Authors: Megan E. Barra, Ken Solt, Xin Yu, Brian L. Edlow
Categories: Current Perspectives, Brain injury, Consciousness, Recovery, Stimulant
Source: Neurotherapeutics
Severe brain injury impairs consciousness by disrupting a broad spectrum of neurotransmitter systems. Emerging evidence suggests that pharmacologic modulation of specific neurotransmitter systems, such as dopamine, promotes recovery of consciousness. Clinical guidelines now endorse the use of amantadine in individuals with traumatic disorders of consciousness (DoC) based on level 1 evidence, and multiple neurostimulants are used off-label in clinical practice, including methylphenidate, modafinil, bromocriptine, levodopa, and zolpidem. However, the relative contributions of monoaminergic, glutamatergic, cholinergic, GABAergic, and orexinergic neurotransmitter systems to recovery of consciousness after severe brain injury are unknown, and personalized approaches to targeted therapy have yet to be developed. This review summarizes the state-of-the-science in the neurochemistry and neurobiology of neurotransmitter systems involved in conscious behaviors, followed by a discussion of how pharmacologic therapies may be used to modulate these neurotransmitter systems and promote recovery of consciousness. We consider pharmacologic modulation of consciousness at the synapse, circuit, and network levels, with a focus on the mesocircuit model that has been proposed to explain the consciousness-promoting effects of various monoaminergic, glutamatergic, and paradoxically, GABAergic therapies. Though fundamental questions remain about neurotransmitter mechanisms, target engagement and optimal therapy selection for individual patients, we propose that pharmacologic therapies hold great promise to promote recovery and improve quality of life for patients with severe brain injuries.
Keywords: Consciousness, Stimulant, Recovery, Brain injury
Disorders of consciousness (DoC) are a continuum of states of impaired arousal and awareness, including coma, vegetative state/unresponsive wakefulness syndrome (VS/UWS), minimally conscious state (MCS), cognitive motor dissociation, and covert cortical processing [[1], [2], [3], [4]]. Severe brain injury impairs consciousness through a broad spectrum of neuroanatomic lesions involving the bilateral cerebral hemispheres, rostral brainstem, diencephalon, or basal forebrain. Therapeutic approaches to restoring consciousness fundamentally depend on understanding how these anatomically diverse lesions cause reversible circuit and network changes that are amendable to modulation [5,6]. Advanced neuroimaging and electroencephalographic tools have been central to this effort, providing new opportunities to identify personalized targets for pharmacologic therapies [7]. Currently, a single pharmacologic therapy, amantadine, is recommended by clinical guidelines to promote recovery of consciousness in patients with traumatic DoC based on level 1 evidence [8,9]. However, multiple pharmacologic therapies are used off-label in clinical practice, including methylphenidate, modafinil, bromocriptine, levodopa, and zolpidem, among others [10]. For clinicians to select the optimal pharmacologic therapy for an individual patient, it is essential to consider each therapy's underlying mechanisms, intended targets, and safety profile.
This review summarizes the state-of-the-science in pharmacologic neurostimulant therapy to promote recovery of consciousness in patients with DoC after acquired brain injury. We begin with an update on the neurochemistry and neurobiology of brain circuits and networks that modulate human consciousness. Next, we discuss how neurochemical and neurobiological insights have been synthesized into a comprehensive mesocircuit model of DoC. Finally, we consider current evidence for clinical application of pharmacologic modulation of these circuits, and we propose future directions for promoting recovery of consciousness after severe brain injury.
Numerous neurotransmitters have been identified as contributors to human consciousness over decades of investigation into sleep, anesthesia, and coma [11]. Alterations in the balance of GABA-mediated inhibitory neurotransmission and glutamate-mediated excitatory neurotransmission are well established to play an important role in generating a state of unconsciousness. Beyond GABA and glutamate, monoaminergic neurotransmitters, such as dopamine, have emerged as critical contributors to consciousness, while the contributions of norepinephrine, histamine, orexin, adenosine, and acetylcholine in the pathogenesis of DoC continue to be explored.
