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Abstract

Objective

The objective of the current article is to review the shared pathophysiological mechanisms which may underlie the clinical association between headaches and sleep disorders.

Background

The association between sleep and headache is well documented in terms of clinical phenotypes. Disrupted sleep-wake patterns appear to predispose individuals to headache attacks and increase the risk of chronification, while sleep is one of the longest established abortive strategies. In agreement, narcoleptic patients show an increased prevalence of migraine compared to the general population and specific familial sleep disorders have been identified to be comorbid with migraine with aura.

Conclusion

The pathophysiology and pharmacology of headache and sleep disorders involves an array of neural networks which likely underlie their shared clinical association. While it is difficult to differentiate between cause and effect, or simply a spurious relationship the striking brainstem, hypothalamic and thalamic convergence would suggest a bidirectional influence.

Keywords

Headache sleep pathophysiology hypothalamus brainstem

Introduction

Primary headache disorders are a group of extremely common, often severe and debilitating conditions. There are estimated to be approximately 153 million sufferers in Europe with a socioeconomic impact of greater than €43 billion per annum (1). Given the common occurrence of headaches, it is not surprising that co-morbidities exist with a number of neurological disorders including depression, epilepsy and sleep disturbances (2 –5). A clear association between headache and sleep is observed in multiple headache syndromes including migraine, hypnic (6) and cluster headache (7). In migraine patients sleep disturbances are commonly reported to trigger attacks (∼50% of sufferers) (6), has been associated with disease chronification (8) and is often used as an abortive mechanism (9). Thus it would appear on the surface that sleep disturbances can predispose individuals to headache attacks, may play a role in disease progression and at least at some level modulate the pain-processing trigeminovascular system. The reverse is also likely, with a central neural dysfunction in headache sufferers leading to an imbalance in sleep-wake regulation.

The clear integration of headache and sleep or sleep disruption highlights the involvement of key brainstem and diencephalic structures which will be discussed. While the exact mechanism of this association is beyond the scope of the current literature, it is clear that the trigeminal pain-signalling networks converge at multiple levels with the neural networks regulating arousal and sleep. This is elegantly highlighted by the presence of fatigue as a common premonitory symptom in migraine (10) pointing towards a disruption of hypothalamic networks which precedes the onset of pain and may predispose individuals both to headache attacks and altered sleep patterns.

Pathophysiology of headache

The pathophysiology of headache is relatively complex, which is unsurprising given the array of associated features which may precede, accompany or outlast the pain component (11). The peripheral innervations of the pain-sensing cranial vasculature and dura mater (12 –14) consist of mainly unmyelinated (C-fibres) or thinly myelinated (A-fibres) nociceptors which have their cell bodies in the trigeminal ganglion and project to the trigeminal nucleus caudalis and associated cervical levels, giving rise to the trigeminocervical complex (TCC). In addition to the sensory trigeminal innervation which contains calcitonin-gene related peptide (CGRP) and substance P, the cranial vasculature and dura mater also receive vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) containing parasympathetic fibres (via sphenopalatine ganglion) and noradrenaline and neuropeptide Y containing sympathetic fibres (via superior cervical ganglion) (15). Their central processes terminate in the superficial lamina of the dorsal horn (I–V) and synapse on second-order dorsal horn neurons (16 –20) giving rise to three major ascending pathways (trigeminothalamic, trigeminoreticular and trigeminomesencephalic). In addition to the ascending projections there is also a reflex connection from the TCC to the parasympathetic system via the sphenopalantine ganglion resulting in cranial autonomic features (21,22) and efferent connections from the facial and cervical dermatomes (23,24).

Ascending pathways

The TCC has direct and indirect ascending projections with a number of brainstem structures (25) (Figure 1(a)), including the periaqueductal grey (PAG), rostal ventromedial medulla (RVM), locus coeruleus (LC) and parabrachial nucleus which are activated following nociceptive trigeminovascular stimulation (26 –30). The trigeminothalamic tract terminates in multiple thalamic nuclei (25,31 –33) involved in the parallel processing of nociceptive information including the posterior and ventrobasal complex on route to higher cortical processing areas. Thalamic activation is seen following migraine, cluster headache and trigeminovascular activation (34 –38). Additionally the trigeminohypothalamic tract conveys somatosensory and visceral nociceptive signals to hypothalamic nuclei (39 –42), which are activated in multiple headache conditions and following trigeminovascular activation (30,34,36,39). The TCC is likely to have connections with multiple other brain structures including the hippocampus and amygdala (43,44).

Figure 1.

