Perspective on insomnia in disorders of consciousness

In most individuals, consciousness waxes and wanes in a circadian (24 h) rhythm in the sleep-wake cycle. However, this cycle can be majorly disturbed in disorders of consciousness (DoC1), to the point where it is unclear between what states an individual may alternate given the absence of full-blown wakefulness or all usual characteristics of sleep. Diagnostic groups, like vegetative state/unresponsive wakefulness syndrome (VS/UWS), that show some arousal but no awareness, and minimally conscious state (MCS), where arousal is coupled to partially preserved awareness, can be differentiated based on sleep characteristics that are less prominent in the former.2-4 Etiologies for these DoC's (e.g., traumatic brain injury [TBI], hemorrhage, anoxia, or an infection) vary wildly, as does to the resulting brain injury; however, despite these differences, there is a clear commonality that the sleep-wake regulating areas of the brain are often affected.1 In fact, injury to these areas, such as the ascending reticular activating system and the thalamus, has been implied to be the cause for DoC5 as they have a crucial role in the regulation and maintenance of arousal.6 These areas are associated to regular sleep too7 and are often affected in sleep disorders (see https://neurosynth.org/analyses/terms/sleep/, for instance, for the prominent role of the brainstem arousal systems). It is well recognized in the general population that poor sleep leads to a wide array of mental and physical changes that are deleterious to our well-being.8, 9 Self-reported regular problems with sleep (i.e., 3 nights a week for 3 months) are diagnosed as insomnia disorder (DSM-5-TR10). Although insomnia disorder can occur on its own, it is often comorbid with many other diseases like Parkinson's disease11 and concussions resulting from a mild TBI.12 Insomnia disorder is also considered a risk factor for the development of various disorders, from major depression13 to obesity.9 Although these are just examples, a large body of literature suggests that insomnia disorder is a major player in a vast matrix of disease. Crucially, a core feature of insomnia disorder is the self-report of sleep complaints, something DoC patients cannot communicate. Yet, there are various hints toward the existence of insomnia disorder in this population. With the crucial absence of self-report in the DoC population, there is no DSM-5-based diagnosis. The current research will focus on objective markers of sleep disturbances that in the self-reporting population correlate with their symptoms of insomnia disorder. Because of this focus on symptoms of sleep loss, we generally refer to this as putative insomnia (i.e., not insomnia disorder per DSM-5 criteria) in the DoC population. First of all, about 10% of the general population would be diagnosed with insomnia,14 whereas up to 40% suffer intermittently from insomnia-related complaints.15 Perhaps sleep complaints increase the chance of suffering a DoC, from the increased risk of an accident that could cause a TBI16 to increased risk of a stroke that could cause a DoC.17 Moreover, as stated above, the brain structures affected in DoC are likely including sleep-wake regulatory systems, which arguably makes insomnia-kind complaints more likely. Furthermore, a study on medical complications during the recovery process of DoC patients noted that 6.2% (third most common) of all complications were related to sleep disturbances.18 In a notable comment they say: "These problems may appear less often in the literature on medical complications, because they are viewed as intrinsic parts of the sequelae and recovery process of TBI." Importantly, early diagnosis and treatment of comorbid sleep disturbances in DoC have been added to recent guidelines by the American Academy of Neurology.19 A mild TBI, not resulting in a DoC as considered in this review but with post-concussive symptoms20, 21, leaves an astounding 46% of patients diagnosed with a sleep disorder.22 Others have reported a prevalence of insomnia complaints in 30% up to 70% of TBI patients,23 half of which may be related to a circadian rhythm disorder.24 Even in the whole population of hospitalized patients, sleep is already poorer than in the general population.25 Based on this evidence, we pose that sleep disorders may play an underestimated role in the disease of recovery of DoC patients. In this perspective, we delve into the seemingly unseen consequences of the tight relation between insomnia and DoC. To this end, we discuss the intersection of the alterations and treatment of both. First, we will discuss remarkable similarities between alterations found in insomnia and DoC on a behavioral and neuroimaging level. Next, we will discuss a physiological common ground that may pave the way for future research and their relationship. Finally, we will discuss treatments with effects on both, while they are often only meant to target one. As introduced, there is a range of commonalities between DoC and insomnia-related alterations. Evidence