Understanding the pathophysiologic drivers of DoC is crucial to identifying targets for pharmacologic therapies that promote recovery of consciousness. Growing evidence from preclinical models and clinical trials indicates that multiple neurotransmitter systems can be stimulated to restore human consciousness. These neurotransmitter systems include amino acids, monoamines, orexin and acetylcholine, among others (Fig. 1 and Fig. 2A). However, there is currently a lack of animal models of DoC to investigate the relative contributions of these neurotransmitter systems to the two components of arousal and awareness. Animal models have historically used a lesional approach to induce coma using invasive surgical procedures. Each animal model has limitations that are beyond the scope of this review but include preservation of purposeful behaviors [[12], [13], [14], [15], [16]], inability to distinguish the effects of lesional injury from global cerebral hypoperfusion at the time of coma induction [17], and uncertain neuroanatomic translation of lesional effects to humans with DoC [18]. Much of what we have learned has come from inducing transient coma with anesthetic agents and promoting reermergence of consciousness after anesthesia [11,19].
Fig. 1 Neurotransmitter and receptor targets of commonly prescribed pharmacologic neurostimulantsThree presynaptic neurons releasing noradrenaline, dopamine and 5-hydroxytryptamine, respectively, are shown synapsing with a single post-synaptic neuron for illustrative purposes. Abbreviations: 5-HT = 5-hydroxytryptamine; DA = dopamine; DAT = dopamine transporter; GABA = γ-aminobutyric acid; MAO = monoamine oxidase; NE = norepinephrine; NET = norepinephrine transporter; SERT = serotonin transporter; VMAT = vesicular monoamine transporter. Figure adapted from Barra et al. Seminars in Neurology, 2022 [10]. Artwork by Sarah Pyle.
Fig. 2 Neurotransmitter systems and neural circuits of arousal(A) Subcortical arousal circuits projecting from the brainstem, hypothalamus, and basal forebrain to the frontoparietal cortex are shown, color-coded by their primary neurotransmitter (inset, top right) for illustrative purposes. (B) A disrupted mesocircuit is shown, in which loss of striatal (Str) inhibition of the globus pallidus interna (GPi) leads to inhibition of the central thalamus, including the central lateral nucleus (CL). This type of mesocircuit disruption is hypothesized to cause decreased thalamocortical activation of the frontoparietal cortex in a subset of patients with disorders of consciousness. Artwork by Sarah Pyle is superimposed upon sagittal images from the 100 μm MRI dataset [164]. Abbreviations: PTg = pedunculo tegmental nucleus; Ret = reticular nucleus of the thalamus. Panel B is adapted from Ref. [3]. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Below we consider the current state-of-the-science in neurotransmitter systems, recognizing that substantial additional work in preclinical models is required to determine the neurotransmitter systems that hold the greatest promise for pharmacologic modulation to restore consciousness.
Glutamate is the predominant excitatory neurotransmitter in the brain, while ɣ-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter. Glutamate binds to N-methyl-d-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to potentiate excitatory signaling, while GABA binds to GABAA or GABAB receptors to potentiate inhibitory signaling [21]. Alteration in neurotransmitter availability along with NMDA, AMPA, and GABA receptor subunit composition, expression, and function after acute brain injury may induce imbalance in excitatory and inhibitory circuits, causing widespread dysfunction in neural network connectivity [21]. Animal models indicate that even activating networks such as the subcortical ascending arousal network (i.e., ascending reticular activating system) require a delicate balance of inhibitory GABAergic signaling to sustain wakefulness [[22], [23], [24], [25]].
It is also important to consider that enhancement of excitatory signaling is not always beneficial, as an increase of glutamate release in the hyperacute period after acquired brain injury may provoke secondary neuronal injury through excitotoxic mechanisms [26,27]. Glutamate excitotoxicity is thus a key consideration in the timing and selection of pharmacologic therapies to restore consciousness. While NMDA receptor antagonists dexanabinol and dizocilpine and AMPA receptor antagonist NBQX were found to be neuroprotective in preclinical models of traumatic brain injury, they have so far failed to improve outcomes in clinical trials [28,29]. Glutamate-activating NMDA receptors are diverse and may mediate either neuroprotective or neurotoxic effects depending on subunit composition [30]. Non-discriminatory blockage of NMDA receptors or development of selective pharmacotherapies thus warrants further investigation.
