General anaesthesia disrupts complex cortical dynamics in response to intracranial electrical stimulation in rats

Abstract

The capacity of the human brain to sustain complex dynamics consistently drops when consciousness fades. Several recent studies in humans found a remarkable reduction of the complexity of cortical responses to local stimulation during dreamless sleep, general anaesthesia, and coma. So far, this perturbational complexity has never been estimated in non-human animals in vivo. Here, we quantify the complexity of electroencephalographic responses to intracranial electrical stimulation in rats, comparing wakefulness to propofol, sevoflurane, and ketamine anaesthesia. We confirm the changes previously observed in humans: from highly complex evoked activity during wakefulness, to simpler responses, suppression of high frequencies, and reduced phase-locking with propofol and sevoflurane.We then deepen our mechanistic understanding by analyzing functional connectivity, and by showing how these parameters dissociate with ketamine, and depend on intensity and site of stimulation. This approach opens the way for further direct investigations of the mechanisms underlying brain complexity and consciousness. hypothesis that neuronal hyperpolarization might prevent cortical neurons from engaging in durable, complex interactions 12,13,14,15 . RESULTS Single pulse electrical stimulation triggered complex ERPs during wakefulness, but not during propofol anaesthesiaWe recorded epidural EEG activity from 16 screw electrodes chronically implanted through the skull in head-and body-restrained male, adult rats. Recording electrodes were in contact with the dura and organized in a symmetric grid, covering most of the cortex in both hemispheres (M2, secondary motor cortex; M1, primary motor cortex; S1, primary somatosensory cortex; RS, retrosplenial cortex; PA, parietal associative cortex; V1, primary visual cortex; V2, secondary visual cortex; GND, ground electrode over cerebellum). We stimulated right M2 by single monophasic, electrical current pulses (typically: 1 ms duration, 50 µA amplitude, at 0.1 Hz) via a chronically implanted bipolar electrode, located 4.38 ± 0.26 mm rostral from bregma, 0.47 ± 0.09 mm below the cortical surface, mainly corresponding to layer II/III (based on histology after recording, 8 rats; Fig. 1a; all values are reported as mean ± SEM). Pulse trains delivered at similar coordinates triggered coordinated whisker deflections 16 , whereas EEG responses following single stimuli were not measurably contaminated by movements ( Supplementary Fig. 1, Video 1-2) and were reproducible throughout recording sessions and across days (Supplementary Fig. 2). No correlation between the stimulating electrode locations and ERP amplitude or duration was found (Supplementary Fig. 3).We performed electrophysiological recordings in 9 rats during wakefulness and propofol anaesthesia (∼1.1 mg/kg/min, i.v.) at a depth that produced spontaneous, slow, high-amplitude EEG oscillations and was sufficient to abolish any detectable motor response to pain stimuli. The redistribution of EEG power from high to low frequencies was confirmed ...

Apical drive—A cellular mechanism of dreaming?

“…At the neuronal level, slow waves reflect the bi-stability of cortical neurons and circuits between periods of depolarization and increased neuronal firing (up-state, on-period) and periods of hyperpolarization and neuronal silence (down-state, off-period) (Steriade et al , 2001), each lasting a few hundred milliseconds. Off-periods associated with slow waves have been shown to interfere with causal relations between different brain regions and to lead to a breakdown in cortico-cortical connectivity (Massimini et al , 2005;Pigorini et al , 2015;Arena et al, 2020).…”

Does the posteromedial cortex play a primary role for the capacity for consciousness in rats?

“…1 for detailed electrode locations with respect to bregma; Paxinos & Watson, 2007). Standard surgical procedure under a regime of controlled general anaesthesia/analgesia was adopted for implantation of chronic electrodes, and after 3 days of recovery, rats were habituated to head and body restriction in at least 3 subsequent days, as previously described (Arena et al, 2020). The electrophysiological recording/stimulation began only when rats did not show any sign of distress and were calm within the recording setup, with the head connected to a fixed head-bar by two chronically implanted clamps and with the body inserted in a transparent acrylic tube, with a natural posture.…”

“…In addition to new data from six rats, we also used data from a set of previously published experiments (Arena, Thon and Storm, 2019), in which we recorded epidural EEG continuously and in response to electrical stimulation of secondary motor cortex in 12 head-restricted rats (Arena et al, 2020). For 8 of the rats, the recordings were performed during wakefulness and subsequent light ketamine anaesthesia.…”

“…The acquired electrophysiological data were analysed in MATLAB2016a (Math Works, Natick, Massachusetts, USA) and Origin 9.1 (OriginLab, Northampton, Massachusetts, USA) and preprocessed as described before (Arena et al, 2020). Raw epidural EEG was band pass filtered (0.5-80 Hz, butterworth, 3rd order), down-sampled to 500 Hz and ERP epochs of 10 s were extracted for each channel, centred at the stimulus onset (from -5 to 5 s).…”

“…Specifically, the perturbational complexity index (PCI; Casali et al, 2013), and the more general measure PCI ST ("PCI-state transition"; Comolatti et al, 2019), have been shown to reliably and consistently assess the state of consciousness in humans in accordance with the subjects' immediate or delayed reports of experience (Sarasso et al 2015;Casarotto et al 2016;Rosanova et al 2018). Recently, PCI ST has also been shown to work consistently in rodents undergoing propofol, sevoflurane, and ketamine anaesthesia (Arena et al, 2020). PCI and PCI ST quantify the spatiotemporal complexity of repeatable, global, cortical, electrophysiological responses to a local, direct cortical stimulation, thus estimating how much the resulting deterministic neuronal activations are both integrated and differentiated across cortical areas and time.…”