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. Author manuscript; available in PMC: 2024 Oct 1.
Published in final edited form as: Eur J Pain. 2023 Jul 8;27(9):1126–1138. doi: 10.1002/ejp.2158

Central generators of migraine and autonomic cephalalgias as targets for personalized pain management: Translational links

Rodrigo Noseda 1, Luis Villanueva 2
PMCID: PMC10979820  NIHMSID: NIHMS1974390  PMID: 37421221

Abstract

Background and Objective:

Migraine oscillates between different states in association with internal homeostatic functions and biological rhythms that become more easily dysregulated in genetically susceptible individuals. Clinical and pre-clinical data on migraine pathophysiology support a primary role of the central nervous system (CNS) through ‘dysexcitability’ of certain brain networks, and a critical contribution of the peripheral sensory and autonomic signalling from the intracranial meningeal innervation. This review focuses on the most relevant back and forward translational studies devoted to the assessment of CNS dysfunctions involved in primary headaches and discusses the role they play in rendering the brain susceptible to headache states.

Methods and Results:

We collected a body of scientific literature from human and animal investigations that provide a compelling perspective on the anatomical and functional underpinnings of the CNS in migraine and trigeminal autonomic cephalalgias. We focus on medullary, hypothalamic and corticofugal modulation mechanisms that represent strategic neural substrates for elucidating the links between trigeminovascular maladaptive states, migraine triggering and the temporal phenotype of the disease.

Conclusion:

It is argued that a better understanding of homeostatic dysfunctional states appears fundamental and may benefit the development of personalized therapeutic approaches for improving clinical outcomes in primary headache disorders.

Significance:

This review focuses on the most relevant back and forward translational studies showing the crucial role of top-d own brain modulation in triggering and maintaining primary headache states and how these central dysfunctions may interact with personalized pain management strategies.

1 |. INTRODUCTION

The contribution of central nervous system (CNS) processing mechanisms to sustained or chronic primary headache states is probably crucial. A preclinical approach for investigating such maladaptive mechanisms is based on the characterization of the functional architecture of brain networks that process trigeminovascular pain and multisensory functions in healthy and disease rodent models. In the clinical field, non-invasive approaches including electrophysiological and functional imaging explorations of brain processing mechanisms in patients make them particularly well-suited for the study of cyclic activity changes associated with migraine and trigeminal autonomic cephalalgias (TACs). However, although significant advances have been made in the knowledge of primary headache mechanisms, the discovery of effective treatments has been hampered by the fact that their pathogenesis remains largely unknown.

In this review, we selected relevant back-and-forward translational studies devoted to the assessment of CNS dysfunctions involved in primary headaches and discussed the role they play in rendering the brain susceptible to headache states. We focus on medullary, hypothalamic and corticofugal modulation mechanisms that represent strategic substrates for elucidating the links between trigeminovascular maladaptive states, migraine triggering and development. Hence, a better understanding of such dysfunctional states appears fundamental and may provide deeper insights to develop personalized therapeutic approaches for improving clinical outcomes.

2 |. HYPOTHALAMIC MALADAPTIVE REGULATIONS, MIGRAINE AND TACS: MAIN OR SUPPORTING ACTOR IN THE PATHOGENESIS?

By operating as a hub of several neuroendocrine and autonomic mechanisms crucial for homeostasis, the hypothalamus acts as a main link of processing mechanisms underlying emotions and motivations. Despite the technical difficulties in determining the temporal association between the preictal phase and migraine triggering, clinical imaging studies have identified hypothalamic activation before spontaneous headache onset (Denuelle et al., 2007). In addition, another study that employed glyceryl trinitrate to trigger migraine showed hypothalamic activation in association with premonitory symptoms in the absence of pain, which were later followed by migraineous headache (Maniyar et al., 2013). Interestingly, experimental pain paradigms applied to the ophthalmic trigeminal dermatome in migraine patients for 30 consecutive days, unveiled a cyclic behaviour of the hypothalamus in which the activity elicited by such nociceptive stimulation increases during the 24 h preceding the next migraine attack, and displays altered functional coupling with the Sp5C and dorsal rostral pons during the preictal day (Schulte & May, 2016).

