Narcolepsy is a disorder in which sleep intrudes on daily activity while nocturnal sleep is frequently fragmented, and is classified by the ICDS-2 as a hypersomnia of central origin (46). Narcolepsy is clinically defined by a short sleep latency and two or more sleep onset REM periods (SOREMPs) during a multiple sleep latency test (MSLT) in which individuals are given four to five standardized daytime nap opportunities (46, 47). Two forms of narcolepsy are recognized; narcolepsy with cataplexy, currently named narcolepsy/hypocretin (HCRT) deficiency disorder (47), and narcolepsy without cataplexy. Narcolepsy with cataplexy is due to low levels of hypocretin-1, which can be confirmed by measurement in cerebrospinal fluid (47), and it has a strong linkage to human leukocyte antigens (48) with HLA-DBQ1*0602 mutations found in 90% of tested patients (49–51).

In 1998, two laboratories announced the discovery of a new hypothalamic peptide, one reporting its importance in feeding [orexin (ORX); (52)] and the other focused on its role in wake and sleep [HCRT; (53)]. The discovery that narcolepsy with cataplexy resulted from loss of ORX/HCRT-containing neurons in the posterior lateral hypothalamic area (pLHA) provided a fuller understanding of the symptomology of this disorder (54–56), and supported an early hypothesis put forward by von Ecomono (21). In this disorder sleep-to-wake transitions are unstable, as patients are generally unable to maintain consolidated sleep during the main nocturnal sleep period, and unable to maintain wake during the normal wake period. Individuals with narcolepsy have early onset of REM sleep; including at sleep onset, during the main sleep period and during naps, indicating a defect in the normal progression of sleep stages. Additional REM phenomena frequently associated with narcolepsy are also due to an instability between wake and REM: hallucinations in sleep–wake transitions (dreaming imagery of REM with awareness of wake), sleep paralysis (paralysis of REM sleep with awareness of wake), and REM sleep behavior disorder (dream imagery of REM sleep with muscle tonus of wake).

As with other HD, narcolepsy patients complain of memory problems and difficulties with concentration and attention (57–59). Attentional deficits, particularly in vigilance tasks, have also been reported (58, 60, 61). Attentional deficits seem to be an effect of the fluctuations of arousal that accompany this disorder, more than a deficit in attentional control in general (58, 59). These lapses of attention result in impaired vigilance over long periods that can be compensated by deploying attention in repeated shorter bouts (62).

The etiology of narcolepsy is currently unknown (63), although recent studies have provided strong experimental support for autoimmune etiology (64–67). Narcolepsy has been reported as secondary to tumors (68), head trauma (68–70), and immune-related disorders (67, 71, 72).

The International Classification of Sleep Disorders (ICDS-2) recognizes idiopathic and recurrent hypersomnia as distinct entities (46). The most common recurrent hypersomnia is Kleine–Levin Syndrome (KLS), a rare disorder that predominantly affects adolescent boys and is characterized by bouts of hypersomnolence during which the patient also exhibits one of the following: cognitive or mood disturbances, compulsive eating, hypersexuality, or disinhibition behaviors (47, 73). Behavioral, sleep, and mood symptoms remit in interictal periods (74).

Cognitive disturbances, unlike behavioral and mood disturbances, have been reported to outlast ictal periods (73–76). Depression and anxiety are common in this population (77, 78), and recent studies suggest that there are long-term deficits in memory and visuospatial function (73, 75, 76, 79). As these mood and cognitive symptoms are similar to those reported for idiopathic HD (iHSD), the pathophysiological mechanisms by which they are generated is expected to be similar.

Neuroimaging studies have provided some clues as to the genesis of cognitive and mood disruptions in this population. Although structural neuroimaging is generally read as normal in KLS, widespread abnormalities have been reported during ictal periods based on functional neuroimaging; with reduced blood flow to thalamus, hypothalamus, basal ganglia, and cortex (73, 80) together with hypometabolism in hypothalamus and cortex (81). Studies have shown hyperactivation in the thalamus of KLS patients during performance of a working memory task using fMRI (75, 76) that significantly differed from the activation seen in healthy control subjects and correlated with performance deficits in KLS patients.

