Cerebral Activity during the Anesthesia-Like State Induced by Mesopontine Microinjection of Pentobarbital

Abstract

Microinjection of pentobarbital into a restricted region of rat brainstem, the mesopontine tegmental anesthesia area (MPTA), induces a reversible anesthesia-like state characterized by loss of the righting reflex, atonia, antinociception, and loss of consciousness as assessed by electroencephalogram synchronization. We examined cerebral activity during this state using FOS expression as a marker. Animals were anesthetized for 50 min with a series of intracerebral microinjections of pentobarbital or with systemic pentobarbital and intracerebral microinjections of vehicle. FOS expression was compared with that in awake animals microinjected with vehicle. Neural activity was suppressed throughout the cortex whether anesthesia was induced by systemic or MPTA routes. Changes were less consistent subcortically. In the zona incerta and the nucleus raphe pallidus, expression was strongly suppressed during systemic anesthesia, but only mildly during MPTA-induced anesthesia. Dissociation was seen in the tuberomammillary nucleus where suppression occurred during systemic-induced anesthesia only, and in the lateral habenular nucleus where activity was markedly increased during systemicinduced anesthesia but not following intracerebral microinjection. Several subcortical nuclei previously associated with cerebral arousal werenotaffected.IntheMPTAitselfFOSexpressionwassuppressedduringsystemicanesthesia.Differencesinthepatternofbrainactivityinthe two modes of anesthesia are consistent with the possibility that anesthetic endpoints might be achieved by alternative mechanisms: direct drug action for systemic anesthesia or via ascending pathways for MPTA-induced anesthesia. However, it is also possible that systemically administered agents induce anesthesia, at least in part, by a primary action in the MPTA with cortical inhibition occurring secondarily.

Cortical and Subcortical Connectivity Changes during Decreasing Levels of Consciousness in Humans: A Functional Magnetic Resonance Imaging Study using Propofol

“…Our experiment cannot distinguish between direct propofol modulation of the striatum itself and striatal deafferentation secondary to drug activity at another site such as the cortex, brainstem or indeed the thalamus (Abulafia et al, 2009). This is a parallel problem to that raised by Bonhomme and colleagues, who found cortical activation to be reduced at lower doses than those required to reduce activation within the thalamus (Bonhomme et al, 2001).…”

Brainstem node for loss of consciousness due to GABAA receptor-active anesthetics

“…Together, they show that: 1) drug delivery to the MPTA is sufficient to induce an anesthetic state virtually identical to systemic anesthesia (Abulafia et al, 2009;Devor and Zalkind, 2001) and that: 2) although not essential for the waking state itself, the presence of MPTA neurons is necessary for anesthetic induction at clinically relevant doses. Together, these findings are inconsistent with the classical idea that ubiquitous distribution and binding of anesthetic molecules is essential to induce clinical anesthesia.…”

“…Rather, they support the idea that MPTA neurons occupy a nodal point in an endogenous network of dedicated neural pathways that connect the MPTA to the far-flung structures that mediate the various components of anesthesia. Specifically, we hypothesize that anesthetics delivered by the circulation (or experimentally, by direct intracerebral microinjection) activate GABA A -Rs on a subset of MPTA neurons, suppressing their activity (Abulafia et al, 2009;Faingold and Caspary, 1987;Nunez et al, 1998). This secondarily triggers a cascade of events, mediated by axonal pathways, that rapidly and reversibly put broad swaths of cerebral function "off-line" (see below).…”

“…The speed of induction (seconds), its spatial resolution (<1 mm), tiny effective volumes (≤100 nL) and agent selectivity (ketamine is ineffective, Minert and Devor, unpublished) all rule out the possibility of redistribution of the anesthetic agent throughout the brain as the underlying mechanism (Abulafia et al, 2009;Devor and Zalkind, 2001;Namjoshi et al, 2009;Sukhotinsky et al, 2007;Voss et al, 2005).…”

Thalamus, Brainstem and Salience Network Connectivity Changes During Propofol-Induced Sedation and Unconsciousness

“…Regions selected for the seed-based analysis were the right anterior insular cortex (33,22,6), thalamus (À7, À16, 6 and 7, À16, 6 combined), mesencephalon (À2, À24, À8), PTA (À3, À18, À27), and hippocampus (25, À16, À15). Literature confirms strong relationships of these regions with cognition and consciousness: the PTA, mesencephalon, and thalamus are of interest because of their roles in cortex activation and coordination (Abulafia et al, 2009;Saper et al, 2005;Schiff, 2008), while the hippocampus has a pivotal role in memory processing and has a close association with the DMN, providing additional information about DMN integrity (Wang and Orser, 2011). The right anterior insular cortex has been associated with the making of go/no-go decisions (Aron et al, 2004;Duann et al, 2009) and is part of the salience network, which is thought to enable switching between internally-oriented thought (DMN-driven) and externally-oriented activity (ECN-driven) (Seeley et al, 2007).…”