Symptoms during this pre-attack phase are commonly associated with changes in homeostasis including sleep disturbances, changes in wakefulness and alertness, mood dysregulation, food craving and thirst, among other functions regulated by the hypothalamus. Additionally, the episodic and repetitive nature of migraine attacks, which are associated with circadian rhythmicity, endocrine fluctuations, particularly in women, and stress as the most common trigger, further implicate a hypothalamic involvement in the initiation of migraine. Likewise, functional imaging studies have convincingly shown abnormal hypothalamic activity during migraine and TACs (Denuelle et al., 2007; Matharu et al., 2006; May, 2005, 2009; May et al., 1998). In support of this concept, deep brain stimulation of the posterior hypothalamus has been proven as an effective treatment in patients with refractory TACs (Leone et al., 2001; May, 2006). Cranial autonomic symptomatology including reddening of the eye, tearing, rhinorrhea, and eyelid oedema, are common in cluster headache (CH) and to a lesser extent in migraine in adults (Karsan et al., 2022) and paediatric/adolescent patients (Gelfand et al., 2013), could be produced by changes in the activity of hypothalamic nuclei that integrate signals to drive autonomic responses. Although migraine and TACs are different clinical entities, many mechanisms are common, and they both appear to have hypothalamic involvement in their pathogenesis.

3 |. PARAVENTRICULAR HYPOTHALAMIC NUCLEUS (PVN): A HUB THAT MODULATES PERIPHERAL AND CENTRAL TRIGE MIN OVA SCU LAR MECHANISMS AT THE ORIGIN OF PRIMARY HEADACHES

A large body of evidence from translational studies indicates that paraventricular hypothalamic nuclei (PVN) represent a main processing centre for the neuro-hormonal and autonomic regulation of stress responses (Hypothalamic–Pituitary–Adrenal; HPA axis), implicating this forebrain area as a relevant contributor in migraine and TACs pathophysiological mechanisms (Figure 1). Parvocellular PVN neurons project to the superior salivatory nucleus (SSN), a pontine region that gives rise to parasympathetic outflow to cephalic and ocular/nasal structures, including the intracranial meninges. These cells modulate SSN neuronal activity that in turn influences postganglionic parasympathetic outflow from the sphenopalatine ganglion, resulting in vasodilation, plasma protein extravasation and local release of inflammatory molecules that activate meningeal nociceptors (Delépine & Aubineau, 1997), indicating that neurogenic inflammation in the dura could be triggered centrally via PVN efferent output to SSN.

FIGURE 1.

FIGURE 1

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Central modulation of cervico-medullary trigeminovascular neurons (Sp5C) which convey nociceptive signals from meningeal afferents to brain regions implicated in headache pain processing. The most widespread source of top-down modulation arises from the paraventricular hypothalamus (PVN) and the cortical pain matrix. Direct hypothalamic projections to the Sp5C originate from the PVN, a key link of the hypothalamic–pituitary–adrenal axis. The PVN innervates both the superficial layers of the Sp5C and the Superior Salivatory Nucleus, which regulates cranial parasympathetic outflow via the sphenopalatine ganglion (SPG). Direct, monosynaptic excitatory and inhibitory modulations to the Sp5C originate from the contralateral primary somatosensory and secondary somatosensory/insular cortices. Polysynaptic modulation of Sp5C activities arise from the anterior cingulate cortex and PVN, via the brainstem PAG-RVM/SRD descending systems. ACC, anterior cingulate cortex; DNIC, Diffuse Noxious Inhibitory Controls; Ins, insular cortex; PAG, periaqueductal grey matter; RVM, rostral ventromedial medulla; S1, primary somatosensory cortex; S2; secondary somatosensory cortex; Sp5C, spinal trigeminal nucleus caudalis; SPG, sphenopalatine ganglion; SRD, subnucleus reticularis dorsalis; TG, trigeminal ganglion.

PVN-descending axons continue their descending path to terminate in Sp5C laminae I and outer II, which are dense targets of meningeal Aδ and C nociceptors. PVN output is thus anatomically positioned to directly modulate the activity of Sp5C neurons receiving input from meningeal nociceptors. Indeed, pre-clinical studies have shown that under certain circumstances, PVN cells could act as endogenous central triggers, by enhancing background activities of Sp5C cells in the absence of peripheral input from meningeal nociceptors (Robert et al., 2013). Reciprocal influence between the HPA axis and trigeminovascular activity at the PVN level is supported by the strong inhibitory effect of GABAA on the excitatory influence of PVN onto Sp5C neurons, which is also significantly reduced in a model of acute restrained stress (Robert et al., 2013). Interestingly, acute stress reduces the properties of GABAA-inhibitory synapses on parvocellular PVN neurons by down-regulating the transmembrane anion transporter KCC2, which maintains low intracellular Cl− concentration as a pre-requisite for the generation of Cl− hyperpolarizing GABAA mediated responses (Hewitt et al., 2009). It is thus tempting to propose that a specific, stress-induced loss of GABAergic inhibition of the PVN-Sp5C neural circuit represents a plausible dysfunctional mechanism by which headaches may be generated primarily within the hypothalamus. In the clinical field, the mechanisms relating stress and migraine triggering are more complex, as illustrated by a study showing that a reduction in perceived stress from one day to the next is associated with migraine onset; a reduction that could represent a sign of an impending migraine attack (Lipton et al., 2014). These findings suggest that changes in stress states rather than stress itself could have a more relevant impact on migraine triggering. Interestingly, animal studies uncovered distinct temporal windows following stressful experiences that can alter PVN glutamatergic synapses to produce bidirectional changes in endocannabinoid signalling (Bains et al., 2015). The same clusters of parvocellular PVN– Sp5C projecting cells are also densely labelled with corticotropin-releasing hormone (CRH) and encode stress controllability (Daviu et al., 2020). Since PVN is a key link in the neuro-hormonal and autonomic integration of stress responses, it could act as a pivotal structure integrating multiple signals and coordinating a complex response in association with pain, anxiety and autonomic reflexes involved in primary headaches.