for the commonalities between these two conditions stems from behavioral, (functional) magnetic resonance imagining, and electrophysiology (EEG) studies. It is important to note that there are two paths to the shared pathophysiology of DoC and insomnia. Patients with a DoC suffered from a clear initiating factor in the form of severe brain injury, whereas for insomnia patients, the initiating factor is much less clear. However, there seems to be a bidirectional (or even aggravating) effect between insomnia symptoms and behavioral and neurophysiological effects (Figure 1). The commonalities between the two diseases will be discussed in more detail below and are summarized in Table 1. In general, we hypothesize that some of these negative effects can synergize to exacerbate their consequences in isolation. Putatively, symptoms are also interconnected where the existence of one symptom could lead to aggravation in another, but this is beyond the scope of this review. Overview of alterations in insomnia and their potential aggravation of DoC characteristics. In the top left insomnia is shown as its own construct, with its own (unknown, varying) causes, where several symptoms can end up in the outer ring of potentially interacting symptoms (example dashed, two-way lines). In the bottom right is severe brain injury that leads to a DoC. This clear cause has immediate neurophysiological effects (example solid lines) that could also be insomnia characteristics. Together, these interacting symptoms may worsen DoC characteristics. DoC, disorder of consciousness. Behavioral assessment in patients with DoC is challenging, and often limited to tools for the diagnosis of the state of consciousness using adapted scales such as the CRS-R.46 By definition, these patients cannot provide a subjective report on their cognitive state, adding a level of complexity to the comparison. However, few studies on the DoC population or proxy populations can be used to start this investigation. Insomnia may be related to increased experiences of pain,28 also altered in DoC.29 Besides the general association of insomnia with decreased quality of life26 and physical well-being,47 the experience of pain could decrease potentially the quality of life27 in DoC patients, urging increased attention toward insomnia detection and treatment in this population. A study mentioned insomnia may enhance cognitive difficulties that resulted from a TBI,24 but it remains unclear through which process. Potentially, working memory deficiencies may play a role, as they do in non-TBI insomnia,32 and also commonly found following TBI.33 Insomnia has also been shown to decrease motivation and reward sensitivity,30 also a major player in the TBI recovery process.31 Moreover, in akinetic mutism, a disorder characterized by a lack of motivation leading to a DoC-like lack of behavior, sleep has also been shown to be deteriorated.48 In the DoC population, it would be problematic to not detect signs of consciousness based on difficulties that do arise from insomnia (e.g., keeping instructions to a simple task in working memory, decreased motivation to follow them). Insomnia has been related to mood disturbances and depression,34 which is also present in 56.3% of recovering mild TBI patients.35 Investigations of brain organization in insomnia have been mixed, with some reporting atrophy in the superior frontal cortex,49 whereas others found hypertrophy in the orbito-frontal cortex.50 Indeed, studies into insomnia have shown mostly cortical differences from controls,14 whereas the early mentioned neurosynth analysis shows more arousal-related areas (see https://neurosynth.org/analyses/terms/sleep/). A meta-analysis aimed at structural differences at insomnia found a lack of consistent alterations.51 However, as the DoC population, the insomnia population is highly heterogeneous.52 Therefore, some interesting common findings across both populations are discussed in the next paragraph. In patients with DoC, widespread cortical atrophy is a common occurrence.36 Functionally connectivity between areas is decreased in the DoC population.41 This functional connectivity includes the salience network, whose functional connectivity has also been shown to be affected by insomnia.39, 40 Additionally, engagement of task-relevant and suppression of task-irrelevant (i.e., default mode network) has been shown to be altered in insomnia.37 Although a reliable assessment of the default mode network in DoC during tasks is challenging, it has been shown that the integrity of its structural connectivity is severely compromised.38 Furthermore, an auditory irregularity detection task (oddball-task) has been shown to be useful in consciousness assessments in DoC where the detection of the global deviant is associated with the presence of consciousness.42 Interestingly, there is evidence that insomnia leads to increased attention toward irrelevant stimuli (i.e., relatively decreasing the oddball detection).14 This may be related to the prominent observation in insomnia of hyperarousal, a maladaptive increase