Rapid fragmentation of neuronal networks at the onset of propofol-induced unconsciousness

Abstract

The neurophysiological mechanisms by which anesthetic drugs cause loss of consciousness are poorly understood. Anesthetic actions at the molecular, cellular, and systems levels have been studied in detail at steady states of deep general anesthesia. However, little is known about how anesthetics alter neural activity during the transition into unconsciousness. We recorded simultaneous multiscale neural activity from human cortex, including ensembles of single neurons, local field potentials, and intracranial electrocorticograms, during induction of general anesthesia. We analyzed local and global neuronal network changes that occurred simultaneously with loss of consciousness. We show that propofol-induced unconsciousness occurs within seconds of the abrupt onset of a slow (<1 Hz) oscillation in the local field potential. This oscillation marks a state in which cortical neurons maintain local patterns of network activity, but this activity is fragmented across both time and space. Local (<4 mm) neuronal populations maintain the millisecond-scale connectivity patterns observed in the awake state, and spike rates fluctuate and can reach baseline levels. However, neuronal spiking occurs only within a limited slow oscillation-phase window and is silent otherwise, fragmenting the time course of neural activity. Unexpectedly, we found that these slow oscillations occur asynchronously across cortex, disrupting functional connectivity between cortical areas. We conclude that the onset of slow oscillations is a neural correlate of propofol-induced loss of consciousness, marking a shift to cortical dynamics in which local neuronal networks remain intact but become functionally isolated in time and space. electrophysiology | single units | GABA | cortical networks G eneral anesthesia is a drug-induced reversible coma commonly initiated by administering a large dose of a fast-acting drug to induce unconsciousness within seconds (1). This state can be maintained as long as needed to execute surgical and many nonsurgical procedures. One of the most widely used anesthetics is propofol, an i.v. drug that enhances GABAergic inhibitory input to neurons (2-4), with effects in cortex, thalamus, brainstem, and spinal cord (5-7). Despite the understanding of propofol's molecular actions, it is not clear how these effects at molecular targets affect single neurons and larger-scale neural circuits to produce unconsciousness.The effects on macroscopic dynamics are noticeable in the EEG, which contains several stereotyped patterns during maintenance of propofol general anesthesia. These patterns include increased delta (0.5-4 Hz) power (8, 9); increased gamma (25-40 Hz) power (9); an alpha (∼10 Hz) rhythm (10-12) that is coherent across frontal cortex; and burst suppression, an alternation between bursts of high-voltage activity and periods of flat EEG lasting for several seconds (13,14). In addition, slow oscillations (<1 Hz) have been well characterized in deeply anesthetized animals and are associated with an alternation of the neuron...

Signature of consciousness in the dynamics of resting-state brain activity

“…Our results are also in agreement with several theories of consciousness (22,24) and earlier observations in sleep, anesthesia, and VS (18,(40)(41)(42)(43). Several theories of consciousness posit that distributed functional networks support conscious states and that loss of consciousness is indexed by alterations of these network patterns (22,24,42).…”

Thalamocortical synchronization during induction and emergence from propofol-induced unconsciousness

“…Notably, unlike propofol-induced α waves, these slow oscillations are spatially incoherent (7,11), implying a state of "fragmentation" of cortical activity (11). Our results are consistent with these previous findings, as slow oscillation power increases significantly at LORR and LOM in both prefrontal cortex and thalamus and dissipates before ROM.…”

“…Our results are consistent with these previous findings, as slow oscillation power increases significantly at LORR and LOM in both prefrontal cortex and thalamus and dissipates before ROM. Our results also point to functional distinctions between slow and δ oscillations: Whereas slow oscillations appear to be incoherent across cortex (7,11), and between cortex and thalamus (Fig. S6), δ oscillations are coherent between cortex and thalamus.…”

“…Previous studies in humans have observed significant increases in slow oscillation power during loss of consciousness (7,12) and have established that these oscillations correspond to ON and OFF states where neurons are periodically silenced (11). Notably, unlike propofol-induced α waves, these slow oscillations are spatially incoherent (7,11), implying a state of "fragmentation" of cortical activity (11).…”

“…Electroencephalogram (EEG) recordings in humans during gradual induction of unconsciousness with propofol show the appearance of frontal β oscillations (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) at the onset of sedation, followed by the appearance of coherent frontal α (8-12 Hz) oscillations (7)(8)(9)(10) and widespread slow (0.1-1 Hz) and δ (1-4 Hz) oscillations (7,11,12) when subjects no longer respond to sensory stimuli. Biophysical models of neuronal dynamics have shown that whereas α and β oscillations can be generated by propofol's actions in cortex alone (13), coherent α oscillations require the participation of both thalamus and cortex (14).…”