4 |. PVN CELLS DRIVE A VARIETY OF MECHANISMS IMPLICATED IN TRIGE MIN OVA SCU LAR PROCESSING

Pre-clinical studies support the notion that descending excitation from the hypothalamus can trigger a headache via facilitatory effects affecting exclusively the baseline activity without altering meningeal-evoked responses of Sp5C neurons. For instance, PVN microinjections of PACAP, a neuropeptide involved in migraine pathophysiology and closely associated with CGRP (Waschek et al., 2018), enhance Sp5C background neuronal activity (Robert et al., 2013), an effect that is mediated by increase firing rate following depolarization of PVN neurons (Uchimura et al., 1996). PACAP-immunoreactive fibres densely innervate CRH-containing neurons in the parvocellular PVN region (Légrádi et al., 1998), suggesting that PACAP inputs onto PVN neurons could elicit pronociceptive descending influences giving rise to a headache, while simultaneously regulating the stress response within the HPA axis. In this respect, upregulation of mRNAs encoding CRH in the PVN is PACAP dependent (Stroth et al., 2011), and behavioural studies using PACAP injections in the PVN showed scored behaviours of stress that were increased in restrained animals (Norrholm et al., 2005), suggesting that PACAP may play an excitatory role in enhancing responses to stress via CRH neurons. Also, it is possible that centrally mediated PACAP effects could participate in the delayed migraine-like attacks observed only in migraineurs following systemic administration of PACAP38 (Schytz et al., 2009). However, it has been suggested that induction of migraine following PACAP38 infusion could be mediated peripherally, through the activation of meningeal nociceptors in the perivascular space of cranial arteries (Schytz et al., 2010) following degranulation of dural mast cells and release of inflammatory mediators such as serotonin (Baun et al., 2012). Along this line, serotoninergic mechanisms may be playing a wide role in both peripheral and central components of the trigeminovascular system. In support of central mechanisms, microinjections of 5-HT1B/D agonist naratriptan into the PVN induce inhibition of both basal and meningeal-evoked Sp5C neurons (Robert et al., 2013), suggesting that triptans could contribute to therapeutic effects via these networks through actions on periventricular hypothalamic structures such as the PVN. The functional link of such descending hypothalamic regulation was tested in rodents, where electrical stimulation of the SSN activates Sp5C neurons and elicits cranial autonomic reactions which are inhibited by therapies currently effective in treating TACs, including oxygen, indomethacin and triptans, suggesting that part of their therapeutic action involves parasympathetic outflow to the cranial vasculature (Akerman et al., 2012). Therefore, hypothalamic mechanisms acting as triggers of some TACs could play a fundamental role in the pathophysiology of such disorders, as shown by the persistence of cluster headaches in a patient, after the total section of the trigeminal sensory root, which continued to respond to sumatriptan (Matharu & Goadsby, 2002). The ventral tegmental area could also participate in primary headaches processing since it is involved in homeostatic and trigeminovascular nociceptive regulation, via serotoninergic and PACAP-r elated mechanisms (Martins-Oliveira et al., 2022).

PVN activities are also influenced by circadian rhythmicity and endocrine fluctuations through efferent targets from the suprachiasmatic nucleus (SCN) to PVN cells containing oestrogen receptors (Hatcher et al., 2020). Interestingly, oestrogens receptors are expressed in a sexually dimorphic pattern in the CNS structures regulating circadian rhythms and modulate sexually dimorphic behaviours through developmental programming of the brain and receptor signalling during adulthood (Anderson & FitzGerald, 2020; Hatcher et al., 2020; Talamanca et al., 2023). Disruption of circadian rhythms by fluctuations in oestrogen signalling at hypothalamic level could thus contribute to attack frequency and cyclicity in migraine disorders. The adrenal gland also exhibits more rhythmic mRNAs in females than males (Talamanca et al., 2023), which corroborates the overall increased rhythmicity in females at transcriptional and physiological levels (Anderson & FitzGerald, 2020; Talamanca et al., 2023).