in arousal that may decrease useful filtering capacities.53 Although DoC patients show some level of arousal, the functionality of this arousal in governing directed behavior is sometimes questionable. As a result, the over-reactivity to the environment in hyperarousal could lead to undirected behavior, while also in patients with a DoC, for instance, through the CRS-R assessment, a separation occurs between directed (conscious) and undirected (unconscious) behavior. This hyperarousal might also be related to the previous observation on the network level, where it alters their temporal dynamics (e.g., more dwell-time in functional states without proper filtering) where similar functional connectivity changes have been observed in patients with a DoC.41 It is known that higher prominence of alpha power has great clinical relevance in a multicenter study of DoC patients.45 Modulations of alpha have been observed in insomnia patients as well, with decreases during wakefulness and increases during sleep in insomnia patients.43, 44 Hyperarousal is also associated with increased high-frequency EEG power (in the beta band) during both sleep and wakefulness.43, 54 Now, higher frequencies such as in the alpha and beta range are associated with better diagnosis and outcome in the DoC population,55, 56 but this research also highlights that often the brain is pathologically slowed down. As a consequence, hyperarousal in patients with a DoC does not necessarily mean the appearance of beta activity, but it could increase previously slowed down dynamics. In turn, this could potentially lead to the finding of higher frequencies in patients that are not reflected in behavioral signs of consciousness. As a final note, not only does disturbed sleep have brain-related effects, it has been argued that the whole body may be affected by its effects (e.g., insulin resistance).57 As will become apparent below, the regulation of slow oscillatory activity of the brain, as cornerstone of healthy sleep and thereby potentially affected in insomnia, is altered in DoC.45 As the foundation of electrical brain activity in general, with such a prominent role in the damaged and sleeping brain, a discussion on slow waves is here at its right place. As will be seen in the next section, sleep-affecting treatments of DoC seem to alter slow-wave physiology too. On a physiological level, loss of consciousness is associated with general slowing of cortical activity.58 Whole-brain monotonic slow oscillatory activity as background activity or in the absence of most sleep characteristics has been reported in DoC patients. This pattern may originate from neuronal networks that, even in vitro, generate slow (∼1 Hz) oscillations originating from recurrent excitation that is regulated by inhibitory networks.59 As such, slow oscillations around the 1 Hz (i.e., in the delta range) were proposed as the default activity of the cerebral cortex, that in that form also give rise to slow oscillating phenomena observed during sleep.60 Brain pathologies can also present with slow oscillations, and as such, "pathological slow waves" are defined as slow waves that occur during wakefulness, as opposed to sleep slow waves. One way of distinguishing slow oscillations and such "pathological slow waves" is by including electromyography in addition to EEG activity (i.e., high muscle tone suggests the presence of pathological slow waves).61 The distinction of physiological and pathological slow waves is considered when performing sleep scored, with slow activity measured on electrodes over damaged brain areas being excluded from sleep-scoring patients with a DoC.62 However, problems with this assumption arise from the fact that even outside of the DoC population, sleep can be organized locally.63-65 Slow waves and spindles specifically are a local process based on scalp EEG,66 arising/fading with the paired breakdown/emergence of long-range connectivity.67 Interestingly, these local slow waves also occur in healthy controls.68 Moreover, eye-opening that has previously been interpreted as signaling wakefulness in DoC patients can be associated with both objective markers of sleep and wakefulness,1 with one study finding that sleep can be predicted based on eye-opening and -closure in less than half (11 out of 23) of the patients.69 With these findings, it becomes clear that separating pathological slow waves from sleep slow waves is not an easy task, especially in the absence of clear other physiological signs (e.g., originating from a source of injured brain tissue, potential characteristics like slow or amplitude that could separate them). In the discussed literature, this distinction is not taken into account (e.g., it is unclear if slow-wave sleep was sometimes scored because of the presence of pathological slow was too). By highlighting their prominence here, in both insomnia and DoC, we hope that future empirical research will dive deeper into this distinction. The pattern of low functional connectivity is a defining feature of decreased consciousness in DoC.45, 70 Indeed, the network