Therapies to Restore Consciousness in Patients with Severe Brain Injuries: A Gap Analysis and Future Directions

Treatments for patients with disorders of consciousness (DoC) are currently limited. The cornerstone of therapy is early intensive neurorehabilitation combining physical, occupational, speech/language, and neuropsychological therapy, which appear to improve long-term functional recovery [1‐4]. Pharmacologic stimulant therapies are also used throughout the rehabilitation process to promote recovery of consciousness [5]. However, of the few rehabilitative or pharmacologic therapies that have reached late-phase clinical trials, only amantadine has evidence from a multicenter, double-blind randomized controlled trial to support its efficacy in accelerating recovery in patients with posttraumatic DoC [6‐8].

Network-based insights into mechanisms of consciousness [9] now raise hope for developing new consciousness-promoting therapies for patients with DoC [5]. A fundamental goal is to modulate the neural networks underlying arousal and awareness, the two components of consciousness [10]. Central to this effort has been the development of network-based conceptual models of consciousness [11, 12] as well as methodologic advances in neuroimaging [13], electrophysiology [14], and neuromodulation [15, 16]. These conceptual and methodologic advances now make it possible to test precision therapies [17, 18] that modulate brain activity at a range of scales [19‐22].

Yet measuring the effects of therapies remains a challenge. Even with advances in the bedside assessment of patients with DoC [23, 24], consciousness may evade detection by behavioral examinations, and thus therapeutic effects may go unnoticed. The recognition that up to 15–20% of patients who appear unresponsive may be covertly conscious [25‐29] (i.e., cognitive motor dissociation [30]) has led to a reappraisal of behavioral outcome measures in clinical trials and a search for new electrophysiologic and imaging biomarkers of therapeutic efficacy [17, 18]. Furthermore, the optimal time window for evaluating efficacy has not been defined because some treatments produce an immediate, transient effect on a patient’s level of consciousness, whereas others may cause a delayed, long-term change in a patient’s course of recovery.

In this white paper, we report the results of a gap analysis performed by the Coma Science Work Group of the Curing Coma Campaign [31], in which we examine therapies that aim to promote recovery of consciousness in patients with DoC. We identify gaps in knowledge that have impeded the development of effective therapies, and we propose strategies for filling these gaps in future clinical trials. We make suggestions for the development and rigorous assessment of new therapies based on emerging insights into mechanisms of consciousness and its disorders.

The Curing Coma Campaign convened a Coma Science Work Group that included nine clinicians and neuroscientists with expertise in DoC. The work group represented six international academic medical centers and the fields of neurology, neurosurgery, physical medicine and rehabilitation, neuropsychology, and neuroscience. The work group met online biweekly and performed a gap analysis over a 6-month period from June to December 2020. During this period, we reviewed the literature on therapies for DoC using reference libraries from recent systematic reviews [5, 10, 32] as well as our own reference libraries. We focused on therapies that directly modulate brain networks involved in human consciousness. We therefore did not consider brain–computer interfaces that translate neural activity into self-expression [14, 33], nor did we cover treatments that ameliorate specific symptoms or neurological deficits associated with DoC, such as spasticity [34], pain [35], dysautonomia [36], nonconvulsive seizures [37], pituitary failure [38], or hydrocephalus [39]. Although the successful treatment of such symptoms can facilitate self-expression and reduce confounding of behavioral assessments [1], these treatments were beyond the scope of the present gap analysis.

We categorized current experimental therapies into five types: (1) pharmacologic, (2) electromagnetic, (3) mechanical, (4) sensory, and (5) regenerative (Fig. 1). These therapeutic classes act via distinct mechanisms, with a diverse set of stimulation targets (Table 1). We summarized the state of the science for each therapy then analyzed current gaps in knowledge (Table 2) and proposed future experimental directions (Table 3). All recommendations by our work group were based on consensus agreement. We focused on how the design of future clinical trials can be optimized for patients with DoC, recognizing that recent innovations in clinical trial design, such as adaptive designs [40] and patient-centered outcomes [41, 42], are likely to also influence future trials of consciousness-promoting therapies.

The development of effective consciousness-promoting therapies for patients with DoC will require a coordinated effort by the international community and a commitment to optimizing the design of clinical trials. We recommend that future studies implement multicenter, placebo-controlled, randomized, double-blind designs with complementary behavioral, neuroimaging, and electrophysiologic outcome measures to assess treatment efficacy. Mechanistic biomarkers that predict a therapeutic response are also needed to improve the efficiency of clinical trials by enrolling patients whose brain networks are amenable to therapeutic modulation. This precision medicine approach will require a broad range of methodological advances, including the rigorous characterization of patient endotypes [221].

