Perusal of the scientific literature reveals that the word “ fatigue ” is used liberally as a hypothetical construct generally reflecting both subjective feelings of malaise and lethargy and objective evidence of reduced capacity for mental and/or physical performance. It has also sometimes been used as a synonym for sleepiness. For the purpose of this chapter, a conceptualization similar to that proposed by Balkin and Wesensten [2] is used: fatigue is a physiologically based deficit in subjective inclination and mental/physical capacity to continue performance of a task that varies as a function of work (the product of “time on task” and workload). And although fatigue can be exacerbated by sleepiness, it is an entity that is clearly distinct from sleepiness – as evidenced by the fact that it can be reversed by simple rest (time off task). This is illustrated in Fig. 3.3 (adapted from [58]).

As depicted in Fig. 3.3, response speed on a 10-min psychomotor vigilance task (PVT; see [12]) was measured every 2 h during a 40-h period of total sleep deprivation. Fatigue (“time-on-task”) effects were clearly evident as mean RT speed declined within each 10-min test session but then recovered (at least partially) by the time the next test session was initiated (despite the fact that there was no intervening sleep). That sleepiness actually interacts with fatigue effects is clearly evidenced by (a) the finding that the slope of performance decline within the 10-min PVT tends to steepen as sleep loss is extended (e.g., compare initial performance (at 0800 h on day 1) with performance 24 h later), and (b) there is a clear circadian rhythm of performance that corresponds to the circadian rhythm of alertness [58].

Clearly, these results show that sleepiness interacts with “ fatigue” even when the latter is rather narrowly operationally defined as “time on task on a reaction time test.” Therefore, to the extent that the definition of fatigue in such literature specifically subsumes the concept of “sleepiness” (e.g., [2]) or regardless of the extent to which the definition of fatigue is left nebulous, one can be confident in the assertion that sleepiness interacts with fatigue and serves to confound efforts to specify fatigue as a pathological symptom (of PTSD and/or mTBI/PCS) independent of “sleep disturbance.”

The hyperarousal symptom cluster for PTSD includes difficulty falling or staying asleep [1]. The research criteria for post-concussion disorder list “disordered sleep” as one of the symptoms that must occur shortly after the trauma and that must last for at least 3 months [1]. “Disordered sleep” is very vague because there are many ways normal sleep physiology can be disrupted. A specific sleep disorder that is common to both PTSD and TBI (especially mild TBI) is insomnia. Approximately 30% of TBI patients report insomnia that meets diagnostic criteria, and this number grows considerably if reports of insomnia that fall short of meeting full diagnostic criteria are also counted [34]. Approximately 44% of PTSD patients report difficulty falling asleep and approximately 91% report difficulty staying asleep [31].

PTSD and TBI are both highly comorbid with depression. Because insomnia is essentially chronic, partial sleep deprivation, it is likely that to a significant extent the depression experienced by these patient groups has been precipitated by, or at least exacerbated by, inadequate sleep [21]. Indeed, it has been found that insomnia precedes the initial occurrence of depression [17], it precedes the reoccurrence of depression [35], and it is predictive of depression [37, 61].

On the other hand, it is important to note that the effects of sleep loss are not always, nor exclusively, deleterious. For a subgroup of depressed patients , acute, total sleep deprivation has been shown to have a transient antidepressant effect (i.e., that is reversed by subsequent recovery sleep). Similarly, it has been observed that in some bipolar patients, sleep disruptions may trigger episodes of mania rather than lethargy [24]). Such paradoxical reactions to sleep loss serve to demonstrate the extent to which individual differences exist and can potentially complicate efforts to discern the role of sleep/sleep disturbance plays in the pathogenesis of PTSD, PCS, depression , and other various disorders.

In the present chapter, “concentration ” refers to the ability, by dint of will, to maintain appropriate mental focus on specific external stimuli. In the case of a student, that focus may be on written text, with “adequate concentration” evidenced by comprehension of the written material, consolidation of that material into memories, and integration of those memories into existing knowledge schemas. For a truck driver, adequate concentration would be evidenced by appropriate handling of his/her vehicle in accordance with extant weather, road, and traffic conditions; adequate attention to navigation and dashboard gauges; and the ability to recognize and avoid potential hazards as they develop up the road. Of course, the amount of sleep needed to maintain nominally adequate concentration varies by task and by individual.