The pathophysiology of headache and arousal. (a) The trigeminal ganglion (TG) gives rise to pseudo-unipolar trigeminal primary afferents which synapse on intra and extra-cranial structures (blood vessels) as well as the spinal cord trigeminocervical complex (TCC). Second-order neurons from the TCC ascend in the quintothalamic (trigeminothalamic) tract synapsing on third-order thalamocortical neurons. Direct and indirect ascending projections also exist to the locus coeruleus (LC), periaqueductal grey (PAG) and hypothalamus. The third-order thalamocortical neurons in turn synapse on a diffuse network of cortical regions including the primary and secondary motor (M1/M2), somatosensory (S1/S2) and visual (V1/V2) cortices. A reflex connection from the TCC to the superior salivatory nucleus (SuS) exists which projects via the sphenopalantine ganglion (SPG) providing parasympathetic innervation to the extra and intra-cranial structures. (b) Monoaminergic neurons including the noradrenergic LC, glutamatergic parabrachial and precoeruleus area, serotoninergic dorsal raphe (DR), dopaminergic ventral periaqueductal grey (PAG) and tuberomammillary nucleus (TMN) project to the hypothalamus (orexin) and basal forebrain (BF, cholinergic and GABA-ergic). Combined these systems innervate the cortex to promote arousal. Additionally the cholinergic laterodorsal tegmental nuclei (LDT) and pedunculopontine (PPT) project to the thalamus which controls thalamic sensory gating.

Descending modulatory pathways

It is now widely accepted that disruption of normal endogenous descending modulatory tone plays a critical role in primary headache disorders (11,16). Multiple brain regions make up the descending pain modulatory system (45), which is a powerful regulator of TCC nociceptive activity (Figure 2). At the level of the brainstem multiple nuclei which can have both inhibitory and facilitatory influences exist. These include the PAG, RVM and nucleus raphe magnus (NRM) (46 –51), all of which receive ascending trigeminovascular projections and as such are ideally placed to integrate nociceptive processing and context dependent modulation. Higher order structures including the hypothalamus, amygdala and various cortical regions also form direct or indirect (via brainstem networks) connections with the TCC (for review see Akerman et al. (16)).

Figure 2.

Descending trigeminovascular modulation. The trigeminocervical complex (TCC) receives direct and indirect descending modulatory pathways. Direct projections exist from primary somatosensory (S1) and insular (Ins) cortices while indirect projections arising in S1 project via the hypothalamus (hypo). A local corticothalamic circuit also exists which can modulate trigeminothalamic processing. There are direct hypothalamic projections to the TCC as well as indirect projections via the locus coeruleus (LC) and periaqueductal grey/rostral ventromedial medulla (PAG/RVM). This complex network of descending modulatory circuits potently regulates the TCC, providing pro- and anti- nociceptive drive.

Pathophysiology of sleep

Sleep is critical in the maintenance of cognitive and physical well-being, alterations of which can have profound effects on the individual. The initiation, maintenance and cessation of sleep involve a variety of different mechanisms which integrate the homeostatic (including duration), cyclic alterations (rapid eye movement (REM) or non-REM components) and the circadian pattern of sleep (day and night). The following section will briefly discuss the neural circuits responsible for the different components of sleep and their integration.

Circadian rhythms

Almost every biological function is regulated by some form of circadian rhythm which is most prominently demonstrated by the striking pattern of the sleep-wake cycle (52). The suprachiasmatic nucleus (SCN) is the circadian control centre which resides within the hypothalamus receiving direct and indirect retinal projections mediating the entrainment of the circadian clock to light-dark cycles (Figure 3(a)). Direct projections link retinal ganglion cells with the SCN as well as sparse projections to other hypothalamic nuclei (53,54), while indirect projections influence the SCN via relays in thalamic nuclei (55,56). The SCN also receives ascending projections from brainstem structures for the integration of behavioural state information (arousal, locomotion) and the basal forebrain (56 –60). The cyclic rhythms are generated by multiple transcriptional factor feedback loops which give rise to the approximately 24-hour variable expression pattern of several gene sets (61).

Figure 3.

Impact of light on the circadian clock and convergent trigeminovascular nociceptive projection neurons. (a) The hypothalamic (hypo) suprachiasmatic nucleus (SCN) receives direct input from the retinal ganglion cells, and indirect inputs via thalamic nuclei enabling the integration of external environmental cues (light-dark) on its circadian rhythmic expression of genes, hormone secretion and neuronal activity. The SCN forms local connections with other hypothalamic nuclei (including orexinergic neurons) which provide afferents to the wake-promoting circuitry of the basal forebrain (BF) and brainstem as well as to sleep-promoting ventrolateral preoptic neurons. (b) Recent findings propose a posterior thalamic population of neurons which receive convergent photic signals from the retina as well as trigeminovascular nociceptive inputs from the dura mater. These thalamic neurons then project to the sensory (S1 and S2) and visual cortices (V1 and V2), providing a neural substrate for the exacerbation of migraine headache by light, and the hypersensitivity to light itself.

Output signals from the SCN are conveyed to a number of local hypothalamic nuclei including the dorsomedial nucleus via the subparaventricular zone (56). Projections from the dorsomedial nucleus then innervate wake-promoting regions including the lateral and posterior hypothalamic nuclei, basal forebrain and brainstem nuclei (62,63) as well as sleep-promoting structures including the ventrolateral preoptic area (64 –66). Additionally the SCN releases diffusible agents (67) which are capable of modulating circadian systems, since complete transaction of the SCN is not sufficient to abolish circadian rhythms.