The pathophysiology of the disorder is unknown and its diagnosis remains based upon symptomology (73, 76, 81). Interestingly, and in common with EL, a viral infection potentially associated with a subsequent autoimmune response has been proposed as a causative agent and two autopsy cases have reported inflammatory infiltrates in hypothalamus and thalamus (73, 77, 82).

Hypersomnolence disorder (47) may include only non-refreshing sleep despite nocturnal sleep durations (idiopathic) but is more frequently coexistent with other neurological, psychological, mental, and sleep disorders (83, 84). EDS in spite of normal or long duration nocturnal sleep is characteristic of the disorder though insufficient to define it (45–47). A characteristic deterioration in waking function and general alertness is generally remarked and symptom duration must exceed 3 months with a sleep onset latency of <10 min for a clinical diagnosis to be made.

Idiopathic hypersomnia (iHSD) occurs in two forms: (1) long sleep duration, in which patients sleep in excess of 10 h per day while reporting non-refreshing sleep and EDS, and (2) normal sleep duration where sleep bouts are within normal range but EDS and non-refreshing sleep remain primary complaints. Patients report constant fatigue or a constant lack of alertness during wake periods more than sleepiness (85–87) together with great difficulty in waking after sleep. Sleep efficiency is good in these patients, and REM sleep onset latencies and durations are generally within normal range. However, changes in nocturnal sleep architecture during polysomnography (PSG) have been reported, including a reduction in the amount of SWS in the main sleep bout with normal homeostatic reduction (87–89).

In addition to non-refreshing sleep, patients report memory and attention deficits and commonly present with digestive system disorders, depression, and anxiety (84, 86). In a recent study based on self-reported cognitive changes, 79% of patients with hypersomnolence disorder (HSD) reported memory problems that included frequent forgetfulness (86). A recent study assessing sustained attention in a range of HSD patients found impaired vigilance that did not differ significantly between patient groups (90), suggesting that this is a common feature of HSD. Mood disorders are also commonly reported by individuals with iHSD, with prevalence between 15 and 25% in this population (78, 91) during asymptomatic periods. The prevalence of depressive symptoms during symptomatic episodes is greater (82), with up to 40% of patients exhibiting symptoms. The pathophysiological mechanisms for mood and cognitive symptoms in iHSD have yet to be specifically explored, although they are similar to those reported for KLS.

Control of the sleep–wake cycle depends upon a widely distributed and complex neural system, many components of which have been shown to be affected by HD. The hypothalamus represents a primary control center in the regulation of this system; acting as the interface between circadian, energetic, sleep, and autonomic circuits that are all modulated in sleep (92–94). The circadian system provides information critical to the function of the sleep–wake control system, contributing one arm of the two-process model of sleep regulation (95) and interacting closely with subcortical regions to link this to the ultradian sleep–wake rhythm (96, 97). In the following, we provide a brief overview of the subcortical brain circuits involved in the regulation and control of sleep and wake together with the interactions between these systems and the cortex.

The preoptic region of the hypothalamus is currently recognized as the major sleep-promoting brain region (27–29, 98–100), with the ventrolateral preoptic area (VLPO) and the median preoptic nucleus (MnPO) providing inhibitory drive to brain regions engaged in the induction and maintenance of the waking state (Figure 2). Recent studies have pointed to an important role for melanin concentrating hormone (MCH) neurons of the lateral hypothalamic area (LHA) in sleep-promotion (101–105). MCH neurons co-release gamma-amino butyric acid (GABA) in wake-promoting regions, thus promoting sleep (106, 107). MCH neurons are active in both NREM and REM sleep and there is evidence suggestive of a specific role in the control of REM sleep, perhaps together with GABAergic neurons found interspersed with them in the lateral hypothalamus (101, 106, 108).

