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Abstract

Background

Although there is a great wealth of knowledge about the neurobiological processes underlying migraine and its accompanying symptoms, the mechanisms by which an attack starts remain elusive, and the disease remains undertreated. Although the vast majority of literature focuses on the involvement of the trigeminovascular systems and higher systems it innervates, such as thalamic and hypothalamic nuclei, several lines of evidence implicate the cerebellum in the pathophysiology of migraine.

Aim

In this review, we aim to summarize potential cerebellar involvement seen from different perspectives including the results from imaging studies, cerebellar connectivity to migraine-related brain structures, comorbidity with disorders implying cerebellar dysfunction, similarities in triggers precipitating both such disorders, and migraine and cerebellar expression of migraine-related genes and neuropeptides. We aim to inspire an increase in interest for future research on the subject.

Conclusion

It is hoped that future studies can provide an answer as to how the cerebellum may be involved and whether treatment options specifically targeting the cerebellum could provide alleviation of this disorder.

Keywords

Migraine cerebellum ataxia trigeminal system

Introduction

Migraine is a common, debilitating headache disorder characterized by recurrent episodes of moderate to severe, often unilateral, headache lasting 4–72 hours, frequently coinciding with a variety of symptoms including nausea, hypersensitivity to various sensory inputs, and cognitive, emotional and motor symptoms (1). About one third of migraines are preceded by an aura, a transient occurrence of focal neurological symptoms that usually takes place prior to the onset of the headache (2). Given the extent of the diversity in symptoms preceding or coinciding with the headache, it is not surprising that migraine is a complex disorder involving many cortical and subcortical brain areas. The headache is believed to be caused by activation of the trigeminovascular system innervating the intracranial vasculature and meninges and conveying nociceptive and somatosensory information to a number of brainstem and higher brain areas (2 –8). Although the majority of migraine literature focusses on the trigeminal system and trigeminal associated areas, the cerebellum has been implicated in migraine and interictal neurological signs for many years.

The cerebellum is a highly-organized brain area located in the hindbrain dorsal to the brainstem. It is structurally distinctive from, but heavily connected to, the cerebrum, brainstem, and spinal cord. The cerebellum has canonically been implicated in various forms of motor control and coordination (9 –11), but more recently it has also been suggested to play a role in non-motor functions including cognition (12) and pain processing (13 –15). Several studies have shown increased cerebellar activity in response to noxious stimuli (16 –18), although until recently these results and the implications were rarely discussed (19,20). An increased prevalence of well-known symptoms of cerebellar dysfunction such as ataxia and oculomotor deficits, as well as structural cerebellar changes, has also been shown in migraine patients (21). Additionally, the expression of genes and neuropeptides implicated in migraine in general (22) or familial hemiplegic migraine (FHM) specifically (23) has been shown to be particularly high in the cerebellum.

Considering these various lines of evidence implicating a cerebellar role in migraine, we aim to provide a comprehensive overview of the literature to date on the subject. By doing so, we hope to inspire an increase in interest for future research aimed at further elucidating how the cerebellum may be impacted by migraine-related neurobiological changes or how it may modulate these changes.

Cerebellar connectivity with neuronal networks involved in migraine

The cerebellum is constituted of two components: The cerebellar cortex, a beautifully folded outer layer, and the cerebellar nuclei situated deep in the white matter. Cerebellar nuclei neurons form the main output station of the cerebellum and innervate several areas in the brainstem and forebrain (24 –26). They receive the majority of their inputs from GABAergic Purkinje cells that form the principal output neurons of the cerebellar cortex (27). Both the cerebellar cortex and the cerebellar nuclei receive inputs via two pathways: The mossy fiber system predominantly originating in the pontine nuclei and the climbing fiber system exclusively originating in the inferior olive (10,11).

Afferent migraine related cerebellar inputs include various brainstem and cervical spine areas including the trigeminocervical complex. One of the key structures involved in migraine pathophysiology is the trigeminal spinal nucleus (SpV) that receives information from the trigeminal ganglion cells innervating the meninges and cranial vasculature (28). The SpV is known to innervate several migraine-relevant structures such as the thalamus and hypothalamus, but nociceptive neurons in the SpV have also been shown to directly project to the cerebellum in cats (29,30) and rodents (31 –34) and to precerebellar areas such as the inferior olive and pontine nuclei (31,33). Additionally, cerebellar nuclei projections to the SpV have been shown in the rat (24). Interestingly, a direct cerebellar projection originating from the trigeminal ganglion cells has also been described in rats (35). The cerebellum has also been found to be reciprocally connected to the periaqueductal gray (24,36), and receive input from the locus coeruleus and parabrachial nucleus (37,38), areas thought to have the capacity to modulate activity of the trigeminal pathway (28,39) (Figure 1).