GABAA receptors are heteropentamers with varied combinations of 19 known subunits resulting in numerous isoforms with distinct physiologic properties [31]. GABAA receptor surface expression is broadly represented throughout the brain, though some isoforms have selective expression in the thalamus, hypothalamus, cerebral cortex, cerebellum, or mesencephalon [32]. It is postulated that GABAB receptors modulate orexin A and B neurons in the hypothalamus and brainstem [33,34], as well as histaminergic neurons in the tuberomammillary nucleus [35], to promote wakefulness.
The role of GABA-mediated inhibition in modulating consciousness is clearly demonstrated in drug-induced coma with intravenous anesthetics [11]. Similarly, after acquired brain injury, alterations in GABA receptor function or GABA neurotransmitter release may result in prolonged brain suppression and neurodormancy in patients with DoC [20]. Whether this state of altered GABAergic signaling is a marker of irreversible neuronal injury, or a reversible and protective down-regulated state, is currently being debated and may differ among patients, or perhaps even among neuroanatomic regions in an individual patient's brain [36].
Although GABA is traditionally considered an inhibitory neurotransmitter and GABA receptor stimulation induces unconsciousness, paradoxical excitation of the cerebral cortex after GABAergic therapy has been reported in patients with and without severe brain injuries [[37], [38], [39], [40]]. This paradoxical observation, which has been replicated with zolpidem and benzodiazepines, suggests that restoration of normal GABA signaling may reverse excessive inhibition, restore thalamocortical signaling within the mesocircuit, and promote functional recovery in a subset of patients with DoC [41]. The development of neuroimaging biomarkers to identify this subset of patients with DoC who respond to GABAergic therapy is an area of active inquiry [[42], [43], [44]].
Monoaminergic arousal circuits arise through norepinephrine release from the locus coeruleus, serotonin release from the median and dorsal raphe, histamine release from the tuberomammillary nucleus, and dopamine release from the ventral tegmental area (Fig. 2A) [11]. The dopaminergic system is thought to be a primary neurochemical driver of consciousness, based on pharmacologic [45,46], electrophysiologic [47], optogenetic [48,49], and chemogenetic [50] methods, as well as behavioral experiments in dopamine knock-out mice [51]. The ventral tegmental area is interconnected through dopaminergic neuromodulation with the posterior cingulate cortex and precuneus, a central node in the brain's default mode network [[52], [53], [54]]. In preclinical models of anesthetic-induced unconsciousness, pharmacologic stimulation of D1 receptors with amphetamine, chloro-APB, and methylphenidate induced emergence, highlighting the important role of dopamine signaling in higher levels of consciousness [45,46,[55], [56], [57], [58]]. Stimulation of the ventral tegmental area but not the substantial nigra during general anesthesia activates emergence, further supporting the role of the ventral tegmental area and dopamine signaling in consciousness [47].
It has been postulated that depletion of monoamines or suppression of brain regions reliant on monoamines for function may play an important role in disorders of consciousness [20,59], a hypothesis that is supported by emerging evidence from human neuroimaging studies revealing presynaptic dopamine neurotransmitter deficits in the striatum and central thalamus [60]. In addition to dopamine, release of other monoamines, such as serotonin (5-hydroxytryptamine, 5-HT), norepinephrine, and histamine, promotes wakefulness in animal models [61]. Animal models also indicate that bilateral lesions in arousal-promoting noradrenergic neurons in the locus coeruleus reduced norepinephrine levels in the paleocortex, neocortex, thalamus, and midbrain that resulted in transient electroencephalogram (EEG) suppression with reactivation within 12–48 h post-injury [62]. Interestingly, behavioral arousal and EEG activation induced by amphetamine administration was not influenced by lesional injury in the locus coeruleus in cats or by anesthesia in rats [46,62]. The extent to which pharmacologically induced increases in extracellular norepinephrine augment dopaminergic stimulation of arousal in preclinical models of anesthetized animals is unknown [45,58]. Histaminergic pathways in the tuberomammillary nucleus also appear to play a role in modulation of arousal and emergence from anesthesia in pre-clinical models. Histamine levels are increased during awake states and decreased during sleep or anesthetized states [63]. Histamine is thought to modulate arousal through innervation of cholinergic and GABAergic neurons in the basal forebrain [64]. Administration of histamine into the nucleus basalis magnocellularis in the basal forebrain induced EEG activation and accelerated emergence from isoflurane-induced anesthesia in rat models [65]. The tuberomammillary nucleus likely exerts its effects in concert with other monoaminergic and orexinergic pathways, as histaminergic neurons do not necessary regulate global spontaneous wakefulness [66].