Orexin producing cells in the LHA have been shown to play a major role in the induction and maintenance of the waking state (109–112) while linking autonomic and metabolic centers (113), thus acting as a major integrative system (Figure 3). Sleep-promoting MCH and GABA neurons are interspersed in the LHA with wake-promoting ORX neurons, providing for rapid mutual inhibition in state transitions. The waking state is generated by the inhibition of hypothalamic sleep-promoting centers together with excitation of wake-promoting centers in the hypothalamus, brainstem, and basal forebrain (Figures 2 and 3). Wake centers of the hypothalamus include both ORX cells of LHA and histaminergic (HIST) neurons of the tuberomammillary nucleus (TMN). The brainstem reticular activating system (RAS) represents the primary control system for wake (6, 26, 114–117) and consists of acetylcholine (Ach)-containing neurons in the pedunculopontine (PPT) and laterodorsal tegmental (LDT) nuclei, noradrenaline (NE)-containing cells in the locus coeruleus (LC), serotonergic (5HT) neurons of the dorsal and median raphe nuclei (RN), glutamatergic cells of the subcoeruleus complex (SCC), and dopaminergic cells of the ventral periaqueductal gray (vPAG) that are reciprocally connected to wake-promoting hypothalamic centers. Considered by some a rostral extension of the RAS, the basal forebrain includes a small population of Ach cells that are active in both wake and REM sleep, playing an important role in the generation of desynchronized electrical activity of the cortex in both states (118, 119). Basal forebrain neurons receive input from both hypothalamic and brainstem wake centers (Figure 2) and may represent a key mediating center of cortical arousal (120).

Cells of the LHA provide glutamatergic and orexinergic inputs to brainstem wake-promoting regions of the RAS and receive inhibitory drive from the VLPO. Sleep onset is initiated by activation of the sleep-promoting VLPO, which acts to inhibit both RAS and LHA. The balance between sleep-promotion and wake-promotion is accomplished by a feedback mechanism that enables the relatively rapid switch in state with a mechanism resembling an electronic switch; an analogy that led Saper and his colleagues to develop the flip–flop switch model of this state transition (26, 121). This mechanism provides for the rapid stabilization of a newly entered state, but disruption of this balance can lead to state instability where inappropriate state switches can occur.

Under normal conditions, sleep initiation moves the system into NREM sleep, following which cyclic alternations between NREM and REM sleep develop (Figure 1B) that constitute the ultradian sleep rhythm. A normal sleeper will exhibit two to seven such cycles over a nocturnal sleep bout. It is generally agreed that mesopontine brainstem nuclei contain the regulatory circuitry for the stereotypic alternations of NREM and REM sleep. Glutamatergic neurons of the SCC are proposed to be the primary inducer of REM sleep (122, 123), with current studies suggesting that hypothalamic MCH cells act to stabilize this state (106). SCC innervation of cholinergic neurons of the LDT/PPN and basal forebrain result in the desynchronized EEG characteristic of REM while inhibitory drive to wake-promoting areas such as DRN and LC aid in state stabilization. Skeletal muscle atonia is a unique characteristic of normal REM sleep and is due to SCC excitation of medullary reticular centers that act to inhibit spinal motor neurons (122–124).

In a normal nocturnal sleep bout, there is a gradual reduction in the duration of NREM sleep periods with the longest period occurring in early cycles and the late cycles frequently containing only N2 sleep. In contrast, REM sleep durations are longest in the final cycles of the nocturnal sleep bout. The reduction in N3 content over the night represents the reduction in sleep drive that is currently conceived as a homeostatic regulatory mechanism.

Sleep homeostasis is the process by which sleep propensity increases over the wake period and is dissipated during the sleep period. Early observations pointed to a strong tie between prior wake time and deep NREM sleep (125–128). The proposal of a two-process control system for the regulation of sleep and waking was put forward by Borbely and Acherman (127, 129) in a model where circadian and homeostatic processes interact to maintain and regulate sleep/wake cycling. Substantial support for this model has accrued, leading to general acceptance of its central tenets, which include the importance of slow wave activity (SWA) as a marker of both sleep need and its dissipation (126, 128, 130–134). While no central regulatory center for sleep homeostasis has been defined, a number of studies have implicated circulating neuroactive molecules as potential mediators of homeostatic control (43, 135–138).