The above translational studies suggest that the modulation exerted by circadian and hormonal rhythmicity could be implicated in migraine occurrence and its prevalence, that is age-and sex-dependent (Gazerani & Cairns, 2020). This concept is supported by neuroimaging studies in migraineurs showing that the hypothalamus is more active about a day before migraine onset while reaching the greatest functional coupling with the Sp5C. During the ictal state, the hypothalamus becomes more functionally coupled with the dorsal rostral pons (Schulte & May, 2016), a pivotal region that has been considered a possible ‘migraine generator’ (Bahra et al., 2001; Denuelle et al., 2007). Unfortunately, current imaging techniques used in humans lack the anatomical resolution to localize with precision which regions within the hypothalamus and brainstem are involved in these processes, and it is not possible to determine whether changes in regional cerebral blood flow are correlated with neuronal excitation and/or inhibition. Although migraine and TACs can only be modelled in animals, anatomical and functional studies in rodents can provide significant insight into these unknowns. For instance, PVN hypothalamic outflow elicits specific changes in trigeminovascular processing, likely by directly engaging a variety of pontine structures such as the SSN, PAG and more caudally the medullary Sp5C, having thus, a strong impact on central sensitization mechanisms related to headaches (Akerman et al., 2011; Robert et al., 2013).

Exogenous environmental stimuli such as light, exert significant influences on these neural systems, in which retinal photoactivation by external illumination allows the SCN to coordinate internal physiological and behavioural rhythms. In this regard, psychophysical evidence in migraineurs showed that photic stimulation triggers more changes in autonomic functions and negative emotions during, rather than in the absence of migraine. Interestingly, the neuronal pathways through which electrical signals generated by light travel from the eye through the hypothalamus to neurons that regulate autonomic functions and emotions, strongly implicate the PVN, as well as other hypothalamic nuclei (Noseda et al., 2017). In addition, some of these hypothalamic nuclei project directly to posterior thalamic areas implicated in migraine pain and photophobia (Kagan et al., 2013), suggesting a wider impact of hypothalamic activity in migraine symptoms.

5 |. THE CEREBRAL CORTEX AS A MULTISENSORY SOURCE OF TOP-D OWN, TRIGEMINAL MODULATION

In the last two decades, clinical neurophysiological studies have provided convincing support to the concept that migraine patients have cyclic states characterized by abnormal cortical processing of multisensory stimuli. Manifested as an hyperresponsiveness to many forms of sensory input, particularly visual, these hypersensitive episodic states have been associated with a ‘thalamo-cortical dysrhythmia’ caused by deficits in habituation to repetitive stimulation (de Tommaso et al., 2014), and interpreted as insufficient cortical inhibition during the interictal period (Aurora & Wilkinson, 2007; Coppola, Pierelli, & Schoenen, 2007). Such dysfunctional balance between excitation and inhibition within the cerebral cortex, certainly affects neural processing at multiple downstream brain regions, but particularly those under direct corticofugal control.

The pioneer series of preclinical studies from Ronald Dubner’s group showed that corticofugal controls are likely involved in the modulation of Sp5C neurons by behaviorally significant stimuli in trained monkeys. Such modulation, termed ‘task-related’, was shown to produce greater neuronal responses in Sp5C trigemino-thalamic neurons than those evoked by equivalent stimuli in the absence of relevant behavioural states (Bushnell et al., 1984; Duncan et al., 1987). Specifically, Sp5C cells responding to thermal stimuli applied on the face exhibit an additional task-related response to visual or motor cues involved in the behavioural task, but not to similar stimuli presented outside the task. Given that neither visual stimuli nor motor responses such as hand movement are related to functions normally ascribed to Sp5C neurons, the fact that these task-related responses exhibit a contextual association with ‘non-trigeminal’ input, indicates that a behavioural modulation is at play and likely mediated by distinct neural networks involved in either sensory acquisition or motor preparation. Interestingly, a recent study showed that the neuronal activity of a nociceptive, dura-responding thalamo-cortical pathway that underlies migraine pain is modulated at the level of the thalamus by retinal photoactivation. This photomodulation is exerted by axonal projections of retinal ganglion cells that converge on dura-sensitive neurons, in areas of the posterior thalamus that form widespread axonal terminal fields spanning layers I–V of somatosensory cortices, and additional projections to a variety of cortical areas involved in cognitive, motor, auditory and visual functions (Noseda et al., 2011; Noseda, Kainz, et al., 2010). These observations agree with Dubner’s seminal studies indicating that multisensory, relevant information regarding the environment is disseminated throughout multiple regions of the CNS involved in the animal’s ongoing behaviour. Neuronal responsiveness may thus not always bear a direct relationship to the type of peripheral stimuli that Sp5C neurons are capable of processing and be dependent on the behavioural context in which sensory signals are received. We will see below that back and forward translational studies have tried to answer fundamental questions on the existence of a direct link between multisensory cortical maladaptive processing in the migraineous brain, and the resulting trigeminovascular dysfunction that generates headache pain.