Serotonin plays an important role in promotion of wakefulness and regulation of the sleep wake cycle [67,68]. Serotonin levels have been reported to be markedly increased in postmortem evaluation of patients with hepatic and uremic coma, while decreased serotonin synthesis and serotonin transporters have been reported in rats with traumatic brain injury [69,70]. There are 14 different serotonin receptor subtypes, with varied localization and expression throughout the brain, that have been explored as therapeutic targets in a variety of disease states [71,72]. Serotonin receptors have a role in modulation of 5-HT, acetylcholine, norepinephrine, dopamine, glutamate, and GABA neurotransmission depending on receptor subtype and location. High density of 5-HT2A receptors has been identified in association cortical areas of the default mode network and thalamo-cortical system [[73], [74], [75]]. Interestingly, various anesthetics have opposing effects on the 5-HT3 receptor, which is widely distributed throughout the central nervous system. Therefore, 5-HT3 contributions to anesthesia induction may occur through indirect mechanisms [76].
Acetylcholine modulates arousal via cholinergic circuits emanating from the basal forebrain, lateral dorsal tegmental nuclei, and pedunculopontine tegmental nuclei [11,77]. Acetylcholine release is closely coupled with arousal state switching [78]. Different synchronization releasing patterns of acetylcholine (tonic versus phasic) are involved in regulating sleep stages and contribute to states of high-arousal [79,80]. Interruption of central cholinergic muscarinic neurotransmission may be a mechanism by which anesthetic agents contribute to loss of consciousness [11]. Cholinergic stimulation with carbachol, a mixed cholinergic agonist, in the prefrontal prelimbic cortex but not the parietal cortex reversed sevoflurane-induced anesthesia in rats [77]. However, physostigmine, a cholinesterase inhibitor that increases acetylcholine levels, has shown mixed results at reversing anesthesia-induced unconsciousness in preclinical models [81,82].
Orexinergic neurons also play a critical role in arousal. Increased orexinergic neuronal activity is observed during wakefulness, in contrast to the decreased discharge of orexin neurons during low vigilance states in animals [83,84]. Further, orexin interacts with other neuromodulatory systems in the locus coeruleus, ventral tegmental area, and basal forebrain to influence arousal state changes [[85], [86], [87]]. Recently, the orexin receptor 2 agonist danavorexton was found to accelerate recovery from general anesthesia and opioid-induced sedation in animal models [88]. Interestingly, stimulation of orexinergic neurons has only been shown to impact emergence from and not impede induction of anesthesia [89,90].
Lastly, adenosine is a ubiquitous signaling molecule that is essential to cellular activity throughout the body, including the central nervous system. Adenosine-facilitated inhibition of the locus coeruleus leads to downstream inhibition of ascending arousal circuits in non-REM sleep [11]. In states of stress, such as hypoxic/anoxic conditions, adenosine may protect cells from metabolic stress through decreased excitatory neurotransmission, maintenance of intracellular calcium concentrations, and decreased membrane depolarization. While initially serving as a neuroprotectant, accumulation of adenosine may impede recovery through delayed return of synaptic transmission [91]. Caffeine, an adenosine receptor antagonist, was found to accelerate recovery from isoflurane and propofol anesthesia in preclinical and early clinical models [92,93].