But as any college student who ever “pulled an all-nighter” can attest, “difficulty concentrating” is a hallmark consequence of sleep loss. Despite concerted effort to maintain focus and make sense of written text, the sleepy student experiences progressively greater difficulty studying across the night: first, reading becomes a chore in which paragraphs and sometimes pages are read but not absorbed, written words fail to coalesce into meaningful sentences, and the mind – faced with this paucity of meaningful information from the external world (i.e., the written page) – inclines toward reverie, eventually succumbing to frank sleep onset.

It is therefore not surprising that “difficulty concentrating ” has also long been recognized by the scientific community as a consequence of sleep loss. For example, in his seminal work to determine the factors that make a neurocognitive performance test sensitive to sleep loss, Wilkinson [59] identified several factors, including “duration” (the longer the test, the more sensitive to sleep loss) and “inherent interest” in the test material (the more interesting/engaging the test material, the more “stimulating” and thus resistant to the effects of sleep loss). Thus, those qualities or parameters of a test that make concentration on that test easier (i.e., short duration and interesting content) also make that test relatively insensitive to the effects of sleep loss – indirect but compelling evidence that sleep loss impacts our ability to concentrate.

Sleepiness is currently thought to be characterized by “state instability” [13] – i.e., it is wakefulness made tenuous by repeated incursions of sleep-promoting processes (see [14]). As described by Olofsen et al. [33], the physiological basis of “state instability” is a flip/flop switch [of the sort proposed by Saper et al. [44]], in which sleep-promoting neurons in the ventral lateral preoptic nucleus are reciprocally inhibited by monoaminergic wake-promoting neurons. Sleep results when sleep-promoting neuronal activity is preponderant (exerting pressure on one end of the flip/flop switch) and wakefulness ensues when wake-promoting cell activity is preponderant (exerting pressure at the other end of the flip/flop switch). State instability increases as activity levels of these two cell groups approach equilibrium, essentially balancing the pressure on both sides of the switch. The resulting instability of the flip/flop switch causes rapid fluctuations between ascendant sleep- and wake-promoting processes.

Since sleepiness is an unstable brain state characterized by rapid, transitory fluctuations between sleep- and wakefulness-promoting mechanisms, it is not difficult to understand why sleepiness is characterized by “difficulty concentrating,” since by its very nature concentration would be presumed to involve and require continuous engagement of wake-promoting processes (so as to facilitate the continuous focus on external stimuli over time).

In addition to insomnia, one of the hallmarks of PTSD is general hyperarousal (as exemplified by an exaggerated startle response). TBI patients do not show an exaggerated startle response. In fact, if anything, they have a sort of emotional blunting, since it has been shown that they do not display the normal startle potentiation that results from viewing stimuli with a negative emotional valence [30, 45]. This is an interesting observation because patients with narcolepsy display a similar absence of startle potentiation following presentation of unpleasant stimuli [25]. Finally, it is important to point out that hyperarousal is more likely to contribute to insomnia and subsequent excessive daytime sleepiness than vice versa. In fact, sleep deprivation in healthy controls generally blunts the startle response [28].

Excessive daytime sleepiness is a common complaint in mTBI patients [34]. For 25% of these patients, the subjective complaint of sleepiness is substantiated by objective measures [3]. And the finding that TBI patients tend to have low levels of hypocretin/orexin in their cerebrospinal fluid (e.g., [40]) suggests that the pathophysiology of TBI-related sleepiness may be similar to that of narcolepsy.

One of the symptoms of PTSD is difficulty falling or staying asleep, and the full diagnostic criteria for insomnia include subjective impairment in daytime function/alertness. However, as measured by the multiple sleep latency test (MSLT; see [10]), PTSD patients do not display objective signs of sleepiness [6, 23]. This is not surprising because it is likely that hyperarousal  – a problem that contributes to nighttime sleep disturbance – likewise interferes with daytime sleepiness testing on the MSLT, so that mean sleep onset latencies in these patients do not accurately reflect the underlying level of sleep deficit. Nevertheless, similar to TBI patients, PTSD patients have low levels of hypocretin/orexin in their cerebrospinal fluid [51], an observation that is consistent with the notion that PTSD, like mTBI, may share pathophysiological underpinnings with narcolepsy.