Wake-promoting neural systems

A variety of neural systems are involved in an integrated process which promotes wakefulness (Figure 1(b), for review see Rosenwasser (52)). Cholinergic basal forebrain, cholinergic and aminergic brainstem and hypothalamic orexinergic pathways have all been shown to promote arousal, although the specific interactions remain to be fully elucidated. The cholinergic neurons of the pedunculopontine (PPT) and laterodorsal tegmental (LDT) (68) nuclei send excitatory projections to thalamocortical nuclei and the reticular nucleus, preventing the hyperpolarisation of relay neurons which in turn prevents them entering burst mode and sleep patterns. A second group of wake-promoting monoaminergic brainstem nuclei including the noradrenergic LC, dopaminergic ventral PAG, serotoninergic dorsal and median raphe and the histaminergic tuberomammillary nucleus (TMN) project to thalamic, hypothalamic, basal forebrain and cortical structures (69). In addition to receiving ascending brainstem projections, the cholinergic and gamma-aminobutyric acid (GABA)ergic basal forebrain nuclei project to cortical, thalamic and hypothalamic structures to promote wakefulness (70 –72).

While the above systems are considered wake promoting, a further hypothalamic mechanism exists which is thought to be wake stabilizing. The orexinergic system (71) resides exclusively in the lateral and posterior hypothalamic nuclei (73) and similar to the neural systems above are most active during wakefulness (74). The involvement of the orexinergic system is discussed in more detail below; briefly, they function to increase firing rates in the TMN, LC and dorsal raphe to stabilise the waking state (75 –79). Finally, a group of hypothalamic melatonin-concentrating hormone neurons largely mirror the orexinergic projections, but unlike the above systems are most active during REM sleep and are thought to inhibit the ascending wake-promoting systems (for review see Monti et al. (80)).

Sleep-wake phase transitions

The action of sleep-wake cycling is highly controlled, resulting in rapid shifting between phases. The proposition of a flip-flop switch (Figure 4) was first postulated by Saper and colleagues (81). The orexinergic projections from the LH send excitatory drive to the wake-promoting neural ensembles including the TMN, dorsal raphe and LC, thus enhancing wakefulness. These structures in turn have inhibitory actions on sleep-promoting ventrolateral preoptic (VLPO) neurons. During transition to sleep the VLPO neurons exert an inhibitory tone on the wake-promoting centres including the TMN, dorsal raphe and LC to diminish wake drive. This sleep pressure is further increased by VLPO inhibition of orexinergic LH neurons. Such a mechanism allows for a relatively stable network where two states exist: either sleep or wake with rapid transitions. A similar flip-flop switch has been postulated for REM/nREM sleep transitions (82); briefly, neurons in the vlPAG and lateral pontine tegmentum receive inputs from LH orexin neurons and the VLPO and have mutually inhibitory interactions with REM on neurons in the sublaterodorsal nucleus and precoeruleus. The switch is further influenced by PPT and LDT nuclei which are REM-on areas which may inhibit the LPT and dorsal raphe/LC neurons can activate the REM-off areas.

Figure 4.

The ‘flip-flop’ switch for sleep-wake transitions. To facilitate wakefulness (a), the monoaminergic wake-promoting nuclei (light red) inhibit the sleep promoting ventrolateral preoptic nucleus (VLPO, blue), preventing its inhibitory drive on the monoaminergic nuclei. This inhibition of the VLPO also relieves its inhibitory drive on the wake-promoting lateral hypothalamic (LH) orexinergic system (green) and the laterodorsal tegmental (LDT)/pedunculopontine (PPT) nuclei. The uninhibited hypothalamic orexin neurons send excitatory projections to the ascending arousal system to reinforce the wake promotion. On transition to sleep (b), the VLPO is activated reasserting its inhibitory drive (blue) on the ascending arousal and orexinergic systems. The direct inhibition of the arousal networks and the loss of the wake-promoting orexinergic projections strengthen the sleep state, allowing for rapid transitions from sleep to wake and vice versa.

The pathophysiology of sleep and headache

It is clear from the pathophysiology of headache and sleep briefly outlined above that a variety of central nervous system (CNS) structures and mechanisms play pivotal roles in the regulation of both. It is interesting to speculate that altered homeostatic control of key brainstem and diencephalic neural networks underlies the shared aetiology; in the following section possible interactions at key CNS sites will be discussed in relation to sleep and headache.

Thalamocortical alterations

The role of the cortex in headache has received considerable attention due to a number of key factors. Firstly cortical spreading depression (CSD), the experimental correlate of migraine aura, has been postulated to be the initial triggering step of attacks, although it is more likely that this represents a parallel process which occurs in a proportion of susceptible individuals (83). Secondly there has been contradictory evidence to suggest that the cortex of migraine patients is either hyperexcitable, hypoexcitable or both depending on the stage of the attack (84 –89). CSD is a wave of excitation followed by depression which travels across the cortex and has been shown to modulate the trigeminovascular system including key brainstem nuclei involved in arousal and headache (29,90 –92). The fundamental property of thalamocortical circuits is altered during sleep with the generation of sleep spindles which inhibit ascending sensory information from reaching cortical networks, thus limiting nociceptive responses which may disrupt sleep. It is likely that CSD as a result of cortical perturbation may influence the establishment of sleep cycles within thalamocortical networks. This is highlighted by the increased nREM sleep duration in response to CSD (93,94) with elevated corticocortical evoked responses presenting as prolonged quiet wakefulness. It has been hypothesised that such responses occurring in response to CSD may encourage restorative sleep; however, equally any sleep-related actions of CSD may result from modulation of brainstem arousal centres (95).