In summary, numerous neurotransmitters contribute to wakefulness and to recovery of consciousness after anesthetic-induced unconsciousness or severe brain injury. Yet the neurotransmitter systems that are essential to sustaining human consciousness, and that are most important for recovery of consciousness after a severe brain injury, have yet to be fully identified. The roles of GABA-mediated inhibitory neurotransmission and glutamate-mediated excitatory neurotransmission are well established in the induction of coma or altered levels of consciousness. Dopaminergic signaling has emerged as a critical factor in consciousness and its disorders, while the contributions of norepinephrine, histamine, orexin, adenosine, and acetylcholine in the development of DoC after brain injury continue to be elucidated.
Whether impaired neurotransmitter synthesis, release or receptor function are the primary drivers of DoC in patients is unknown. As a result, there is currently a broad spectrum of therapeutic approaches being used in the investigational and clinical domains to target pre-synaptic and post-synaptic function (Fig. 1). Pharmacologic agents that modulate neurotransmitter release and/or re-uptake rely on the retained ability of the pre-synaptic neuron for neurotransmitter synthesis. Pharmacologic agents that act as positive allosteric modulators at neurotransmitter receptors also rely on preserved pre-synaptic neuronal function, augmenting neurotransmitter action on post-synaptic receptors. Finally, pharmacologic agents that act as direct agonists may reestablish post-synaptic neuronal function even in the presence of damaged pre-synaptic neurons that release decreased or absent levels of neurotransmitters. Future identification of pre-synaptic and/or post-synaptic neuronal dysfunction in individual patients with DoC will be a crucial step toward the development of novel, personalized therapeutic approaches.
The mesocircuit model of DoC is based on the broad withdrawal of excitatory neurotransmission across the frontoparietal cortical regions, central thalamus, brainstem, and striatum, leading to arousal dysregulation (Fig. 2B) [94]. Structural injury inducing forebrain neuronal death, deafferentation and disconnection, as well as functional disturbances of neuronal connections, may result in the large-scale forebrain dysfunction observed in DoC [95]. The anterior forebrain mesocircuit is interconnected with fronto-parietal networks that contribute to conscious awareness, including the default mode, executive control, and salience networks [3]. In DoC, loss of striatal inhibition of the globus pallidus results in excessive inhibition of a hypoactive thalamus, leading to reduced thalamocortical activation of frontoparietal regions [96]. As predicted by the mesocircuit model, disruptions in default mode network functional connectivity correlate with decreased level of consciousness [[96], [97], [98], [99], [100]]. Electrical stimulation of central thalamic nuclei (including intralaminar nuclei and mediodorsal thalamus) has aroused unconscious monkeys anesthetized with propofol [101,102], and has led to increased behavioral responsiveness in a patient with chronic minimally conscious state [103], strengthening the mechanistic link between thalamocortical signaling and consciousness. The development of neuroimaging and electrophysiologic biomarkers that measure the integrity of the mesocircuit in patients with DoC is an area of active inquiry that has the potential to guide selection of therapies aimed at upregulating mesocircuit function [[42], [43], [44],[104], [105], [106]]. An extension of the mesocircuit model has recently been proposed to incorporate dysfunction of monoaminergic pathways from the brainstem as additional key contributors to the development of DoC [107].
Pharmacologic therapy offers an accessible and inexpensive pathway to modulate neurotransmitter systems that have been identified as key contributors to the pathophysiology of DoC (Fig. 1, Fig. 2A). Pharmacologic therapy for the treatment of DoC aims to restore the functional integrity and homeostatic balance of neurotransmitter systems, thereby stimulating emergence of consciousness and maximizing rehabilitative efforts. Current therapeutic options modulate dopamine (amantadine, bromocriptine, levodopa, apomorphine), mixed monoamine neurotransmitters (methylphenidate, modafinil), or GABA receptors (zolpidem, benzodiazepine, baclofen), as detailed in Table 1 and Fig. 1. Amongst surveyed healthcare practitioners caring for patients with DoC in the acute, subacute, or chronic setting, amantadine was the most commonly prescribed neurostimulant (51%), followed by modafinil (37%), methylphenidate (30%), amphetamine salts (12%), levodopa (12%), and zolpidem (8%) [108].