Chief among the cognitive symptoms of mTBI that are important to consider within the context of sleep are those relating to memory. Evidence is mounting that memory consolidation is facilitated by – and may for some types of memory in fact be dependent upon – adequate sleep [56]. The relevant evidence comes from an ever-expanding number of studies designed to measure sleep-dependent improvement in performance on a variety of declarative and procedural memory tasks [15]. Although alternative explanations for positive results from such studies remain possible – e.g., it has been suggested that at least some of the salutary effects of sleep may simply be “passive protection from interference” (i.e., deficits resulting from acquisition of new, nontarget learning/memories during the intervening period between initial acquisition of the target material and testing for that material) – such alternative explanations are becoming less tenable as evidence from various laboratories continues to mount. For example, the finding by Marshall et al. [29] that experimental enhancement of slow wave EEG activity during sleep enhances next-day performance on memory tests clearly suggests that sleep does, in fact, play an active role in memory consolidation – i.e., something above and beyond what occurs passively as a result of freedom from interference.

Memory deficits (both retrograde and anterograde amnesia) can result from mTBI events, and recent evidence suggests that at least some aspects of resulting deficits (e.g., in declarative memory) are mediated by impaired medial temporal lobe function (e.g., see [52]). It has also been shown that PCS patients tend to experience difficulty forming new memories, perhaps as a secondary effect of deficits in short-term (working) memory (the ability to maintain and manipulate multiple pieces of information simultaneously) [19]. Individuals with PTSD have likewise been shown to experience short-term memory deficits [7].

As with the other symptoms of these disorders, the question becomes whether the memory deficits are specific to each disorder or whether they are (at least partially) attributable to the sleep disturbance that characterizes both disorders. If impaired memory formation is caused by deficits in encoding or retrieval, the link is easy to establish. Disordered sleep would lead to excessive daytime sleepiness , which would lead to deficits in concentration, and this in turn would lead to a decreased ability to form a strong memory trace during encoding or a decreased ability to recall the memory during retrieval.

On the other hand, if memory impairments are the result of deficits in consolidation, the link becomes more difficult to establish because few studies have measured long-term memory in these patients across delay periods greater than 24 h. Although there are as yet no relevant studies for PTSD or TBI, investigators from one study did establish sleep-dependent memory consolidation deficits in patients with insomnia [32], which is itself a frequently reported symptom of both PTSD and mTBI.

It is currently thought that PTSD may be a disorder characterized by contextual fear conditioning and that abnormal hippocampal (memory) functioning in PTSD results in (a) generalization of the fear (stress) response to inappropriate (nonthreatening) environments along with (b) an impaired capacity for extinguishing fear responses [38]. Functional brain imaging studies of PTSD patients have provided evidence that is consistent with such hypotheses, revealing elevated activity in the amygdala (reflecting elevated emotional responsivity), reduced activity in prefrontal regions (mediating executive mental functions and providing inhibitory feedback to limbic regions including the amygdala), and abnormal activity in the hippocampus (mediating memory consolidation – sometimes found to be abnormally elevated and sometimes abnormally reduced in PTSD patients, depending upon the particular study situation).

Because (a) it is known that memory for emotion-laden events is enhanced (i.e., compared to emotion-neutral events; see [8]) and because sleep loss has been shown to result in disinhibition of the amygdala and hyperresponsiveness to emotional stimuli [62], it is reasonable to hypothesize that sleep-deprived individuals may be especially vulnerable to development of PTSD. That is, it is possible that sleep loss-induced deactivation of prefrontal cortices results in a disinhibited, hyperreactive amygdala that, by virtue of a relatively exaggerated fear response, contributes to development of PTSD by making subjectively bad experiences worse. Such heightened reactivity to aversive stimuli could contribute to the strength (and thus resistance to extinction) of those memories that subsequently form the basis of reexperiencing in PTSD patients.