Beyond advances in clinical trial design, we also recommend the development of new therapeutic approaches in which multiple therapies are administered concurrently to individual patients. Just as no single therapy is likely to be efficacious in all patients, it is possible that more than one therapeutic modality is needed to stimulate neural networks via synergistic mechanisms. For example, electromagnetic stimulation (e.g., rTMS) may be combined with pharmacologic stimulation [222], or electromagnetic top-down stimulation (e.g., tES) with bottom-up approaches (e.g., transauricular VNS), administered either concurrently or consecutively. We encourage the development of adaptive clinical trial designs featuring conditional therapeutic additions or changes based on the patient’s clinical evolution.

For these new approaches to reach their full potential, we will need a unifying conceptual framework—one that accounts for the diverse pathophysiologic mechanisms underlying DoC. This conceptual framework will help guide the development of surrogate end points, or pharmacodynamic biomarkers, of therapeutic efficacy in early-stage clinical trials (i.e., phases 1 and 2). When testing whether a new therapy is engaging its target, it is likely that subclinical responses will be detectable before behavioral responses [17, 141‐143, 223]. Pharmacodynamic biomarkers derived from EEG [17, 183, 223, 224], fMRI [17, 225], positron emission tomography [225], TMS–EEG [141‐143], or near-infrared spectroscopy [226] can thus be used to measure brain responses to new therapies, identify optimal dosing regimens, and inform the design of phase 3 trials that aim to detect behavioral and functional responses.

In parallel with the need for surrogate measures in early-phase trials, there are fundamental unanswered questions about the optimal outcome measures to use for phase 3 trials that enroll patients with DoC. Historically, the Glasgow Outcome Scale-Extended (GOSE) [227] has been the outcome measure recommended by regulatory agencies for phase 3 clinical trials of patients with severe brain injuries [228, 229]. However, the GOSE is an ordinal eight-point scale with outcome categories that do not provide the granular assessment of consciousness or cognitive function that may be required to detect subtle, yet clinically meaningful, therapeutic effects. A patient who transitions from a VS/UWS to a low-level MCS, for example, would not be defined as a treatment responder by using the GOSE because the score would remain a 2 [230]. Indeed, the reliance on the GOSE as an outcome measure has been proposed as a contributing factor to the high failure rate of phase 3 clinical trials in patients with severe brain injuries [229]. The Disability Rating Scale [231] provides a more comprehensive assessment of functional outcome and was used in the phase 3 trial of amantadine [6], but the Disability Rating Scale does not account for behavioral changes in the visual and auditory domains that would be captured by the Coma Recovery Scale-Revised [23]. Yet even if future phase 3 trials include additional behavioral and cognitive outcome measures derived from the Coma Recovery Scale-Revised and the Confusion Assessment Protocol [232], fundamental questions remain, such as the following: (1) What is the minimal clinically important difference [233] for outcome measures that assess patients with DoC? (2) Does the minimal clinically important difference depend on the level of consciousness at the time of trial enrollment? and (3) Are outcome measures that rely on overt behaviors suboptimal for patients with covert consciousness, who may only be able to communicate via brain–computer interfaces [33]? Answering these questions may require new partnerships between clinicians, investigators, ethicists, recovered patients, caregivers, and regulatory agencies.

Another key consideration in future clinical trial design will be the timing of enrollment, particularly for patients with cognitive motor dissociation [30] (i.e., active command-following on task-based fMRI or EEG) or covert cortical processing [10] (i.e., passive responses to language or music on stimulus-based fMRI or EEG). Emerging evidence suggests that these two groups of patients have a better chance of long-term functional recovery than do patients without responses on task-based or stimulus-based diagnostic tests [26, 234], which may also suggest an increased receptivity to therapeutic stimulation. Investigators will have to consider whether these patients should be analyzed as prespecified subgroups in future studies and whether a transition from unresponsiveness to cognitive motor dissociation or covert cortical processing should be defined as a favorable therapeutic response.

In summary, the future development of all five classes of therapeutic modalities investigated in this gap analysis will require multicenter trials to achieve adequate statistical power to test hypotheses about therapeutic efficacy. We call for the creation of a global DoC clinical trials network to support this long-term goal. Central to this international effort will be the selective enrollment of patients based on their physiological receptivity to targeted therapies [17, 18, 94, 95], as well as the implementation of new pharmacodynamic biomarkers and standardized outcome measures for the comprehensive evaluation of brain function, behavior, and cognition. Advances in clinical trial design and precision medicine are essential for the future development of therapies that will improve the lives of patients with DoC.