Based on robust evidence for dopaminergic pathway disruption in preclinical and clinical models of DoC, pharmacologic neurostimulants that modulate dopaminergic transmission are currently the most widely utilized intervention to promote arousal. Amantadine is the only neurostimulant recommended by the 2018 practice guidelines for DoC in adults with traumatic DoC at 4–16 weeks post-injury [9]. Amantadine is currently the only therapy that has been shown in a randomized controlled trial to promote functional recovery in patients with severe brain injury [8]. In this double blind, randomized, placebo-controlled trial of patients in a VS/UWS or MCS 4–16 weeks after traumatic injury, amantadine treatment was associated with a higher proportion of patients who were moderately-severe-to-severely disabled (25.6% versus 16.8%), a lower proportion of patients in a vegetative state (18.6% versus 31.6%), and higher rates of recovery in all six domains of the Coma Recovery Scale-Revised at the end of the trial. The efficacy of amantadine in this study supports the hypothesis that dopaminergic pathway disruption plays a role in regulation of consciousness. Despite limited high-quality evidence, pharmacologic neurostimulation with amantadine continues to be reported in observational analysis and single-center studies in patients with acute traumatic DoC (i.e., before 4 weeks post-injury) and in non-traumatic DoC [[109], [110], [111], [112], [113], [114], [115], [116], [117], [118]]. Case reports and case series have reported consciousness-promoting effects of dopaminergic stimulation with levodopa, apomorphine, and bromocriptine [[119], [120], [121], [122], [123], [124]], but evidence from randomized controlled trials is currently lacking.
Methylphenidate inhibits dopamine reuptake, inhibits norepinephrine reuptake and is a weak agonist at the serotonin receptor [125]. Few studies have examined the effectiveness of methylphenidate in promoting recovery from DoC [7,126], and evidence from randomized controlled trials is similarly lacking. Nevertheless, methylphenidate therapy continues to be reported as a pharmacologic neurostimulant utilized off-label in clinical practice in patients with DoC [108,127,128]. Mechanistic support for this approach comes from a study of TBI patients without DoC, in whom methylphenidate administration increased connectivity between the ventral tegmental area and posteromedial complex (i.e., posterior cingulate cortex and precuneus) [52].
Modafinil is believed to have therapeutic effects in patients with DoC through stimulation of histamine, norepinephrine, serotonin, dopamine, and orexin neurotransmitters and potential anti-oxidative effects [129]. Neuroimaging studies found modafinil increased cerebral blood flow in the thalamus, locus coeruleus, limbic system, and insular cortex [129,130]. However, observational reports of modafinil use in patients with DoC have revealed mixed results [[130], [131], [132]].
Paradoxical awakening after administration of GABAA receptor agonists zolpidem and benzodiazepines or the GABAB receptor agonist baclofen have been reported [[133], [134], [135], [136], [137]], leading to intense interest in identifying patients who are physiologically receptive to GABAergic therapy. Paradoxically increased conscious behaviors after zolpidem administration have been reported to occur in approximately 5% of patients with DoC [136], [138], [139], [140]. Zolpidem's preferential binding to the GABAA omega-1 receptor subtype in the globus pallidus interna may in part explain the paradoxical effectiveness of zolpidem in patients with DoC and supports the mesocirciut model [134,138,141]. Baclofen has been theorized to promote emergence of consciousness either 1) through modulation of impulse transmission from spine to cortex, interfering with spasticity-induced proprioceptive outputs that may interfere with maintenance of alertness and awareness; or 2) through modulation of neurotransmission and functional restoration of cortico-thalamo-cortical connections [142].