Figure 1.

Efferent and afferent connections between cerebellum and migraine-associated areas. Connectivity of migraine associated brain structures (black arrows) and afferent (blue arrows) and efferent (red arrows) connections between these areas and the cerebellum.

The most important efferent projections of the cerebellum to migraine-relevant areas, aside from the projection to the SpV mentioned above, include several thalamic and hypothalamic areas. Thalamic structures implicated in migraine pathophysiology include the zona incerta and ventral posteromedial, posterior, and parafascicular thalamic nuclei (7,28,40,41). Cerebellar nuclei neurons send divergent, excitatory axonal projections to various thalamic nuclei that include extensive innervation of all these migraine-related thalamic areas (24,42 –45). Through these connections, the cerebellum has been shown to robustly affect thalamocortical network activity (45,46). Areas in the hypothalamus implicated in migraine include the anterior, lateral, perifornical, dorsomedial, suprachiasmatic, and supraoptic hypothalamic nuclei, again showing considerable overlap with hypothalamic areas innervated by the cerebellum (24,47). The cerebellum is also heavily and reciprocally connected with the vestibular system (48), thought to play an important role in vestibular migraine, a syndrome including a combination of episodic migraine headaches and vestibular symptoms like vertigo (49).

In line with these anatomical studies connecting the cerebellum to networks involved in migraine, recent functional imaging studies found robust functional connectivity during nociception between many of the known migraine-relevant brain areas in the brain stem, midbrain, and cortex, indicating that the cerebellum may play an important role in pain processing (19,50).

Migraine related cerebellar changes in activity and structure: Results from imaging studies

Most studies using functional imaging techniques investigate migraine-related activity changes in between attacks (interictally) due to the difficulty in planning an imaging session during something as unpredictable as a migraine attack (51). However, some managed to image brain activity during attacks (ictally). Functional MRI imaging of patients suffering from a migraine episode evoked by olfactory stimuli showed significantly increased cerebellar activity compared to interictally-recorded activity prior to the migraine (52). Significant cerebellar activation soon after the onset of a spontaneous migraine in patients with and without aura (20,53) and in patients with vestibular migraine (54) has also been demonstrated. No such cerebellar activation was, however, found prior to the onset of the headache (20). Increased cerebellar activity has furthermore been shown in response to trigeminal noxious stimuli in migraine patients (16 –18) and healthy subjects (55). Additionally, a group studying activation patterns in chronic migraine patients treated with either suboptimal or optimal occipital nerve stimulation found increased cerebellar activation during optimal stimulation but not during a suboptimal paradigm, suggesting cerebellar activity may be associated with migraine relief (56).

Several studies used various imaging techniques to investigate possible structural changes in migraine patients. The cerebellum seems to be particularly vulnerable to atrophy and lesions. Several studies found ischemic cavities, subclinical infarcts and lesions in the cerebellar cortex and white matter in patients with migraine with aura (57 –61), without aura (57,58,61,62) and vestibular migraine (63), but others found that most headache-related lesions were located outside the cerebellum (64). The presence of white matter lesions in migraine patients has been associated with immunoreactivity against the cytoplasm of neurons and the cerebellar molecular layer and Purkinje cells in particular, leading the authors to suggest a relation between migraine-related inflammatory responses and these lesions (65). Severity of cerebellar damage has been correlated with the frequency of migraine attacks and disease duration, and the worsening of damage has been attributed to the exacerbation of the headache disorder (61). Additionally, patients with cerebellar lesions have been shown to perceive noxious stimuli as more painful than age-matched controls, suggesting that the cerebellum may modulate pain (66). The possibility that cerebellar dysfunction may contribute to an increased severity or frequency of migraine attacks is therefore also something to consider.

Cerebellar atrophy, most pronounced in the superior vermis, has also been found in patients suffering from chronic migraine (67) and FHM (68). The latter group was also found to have vermal metabolite alterations, notably decreased N-acetyl aspartate (69) and glutamate concentrations and increased myo-inositol levels (68). These changes remained significant after correcting for differences in cerebrospinal fluid and gray matter volume, indicating cerebellar dysfunction beyond the level of atrophy (68).