6 |. CORTICAL SPREADING DEPOLARIZATION INFLUENCES ON TRIGE MIN OVA SCU LAR MECHANISMS AND ITS POSSIBLE RELATIONSHIP WITH MIGRAINE HEADACHE

Spreading depolarization (SD), also known as Leão’s cortical spreading depression (Leao, 1944; Somjen, 2005), is a neurovascular phenomenon widely accepted as the pathophysiological substrate of migraine aura and has been proposed as an endogenous trigger of headache pain (Brennan & Pietrobon, 2018; Charles & Baca, 2013; Dreier & Reiffurth, 2015; Lauritzen, 1994; Noseda & Burstein, 2013). SD, which in animals can be induced by focal stimulation of the cerebral cortex, is a slowly propagating wave of neuronal depolarization and glial activation, followed by several minutes of inhibition, and in close association with multiphasic vascular changes (Dreier & Reiffurth, 2015; Hartings et al., 2017; Parker et al., 2021; Piilgaard & Lauritzen, 2009). Early functional imaging studies during migraine attacks showed a propagation of cortical oligemia followed by hyperemia, involving widespread areas of the cortex (Olesen et al., 1990; Woods et al., 1994). These studies were followed by a report showing a temporal correlation between changes in blood oxygenation level-dependent (BOLD) signals within the occipital cortex and the perception of visual aura (Hadjikhani et al., 2001). Altogether, these initial observations provided strong evidence linking migraine aura and SD, but the relative contribution of peripheral versus central mechanisms in migraine headache features and associated symptomatology has not been clearly established.

Functional studies performed in anaesthetised rodents suggest that SD waves trigger peripheral, bottom-up mechanisms that involve the release of pro-inflammatory mediators and local neurogenic inflammation that enhances meningeal nociceptors excitability (Bolay et al., 2002; Carneiro-Nascimento & Levy, 2022; Zhang et al., 2010). SD is also capable of altering, via central mechanisms, the activities of Sp5C neurons that convey messages to thalamocortical areas involved in headache processing (Noseda et al., 2008; Noseda, Constandil, et al., 2010). The existence of top-down monosynaptic connections conveying descending control from the cortical pain matrix onto Sp5C neurons was determined by combining anatomical and functional studies. For instance, restricted, lateralized regions within the rat primary somatosensory (S1) and insular (INS) cortices send descending projections confined to medullary areas receiving direct input from the ophthalmic branch of the trigeminal nerve (Figure 1). Functionally, SD induced from INS and S1 elicited corticofugal modulation in a differential manner, by evoking an enhancement and an inhibition of Sp5C neurons responding to meningeal nociception, respectively (Noseda, Constandil, et al., 2010). Such corticofugal mechanisms could contribute to the development of migraine headache in terms of topographic localization, laterality and ‘pain tuning’ during an attack, since SD triggered from the primary visual cortex (V1) selectively affects interoceptive (meningeal) over exteroceptive (cutaneous) nociceptive responses of Sp5C neurons (Malmierca et al., 2014; Noseda, Constandil, et al., 2010). These findings shed new light on the role of corticofugal mechanisms as a direct link for topographically organized, differential, ‘top-down’ processing mechanisms that modulate trigeminovascular activities at the origin of migraine.

S1 and INS cortices are major targets of medullary trigemino-thalamic nociceptive afferents (Craig, 2004; Noseda et al., 2008). In humans, S1 and INS have been implicated in migraine attacks (Borsook et al., 2016; Youssef et al., 2017), and direct INS electrical stimulation can elicit headaches (Afif et al., 2008; Hotolean et al., 2021) probably by central mechanisms, since the spread of current to the meninges seems unlikely. Accordingly, the pain elicited by electrical stimulation of the insula was often bilateral or contralateral to the stimulation, whereas stimulations of dura mater, falx, pia matter and small cerebral vessels induced sharp, intense and brief pains mainly in the sensory territories of the trigeminal nerve ipsilateral to the stimulus (Fontaine et al., 2018). A cortical involvement in triggering migraine attacks is also supported by data from patients with local seizures, experiencing migraine-like headache symptoms concomitant with paroxysmal EEG features, and cases of headache preceding the seizure (Cianchetti et al., 2013). More recently, an interesting study showed that seizure can trigger SD’s, and that the SD itself may serve as an effective antiseizure mechanism by limiting the spread and/or completely aborting epileptic activity (Tamim et al., 2021). The precise cortical mechanisms involved in these processes and how they can lead to headache are nevertheless, far to be fully understood.