Optimal timing of pharmacologic neurostimulant initiation after acquired brain injury remains controversial. When and which neurostimulant therapy is initiated is often clinician and patient specific. Recent international survey data indicate that amantadine is the most commonly prescribed stimulant worldwide [108], as it is currently the only neurostimulant recommended by clinical guidelines [9]. Prior to initiation, reversible etiologies of DoC should be evaluated and corrected or ruled out to reduce polypharmacy. Agent-specific interactions with comorbid conditions (e.g., renal dysfunction, hepatic dysfunction, cardiovascular disease, urologic disorders), drug-interactions, and adverse effect profiles (Table 1) should be considered when selecting the optimal agent.
After initiating a pharmacologic neurostimulant, close observation by clinicians and families for neurobehavioral changes is essential, and it is important to allow sufficient time (i.e., 4–6 weeks) to assess a therapeutic response. In the subacute-to-chronic setting, the Coma Recovery Scale-Revised (CRS-R) [143] and revised Motor Behavioral Tool (MBT-r) [144] may be used to optimize detection of subtle changes in behavior. In the acute ICU setting, the recently developed Coma Recovery Scale Revised For Accelerated Standardized Testing (CRSR-FAST) [145] may enhance opportunities to detect changes in behavior, given the insensitivity of the Glasgow Coma Scale at detecting changes in level of consciousness [146]. In patients with an inadequate or partial response to initial therapy selection, an alternative neurostimulant may be considered as monotherapy or in combination. Whether combination provides additive or synergistic effects is unknown and may depend upon patient-specific pathophysiologic factors.
Elucidating the neurochemistry and neurobiology of consciousness and characterizing brain network disruptions with advanced imaging and electrophysiologic techniques are expected to pave the way for personalized pharmacotherapy approaches in patients with DoC. Given varying response to pharmacologic stimulant therapy in clinical practice, it is likely that the pathogenesis of DoC is not universally regulated by the same neurotransmitter alterations across all patients. Yet standardized diagnostic tools to detect patient-specific alterations in neurotransmitter pathways are not currently available, resulting in potentially inefficient treatment trials that enroll patients with a low likelihood of therapeutic target engagement.
The mesocircuit model provides a neurobiological basis for therapy selection to promote recovery of consciousness – both for investigation in clinical trials and for off-label use in clinical practice. The mesocircuit model further supports the use of dopaminergic therapy for initial selection in patients with DoC [44,52]. Cerebral spinal fluid sampling and microdialysis may identify neurotransmitter metabolites and thus surrogate markers of neurotransmitter deficits [147,148]. However, these invasive diagnostic approaches do not distinguish the cause of the neurotransmitter deficiency in DoC. New diagnostic tools are needed to identify whether synthesis, release, or reuptake pathways are impaired and to elucidate the functional integrity and expression of neurotransmitter receptors. Advanced neuroimaging tools such as functional MRI (“pharmacological MRI”), positron emission tomography (PET), and single photon emission computed tomography (SPECT) may identify alterations of neurotransmitter function but are not widely available, costly to implement, and no standardized biomarkers to guide therapy selection in patients with DoC currently exist [[149], [150], [151]].
A connectome-based clinical trial platform has been proposed to identify predictive biomarkers that will facilitate enrollment in clinical trials based on a mechanistic assessment of a patient's potential for a therapeutic response [7]. A phase 1 clinical trial that leverages this connectome-based approach is evaluating the safety of intravenous methylphenidate in patients with acute traumatic DoC (NCT03814356) [7]. In addition, a prospective double-blind placebo-controlled trial (NCT03623828 and NCT05213169) is investigating the efficacy of apomorphine for patients with prolonged DoC.