and cellular generation of slow waves is a primarily local process,60 but horizontal layer 5 neurons and synchronization with the thalamus may provide a global appearance.71 Local generation may also be observed in the VS/UWS patient with thalamic lesions that were associated with delta activity over all electrodes.62 However, slow activity specifically in the parietal cortex and its connection to the thalamus has been noted to be an important contributor to consciousness, as measured in awake, sleeping, and anesthetized macaques.72 This parietal slow-wave activity in children with DoC is reduced, but more parietal slow-wave activity is related to better outcomes.73 Moreover, the gray matter volumes in both the parietal cortex and thalamus have been shown to discriminate VS/UWS from MCS patients.74 In combination with a relation between the gray matter volume and slow-wave amplitude,75 this findings could increase interest in parietal slow waves as, unlike global slow waves, they could be associated with higher level of consciousness. Slow waves are reliably associated with unconsciousness,76 but the reason for their occurrence in DoC patients remains speculative. From the perspective of a neuronal circuit, slow-wave activity may be the rhythms isolated networks resort to as a default, as was discussed above. Whether this return to default activity is maladaptive, for example, blocking possibilities for neuronal activity that could support more complex functions, or compensatory, for example, allowing for basic neuronal functions in areas that otherwise would not function are hypotheticals. As such, although unconsciousness is correlated with slow-wave activity, this relation is not necessarily causal. To the best of our knowledge, separation of slow waves that occur during sleep, those that occur during wakefulness in sleep deprivation,77 and those prominent in DoC is challenging. In fact, there is no evidence to assume they are different besides the behavioral state in which they occur. Similar cellular and local circuitry may underlie their generation and maintenance, from the viewpoint where the neuronal population resorts to the most efficient way of rest while maintaining the possibility to go into an active state.60 These periods of rest may be necessary for cellular maintenance,78 but the mantra in pathological states seems to relate them to damage rather than having any functional role. Yet, there is, for instance, no evidence for slow waves that occur in the awake and aware brain to have different origins (and putative functions) than those occurring during sleep.71 Importantly, slow waves are not only implicated in cellular regulation but also in behavioral improvements through memory consolidation.79 Given these putative functions of slow wave that are essential to life, it seems striking that the literature has reported that patients with a DoC have prominent slow activity,80 but the amplitude for these delta waves does often not reach the required threshold to score it as sleep,1 although it has been described that a great reduction in the ability to generate slow-wave sleep is fatal (i.e., a condition called fatal insomnia81). This suggest that the slow waves in patients with a DoC might perform a similar function as during sleep, albeit that sleep physiology has changed. Supporting this suggestion, others claim that all animals sleep regardless of any nonfatal lesion, even when their injury affects sleep regulatory systems.65 Some have argued that sleep is the price to pay for wakefulness, allowing for a necessary downscaling of synapses.78 This argument presents an interesting perspective in DoC, where the border between sleep and wakefulness is arguably shifted, with less full-blown wakefulness possibly decreasing the need for sleep. On the other hand, the need for sleep may also increase, as it is implicated in tissue repair.82 The potential implication of unnecessary downscaling for the progression of a DoC is hard to estimate. There are others that show sleep slow waves have also been implicated in the widespread up-regulation of cortical synapses.83 Answering this question remains challenging, but if either process is present during slow oscillatory activity in DoC patients, this may present a mechanism for the internal improvement of brain function, noting that not all improvement is necessarily functionally measurable at the behavioral level. Finally, slow waves are not necessarily only associated with unconsciousness,76 as the up-state of a slow wave may provide opportunities for consciousness.84 Slow-wave sleep has indeed been shown to be an active state, where wake-like neural activity patterns emerge during the up-states.85 These local desynchronized patterns in the EEG are remarkably similar to the EEG during full-blown wakefulness, suggesting a potential for similar functions.84 In children with Angelman syndrome, delta oscillations are even very prominent during normal wakefulness.86 While asleep, slow waves may be crucial for the generation of spindles and they have also been shown to group