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 potentially affected in is altered in As the of brain activity in general, with such a prominent role in the and brain, a on slow is at its right As will be in the next treatments of DoC to a physiological level, of consciousness is associated with general of cortical slow oscillatory activity as activity or in the absence of most sleep characteristics has been reported in DoC patients. 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