With regards to cortical hyper- or hypoexcitability, the data are conflicting. Many migraineurs are susceptible to visual triggering and have heightened sensitivity to light which may result from hyperexcitability, particularly in patients with aura (87), as demonstrated by decreased thresholds for the production of phosphenes (85,86,89). However hypoexcitability states have also been reported (84,88), suggesting a dysregulation of cortical excitatatory and inhibitory drive. Similarly, sleep deprivation has been shown to result in both hyperexcitability, and altered inhibition-facilitation balance in the motor cortex suggesting dysregulation of cortical circuits (96,97). It is plausible that this alteration in thalamocortical circuits could predispose individuals to sleep and headache disturbances, as has been postulated for sleep and epilepsy (98,99). A common phenotype of transgenic ‘migraine mice’ is a lowered threshold for the induction of CSD (100), recent data have highlighted that this decreased threshold is conserved in a proposed migraine model which is comorbid with familial advanced sleep phase syndrome (FASPS; discussed in more detail below, Brennan et al. (101)), and familial hemiplegic migraine type 1 (FHM1) mice show fragmented sleep patterns (102). While thalamocortical networks play a critical role both in headache and sleep, many of the alterations observed may result from alterations in ascending subcortical systems, which we will discuss in the coming sections.

Thalamus

The thalamus is a key relay centre both for pain and sleep; it receives direct ascending projections from the TCC where trigeminovascular dural nociceptive inputs are processed in the ventral posteromedial nucleus (VPM), the ventral periphery of the VPM, the medial nucleus of the posterior complex and the intralaminar thalamus (35,37,38,103). The ascending trigeminothalamic projections form part of a pain neuroaxis which terminates in the primary, secondary, somatosensory, anterior cingulated and prefrontal cortex which is crucial for nociceptive processing and the integration of sensory, cognitive and affective responses to pain. The majority of these structures including the thalamus are activated during migraine and cluster headache (34,36,104,105), and preclinical studies have identified thalamic activation following experimental activation of the trigeminovascular system (37 –39). These VPM and VPM ventral shell neurons are inhibited by 5-HT_1B/1D agonists, propranolol, CGRP antagonists, GABA antagonists and valproate amongst others highlighting their possible importance in headache disorders (106 –109). Recent data have further supported thalamic modulation as a key site of altered trigeminovascular modulation. The FHM1 mouse which harbours a missense mutation in the CACNA1A gene, encoding the pore-forming α1 subunit of the voltage-gated neuronal CaV2.1 (P/Q-type) calcium channels shows altered thalamic responses to trigeminovascular activation (110) and sleep responses to adenosine (102).

Thalamic neurons demonstrate distinct activity patterns during the sleep-wake process (111); during wakefulness thalamic neurons are depolarised resulting in tonically active thalamocortical circuits and the transmission of sensory information to cortical structures (112). As the brain transitions to slow-wave sleep the neurons switch to a hyperpolarised state allowing rhythmic burst patterns which likely limit the sensory transmission and as such support sleep maintenance via a form of sensory dissociation. As highlighted above this rhythmic burst pattern can be inhibited by basal forebrain and ascending brainstem wake-promoting circuits, placing the thalamus as a key regulatory nuclei in both conditions.

While light-dark cycles are classically entrained in the hypothalamic suprachiasmatic nucleus (SCN), retinal ganglion cells send indirect projections via thalamic nuclei suggesting a plausible role in light integration. Further the paraventricular thalamic nuclei receives direct input from the SCN (55,56) and boasts one of the densest orexinergic innervations in the entire brain along with the noradrenergic wake-promoting LC (113). It is likely that this direct photic input is involved in entraining the thalamocortical circuits to the light-dark cycle; however, direct photic input to the posterior thalamus has been postulated to play a key role in the photophobia often observed in migraine patients and experimental models (114). This aversion to and pain-exaggerating effect of light has been linked to neurons of the dorsal border of the posterior thalamic group of nuclei which receive convergent inputs from retinal ganglion cells and the dural vasculature (Figure 3(b)).

Hypothalamus

Functional imaging studies have identified the hypothalamus as a key target in multiple pain states including migraine and cluster headache (36,115 –117). In the case of migraine the hypothalamic activation can be seen during the premonitory phase (118). The hypothalamus is intrinsically linked with key areas of the pain neuroaxis (including the cortex, thalamus, amygdala, PAG and the spinal cord dorsal horn), and stimulation of hypothalamic nuclei can exert antinociceptive drive on spinal cord neurons (119). Perhaps the clearest link between the hypothalamus and headache is seen in cluster headaches with their characteristic seasonal and circadian rhythms, endocrine abnormalities (see melatonin section below) and links to sleep. The hypothalamus of cluster patients was shown to be abnormal (120) and stimulation of posterior hypothalamic nuclei has been used as a promising treatment strategy (121), although increased sleep disturbances have been reported in stimulated patients (122).