Comorbidity of migraine and cerebellar dysfunction

Considering the involvement of the cerebellum in motor behavior, it is not surprising that cerebellar dysfunction can result in a variety of motor disorders. Another clue implicating cerebellar involvement in migraine stems from the high comorbidity of this headache disorder and both clinical and subclinical motor abnormalities in which the cerebellum has been implicated (21).

One of the most common disorders associated with cerebellar dysfunction is ataxia, which manifests itself as impaired balance and lack of coordination in voluntary movements and can coincide with tremor and oculomotor deficits (70). The co-occurrence of either episodic or chronic ataxia and migraine has most commonly been described in patients suffering from FHM caused by mutations in the Cacna1a (FHM1), ATP1A2 (FHM2) or SCN1A gene (FHM3) (39). Prevalence of ataxia seems to be particularly high in FHM1 patients (∼20%) (71), and murine models with a human S218L FHM1 mutation (72), but its occurrence has also been described in several FHM2 families (73 –75) and patients with migraine with aura (71). Conversely, patients with a primary diagnosis of ataxia have also been reported to suffer from migraine headaches (76,77). In episodic ataxia type 2 (EA2), a disorder caused by a different mutation in the same ion channel associated with FHM1, a migraine prevalence of up to 50% has been described (76,78). Additionally, migraine with brainstem aura (formerly named basilar type migraine) is characterized by the occurrence of ‘brainstem’ symptoms during the aura, which include symptoms that can have a cerebellar component such as ataxia, dysarthria, and vertigo (1,79,80).

Another movement disorder associated with cerebellar dysfunction is dystonia, a disorder characterized by involuntary sustained postures and/or repetitive movements often produced by co-contraction of agonist and antagonist muscles (81 –83). Although literature describing dystonia in primary migraine patients is less common, some case reports of its co-occurrence in FHM patients exist (84 –86). Additionally, studies have reported the occurrence of migraine episodes in patients with primary dystonic disorders (87 –93).

The higher incidence of subclinical cerebellar signs as well as nystagmus and essential tremor in patients with migraine suggest the cerebellum may be involved in the pathophysiology of this disorder (94 –98). Eye blink conditioning, an associative learning task for which correct cerebellar functioning is essential, has been shown to be subclinically impaired in patients (94). The same subclinical signs of cerebellar dysfunction have been found for smooth pursuit tasks (95), accuracy of saccadic eye movements (96), hypermetria in reaching movements (97) and time perception in the millisecond range (99). All these studies found these subclinical signs in both patients with and without aura, with the former group performing consistently worse. However, another recently conducted study found no cerebellar dysfunction in migraine patients, despite a higher prevalence of cerebellar lesions, whereas FHM1 patients did show severe cerebellum-mediated impairment (100).

Due to the robust interconnectivity of the cerebellum and the vestibular system, it is not surprising that behavioral symptoms observed in relation to vestibular dysfunction can also be caused by cerebellar dysfunction (48). Symptoms like disturbances in vestibulo-ocular reflex – a compensatory eye movement upon rotation of the head to allow eye fixation during movement – nystagmus and motion intolerance are examples of potential consequences of either vestibular or cerebellar dysfunction or damage (48,101). Many of these vestibulocerebellum-mediated functions have been shown to be affected in vestibular migraine patients (102). Yet the potential impact of cerebellar functioning on vestibular migraine remains unknown, with some studies suggesting that vestibular migraine may be cerebellar in origin, whereas others indicate that aberrant cerebellar activity may be compensatory to vestibular dysfunction (102,103).

Migraine triggers and the overlap with triggers of cerebellum associated episodic disorders

Migraine attacks are often reported to be preceded by a great variety of triggers such as stress, hormonal fluctuations, dietary changes (including alcohol, skipping a meal and caffeine withdrawal), physical exercise, fatigue, and sensory inputs (such as bright light or certain odors) by patients, with stress being the most common (104 –106). Possible mechanisms by which such heterogeneous factors might result in the activation of the trigeminovascular system or why they are not consistently followed by an attack remain unknown. Neither has it been established whether these triggers converge on one mechanism, or different triggers result in meningeal nociceptive activation through separate pathways (105). Another interesting yet unresolved finding is the similarity in triggers in both migraine with and without aura, suggesting that the same triggers can either provoke cortical spreading depression, the neurobiological process thought to underlie the migraine aura, or result in direct activation of the trigeminal system without the preceding aura.