Based on a series of studies pointing to the importance of the rostral brainstem in arousal (3, 139, 140) and REM sleep (141, 142), the majority consensus among physiologists in the 1990s was that the brainstem reticular system controlled the oscillatory network responsible for wake and sleep. A large body of evidence followed these studies, reporting the importance of brainstem cholinergic systems in the behavioral and electrophysiological expression of wake and arousal. The discovery that the thalamus did not present a passive, quiescent response to the shift from wake to sleep, but instead exhibited dual processing led to the conception of sleep as a process in which the thalamus acted to “gate out” external information and thus prevent arousal (143).

A different role for the thalamus, and thalamo-cortical interaction, was provided by seminal studies investigating electrophysiological rhythms in the cortex during sleep and wake. In a series of studies investigating the role of the thalamo-cortical circuitry in sleep, Steriade and his colleagues (30–32) introduced a new, ultraslow (<1 Hz) cortical rhythm distinct from SWS that was generated in cortical neurons and projected to thalamus (32) where it served to organize the slower sleep rhythms of spindles and slow waves (30). Emphasizing its cortical origin, studies showed that thalamic lesions did not abolish the rhythm (143, 144) and that the cortex itself maintains SWA even in an isolated slice preparation (38). Further, the ultraslow rhythm is also seen in thalamic nuclei, most strongly in the reticulothalamic cells that have been shown responsible for the generation of the spindles of sleep (32). The importance of these seminal papers was in the understanding that thalamo-cortical interactions are ultimately the generators of the major sleep rhythms recorded at the scalp by which sleep states are defined. Thus, the thalamus acts as a major integrating center, generating the rhythms of both wake and sleep in concert with a widespread network encompassing brainstem, hypothalamus, and cortex. In the current understanding of sleep–wake circuitry, sleep is a state actively generated by a large and complex neural network.

In keeping with current theories of brain network function in sleep, the thalamus has been shown to continue to transmit external information to the cortex in both NREM and REM states (145–153). However, while information continues to be transmitted from the thalamus to the cortex, there are distinct differences between wake-state responses and those seen in either NREM or REM sleep. During NREM sleep, neuroimaging studies have shown that higher order cortical regions show significantly reduced or absent responses to stimuli (146, 147, 150) while responses in primary cortices appear to remain near to those noted in wake (145, 152). Further, the timing of inputs relative to thalamo-cortical waveforms characterizing NREM sleep significantly impacts the degree to which further processing occurs (150). In REM sleep, where cortical activity resembles that of wake, recent reports suggest that more complex processing may occur than seen in deep NREM sleep (149, 153) while yet remaining suppressed relative to that of wake.

While further research is required to fully describe the complex network interactions resulting in normal sleep/wake transitioning, it is increasingly clear that the hypothalamus and thalamus represent critical integration and control centers by which these states are fully expressed. As noted by von Economo and illustrated by the clear instability of state in narcolepsy and other HDs, the hypothalamus plays a critical role in the transitions between and maintenance of the states of wake and sleep. Yet, Llinas and Steriade (39) point to the thalamus as the fundamental determinant of system state, and this view is upheld by studies showing that thalamic ablation leads to a pathologically prolonged state of wake in both animals and humans (154–156). To complicate matters further, as research focuses on the role of diffusible somnogens as potential mediators of the homeostatic sleep drive (43, 135–138), some are suggesting a central role for the neocortex in the control of sleep and waking. This suggestion has received some support from recent studies showing that sleep may not be globally exhibited, but occur locally in specific cortical areas even as the organism displays behavioral wake (157–161).

Increasing evidence thus points to a widespread and highly connected network that acts in concert with the circadian rhythms generated in the suprachiasmatic nucleus of the hypothalamus to not only control the cycling of neural state between wake and sleep, but to integrate that state with metabolic and physiological systems sharing the same circadian timing (92, 96, 97). At present, recognition of the complex and redundant anatomical linkages by which the thalamo-cortical, hypothalamic, subcortical, and brainstem sleep/wake control centers interact (Figures 4 and 5) leads to a better understanding of the huge array of behavioral and physiological responses that could result from dysfunction at any level of this network.