Preclinical data support hypothalamic activation in response to trigeminovascular nociception (39), with a proportion of activated neurons expressing orexin (123), which is involved in stabilising the sleep-wake transition via indirect promotion of wakefulness (a more detailed summary of orexin involvement is included in the following pharmacology section and in a further issue within this series). While cluster headache demonstrates the most striking circadian phenotype, such cyclic features are present in other primary headache syndromes, and as such a role for the SCN has been postulated. Headache is often considered a condition of altered homeostasis, in that it is not triggered by extreme conditions, but alterations in patterns including sleep and stress (124).

While the evidence for a clear role of the SCN is lacking, it is plausible that circadian and seasonal fluctuations driven by the hypothalamus may alter the threshold for attack initiation, a theory supported by posterior hypothalamic modulation of nociceptive processing (125,126). The SCN generates rhythmic expression patterns based on interlocking positive and negative feedback control of multiple proteins. One such protein, PERIOD, is known to be regulated in part by casein kinase 1δ (CK1δ), mutations of which are responsible for FASPS (101). Recent evidence has highlighted that migraine is comorbid with the disorder and exciting preclinical data exist from a transgenic mouse harbouring the human mutation. Firstly, the mice have increased nociceptive sensitivity to a known headache trigger, nitroglycerin, demonstrated decreased thresholds for CSD with subsequently enhanced vascular responses and altered astrocytic calcium signalling. The ability of CK1δ alterations to influence such a diverse array of neurological and cellular functions is not surprising given the breadth of hypothalamic influence and clearly highlights the potential for SCN involvement in primary headaches. The SCN is ideally placed as an interface between sleep and headache disorders, it receives afferents from the retina, thalamic intergeniculate leaflet and serootonergic projections from the midbrain raphe involved in the setting of state-related signals (arousal etc., (53 –60)).

While it has been recently shown that SCN PERIOD-expressing neurons receive orexinergic afferents from the lateral hypothalamus which act to suppress their activity and facilitate phase shifting, raising a potential role for orexin in circadian modulation (127). In turn the SCN output projects to a variety of hypothalamic nuclei including the VLPO and the orexinergic neurons of the lateral hypothalamus (53,56,62,64 –66). The inhibitory GABA-ergic projections to the lateral hypothalamus (orexin), LC (norepinephrine), raphe (serotonin) and TMN (histamine) act to promote sleep and decreased inhibitory drive to the orexin neurons promotes wakefulness. The control of this sleep-wake transition switch remains poorly understood, but the thalamus is proposed to play a key role integrating thalamic sensory gating, hypothalamic sleep regulation and pain-modulatory structures. A further hypothalamic nuclei which may be involved in the pathophysiology of both conditions is the dopaminergic A11 nucleus. It has direct inhibitory actions on the spinal cord dorsal horn, its activation along with local dopamine delivery inhibits TCC neuronal firing and its inactivation has pro-nociceptive actions suggesting a tonic inhibitory drive on the trigeminovascular system (128,129). With regards to sleep, the A11 nucleus is postulated to play a causative role in the sleep-associated restless leg syndrome, an unpleasant limb sensation which is worsened by immobility and sleep (130).

Brainstem

A major discovery in the pathophysiology of headaches involved the observed activation of brainstem areas during attacks which form part of the pain neuroaxis (34,131,132). The regions are intrinsically linked to the trigeminovascular system (providing pain modulatory drive, Figure 2) and to higher order structures including the thalamus and hypothalamus. This descending pain modulatory system exerts powerful control over spinal cord nociceptive processing (133 –135) and as such is crucial in context dependent sensory processing (16,136). The system includes the RVM, NRM and PAG among others and can exert both anti- or pro-nociceptive effects. Accumulating evidence has highlighted a role for increased nociceptive facilitation driven by RVM on cells in the maintenance of heightened pain states including allodynia in experimental models of trigeminovascular modulation (26).

Sensitisation of trigeminovascular afferents results in increased on-cell firing and inhibition of off-cells resulting in a net increase in nociceptive ascending information. As the RVM on-cells are state-dependently active during wakefulness, any facilitation of their activity may have an impact on sleep; in parallel off-cells are most active during sleep where they are thought to prevent wakening as a result of non-nociceptive sensory stimulation. Certainly the RVM-PAG network is involved in the modulation of pain signals and the PAG and its ventrolateral (vlPAG) component is critical in the modulation of trigeminovascular tone. Stimulation or activation of the vlPAG inhibits trigeminovascular afferents in the TCC which can be modulated by P/Q-type voltage-gated calcium channel blockers (46 –48,137,138). Given the aforementioned sleep disruption (102) and increased propensity for CSD (100) in the FHM1 mouse which harbours a mutation of these P/Q-type channels, it is likely that this altered function is responsible for disrupted brainstem modulation both in headache and sleep conditions. The vlPAG along with the LPT forms part of a REM-off region which receives orexinergic afferents (71,113) and is active during wakefulness and silent during REM sleep (139). Intriguingly, lesioning of this region results in significantly disrupted sleep-wake patterns (82,140), while pathological PAG lesions (141 –143) and electrode implantation may result in headache (144,145), although this association has been questioned (146).