high-frequency oscillations to increase the effectiveness of information transfer.71 This high-frequency activity relies on local circuits of excitatory and interneurons and is crucial for a wide range of cognitive functions.87, 88 The grouping may also facilitate coherence between oscillations of separate neuronal populations, thereby possibly enabling communication89 though this is debated. A wakeful behavioral state can be characterized by slow-wave activity, but evidence investigating complexity shows that slow-wave activity is not necessarily equal across behavioral states with, for instance, complexity dropping from wakefulness to sleep in Angelman syndrome despite both having slow waves.80 Slow oscillation seems to be important for the organization of brain activity from the ground up while having a potentially nonlinear relation with consciousness. Together, this also provides angles for research in insomnia, for example, does the reported lack of sleep originate in periods of consciousness during slow waves? It is interesting to know that the transition of a down-state to an up-state depends on the size of the network, with increasing transition probability if more synapses impinge on a neuron with their excitatory post-synaptic potentials.71 The widespread cortical atrophy in DoC of course may limit these possibilities. The persistence of an up-state is mainly maintained by recurrent excitatory synaptic activity, with a minor role for inhibitory, gamma-aminobutyric acid (GABA) distributing neurons.71 The inhibitory regulation is constant, except during up-state initiation and termination where excitation dominates. Specifically the slow-acting GABAB receptors are implicated instead of the fast GABAA, but the integrity of structural connections may determine these effects as fast acting GABAA may also be effective cortical slices in the absence of a thalamocortical loop.90 Interestingly, while the brainstem plays no major role in slow-wave generation, transitions from up to down-states were abolished when it was stimulated.91 In this section, we discuss treatments under investigation in DoC patients or in insomnia, but we select only a limited number to provide some context on them in relation to each other (for an overview of all treatment options see Ref. 92). A general remark is that when treatment is aimed at increasing consciousness (e.g., increase arousal), it is likely to influence sleep. Yet, treatments successfully increasing arousal seldom report if this affected sleep (e.g., improved subsequent sleep or disturbed sleep). As a take-home from the section on insomnia above, we know that arousal can be maladaptive and should thus also be balanced. Circadian rhythms may also play a role in treatments, because stimulation might be more effective during the physiological day time rather than the night. The only recommended pharmacological treatment for DoC, the glutamatergic antagonist amantadine, has been shown to accelerate recovery in TBI patients, but not affect the sleep-wake cycle in DoC and will not be discussed in this Section.19, 93 Zolpidem is an indirect GABAA agonist that depresses the central nervous system (CNS) and is an approved and widely prescribed treatment of insomnia.94 It has been applied in DoC patients who showed sleep disturbance or restlessness and led in several cases to sudden, but temporary improvements in consciousness.95 In a case report investigating the EEG response to zolpidem, slow oscillations were not investigated and the response mainly related to increased connectivity in faster frequencies (beta band, 15–30 Hz).96 An increase in power and coherence in the same range was also seen in 3 other patients, now also coupled with a decrease in power and coherence in the slower 6–10 Hz range.97 Yet, the precise mechanisms of this contradictory event, especially on slow oscillatory activity, remains unknown. Purely speculative, it would be interesting to see what the effect of zolpidem is on slow waves, as in some cases, GABA is known to increase the persistence of the up-state, which in turn is associated with consciousness, possibly partly mediated through local excitatory/inhibitory loops that also involve GABA signaling.80, 87 Indeed, GABA has been shown to have a crucial role in the persistence of high frequency oscillations.98 Burst-suppression in DoC patients has been successfully reduced by treatment with zolpidem.99 Indeed, a GABA agonist can cause a hyperpolarization that limits action potential generation, disorganizes and speeds up slow waves, and counters burst-suppression.100 The anesthetic propofol, a GABAA agonist, has been shown to also incur a paradoxical effect on DoC patients.101 The reconfiguration that happens under this anesthesia might be indicative of recovery.102 There is an ongoing debate on the role of GABA in slow-wave generation.103 Where some research suggests the inhibitory properties of GABAergic neurons shape the slow oscillation,104 others propose the continuation of hyperpolarization in sleep is not affected by GABA.105 Most likely, GABAergic inhibition