness is not simply an inverse of loss of consciousness, suggesting a unique process.

Perioperative neurocognitive disorder (PND) is a growing concern, affecting several million elderly patients each year in the United States, but strategies for its effective prevention have not yet been established. Humeidan et al. recently demonstrated that preoperative brain exercise resulted in a decrease in postoperative delirium incidence in elderly surgical patients, suggesting the potential of presurgical cognitive optimization to improve postoperative cognitive outcomes. This brief review summarizes the current knowledge regarding preoperative cognitive optimization and highlights landmark studies, as well as current ongoing studies, as the field is rapidly growing. This review further discusses the benefit of cognitive training in non-surgical elderly populations and the role of cognitive training in patients with preexisting cognitive impairment or dementia. The review also examines preclinical evidence in support of cognitive training, which can facilitate understanding of brain plasticity and the pathophysiology of PND. The literature suggests positive impacts of presurgical cognitive optimization, but further studies are encouraged to establish effective cognitive training programs for elderly presurgical patients.