The LC is the principal site of noradrenaline synthesis in the brain which receives afferents from TCC nociceptive neurons and the paraventricular hypothalamic nuclei (25,147). Stimulation of the LC results in reductions in intracranial blood flow (148,149) mediated by α₂-adrenoceptors (150) and it is broadly included within the activation site of pontine regions seen before and during migraine (34,118,131,132). Accompanying this intracranial vasoconstriction is a frequency-dependent increase in extracranial blood flow, indicative of vasodilation, measured by a drop in the vascular resistance in the external carotid (151). As such the LC can generate vascular changes in the intra- and extra-cerebral vasculature that may have important implications for trigeminovascular modulation and the induction of cortical events such as CSD. While the role of the LC in headache is evolving, its role in the ascending wake-promoting network which includes the ventral PAG, dorsal and median raphe and TMN is one of the most studied in relation to sleep. Like many wake-promoting nuclei, activation is greatest during wakefulness and can be further enhanced during stressful situations, indicating a prominent role in stress-related arousal (152). Neuronal activation declines during nREM sleep and falls silent during REM sleep (153) with norepinephrine being a key excitatory neurotransmitter involved in ascending wake-promoting networks (75,154,155) and inhibitory at sleep-promoting nuclei including the ventrolateral and median preoptic hypothalamic nuclei (156,157). Despite the clear role for the LC, its modulation has demonstrated only minor effects on sleep (158) although administration of α₂ agonists in the LC is inhibitory, resulting in decreased waking with increased nREM sleep (159). Further, as mentioned earlier the LC receives one of the densest supplies of the wake-promoting orexinergic fibres (113) which acts to stabilise sleep-wake transitions.

The pharmacology of sleep and headache

Adenosine

Adenosine has gained considerable attention as an endogenous somnogen; it is involved in the integration of energy metabolism (accumulates as a result of energy consumption), neuronal activity and sleep (160). Administration of adenosine promotes sleep and decreased vigilance through a bidirectional mechanism with both inhibitory (A1 receptor) actions on wake-promoting regions (161 –163) and excitatory (A2a receptors) actions on sleep-promoting centres (160,164). Caffeine acts both via A1 and A2a receptors to prevent sleep (165,166), while it is also a commonly used analgesic in headache which has been implicated as a possible precipitating factor (167,168). The levels of adenosine increase throughout the wake period (169), including in the important sleep-wake areas of the basal forebrain and cortex.

Given the integral role of adenosine in sleep, its use in headache is of key interest when discussing the two conditions. It has been shown to have antinociceptive actions at the spinal cord dorsal horn while A1 knockout mice demonstrate a heightened pain response, and A2a knockout mice demonstrate hypoalgesia (170 –172). Thus the impact of adenosine both on sleep and headache is dependent on the site of action and the specific receptor expression therein. This is highlighted by the impact of adenosine on the lateral hypothalamic orexinergic neurons (173,174) which as discussed may play an important role in the association of sleep and headache. Adenosine inhibits the wake-promoting orexin neurons via an A1 receptor mechanism (175), and orexinergic signalling has been shown to modulate the trigeminovascular system at multiple levels (18,125,176,177). In addition via an interaction with serotonin adenosine may act to modulate thalamic sensory gating during sleep states (178), with important implications on thalamocortical networks. In relation to headache A1 agonists can inhibit trigeminovascular nociceptive afferents in experimental models (179) and inhibit the nociceptive blink-reflex in humans (180). The implications for adenosine in headache are further highlighted by genetic association, with a polymorphism of the A2a receptor linked to migraine with aura (181), the presence of increased plasma adenosine levels during attacks (182,183) and its ability to trigger migraine in susceptible individuals (184).

Melatonin

Melatonin is produced by the pineal gland in a 24-hour circadian pattern, with levels highest in the evening and decreasing in the morning (185). As such melatonin is considered a sleep-promoting hormone which has been linked both to sleep disorders and headache. Melatonin targets MT1 and MT2 receptors in the brain, the activation of which demonstrate differential effects on sleep-wake cycles (186). Perhaps the clearest link between melatonin and headache is observed in cluster headache with its striking circadian and circanual phenotype. Studies have identified altered melatonin secretion patterns (187 –190) with both decreased release and altered expression timing, and targeted therapy has shown beneficial outcomes in episodic cluster headache (191). Melatonin alterations have also been observed in migraine (192 –194) with lowered urinary melatonin and 6-sulphatoxy-melatonin demonstrated in independent studies. Given the beneficial effect of melatonin-targeted therapy in migraine as well as cluster headache, it is likely that altered melatonin homeostasis may have an impact on trigeminovascular nociceptive tone.