plays a small role.90 On the level of EEG, slow waves seem to be enhanced by pharmacological interventions with GABA receptor agonists.103 Interestingly, enhancement of slow waves during sleep and thereby enhancing memory is promising, although still inconsistent.106 Besides GABAA, the slow acting GABAB receptor might play a role in consciousness. Many DoC patients suffer from spasticity which can effectively be treated with intrathecal baclofen,107 a GABAB receptor agonist. This treatment has also been reported to be paired with behavioral improvements, such as more sustained eye-opening.108 One of the proposed mechanisms is the GABA-driven normalization of activity in thalamocortical circuits, thereby improving sleep-wake cycles, but these findings remain speculative.109 The repeated observation of GABA-related mechanisms above is striking. There is some literature on how the induction of inhibition may show better effects than excitation.110 Interestingly, it has been proposed that CNS depression (e.g., by providing the brain with inhibitory GABAergic stimulation) is more effective at awakening effects, whereas excitation can be induced to support other functions once this has been established.111 In relation to sleep, the effects of GABA may differ based on the receptors it activates, with GABAA receptors being implicated in sleep induction more often, whereas GABAB may be more associated with active states.112 Although there are some clues for a relation with inhibitory mechanisms, additional research is needed. Sleep-related treatment of DoC patients is not restricted to pharmacological interventions, but can also be done through intervention on the circadian rhythm. This can, for instance, be accomplished by light therapy, that is, regulating light exposure in such a way that it entrains the circadian rhythm. One study piloted this idea and successfully enhanced circadian rhythmicity (i.e., maximum temperature was closer to the optimum of healthy controls) in 3/8 DoC patients which was accompanied with the behavioral improvement of VS/UWS patients being diagnosed with MCS.113 In a follow-up study, it is shown that light therapy improved the fit of body temperature to follow the circadian rhythm, but behavioral improvement was only observed at the trend level and not consistently crossing diagnostic categories.114 In the past, patients have been excluded from studies investigating sleep because light was continuously on in their care environment, acknowledging the potential great influences of the zeitgeber and consequently on sleep.115 Insomnia, as shown to be likely highly prevalent in the DoC population, can be treated relatively effectively using cognitive behavioral therapy for insomnia (CBT-I) in brain-healthy individuals.116 At face value, these therapies may be unsuitable for treatment in a population where cognition and communication are hard to establish, but looking at the content of these therapies hints otherwise. Exemplary is one important component of CBT-I, sleep restriction. Now, most DoC patients get sleep opportunities continuously, whereas more restricted sleep may benefit their (unreported) sleep-related complaints. At least in TBI patients without a DoC, CBT-I has shown increased sleep efficiency in a case study but needs more research.23, 117 From an ethical point of view, some treatments may be invasive and exhausting without benefits and should therefore be applied carefully. To this end, more research is needed to potentially discriminate DoC patients that may benefit from such treatments. Nevertheless, creativity in the separation of day and night (e.g., well-timed physiotherapy, posture changes during the day, for instance, with the aid of a wheelchair, or even changing blankets between day and night) could provide large benefits, whereas negative side effects are not to be expected. Such benefits could potentially be expected from intensive neurorehabilitation programs.118, 119 Treatments for DoC like transcranial direct current stimulation (tDCS) have been shown to moderately improve consciousness.120 Although precise mechanisms remain unclear, tDCS could work through increasing cortical excitability.121 Cortical excitability can be assessed by applying Transcranial Magnetic Stimulation stimulation and calculating the complexity of the response (i.e., the perturbational complexity index) which has been found to be lower in VS/UWS compared to MCS and to controls.122 Since the level of behavioral consciousness123 and cortical entropy124 fluctuates in DoC patients, a study protocol was recently developed to take these fluctuations into account by incorporating tDCS stimulation in a closed-loop fashion with an EEG recording.125 This approach holds great promise for the improvement of the effectiveness of tDCS and other stimulation techniques. Nonetheless, the cortical excitability as a proposed mechanism of action also has a circadian rhythmicity and as such may fluctuate at another scale.126 It was shown that circadian rhythms are variable in DoC patients,1 hinting that incorporating other