Interestingly, a lot of these triggers, such as stress, physical exercise, fatigue, and alcohol, can also precipitate episodic movement disorders associated with cerebellar dysfunction, such as episodic ataxia and dystonia (107 –109). As with migraine, the mechanisms underlying the occurrence of these episodic attacks of abnormal movement following exposure to triggers remain to be elucidated, yet the cerebellum has been implicated to be the instigator of attacks in several studies in rodents. Despite the similarity in triggers precipitating migraine attacks and cerebellar-mediated episodes of abnormal motor behavior, there is not much evidence pointing towards a causal cerebellar role in migraine. Neither spreading depression (110) nor the period prior to headache onset (20) has been associated with changes in cerebellar activity. Spreading depression is a process that can easily be evoked in an experimental setting, not only in the cortex but also in other preparations or areas. Although it is possible to evoke a spreading depression in the cerebellum (21,111,112), there is, to the best of our knowledge, no indication that this can occur in a physiologically-relevant situation, for example as a response to triggers like stress, or that this could possibly lead to headache.

Additionally, whereas a migraine attack seems to occur well after both occurrence and subsidence of the trigger in migraine patients, in patients with episodic motor disorders this relation between trigger and attack seems much more immediate. Considering the lack of knowledge on these trigger mechanisms and the difference in timing of an attack, the possibility that migraine triggers may lead to cortical spreading depression and/or headache via some mechanism involving the cerebellum, as suggested for episodic ataxia and dystonia, remains highly speculative.

Cerebellar expression of migraine associated genes and neuropeptides

A potential modulatory role of the cerebellum in migraine rather than a causal one can not only be hypothesized based on imaging studies, but has also been suggested based on cerebellar expression of some migraine-related genes. Some of the best-studied hereditary forms of migraine involve the different subtypes of FHM. A mutation in the Cacna1a gene, encoding the poreforming α1 subunit of Ca_V2.1 (P/Q-type) calcium channels, causes FHM1 (113,114). The Cacna1a gene is globally expressed throughout the brain, but expression is particularly high in the cerebellum (23). The Ca_V2.1 calcium channel is a high threshold voltage activated calcium channel with an increased open probability when membrane potentials reach a threshold of ∼−45mV. Voltage gated calcium channels play an essential role in neurotransmitter release and a great number of other functions including neurite outgrowth, synaptogenesis, neuronal excitability, activity-dependent gene expression, as well as neuronal survival, differentiation, and plasticity (115). Not only is the cerebellar expression of Ca_V2.1 calcium channels particularly high, different mutations in the same gene can also cause ‘cerebellar disorders’ including episodic ataxia type 2, spinocerebellar ataxia type 6 and paroxysmal dystonia (115). The combination of the previously stated high comorbidity of these disorders and migraine, EA2 in particular, and the extent of cerebellar Cacna1a expression may suggest a cerebellar role in this headache disorder.

A potential link between the cerebellum and FHM1, a relatively rare subtype of migraine, is however not the only genetic clue implicating the cerebellum. One of the major signaling molecules implicated in migraine in general, the neuropeptide calcitonin gene-related peptide (CGRP) (116), has also been shown to be highly expressed in the cerebellum (22,117–120). CGRP is associated with neuro-inflammatory processes and is one of the most important neurotransmitters involved in conveying nociceptive information in the trigeminal system and other migraine associated areas (116,118). Cerebellar expression of this gene has been found to be confined to the cytoplasm of Purkinje cells, whereas the presence of its associated receptor components, calcitonin receptor-like receptors and receptor activity modifying protein type 1, have been reported on the surface of Purkinje cell bodies, Purkinje cell dendrites and afferent fibers (22). Yet the functional role of CGRP in the cerebellum, or whether its cerebellar expression is related to migraine pathophysiology, remains unclear.

Conclusions and future directions

Based on the wealth of literature on functional and structural cerebellar changes found in migraineurs, the comorbidity of migraine with cerebellar symptoms or diseases, and the high cerebellar expression of migraine-related genes and neuropeptides, it seems likely that the cerebellum plays a role in this disorder.

Recent findings suggest that this role is likely a modulatory one. Evidence for this notion stems from several papers. Recent fMRI studies by the group of Dr. May not only found structural abnormalities, increased activity in the ipsilateral cerebellar cortex and an increased functional connectivity between the cerebellum and many subcortical and higher order brain areas involved in pain processing, but also that this activity was modulated by migraine severity (19,20). Furthermore, it has been shown that patients with cerebellar lesions perceive noxious stimuli as more painful than controls and show a decrease in endogenous pain inhibition (66). Additionally, successful treatment of chronic migraine patients by occipital nerve stimulation coincides with cerebellar activation, whereas suboptimal stimulation paradigms did not (56). Together, these results suggest that the cerebellum likely modulates pain perception, where increased activity may lead to a reduction in perceived pain.

