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.

Introduction

Human disorders of consciousness (DOC) reflect a major alteration of the wakeful conscious state and typically arise from severe brain injuries that produce multi-focal neuronal cell death and disconnection (see [1,2•] for review). DOC include the conditions of vegetative state (VS), minimally conscious state (MCS) and confusional state (CS). Collectively, these disorders span a wide range of behavioral levels. VS, by definition, indicates a wakeful appearance without any signs of behavioral responsiveness. Demonstration of limited behavioral evidence of consciousness, such as visual tracking, is consistent with the lower boundary of MCS (labeled as MCS—, [3]). Recovery of command following, with or without an inconsistent communication system, sets the upper boundary of MCS (MCS+, [3]). CS reflects recovery of more complete communication systems, but lack of orientation and attentional control.

DOC are best considered in the context of basic mechanisms linking the internal state of neurons within the cerebral cortex, thalamus and striatum to the global network activation patterns associated with different levels of consciousness. Severe brain injuries of all types produce widespread neuronal deafferentation and thus significantly reduce synaptic input across the corticothalamic system. In experimental studies, at the extreme boundary condition of removing all long-range inputs to the cerebral cortex only low-frequency electrical activity or a complete loss of signal is measurable in the scalp surface electroencephalogram (EEG) [4]. Typically, this level of deafferentation in the human brain only arises following very severe anoxic injuries and is invariably associated with permanent VS if subjects survive. Most DOC arise in the setting of a partially connected corticothalamic system with greater preservation of anatomical connectivity correlating with higher levels of observed behaviors [5].

Neurons in the cortex, thalamus and striatum are very sensitive to small changes in received synaptic background activity [6,7]. As a result, sharp changes in firing patterns of individual cell types and circuits probably explain large shifts in the conscious state that can be induced in some subjects with DOCs by exposure to pharmacologic agents or electrical brain stimulation [8–9,10••]. Moreover, examples of neuromodulation of the conscious state in DOC occurring very late in course of the recovery process (e.g., two decades following injury, see [11]) emphasize the crucial role of neuronal circuit mechanisms underpinning conscious state control after severe brain injury.

Normal brain function diurnally exhibits a wide range of states controlled by complex regulatory mechanisms involving many different brainstem, basal forebrain and hypothalamic neurons and neurotransmitter systems [12,13]. The awake conscious state is the most highly energy-demanding of these states [14] with these demands deriving from complex, high-frequency neuronal firing patterns associated with strong depolarization of neocortical, thalamic and striatal membrane potentials during wakeful states. Large reductions in arousal level progressively occurs across deeper stages of sleep in normal individuals and involves broad hyperpolarization of corticothalamic neurons via withdrawal of excitatory neuromodulatory influences from orexinergic, cholinergic, noradrenergic and other brainstem, basal forebrain and hypothalamic systems [12,13]. Importantly, along with their primary modulation of the neocortex, all of these endogenous neuromodulatory systems innervate and control activity in the central thalamus [15,16].

The highly interdependent and dynamic regulatory mechanisms underpinning brain arousal state control are vulnerable to many different types of dysfunction in the setting of severe brain injuries. For example, selective injuries to axon bundles containing key projections from brainstem arousal systems have been demonstrated to produce DOC. Interruption of the dopaminergic projection system via lesions near the lateral hypothalamus, where the medial forebrain bundle carries dopaminergic fibers to the frontal cortex and striatum, is correlated with DOC responsive to dopamine agonists [17]. Similarly, anatomical studies demonstrate isolated locations where selective interruption of white matter tracts carrying cholinergic projection fibers may lead to global functional impairments [53]. A more general circuit-level mechanism, however, is likely to play a role in all forms of severe brain injury as a result of disruption of the many long-range excitatory projections across the corticothalamic system [18].

Role of anterior forebrain mesocircuit

A common ‘mesocircuit’ mechanism has been proposed to arise across DOC following all types of severe brain injuries and to account for both the grading of the recovery process over time and the mechanism underlying often wide fluctuations in ongoing behavior observed in subjects with severe brain injuries [10••,18,19••]. The mesocircuit hypothesis posits that in all forms of severe brain injury, anterior forebrain function is markedly downregulated because of widespread cerebral deaf- ferentation arising from a variety of mechanisms such as diffuse axonal injury, hypoxia, and ischemia that produce neuronal disconnection and induced cell death (Figure 1). A crucial role is proposed for neurons within the central thalamus based on their broad anatomical connectivity [20], functional role in forebrain arousal regulation [15,16], and pathological studies that demonstrate loss of these neurons in proportion to the severity of structural brain injuries and functional outcomes [21]. Two main effects are predicted: (1) the primary effect is a broad withdrawal of excitation across the corticothalamic system due to the functional consequence of disfacilitation [22] of central thalamic neurons arising via the integrated loss of their wide point-to-point connections [20]; and, (2) a closely related secondary effect is a further reduction of activity across the cortico-striatopallidal–thalamocortical loop system resulting from the loss of afferent input to the medium spiny neurons (MSNs) of the striatum from central thalamic and corticostriatal neurons, leading to the collapse of the level of synaptic background activity needed for the MSNs to reach their firing threshold [23]. Importantly, in addition to high levels of background activity, MSN firing also requires sufficient levels of dopaminergic modulation. As the MSNs provide an active inhibition of neurons within the globus pallidus interna that otherwise will actively inhibit some of the central thalamic neurons, the combined effect of both predicted mechanisms is a broad reduction in global cerebral synaptic activity with the strongest downregulation of activity occurring across the frontal/prefrontal cortex and striatum.