7 |. CORTICAL SPREADING DEPOLARIZATION, MIGRAINE AURA AND CENTRAL MODULATION MECHANISMS INVOLVED IN MIGRAINE

A crucial unresolved issue is whether visual aura and migraine headache are parallel or sequential processes. Insights into this association was recently provided by a study employing in vivo functional ultrasound (fUS) imaging of relative cerebral blood volume (rCBV) in the rodent brain, which allows high spatial and temporal resolution for detection of transient hemodynamic changes (Montaldo et al., 2022). This study used fUS paired with local field potentials (LFPs) recordings to evaluate cortical excitability, and showed that a single wave of SD originating in the primary visual cortex was powerful enough to trigger a cascade of time-locked hemodynamic and sensory changes affecting S1 and INS ophthalmic fields (Bourgeais-Rambur et al., 2022). Accordingly, SD elicited an ipsilateral, multiphasic hemodynamic and electrophysiological response with an early phase consisting of concomitant increases of rCBV and LFPs. The transient hypoperfusion that followed, was correlated with neuronal silence, and then by a strong increase of rCBV while synaptic activities remained inhibited. LFPs and rCBV recovery period was lastly followed by a progressive increase in S1 and INS baseline activities and facilitation of cortical responses evoked by periorbital cutaneous receptive fields stimulation. Such sensitization of cortical ophthalmic fields by SD was bilateral, occurred with precise spatiotemporal profiles and was significantly reduced by pre-treatment with Memantine, an NMDA antagonist, supporting the idea linking SD-induced changes of rCBV with electrophysiological markers of central sensitization. This concept is supported by another functional study in rodents using simultaneous measurement of S1 excitability and hemodynamic changes during somatosensory stimulation, in which SD alters both electrophysiological and hemodynamic cortical maps in S1 by enhancing evoked responses at the receptive field centre but suppressing them in surrounding regions (Theriot et al., 2012). Interestingly, in a genetic mouse model of migraine with aura, it was shown that ‘plumes’ of glutamate release are a consequence of inefficient glutamate clearance, and a flurry of plumes precedes the onset of SD at its origin, while also inducing plumes as it propagates through the cortex (Parker et al., 2021). This mechanistic insight correlates with clinical studies showing that Memantine, as compared to other NMDA antagonists, is well-tolerated in preventive trials and significantly reduces headache frequency with few side effects (Bigal et al., 2008; Charles et al., 2007). A link between SD, visual aura, migraine, and NMDA activation is further supported by the reduction of aura with NMDA blockade and the decrease in the severity of migraine attacks (Afridi et al., 2013).

The complexity of interactions between signalling and modulation mechanisms observed in rodents may explain clinical observations that a simple cause-effect relationship between SD and migraine headache seems unlikely (Dreier & Reiffurth, 2015). This is well-illustrated in human studies using experimental induction of migraine with aura, in which Levcromakalim, an ATP-sensitive potassium channel opener, triggers aura and headache (mostly bilateral) via separate pathways activated by a common mechanism (Al-Karagholi et al., 2021). Although the laterality of the headache was reported in that study, it was not analysed in association with aura laterality, suggesting that it is difficult to establish a clear topographical (spatial) and temporal relationship between SD and headache. Adding support to this concept, the experimental triggering of a single wave of SD in the rodent V1 exhibits a unilateral spread, but its effects in cortical plasticity are bilateral and involve NMDA processing mechanisms (Bourgeais-Rambur et al., 2022). Bilateral effects may result from interactions between mirror-like transcallosal connections established between S1 and INS ophthalmic fields, as well as top-down corticofugal influences, particularly the anatomically-and functionally connected cortico-trigeminal pathways acting as modulators on the same Sp5C neurons that process bottom-up activation of meningeal nociceptors (Noseda, Constandil, et al., 2010). Therefore, sensitization of the cortical pain matrix following SD appears as a sequential maladaptive plasticity process that progressively turns trigeminovascular nociceptive networks into a novel, dysfunctional state.

As reviewed above, during migraine headache attacks, a complex interplay occurs between bottom-up mechanisms triggered by meningeal nociceptors activation and top-down, corticofugal modulation. The pioneer back-forward translational work of Le Bars and colleagues on Diffuse Noxious Inhibitory Controls (DNIC) (Le Bars et al., 1979; Willer et al., 1984) showed that bottom-up and top-down nociceptive mechanisms are interdependent, since they are simultaneously brought into play by painful stimuli of varied origins, eliciting widespread descending inhibitory controls via negative feedback loops acting on the spinal dorsal horn and Sp5C neurons (Villanueva et al., 1996). The anatomical and functional features of DNIC are shared by animals and humans, as shown by lesions of the subnucleus reticularis dorsalis (SRD) in the caudal medulla reducing DNIC (Bouhassira et al., 1992; Broucker et al., 1990). Additional studies in the human showed that DNIC mediates the ‘pain inhibits pain’ or ‘conditioning pain modulation’ (CPM) phenomenon, which refers to any approach based on the application of a localized painful stimulation that produces a diffuse analgesic effect beyond the stimulation period and body location, regardless of the site of application (Damien et al., 2018).