circadian measures in such a closed-loop approach may further improve effectiveness. For such an implementation, we should however increase our knowledge of sleep and circadian fluctuations in DoC patients, keeping in mind treatment goals like these. Finally, one study has shown that tDCS reduces evoked slow-wave activity in DoC patients,127 hinting its mechanism of action may also be related to the default activity of cortical neurons. The guidelines by the European Academy of Neurology suggest to perform sleep EEG monitoring as part of the assessment to distinguish between patients in either a UWS or MCS.128 Though this is a weak recommendation with low evidence, others have recently shown the importance of looking into the presence of sleep characteristics in patients with a DoC.1 The suggestion has also been made that this monitoring does not necessarily have to happen through EEG, as actigraphy may provide a suitable alternative.129, 130 This easy-to-use low-impact wristwatch can help track circadian rhythms over multiple days and work showcasing that usefulness in predicting, for instance, when to perform a behavioral assessment is currently under way. In this perspective, we have argued for the likely prominent presence of insomnia in DoC patients. This should be taken into account whenever approaching DoC-related data, and, preferably, strategies should be developed to minimize this. We have also shown that findings across the research spectrum of DoC show similarities with those altered in insomnia, from altered pain perception to altered oddball detection and reduced functional connectivity. We are not necessarily claiming that the DoC research presented here is false in any way, or just finds the effects of insomnia, yet, we do believe that at least for some of these findings, insomnia could play a major role. This begs questions on how much of insomnia is part and parcel of a disorder of consciousness, where the answer is clearly not black or white. Slow waves provide a means of exploring this gray area, in search of common physiology, and distinctions. In turn, treatments may affect insomnia as well as the "underlying" DoC and these effect should have a greater presence in literature. The perspective presented here is by no means a systematic review, and we do not cover all possible ground that could be covered on the link between DoC and insomnia. The aim here is to start a discussion on these topics, for instance, by highlighting seminal papers in DoC research (e.g.,36, 41, 42, 45) and highlighting that their main findings have also been found to be affected by insomnia. This should spark further discussion on what insomnia-related deterioration means for the interpretation of DoC research, on how we can expand control for this besides the examples mentioned here, and on how this may influence treatment effects. With that, we hope to open up this unexplored avenue and propel DoC research beyond confounding factors of poor sleep. The take-home message from the observations regarding the consequences of sleep disturbances in DoC is two-fold. First, insomnia symptoms are likely very prevalent in the DoC population. Second, these insomnia complaints may pose additional challenges in evaluating consciousness in DoC patients, may have additional deleterious effects on the health of the patients, and may hinder the recovery process. Thus, investigation of sleep and disturbances in patients with a DoC is paramount. Moreover, efforts to promote healthy sleep should be an integrative part of the treatment and clinical management of DoC patients. Glenn J. M. van der Lande: Conceptualization; data curation; formal analysis; writing—original draft; writing—review and editing. Jitka Annen: Conceptualization; data curation; formal analysis; writing—review and editing; supervision. The study was supported by the University and University Hospital of Liège, the BIAL Foundation, the Belgian National Funds for Scientific Research (FRS-FNRS), the FNRS PDR project (T.0134.21), the FLAG-ERA JTC2021 project ModelDXConsciousness (Human Brain Project Partnering Project) and FLAG-ERA JTC 2023—HBP—Basic and Applied Research, project BrainAct, JTC the fund Generet, the King Baudouin Foundation, the Funds Chantal Schaeck Yolande, the Télévie Foundation, the European Space Agency (ESA), and the Belgian Federal Science Policy Office (BELSPO) in the framework of the PRODEX Program, the Public Utility Foundation "Université Européenne du Travail," "Fondazione Europea di Ricerca Biomedica," the Mind Science Foundation, the European Commission, the Fondation Leon Fredericq, the Mind-Care Foundation, the National Natural Science Foundation of China (Joint Research Project 81471100), and the European Foundation of Biomedical Research FERB Onlus, the Horizon 2020 MSCA—Research and Innovation Staff Exchange DoC-Box project (HORIZON-MSCA-2022-SE-01-01; 101131344). J.A. is a postdoctoral fellow at the FWO (1265522N). The authors declare no conflicts of interest. No data was generated for this study. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.