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 [1,15,19••]. 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).

Recent studies support this hypothesis and include demonstrations that resting brain activity in DOC demonstrates patterns consistent with greater functional down-regulation in frontal structures [10••,24]), and evidence of reversal of the resting metabolic pattern of central thalamus and globus pallidus in DOC [19••]. Further supporting this hypothesis are findings that paired lesions of the central thalamus alone can produce enduring DOC [25]. The hypothesis predicts similar changes across the anterior forebrain mesocircuit are present in all settings of reduced synaptic activity; additionally, several phenomena observed in general anesthesia and sleep are consistent with the proposed mechanism [26•]. Importantly, recovery of function within the anterior forebrain mesocircuit covaries with activity in the precuneus, which also receives projections from the central thalamus [19••]. Measures of metabolic activity in precuneus and related structures of the posterior medial complex have demonstrated strong correlation with levels of expressed behavior across recovery from DOC [27]. Similarly, anatomical connectivity of thalamus per se and posterior medial complex correlate with levels of recovery across DOC [5]. Collectively, this hypothesis provides an economical first-order model for the patterns of restoration frontal cortical, striatal and thalamic activity seen in DOC with spontaneous recovery or effective neuromodulation as discussed below.

Neuromodulation of the conscious state in DOC

A surprisingly disparate set of medications and approaches have proven effective in some instances in modulating the conscious state in DOC. Primarily excitatory agents acting via receptor systems receiving ligands from the primary arousal system pathways, such as dopaminergic, noradrenergic and cholinergic agents have been traditionally used; however, strong agonists of the GABA receptor such as zolpidem have also proven effective in a subset of patients [28••]. In addition, there is evidence for the efficacy of direct electrical stimulation of the central nervous system [9].

Dopaminergic agonists have been most commonly employed to attempt to improve the level of consciousness in patients with DOC. However, it is only recently that evidence for the general efficacy of any pharmacologic agent has emerged. In a double-blind, placebo controlled, randomized clinical trial, the drug amantadine was demonstrated to accelerate the speed and rate of recovery of patients in VS and MCS within the first year following severe traumatic brain injuries [29••]. In this study, the positive effects of the amantadine were proposed to derive from the modulatory effect on the nigrostriatal, mesolimbic, and frontostriatal dopaminergic systems. Nonetheless, it is not entirely clear which of several potential mechanisms may underlie amantadine’s effects in DOC all can be framed in the context of the mesocircuit hypothesis as noted below. The cell bodies of dopaminergic neurons are located in the substantia nigra pars compacta and ventral tegmental area within the brainstem and project to the frontal cortex and striatum through the nigrostriatal, mesolimbic, and mesocortical dopaminergic pathways (Figure 1). Additionally, dopaminergic neurons within the ventral tegmental area project to the central thalamus [30]. Of note, the central thalamus demonstrates high levels of dopamine approximating those observed in the substantia nigra [31], and a preponderant distribution of ‘D2-Like’ (D2LR) type receptors [32]. Thus, dopaminergic modulatory effects of amantadine could directly facilitate increased neuronal activity within frontal cortex, striatum, and central thalamus.

At the presynaptic level, amantadine may increase the synthesis of endogenous dopamine by blocking NMDA- receptors that have a positive effect on the enzymedopamine decarboxylase increasing bioconversion of l-DOPA into dopamine [33]. This mechanism is unlikely to play a role in the effects observed in DOC unless exogenous l-DOPA is co-administered as hydroxylation of tyrosine into l-DOPA by the enzyme tyrosine hydroxylase is the rate limiting factor in the synthesis of dopamine. Thus, in the setting of a deficit in the substrate (i.e., endogenous l-DOPA), up-regulation of the enzyme l-DOPA decarboxylase cannot be effective [34]. In addition, it is possible at a presynaptic level that amantadine increases synaptic dopamine availability by blocking the dopamine transporter (DAT) [35]. Finally, there are some suggestions that amantadine acts at the postsynaptic level slightly increasing the expression of D2-like dopamine receptors [36].

Smaller studies have provided more direct evidence of dopaminergic effects in DOC using more powerful dopaminergic agonists such as levodopa [37], bromocriptine [38], apomorphine [39] and pramipexol [40], all of which have shown some successful responses. Unlike amantadine, levodopa may bypass a possible, but still uncharacterized, posttraumatic deficit of the enzyme tyrosine hydroxylase, increasing the biosynthesis of dopamine at a presynaptic level. Conversely, dopaminergic agonists may also directly stimulate D2-like postsynaptic receptors to enhance the membrane excitability [41] or stimulate D1 receptors at the ventral tegmental area [42••]. Direct electrical stimulation of the ventral tegmental area, but not of the substantia nigra, induces emergence from anesthetic coma [43••].