Cognitive fluctuations are spontaneous alterations in cognition, attention, and arousal (187) in which EDS is a prominent component and may include inappropriate sleep periods or decreased responsiveness during normal waking hours (188–190). Individuals with cognitive fluctuations (CFs) not only exhibit a higher propensity to fall asleep (hypersomnia), they also transition from a less alert to a more alert state spontaneously. Thus, the attentional lapses characteristic of CF are a manifestation of a general propensity toward inappropriate alterations in brain state.

Cognitive fluctuations are a core diagnostic criterion of DLB (188, 191), and are also seen in AD, Parkinson’s Disease (PD), and 1–3% of non-demented individuals (192–194). In DLB, CFs are more likely to be associated with daytime sleepiness, lethargy, and sleeping than in AD or vascular dementias (188, 189). Functionally, CFs result in worse clinical dementia ratings and are associated with poorer neuropsychological performance (195), greater functional impairment (193), poorer quality of life, and increased caregiver burden (196).

Diagnosis of CF generally relies upon clinical assessment (192), although caregiver reports (187, 188, 192) may also be useful. The hypothesis that fluctuations of performance on attentional tasks would reflect clinically defined and more long-term CFs has been tested in a number of studies (193, 197) with mixed results. A recent study investigating the relationship between daytime sleepiness and cognitive performance in DLB and PD patients (197), using maintenance of wake to define alertness levels, reported that CFs and level of alertness may be independent of one another, a suggestion endorsed by the study of Escandon and colleagues (195).

Electroencephalogram and neuroimaging data from several groups support the hypothesis that fluctuations reflect abnormal functional brain network interactions. Cortical slowing is a common feature of dementia, with a decrease in alpha-band amplitude in DLB accompanied by a loss of functional alpha coupling between frontal and temporal regions (198–201). While spectral abnormalities are common to a number of neurological disorders, including AD, recent studies have pointed to higher amplitude delta and theta rhythms in DLB relative to AD (199) that, together with other differences in the inter-relationships between magneto-electrical cortical rhythms may provide biomarkers of neurodegenerative disorders to aid in early diagnosis and development of therapeutics (200, 202).

Neuroimaging studies of DLB report metabolic and blood flow reductions in parietal, frontal, and occipital cortices together with gray matter atrophy that is predominant in parieto-temporal regions (203–209). Occipital lobe dysfunction identified using both emission tomography and functional magnetic resonance imaging techniques, has been associated with poor visuospatial performance and visual hallucinations in some studies (203, 207, 210). While fewer studies have focused on the brain regions or networks underlying fluctuating levels of alertness, a single photon emission tomography (SPECT) study reported an association of CFs in DLB with increased perfusion in thalamus (211), a finding partially supported by findings of hyperperfusion in both thalamus and striatum in DLB patients in whom fluctuation status was not reported (212). Additionally, regional deficits in cerebral blood flow in the precuneus and occipital lobes have been reported to differentiate DLB from AD (210, 213, 214). Using diffusion tensor imaging (DTI), loss of white matter integrity in the posterior cingulate and visual association areas has been reported in DLB (215, 216). More recent studies have focused on the role of neural network interactions, with the understanding that disparate brain regions interact to produce different brain states and activities. Increased functional connectivity between precuneus, putamen, and parietal cortex has been reported (217) with a second study reporting increases in connectivity between posterior cingulate regions and thalamus, globus pallidus, and anterior cingulate (218). Using multivariate analytic techniques in SPECT, a recent study has reported that decreased activity in bilateral parietal and parieto-temporal regions distinguished DLB from AD. While more studies are needed, particularly in regard to fluctuations of alertness, these studies point to a pattern of deficits in regional connectivity, metabolism, and blood flow that include areas important in the allocation and maintenance of attention, including the frontal cortex, parietal cortex, posterior cingulate, and precuneus. While data are mixed concerning changes in thalamic activity levels during rest, and studies addressing changes in thalamic connectivity in DLB or CFs are lacking, changes in thalamic function in patients with CF have been reported (211, 212).