Melatonin has been shown to be antinociceptive at spinal cord and supraspinal levels via MT1 and MT2 receptors amongst others (reviewed in Srinivasan et al. (195)). The actions of melatonin are complex and may involve opiate, benzodiazepine, serotonergic and dopaminergic mechanisms. Interestingly melatonin via actions on N-methyl-D-aspartate (NMDA) receptors is able to inhibit a form of spinal cord sensitisation (‘windup’) suggestive of a possible protective role in pain chronification (196). While preclinical studies of melatonin actions on the trigeminovascular system are limited, rats with ablated pineal glands demonstrate enhanced trigeminovascular activation which can be normalised by melatonin replacement (197). In agreement, melatonin may also inhibit CSD and resultant trigeminovascular activation (198), highlighting the benefit of its ongoing targeting for headache treatment.

Orexin

A more detailed review of the role of orexin and potential therapeutic use in headache is included elsewhere within the review series; herein contains a summary of orexinergic mechanisms in the association of sleep and headache (for further review see Holland and Goadsby (176)). The orexins are unique in that they are exclusively synthesised in the hypothalamus yet project to almost the entire CNS (113,199). Their role in sleep is perceived to be wake promoting (71) via stabilisation of the sleep-wake transition ‘flip-flop’ switch (Figure 4) postulated by Saper and colleagues (81). They actively enhance wake-promoting monoaminergic and cholinergic hypothalamic and brainstem neural networks (76,78,79,200) to stimulate wakefulness and disruption of orexinergic signalling results in severe sleep disruptions including narcolepsy (201). The densest orexinergic projections terminate in the LC and paraventricular thalamic nuclei (113,199), two areas which play crucial roles in the sleep-wake cycle as outlined earlier. Given the discussion of associated conditions, it is of interest that orexinergic neurons receive robust projections from limbic structures (202,203), suggesting a further convergence point for the integration of emotional stimuli on arousal and pain states. While this clear role in the sleep-wake cycle has advanced, the orexins as their name suggests were first postulated to be involved in feeding; recently this association has been attributed to arousal effects. However; orexin neurons are modulated by peripheral ghrelin, leptin and glucose, highlighting their possible role in the integration of energy homeostasis which may help explain the proposed links between dietary factors and headache (204).

Given the key role of the hypothalamus in headaches, the orexins have received considerable attention since they were first shown to modulate trigeminovascular tone (125). Direct hypothalamic administration of orexin A was antinociceptive while orexin B was pronociceptive likely via differential actions on the orexin 1 (OX₁R) and 2 (OX₂R) receptors (73). While the receptor expression patterns are similar, the OX₂R is selectively expressed in the TMN and RVM and OX₁R is selectively expressed in the LC (205), with likely important implications for arousal and nociceptive processing. Two key observations are the lack of orexin receptors in the sleep-promoting VLPO, ensuring orexinergic modulation of sleep-wake arousal centres only and the recently demonstrated reciprocal connections with and modulation of the SCN (127).

Modulation of the orexinergic system has highlighted the importance of site-specific actions resulting both in trigeminovascular inhibition (18,177) and facilitation (50). Orexin neurons as such are intrinsically linked with key brainstem and diencephalic areas activated during headache attacks; their activation is highest during wakefulness and fall silent during sleep. While the genetic association between orexin and narcolepsy is clear (201,206 –209), the same is not true for headache despite the two- to four-fold increased prevalence of migraine in narcoleptic patients (210), with a variety of studies reporting positive findings both for OX₁R and OX₂R (211 –214), while additional studies have questioned this association (215). The demonstration that narcoleptic patients developed migraines on average 12.5 years after narcolepsy when the normal risk of developing migraine is relatively low (210) points towards a causative role for orexinergic disruption in the destabilisation of hypothalamic networks which may predispose sufferers to headache. Modulation of the orexinergic system will undoubtedly require further attention, given their prominent modulatory role in nociceptive processing and the recent successful use of dual orexin receptor antagonists in the treatment of insomnia (216), which has shown promise in the trigeminovascular system (217).

PACAP

PACAP has been implicated in the modulation of behavioural patterns during light-dark transitions and the homeostatic regulation of sleep via its actions on the SCN (218 –220). The PACAP-containing retinohypothalamic tract innervates the SCN and is critical for daytime light entrainment with experimental studies identifying conflicting actions based on local concentrations: Low levels recapitulate the effect of light, whereas higher levels result in a phase advance. While PACAP is mostly linked to light entrainment direct pontine administration increases REM sleep (221), in agreement with local receptor expression (222), further highlighting sleep-wake modulatory mechanisms. It has also been shown that PACAP crosses the blood-brain barrier (223) and may act on central sites to induce sleep alterations. This is of great interest to headache given its observed release during attacks and trigeminovascular activation (224,225) and further ability to trigger attacks (226). PACAP is widely expressed throughout the trigeminovascular system (227 –230) including the vasculature where it has potent vasodilatory mechanisms. The pharmacology of PACAP is complex due to its binding affinities to three G-protein coupled receptors which also bind VIP. VPAC1 and 2 bind VIP, PACAP-38 and PACAP-27 in order of descending affinity while PAC1 is relatively specific for PACAP (231). While evidence for a role for PACAP in headache expands, it has been shown that direct hypothalamic administration facilitates trigeminovascular nociception via a PAC1 mechanism (147) and that PACAP may be involved in sensitisation and light aversion (232).