New mechanistic targets are also being investigated in clinical trials of patients with DoC after acquired brain injury. Brain complexity has been used to describe the interplay between functional specialization of local areas and global integration during perception and behavior [152]. Patients with DoC and healthy individuals undergoing propofol anesthesia have both been reported to have decreased brain complexity, providing an empiric basis to use brain complexity as a pharmacodynamic biomarker to evaluate therapeutic target engagement [153]. Psychoactive therapies such as ketamine, lysergic acid, and psilocybin have been reported to increase neural complexity in healthy humans [154]. A double-blind, placebo-controlled, crossover randomized controlled trial (NCT05343507) is investigating whether subanesthetic ketamine promotes emergence of conscious behaviors and higher neural complexity in patients with VS/UWS or MCS. Ketamine, an NMDA receptor antagonist, induces aberrant excitatory activity in the cortex, hippocampus, and limbic system through inhibition of NMDA-mediated glutamatergic inputs to GABAergic interneurons – the proposed mechanism for dissociative anesthesia and hallucinations [11]. In patients with VS/UWS or MCS, investigators of this trial hypothesize that ketamine may facilitate increased neural complexity and thereby promote consciousness. Psylocibin predominately acts as a 5-HT2A receptor agonist at cortical and thalamocortical areas and has been shown to increase brain complexity in healthy humans [[154], [155], [156]]. No trials to date have been performed evaluating psilocybin in DoC, and this therapy is only legal in select countries, complicating comprehensive investigation.
In Europe and South Korea, cerebrolysin, a neurotrophic peptidergic therapy, is being investigated in patients with prolonged DoC after ischemic or hemorrhagic stroke (NCT04427241, NCT04913831). Recovery from brain injury may involve the reemergence or creation of network connections. Cerebrolysin exhibits a multimodal pharmacologic profile, as it may mimic and modulate endogenous neurotrophic factors, promote neurogenesis and oligodendrogenesis through the sonic hedgehog pathway, protect against glutamate excitotoxicity, reduce free radical formation, inhibit apoptosis, modulate the inflammatory response, improve blood brain barrier integrity, and initiate and promote neuroplasticity [157]. Cerebrolysin may have more pronounced effects on neuroplasticity and neurorestoration than on neuroprotection, and thus cerebrolysin is a promising pharmacologic agent for the treatment of various types of brain injuries [158]. Cerebrolysin also modulates Akt/glycogen synthase kinase3β (GSK3β) [159]. The GSK3β pathways and monoaminergic activity have been reported to be interconnected in preclinical models of various neuropsychiatric disorders. For example, impaired serotonergic activity may contribute to abnormally active GSK3β that imparts detrimental effects on neuronal structure, plasticity, and survival [160]. GSK3β may play an important role in the regulation of neurotransmitter vesicle exocytosis that induces pre-synaptic neurotransmitter release [161]. Activation of GSK3β in experimental models has also been found to reduce pre-synaptic glutamate release and lead to nigral dopaminergic neurodegeneration [162,163]. The precise mechanisms by which cerebrolysin may support restoration of neurotransmitter signaling in patients with DoC is yet to be elucidated and a key area of future exploration.
The field of DoC neurotherapeutics is an exciting frontier with tremendous potential to improve the lives of patients and their families. While optimal therapy selection based on patient-specific phenotypes requires further investigation, neurostimulant therapy is generally safe and inexpensive. Therapy selection can be informed by recent insights into the neuroanatomic networks and neurotransmitter systems that contribute to recovery of consciousness in patients with DoC. The mesocircuit model and dopamine neurostimulation have emerged as critical components of conscious behaviors, though other neurotransmitter systems and circuits are also key contributors. As such, dopaminergic therapy with various neurostimulants are frequently utilized off-label in clinical practice for patients with DoC. Pharmacologic neurostimulants offer the potential to accelerate recovery trajectory and support participation in rehabilitative efforts. In patients who do not respond to initial therapy, adjunct or alternative therapies that modulate other neurotransmitter systems may be considered. It is not currently known whether short-term response to neurostimulant administration is predictive of functional recovery, and therefore stimulant responsiveness should not be used to guide decisions about withdrawal of life-sustaining therapy.
Drs. Barra, Solt, Yu, and Edlow all contributed to drafting the manuscript. Dr. Barra created the Table. Drs. Barra and Edlow created the Figures. All authors performed critical review and revision of the manuscript.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
This work was funded by the National Institutes of Health (NIH) Director's Office (DP2HD101400), NIH National Institute of Neurologic Disorders and Stroke (R01NS122904), NIH National Institute of General Medical Sciences (R01GM126155), the MIT/MGH Brain Arousal State Control Innovation Center (BASCIC), and the Chen Institute MGH Research Scholar Award.