Neuromodulation of the conscious state following severe brain injuries

Abstract

Disorders of consciousness (DOC) following severe structural brain injuries globally affect the conscious state and the expression of goal-directed behaviors. In some subjects, neuromodulation with medications or electrical stimulation can markedly improve the impaired conscious state present in DOC. We briefly review recent studies and provide an organizing framework for considering the apparently widely disparate collection of medications and approaches that may modulate the conscious state in subjects with DOC. We focus on neuromodulation of the anterior forebrain mesocircuit in DOC and briefly compare mechanisms supporting recovery from structural brain injuries to those underlying facilitated emergence from unconsciousness produced by anesthesia. We derive some general principles for approaching the problem of restoration of consciousness after severe structural brain injuries, and suggest directions for future research.

Conflict of interest statement

Conflict of interest statement

Nothing declared.

Copyright © 2014. Published by Elsevier Ltd.

Figures

Figure 1

(a) Anterior forebrain ‘mesocircuit’. Image displays key cortical and subcortical components of the anterior forebrain mesocircuit vulnerable to effects of severe brain injuries and widespread cerebral deafferentation. Lines in black represent the direction of the projections for branching axons. Lines in blue represent the direction of the four main dopamine projections from SNc (nigrostriatal) and VTA (mesolimbic, mesocortical and mesothalamic). (+) denotes ‘excitatory’ projections and (−) denotes ‘inhibitory’ projections. Following multi-focal brain injuries that produce widespread deafferentation and neuronal cell loss the deafferentation and functional disfacilitation of the central thalamus reduces or removes activity from these thalamocortical projections to the frontal cortex, posterior medial parietal cortex and striatum [,,••]. Downregulation across these structures is further generate by release of inhibition of the globus pallidus, with an overall result of marked reduction of cerebral metabolism across the mesocircuit following different mechanisms of brain injury. (ST: striatum; GP: globus pallidus; c-TH: central thalamus; LC: locus coeruleus; SNc: substantia nigra pars compacta; VTA: ventral tegmental area). (b) Mesocircuit component downregulation correlates with clinical impairment in DOC. Group data displaying mean normalized uptake values of glucose metabolism in deep brain structures measured with [18F]-FDG PET in NV and BI subjects. Above, the bivariate scattergram demonstrates an inverse linear correlation between glucose metabolic rate of the c-TH (x axis) and the GP (y axis), P < 0.001. Below, the bivariate scattergram demonstrates a linear correlation between glucose metabolic rate of the left precuneus (x axis) and the c-TH (y axis), P < 0.001. (GP: globus pallidus; c-TH: central thalamus; NV: normal volunteer; MCS(+): minimally conscious state ‘plus’, and MCS(−): minimally conscious state ‘minus’, according to [6]; VS: vegetative state). (c) Pharmacological mesocircuit dopaminergic neuromodulation. Bodies of dopaminergic neurons located in the SNc and VTA (presynaptic level) project to target postsynaptic neurons in the sensorimotor (SNc) and limbic striatum, prefrontal cortex and central thalamus (VTA). Dopaminergic neuromodulation can be achieved using drugs that target the selective mechanisms at the presynaptic level (A, B, C), and/or with drugs targeting the postsynaptic level (D). (AMT: amantadine; MPH: methylphenidate; dAMPH: dextroamphetamine; DAT: dopamine transporter; APO: apomorphine; Bro: bromocriptine; Ppx: pramipexole).