CPM-elicited pain inhibition is reduced in trigeminal painful conditions including temporomandibular disorder (King et al., 2009), atypical trigeminal neuralgia (Leonard et al., 2009) and chronic tension-type headache (Cathcart et al., 2010; Pielsticker et al., 2005; Sandrini et al., 2006). These observations suggest that the reduced ability to inhibit pain in these chronic patients could be mediated by a maladaptive dysfunction of the CPM system (for reviews see Damien et al., 2018; Lewis et al., 2012; Yarnitsky, 2010). However, CPM studies in migraineurs have shown either impaired (Nahman-Averbuch et al., 2013; Sandrini et al., 2006) or no differences in CPM magnitude between patients and controls (Coppola, Clemente, et al., 2007; Perrotta et al., 2009; Teepker et al., 2014). It has been suggested that such inconsistency may be due to different CPM-evoking methodologies, and/or to inhomogeneous changes in CPM magnitude in migraineurs, as measured in the interictal period (Kisler et al., 2018). This concept is reinforced by the reported association between CPM magnitude and pain level during an attack after treatment with pain-relieving drugs (Kisler et al., 2018; Nahman-Averbuch et al., 2013).

The existence of patients’ subgroups with different types of CPM dysfunction could be dependent on the bidirectional ability of a population of medullary neurons in the SRD to regulate spinal nociceptive processing via corticofugal modulation, since SRD receives strong, direct descending influences from cortical regions (Desbois et al., 1999) involved in pain inhibition by CPM. In an attempt to identify the cortical sources of CPM variability, a combined brain imaging and psychophysical study in healthy volunteers showed that under certain experimental conditions, nearly half of individuals responded to a conditioning stimulus eliciting analgesia. Interestingly, CPM-responding subjects had no change in functional connectivity between the cortex and SRD. In contrast, a lack of CPM was related to stronger functional connectivity between dorsolateral prefrontal and mid-cingulate cortices with SRD, suggesting altered Cortico/SRD modulation from areas involved in cognitive and emotional processing. The engagement of the prefrontal and cingulate cortices prevents the generation of CPM analgesia, raising the possibility that altered responsiveness in these cortical regions underlies the reduced CPM observed in individuals with chronic pain (Youssef et al., 2016a). CPM magnitude has also been correlated with a reduction in signal intensity increases during each test stimulus in three brainstem regions: the Sp5C, SRD and the Parabrachial nucleus (Youssef et al., 2016b). In agreement with these imaging findings, studies in rodents have shown that the facilitation of spinal nociception from the anterior cingulate cortex (ACC) is relayed by direct influences onto SRD cells (Zhang et al., 2005) and from ACC to the periaqueductal grey matter (PAG), a pivotal region known to modulate Sp5C activities via SRD and RVM neurons (Kobayashi, 2012). In humans, BOLD signal strength and higher resting functional connectivity between the PAG and cortical pain processing regions correlate with greater CPM efficacy (Harper et al., 2018). Also, several cortical regions belonging to the so-called ‘pain matrix’ contribute significantly to the regulation of CPM networks located downstream during the analgesia produced by CPM (Moont et al., 2011; Piché et al., 2009; Sprenger et al., 2011), which could explain why the expectation of hyperalgesia can block CPM in healthy volunteers (Goffaux et al., 2007).

Another factor accounting for the variability in endogenous pain modulation in migraineurs may relate to their unique dynamics of trigeminal responses to noxious stimuli throughout the migraine cycle, as shown by Stankewitz et al. (2011) using BOLD signals in migraineurs interictally. They observed that the activation pattern of cortical and subcortical structures was not different from controls and that the only differences were measured within the Sp5C. Interestingly, migraine patients showed lower activation in the Sp5C at interictal periods, whereas, in the pre-ictal phase, activities were similar to controls. By contrast, during the acute spontaneous migraine attack, lower signal intensities were again detected in Sp5C, similar to the activities measured during the interictal phase. These findings suggest that excitability levels in the spinal trigeminal nucleus of migraine patients tend to oscillate from an abnormal hypoexcitable state to a progressively increased or hyperexcitable pre-attack state that could predispose to the next attack. Interestingly, the temporal pattern of activation within regions of the dorsal pons during the headache phase led the authors to propose that this region could act as a ‘migraine modulator’ instead of a ‘migraine generator’, the latter role being played by the oscillating behaviour of Sp5C since its activity increases as the headache starts.