Finally, the dopamine reuptake inhibitor methylphenidate has shown positive effects inducing emergence from anesthetic coma [44], and improving attention in longterm moderate to severe posttraumatic attention deficit disorders [45], but has failed to induce responses in patients in VS or MCS [46]. The contrasting results for emergence from anesthetic coma and postraumattic attentional deficits with methylphenidate suggest that blockade of the dopamine transporter enhances a D1 receptor mediated response, possibly emanating from the VTA [42••]. By contrast, the lack of improvement with methylphenidate in patients in VS and MCS suggests that blockade of the dopamine transporter cannot increase dopamine background activity possibly as a result of a presynaptic deficit of dopamine biosynthesis resulting from the structural brain injuries.

It was recently demonstrated in vitro that amantadine can also strongly block the noradrenaline transporter [35]. Terminals of noradrenergic cells and norepinephrine transporter are found in the central thalamus [47], and modulation of these receptors and neocortical noradrenergic receptors in frontal and parietal cortices [48] may be a crucial aspect of amantadine’s effects. This observation raises the further possibility that use of other agents producing strong reuptake blockade of the noradrenergic receptor (e.g., atomoxetine) might thus also have a role in DOC.

Beyond acting as an agonist for classical arousal system neurotransmitter receptors, it is probable that amantadine’s strong properties as an NMDA antagonist are linked to its broader activation properties. Paradoxical excitation of the cerebral cortex and striatum arises with the NMDA antagonist ketamine when used as an anesthesia [26•], and is associated with activation of the frontal cortex when ketamine is used in subsedative doses for resistant depression treatment [50]. In DOC subjects with structural brain injuries, paradoxical excitation with sedative agents such as zolpidem have been demonstrated to facilitate behavior in a small percentage of randomly selected and prospectively studied subjects [28••]. In detailed quantitative EEG investigations of a small number of such zolpidem responsive subjects with severe brain injuries, an initial burst of EEG activity consistent with effects in normal subjects (increased 15–30 Hz activity over frontocentral cortical regions) evolved into more narrowband activity lasting hours and replacing dominant low frequency EEG in subjects when behavioral improvements were observed [10••]. Zolpidem may directly bind to GABA-A alpha 1 receptor subtypes in the neocortex, where it may increase thalamocortical and thalamostriatal outflow indirectly, as a result of activation of cortical inhibitory interneuronal networks [51]. In addition, zolpidem may activate within the striatum where GABA-A currents facilitate alpha and beta (~8–30 Hz) rhythms within the striatum and normal MSN function [52]. An important additional proposed activating effect of zolpidem is suppression of increased firing of the GPi via a direct effect of zolpidem on the globus pallidus interna, which as noted above, is hypothesized to be overactive in the setting of the structurally deaffer-ented brain.

No studies have systematically examined the role of cholinergic agonists in the treatment of DOC, but important evidence from studies of emergence from anesthesia suggest their possible role in the context of the mesocircuit hypothesis. Studies of human subjects receiving a systemic cholinergic agonist to initiate emergence from anesthetic coma showed statistically, significant increases in blood flow both in the thalamus and precuneus that selectively correlate with recovery of consciousness during otherwise stable anesthesia [49]. Similarly, in the same study, local decreases of regional blood flow in the same structures distinguished anesthetic coma compared with wakeful baselines. These observations are consistent with the key role of cholinergic innervation of the central thalamus and the correlation of the posterior medial complex and central thalamus in the anatomical and functional studies noted above.

Finally, direct neuromodulation of the outflow from the central thalamus has been demonstrated to improve level of consciousness and goal-directed behaviors in proof-of- concept study in a human subject after 6 years remaining in MCS [9]. Electrical activation of the central thalamus was causally linked in this study to the subjects transition from MCS to CS. The mesocircuit hypothesis predicts that broad activation of the central thalamic neuronal population is a final common pathway supporting a down-regulated anterior forebrain in severe brain injuries.

Summary

The above review emphasizes that neuromodulation of the conscious state in DOC can be linked to broad shifts in activity across the components of the anterior forebrain mesocircuit and its connections with the posterior medial complex. Effective neuromodulation is associated either with: (1) replacement of specific neurotransmitters by pharmacologic agents that are proposed to exert their effects via the release of thalamocortical outflow from central thalamic neurons to their targets in frontal cortex and striatum or at receptors on these targets, (2) via broader effects of bulk excitation via non-selective methods of paradoxical excitation (e.g., ketamine, zolpidem), or (3) by direct electrical stimulation of the central thalamus. Viewed from this perspective, approaches as seemingly disparate as zolpidem, amantadine and central thalamic brain stimulation all have a proposed main effect in restoring a threshold level of synaptic background activity to restore corticothalamic outflow from central thalamus and reestablish activity across the entire anterior forebrain. It is suggested that future research aims to identify a systematic polypharmacy approach to supporting the conscious state after structural brain injuries that build on this existing knowledge.