Neural signatures of loss of consciousness and its recovery by thalamic stimulation

Abstract

We know that general anesthesia produces unconsciousness but not quite how. We recorded neural activity from the frontal, parietal, and temporal cortices and thalamus while maintaining unconsciousness in non-human primates (NHPs) with propofol. Unconsciousness was marked by slow frequency (~1 Hz) oscillations in local field potentials, entraining local spiking to Up states alternating with Down states of little spiking, and decreased higher frequency (>4 Hz) coherence. The thalamus contributed to cortical rhythms. Its stimulation "awakened" anesthetized NHPs and reversed the electrophysiologic features of unconsciousness. Unconsciousness thus resulted from slow frequency hypersynchrony and loss of high-frequency dynamics, partly mediated by the thalamus, that disrupts cortical communication/integration. Unconsciousness is general anesthesia's most intriguing feature 1 . In humans, unconsciousness by propofol-a widely used anesthetic-is linked to structured neurophysiological dynamics: decreases in higher frequency (>15 Hz) but increases in frontal alpha (8 to 12 Hz) 2-5 and slow frequency (0.1 to 1 Hz) oscillations that phaselock neuronal spiking 6 and loss of fronto-parietal connectivity. 7 Nevertheless, the details remain unknown. These dynamics have been investigated using extracranial measures (EEG, fMRI) with limited spatial or temporal specificity or microelectrode recordings with limited spatial coverage in patients. They have yet to be studied at high spatial and temporal resolutions simultaneously. Moreover, previous studies have not included the thalamus, a critical nexus that regulates cortical activity 8,9 .A vascular access port implanted subcutaneously in two non-human primates (NHPs) allowed us to infuse propofol to transition them from awake through loss of consciousness (LOC) and recovery of consciousness (ROC) without interruption of neurophysiological recording (and without introduction of other anesthetics or other confounding factors, see Methods, Figure 1A). We started with a high dose for 15 minutes (0.28-0.58 mg/kg/min, adjusted per individual animal). After LOC (indicated by cessation of airpuff-evoked eyeblinks, reduction in heart rate, pupil dilation, and decreased muscle tone), infusion was lowered to a holding dose (0.14-0.23 mg/kg/min). After infusion ceased, ROC followed after ~60 sec. We recorded spikes and local field potentials (LFPs) from 64-channel "Utah" arrays in frontal cortex (8A, PFC), posterior parietal (PPC, 7A/B), and auditory/temporal (Superior Temporal Gyrus, STG) cortex and LFPs from multiple-contact stimulating electrodes (two in each hemisphere) in frontal thalamic nuclei (intralaminar nuclei, ILN, and mediodorsal, MD, Figure 1B).We compared LFP power during the pre-drug Awake state (-120 to 0 seconds pre drugonset) to every timepoint after drug administration (non-parametric cluster-based randomizations, corrected for multiple comparisons; all effects p<0.01 10 ). Around 60-75 seconds post-drug administration (pre-LOC), theta/alpha (4-15 Hz) power decreased in Fi...

Conscious Processing and the Global Neuronal Workspace Hypothesis

“…A first positive result was reported by (Schiff et al, 2007), who induced a slow but long-term recovery of conscious processing in a patient with minimal conscious syndrome, following stimulation of the central thalamus (the nuclei of which target many high-level cortical regions including prefrontal cortex). This is consistent with recent animal studies demonstrating reversal of the anesthetized state with stimulation of central thalamus (Donoghue et al, 2019;Redinbaugh et al, 2019), leading to a return of functional corticocortical connectivity.…”

“…In addition to its role in transmitting arousal and sensory signals, non-sensory nuclei of the thalamus are thought to play a role in working memory (outlined above) and to facilitate the coordination of cortical communication (Saalmann, 2014;Saalmann et al, 2012), which is of importance to a functional GNW. Indeed, electrical stimulation of the central thalamus has recently been shown to reverse the anesthetized state in nonhuman primates in association with a return of corticocortical connectivity (Donoghue et al, 2019;Redinbaugh et al, 2019;Tasserie et al…”

Distributed harmonic patterns of structure-function dependence orchestrate human consciousness

“…Likewise, it is intriguing that loss of consciousness also tends to increase the prevalence of low-frequency (i.e., slow) temporal oscillations, and vice-versa for psychedelics (Bastos et al, 2021;Ching et al, 2010;Colombo et al, 2019;Donoghue et al, 2019;Ní Mhuircheartaigh et al, 2013;Pal et al, 2019;Stephen et al, 2020;Warnaby et al, 2017). However, temporal frequencies and connectome harmonic frequencies are distinct concepts, each providing a unique perspective, and should not be confused or conflated: recent work has begun to investigate the relationship between connectome eigenmodes and M/EEG temporal frequencies (Glomb et al, 2020;Raj et al, 2020;Verma et al, 2022), opening the door for future multi-modal studies combining fMRI and EEG to elucidate the complex inter-relationships between connectome harmonics, temporal frequencies, and consciousness in the human brain.…”

Growing evidence for separate neural mechanisms for attention and consciousness

“…Accordingly, severing interhemispheric cortical connections in split brain patients may have less of an impact on attention (which in some ways remains intact) than on conscious perception (which appears to be split in half, or otherwise diminished). However, note that there is also emerging evidence that certain subcortical structures, such as higher order nuclei of the thalamus play a crucial role for both levels as well as contents of consciousness (Donoghue et al, 2019;Redinbaugh et al, 2020;Schmid & Maier, 2015;Wilke, Mueller, & Leopold, 2009). Thus, while these novel findings point at dissociable neural processes for attention and consciousness, it is not as simple as attention being a subcortical phenomenon and consciousness a product of the neocortex.…”