8 |. CONCLUSIONS

The neural pathways conveying meningeal interoceptive signals simultaneously collect information from many sources. The functional basis of this anatomical unit, which integrates sensory and autonomic activity, is not only relevant for migraine but could have a role in the continuous selection, transmission and modulation of multimodal information to maintain the integrity of craniofacial tissues. Under normal circumstances, central trigeminovascular neurons convey a variety of signals originating either from the external environment through the skin or the internal milieu through the meninges. These signals, necessary for homeostasis, reach the bulbar and telencephalic regions that in turn enhance or reduce the activity of the trigeminovascular system.

A particular feature of migraine attacks is that they may occur, or cease, independently of any identifiable external, tissue-damaging event. Indeed, primary headaches do not fit with the classical statement related to exteroception, viz. that ‘injury generates pain and pain implies injury’. Migraine states depend on internal, homeostatic dysfunctions in genetically susceptible individuals, subserved by disturbances of biological rhythms and abnormal excitability phenotypes of restricted areas of the CNS that modulate trigeminovascular processing. The question remains about the central origins of the special susceptibility to neuronal sensitization and the topographic specificity in pain gating, unique to migraineurs. The initial triggering probably occurs via hypothalamic enhancement of dural afferents excitability via parasympathetic preganglionic influences, under the regulation of biological rhythms and comorbidities. Once the migraine attack is triggered, its location could be generated by descending lateralized cortico-trigeminal projections that modify and amplify, in a selective way, meningeal inputs conveyed by Sp5C neurons.

Over the last 40 years, Triptans and CGRP-targeted drugs have been the two main groups of substances designed to abort at the meningeal level, the initiation of the migraine attack. As reported by the sumatriptan’s discovery team, early research on triptans was based on the idea that vasodilators can induce migraine-like attacks only in susceptible individuals and vasoconstrictors can abort them. For them, it was crucial to focus on the pharmacology of methysergide, a drug that selectively constricts the carotid arterial bed, which led to the working hypothesis that methysergide acted on an undiscovered serotonin receptor present on cerebral blood vessels, but not in the periphery, opening the way to sumatriptan discovery (Humphrey, 2001). Since serotonin 5HT1B/1D receptors mediating triptans actions are present on both peripheral and central axonal branches of meningeal nociceptors, but absent in Sp5C neurons, it is possible that the main site for triptan’s action against migraine headache is located outside the CNS (Edvinsson & Tfelt-Hansen, 2008; Levy et al., 2004).

Successful development of CGRP-targeted treatments with receptor antagonists or antibodies has revealed the crucial role of this neuropeptide in migraine headache triggering. It has been proposed that blocking CGRP transmission within the trigeminal ganglion is sufficient to abort or prevent migraine attacks (Edvinsson et al., 2018). This proposal is based on observations that CGRP-acting drugs have little or no ability to cross the blood brain barrier (BBB) (Christensen et al., 2020; Hargreaves & Olesen, 2019; Johnson et al., 2019; Noseda et al., 2020); CGRP receptors are expressed in the smooth muscle of dural vessels, causing vasodilation (Russell et al., 2014); dural primary afferents are inhibited by substances that block CGRP actions (Logu et al., 2022; Melo-Carrillo et al., 2017; Strassman et al., 2022); and the sphenopalatine ganglion express CGRP, its receptors and is located outside the BBB (Khan et al., 2013).

Since CGRP-r elated drugs effective for treating and preventing migraine attacks have negligible access to the CNS, and the trigeminovascular areas located outside the CNS containing CGRP and 5HT1B/1D receptors are modulated by PVN, it is possible that migraine triggering process starts centrally, within the PVN, by increasing meningeal excitability via its influence on peripheral autonomic ganglia and direct excitation of Sp5C neurons. Alterations in biological rhythms mediated by SCN influences on PVN-mediated modulation of peripheral and central activities could also account for the cycle-dependent variations in the efficacy of anti-migraine drugs. In this regard, it has been proposed that ictal allodynia has an important impact on the efficacy of triptans (Burstein et al., 2004). Interestingly also, the presence/absence of non-ictal allodynia has been used in migraineurs to identify responders versus non-responders to treatment with the monoclonal antibody against CGRP galcanezumab, with nearly 80% accuracy (Ashina et al., 2023).

Preclinical research on migraine mechanisms should be further developed considering the crucial role of central, nociplastic states in the triggering and maintenance of primary headaches. Novel models employing awake, drug-and surgery-free rodents are in current development, which will allow further assessment of CNS maladaptive plasticity changes at different cortical and subcortical levels by combining high spatiotemporal resolution imaging, electrophysiology and optogenetic manipulations of the different CNS modulation networks. Modern approaches are thus, crucial for better understanding the pathophysiological association between peripheral and central trigeminovascular mechanisms involved in pain initiation, treatment response, and evolution of migraine and other primary headache states, in a sex-and age-dependent manner. The crucial challenge thus remains to find the best way and time to prevent or revert the dysfunctional ‘brain matrix’ to an operating state, liberated from pain.

Footnotes

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

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