Increases in migraine-related cerebellar activity were predominantly found in the ipsilateral cerebellar cortex (19,20). The downstream effect of Purkinje cells, the principal output neurons of the cerebellar cortex, is an inhibitory one. They form converging GABAergic synaptic connections on cerebellar nuclei neurons (27). An increase in cerebellar cortical activity is therefore likely to lead to a decrease in cerebellar nuclei neuronal firing. With the exception of some direct Purkinje cell to vestibular nuclei projections, the cerebellar nuclei form the sole output station of the cerebellum, innervating a wide range of brainstem and forebrain areas (24,25,121). These connections are predominantly excitatory, save GABAergic innervation of the inferior olive and glycinergic vestibular nuclei projections. We would therefore hypothesize that cerebellar cortex-mediated dampening of activity in the cerebellar nuclei leads to a decrease in excitatory inputs to several nociception-related areas, subsequently leading to a reduction in perceived pain during nociception.

This potential alleviating effect of the cerebellum on pain perception suggests that the cerebellum may be utilized for migraine treatment. Yet specific mechanisms underlying the effects of changes in cerebellar activity on areas involved in pain processing remain to be elucidated. The availability of mutant mice selectively expressing channelrhodopsin in Purkinje cells (122) provides opportunities to investigate the impact of cerebellar cortex stimulation on activity in different nodes in the pain-associated neural networks during nociception, and how these changes may contribute to a reduction in perceived pain. Hypothalamic deep brain stimulation has, for example, already been applied successfully in patients with chronic headache (123), and cerebellar stimulation or pharmacologically-altered cerebellar activity may similarly contribute to alleviation of pain in patients with particularly severe chronic migraines that do not respond to medication. Both the possibility of reducing headache through manipulation of cerebellar activity and the possible mechanism by which it affects nociception-related areas should be investigated.

In light of the finding that cerebellar lesions may worsen perceived pain (66), the increased susceptibility of the cerebellum to ischemic lesions in migraine patients (57–62,64) seems even more detrimental. Both processes could putatively worsen each other, with the presence of lesions worsening perceived pain and the migraines worsening the susceptibility to cerebellar lesions. It remains, however, unclear what causes the predisposition to cerebellar atrophy or abnormalities. Considering the emerging evidence of a modulatory rather than epiphenomenal role of the cerebellum in pain processing in general and migraine specifically, both the reasons behind the susceptibility to cerebellar damage and potential treatment options involving utilization of the cerebellum should be investigated. This could, for example, be done by repetitive elicitation of spreading depression, which has been shown to induce activation of the trigeminal system, in migraine mouse models and wild-type littermates. Subsequent investigation of potentially toxic levels of proteins and transmitters like glutamate and histological examination of cerebellar tissue may provide answers as to what may mediate potential lesion occurrence.

Clinical implications

Migraine is a disorder with a complex pathophysiology, and identifying the multiple areas of the nervous system involved can help further elucidate targets for assessment, prevention, and treatment.

Emerging evidence suggests the cerebellum may modulate pain perception and processing, which might be relevant for the headache, as well as for accompanying allodynia. Therefore, therapeutic interventions targeting the cerebellum could contribute to decrease the frequency, severity, or duration of pain.

The cerebellar predisposition to lesions not only leads to potential interictal motor abnormalities, but may also cause a heightened perception of noxious stimuli.

More research investigating the cerebellum as a migraine treatment target, reasons behind the susceptibility to lesions, and preventative treatment options should be conducted.

Footnotes

Acknowledgements

We thank the Khodakhah lab for constructive discussions.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding was provided by the NIH (NS050808).

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Cerebellar involvement in migraine

Abstract

Background

Aim

Conclusion

Keywords

Introduction

Cerebellar connectivity with neuronal networks involved in migraine

Migraine related cerebellar changes in activity and structure: Results from imaging studies

Comorbidity of migraine and cerebellar dysfunction

Migraine triggers and the overlap with triggers of cerebellum associated episodic disorders

Cerebellar expression of migraine associated genes and neuropeptides

Conclusions and future directions

Clinical implications

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

References