Objective and graded calibration of recovery of consciousness in experimental models

Abstract

Purpose of review: Experimental preclinical models of recovery of consciousness (ROC) and anesthesia emergence are crucial for understanding the neuronal circuits restoring arousal during coma emergence. Such models can also potentially help to better understand how events during coma emergence facilitate or hinder recovery from brain injury. Here we provide an overview of current methods used to assess ROC/level of arousal in animal models. This exposes the need for objective approaches to calibrate arousal levels. We outline how correlation of measured behaviors and their reestablishment at multiple stages with cellular, local and broader neuronal networks, gives a fuller understanding of ROC.

Recent findings: Animals emerging from diverse coma-like states share a dynamic process of cortical and behavioral recovery that reveals distinct states consistently sequenced from low-to-high arousal level and trackable in nonhuman primates and rodents. Neuronal activity modulation of layer V-pyramidal neurons and neuronal aggregates within the brainstem and thalamic nuclei play critical roles at specific stages to promote restoration of a conscious state.

Summary: A comprehensive, graded calibration of cortical, physiological, and behavioral changes in animal models is undoubtedly needed to establish an integrative framework. This approach reveals the contribution of local and systemic neuronal circuits to the underlying mechanisms for recovering consciousness.

Figure 1.. Detailed cortico-motor regimens in rodents and non-human primates while emerging from propofol-induced anesthesia.

(A) Schematic depicting the behavioral and physiological phases during emergence from anesthesia (top panel) compared to recovery from coma (bottom panel). Arrows indicate graded levels of recovery modeled in rodents and nonhuman-primates. Question marks denote unexplored cortical and behavioral arousal states that remain to be identified in animal models. (B) Representative trace of motor cortex LFP during propofol bolus injection (15mg/Kg; purple line) and normalized spectrogram of LFP. (C) Segmented cortical periods and averaged density estimation per cortical state for each period (500 s interval) and averaged percentage distribution of motor behavior while emerging from propofol (n=5). Gao S and Calderon DP, unpublished data. (d) Change of power in different cortical bands in somatosensory cortex (S1 (red) and S2, (brown) versus ventral promotor area, PMv, (blue). Bands shown are slow-delta [0.5–4 Hz, (i)], theta [4–8 Hz, (ii)], alpha [8–12 Hz, (iii)], low beta [12–18 Hz, (iv)], high beta [18–25 Hz, (v)], low gamma [25–34 Hz, (vi)]. Power was normalized using z-scores. Propofol was infused for 60 min (1800–5400 s, grey solid lines. LOC (loss of consciousness) is shown with a black arrow and dotted lines, ROC (recovery of consciousness) with a purple arrow and dotted lines, and ROPAP (return of preanesthetic performance) with an orange arrow and dotted lines. Reproduced with permission from[38].

Figure 2. Integrating physiological changes at the cellular and circuit level with phases of behavioral recovery from coma-like behaviors.

The schematic displays the powerful potential for linking functional changes at the cellular level (neuronal cell types), local circuits, and broader networks involving multiple neuronal pathways located in the brainstem, thalamus and cortex with behavioral stages of recovery of consciousness.