Nitric oxide (NO)

NO is an abundant gaseous signalling molecule which is involved in a variety of functions including endothelial-dependent vasodilation (233). NO synthases (NOS) are a family of enzymes which catalyse the production of NO consisting of endothelial (eNOS), neuronal (nNOS) and inducible (iNOS). nNOS is localised within REM modulating structures including the PPT, LDT and dorsal raphe nuclei (234,235). Disruption of nNOS mechanisms either via complete knockout or local pharmacological modulation results in decreased REM sleep (236,237), whereas iNOS knockout increases REM sleep and decreases nREM sleep (236). Like PACAP above, NO donors (such as glyceryltrinitrate) can trigger headaches in patients (233,238,239) including premonitory symptoms (118,240). Preclinicaly they produce vasodilation (241,242) and biphasic trigeminovascular activation (243). Non-specific blockade of NOS prevents neurogenic dural vasodilation (244), TCC neuronal activation (245,246) and has demonstrated some clinical efficacy (247). Given the potent role of NO donors in the triggering of headaches and their ongoing pharmacological targeting, their involvement in the association between sleep and headache may become clearer.

Neuroinflammatory mediators

While the underlying pathophysiology of migraine is now thought to result from a central neuronal dysfunction (16), the activation and sensitisation of primary afferent nociceptors that innervate the cranial vasculature and dura have been proposed to play a role in the throbbing nature of the pain (248). One such mechanism is the interaction between meningeal nociceptors and the neuroimmune system, with a number of factors including interleukin 1 beta (IL-1β) and tumour necrosis factor alpha (TNFα) shown to modulate these nociceptors. The broad use of nonsteroidal anti-inflammatory drugs for the treatment of headache would appear to lend support to this theory (249); however, multiple additional modes of action have been described. In agreement with a possible neuroimmune association, sleep disturbances are known to alter immune responses and as such may predispose individuals to a proinflammatory state.

Several cytokines and their receptors are localised within the CNS, including the hypothalamus and brainstem where they contribute to normal physiological processes including sleep (250 –252). During migraine levels of proinflammatory cytokines increase significantly (253,254) and local dural administration in experimental models enhances the activation and mechanical sensitivity of meningeal nociceptors (248,255). Thus early in response to migraine circulating levels of proinflammatory mediators increase, which may via cytokine-induced vagal nerve stimulation be sensed by the hypothalamus. As highlighted previously, the hypothalamus is a critical regulator of sleep and headache, while local dural application of an inflammatory soup activates parabrachial and paraventricular hypothalamic neurons likely via the vagal nerve projections (30). The exact role of proinflammatory mediators in the association of sleep and headache is not clear; both IL1β and TNFα show diurnal variations with IL1β levels peaking and sleep onset (256), while administration of both is known to increase nREM sleep (257). As such neuroinflammation may play a role in the association of sleep disturbances and headache, predisposing susceptible individuals to or exacerbating trigeminovascular activation.

Conclusion

The pathophysiology and pharmacology of headache is complex and is further complicated when considering its association with the sleep-wake cycle and sleep disturbances. As highlighted the pathophysiology of headache and sleep have many commonalities which makes discerning individual contributions a difficult task. Sleep disruption appears to be a risk factor for headache attacks and chronification, further highlighted by the increased prevalence of migraine in narcoleptic patients, while sleep is one of the longest established abortive strategies. Despite the lack of a clear consensus the development of our understanding of headache attacks may hold key information. The hypothalamus has long been postulated to be involved in the pathophysiology of several headache disorders, indeed altered hypothalamic activation occurs during and likely results in certain migraine premonitory features. As such dysfunctional hypothalamic networks may be a hallmark both of headache and sleep disorders irrespective of the primary driver resulting in altered triggering thresholds for headache attacks and disrupted sleep-wake control mechanisms. Ongoing technological advances in brain imaging (258), physiological and transgenic approaches are likely to herald a new generation of translational research. This is evidenced by the emerging use of optogenetic strategies in the understanding of REM/nREM sleep (259) and genetic advances which have enabled the detection of comorbid sleep and headache phenotypes in transgenic mice (101,102).

Clinical implications

Key brainstem nuclei play critical roles in headache and arousal.

The hypothalamus is the master circadian pacemaker with important implications for headache disorders.

The orexinergic and melatoninergic systems are intrinsically linked with sleep and headache.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

None declared.

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Headache and sleep: Shared pathophysiological mechanisms

Abstract

Objective

Background

Conclusion

Keywords

Introduction

Pathophysiology of headache

Ascending pathways

Descending modulatory pathways

Pathophysiology of sleep

Circadian rhythms

Wake-promoting neural systems

Sleep-wake phase transitions

The pathophysiology of sleep and headache

Thalamocortical alterations

Thalamus

Hypothalamus

Brainstem

The pharmacology of sleep and headache

Adenosine

Melatonin

Orexin

PACAP

Nitric oxide (NO)

Neuroinflammatory mediators

Conclusion

Clinical implications

Footnotes

Funding

Conflict of interest

References