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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 38  |  Issue : 2  |  Page : 81-89

Migraine and frontostriatal circuit disorders: What have we learned until now?


1 Department of Neurology, Algology and Clinical Neurophysiology, Mersin University School of Medicine, Mersin, Turkey
2 Department of Neurology, Van Research and Education Hospital, Van, Turkey
3 Department of Child and Adolescent Psychiatry, Mersin University School of Medicine, Mersin, Turkey
4 School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey

Date of Submission15-Jan-2021
Date of Acceptance03-May-2021
Date of Web Publication15-Jun-2021

Correspondence Address:
Gülen Güler Aksu
Department of Child and Adolescent Psychiatry, Mersin University School of Medicine, Mersin
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/nsn.nsn_9_21

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  Abstract 


Even though there is a recognized association, the causation between chronic migraine (CM) and frontostriatal circuit (FSC) disorders that were commonly presented as anxiety disorders, depression, tic disorders, and attention-deficit hyperactivity disorders in routine headache outpatient is yet to be fully disclosed. Medication-overuse headache (MOH) and CM recognizedly affect complex neural systems, including the FSC. Referenced circuits constitute a part of a circle that consists of the cortex, striatum, and thalamus regions and they transmit the data from the cerebral cortex to the subcortex. The above-mentioned circles end up once again in the determined region of the cerebral cortex. Five different FSCs have been described above which circulate among the specific parts of the cortex, namely supplementary motor area, frontal eye fields, dorsolateral prefrontal cortex, lateral orbitofrontal cortex, and anterior cingulate cortex with various subconnections and serve to various functions. Based on the scientific data with an emphasis on the clinical perspective, this paper aims to show the potential causative relationship between common FSC disorders and CM with or without MOH. The results also highlighted the importance of psychiatric comorbidities, as being far from a coincidence, and promoted the application of preventive medicine and interventions including lifestyle changes, cognitive–behavioral treatment, and neuromodulation. Integrative and multidisciplinary management strategies are essential for a comprehensive migraine coping approach in the society.

Keywords: Anxiety disorders, attention-deficit hyperactivity disorders, constant headache, depression, headache, medication-overuse headache, migraine, tic disorders


How to cite this article:
Ozge A, Genç H, Aksu GG, Uludüz D. Migraine and frontostriatal circuit disorders: What have we learned until now?. Neurol Sci Neurophysiol 2021;38:81-9

How to cite this URL:
Ozge A, Genç H, Aksu GG, Uludüz D. Migraine and frontostriatal circuit disorders: What have we learned until now?. Neurol Sci Neurophysiol [serial online] 2021 [cited 2021 Sep 18];38:81-9. Available from: http://www.nsnjournal.org/text.asp?2021/38/2/81/318499




  Introduction Top


Utilitarian anatomic foundation of frontostriatal circuits

There is restricted information about the causative connection between frontostriatal circuits (FSCs), pain matrix, and, in particular, migraine-like headache disorders. However, current neuroanatomical, neuropsychological, and functional imaging research demonstrated substantial evidence based on the data obtained from the subcortical structures as they generate more advanced cerebral functions such as controlling cognition, making decisions, developing more complicated behavioral patterns of complex nature, and various neuropsychiatric symptoms including migraine-associated behavioral changes and medication overuse.[1] Substantially frontal–subcortical circuits or in the other words “FSCs” are known to serve as a functional link from defined regions of the frontal cortex to the striatum, globus pallidus (GP) and substantia nigra (SN), and thalamus occasionally together with specific connections with subthalamic nuclei (STN) and specific brainstem areas.[1],[2],[3] [Table 1].
Table 1: Functional anatomic components of five main frontostriatal circuit[1],[2],[3]

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The aforementioned five circuits therefore are comprised of basic patterns which are parallel and approximal; on the other hand, they remain remarkably segregated anatomically with a topographic organization, even though subsequent projections are focused continuously on smaller numbers of neurons.[2] Circuit structures assume projections from noncircuit cortical areas, thalamic nuclei, and the amygdala nuclei, and also stand out in the regions outside the five circuits, involving inferotemporal, posterior parietal, and prestriate cortex. The parts of the brain occupied by these afferent or efferent projections are organized in a functional manner. This complex structure explains the reason for complex behavioral reactions.[3]

Frontostriatal circuits physiology and neurochemistry on the focal point of orbitofrontal circuits

Circuits work through similar principles. Each one has two major pathways: first, a direct route, in place of a monosynaptic link between the Globus pallidus interna (GPi)–SNr complex and the second, an indirect route that extends from striatum to Globus pallidus externa (GPe), linking to the GPi–SNr complex using STN.[4],[5]

This system fundamentally implies that D1 receptor of dopamine (orange line), D2 receptor of dopamine (red spot), excitatory glutamatergic (green line and spots), and inhibitory GABAergic (red line) networks. As appeared in [Figure 1], the last pathways start from thalamus to frontal cortical regions which are glutamatergic and working as excitatory.[6]
Figure 1: Summary of frontostriatal circuit network

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Dorsal striatum has two primary cytochemical parts named striosome and matrix. Among them, matrix has explicit connections from sensorimotor cortex, parietotemporo or parieto-occipital association cortex, and cingulate gyrus.[6],[7] In any case, GABAergic inputs originate from GPi, GPe, and SN of matrix. Chronic pain disorders have different effect on matrix and striosomes not only chemical but also neurobehavioral consequences.[7]

There are several neurotransmitter systems on FSCs depending on the challenging function. Dopaminergic pathway started from SN and anticipated to the striatum and they are influenced entire of the frontosubcortical capacities. Dopaminergic pathway organized depending on the receptor subtype of the network. Cholinergic interneurons that started from Meynert's basal nuclei are situated on striatum and primarily manage thalamic activation. Acetylcholine increases striatal dopaminergic motion of striatum by means of presynaptic nicotinic and muscarinic receptors. Then again, serotonin (5-HT) receptors disperse various degrees of FSCs with various subtypes. There is a causative connection between FSC dysfunction and synapse dysregulations. In addition, glutamate serves through the corticostriatal or thalamocortical system on NMDA receptors as excitatory pathways. It is firmly identified with striatal dopaminergic motions and corresponding relationship to acetylcholine, including direct and indirect FSC networks. Another significant neurotransmitter is GABA, the primary synapse of direct pathways started from the thalamus to SN or GPi lastly cortical areas.[6],[8],[9],[10] [Figure 2].
Figure 2: Hierarchical network of frontostriatal circuits on pain matrix on neurobehavioral responses

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Low 5-HT levels increase the marking and arrival of calcitonin gene-related peptide from the trigeminal ganglion and refine trigeminal nociceptors.[11] Along these lines, the disorder in the central modulation of the trigeminal system as a consequence of chronic medication use may elevate sensitivity toward the perception of pain and trigger or intensify headache caused by medication overuse.[11]

Pain matrix and focal coordination of pain

Even we know about the central aspect of the pain, the current neuroimaging and neurophysiological researches have displayed that nociceptive stimuli reveal reactions in cortical network in a comprehensive manner encompassing somatosensory insular and cingulate areas, especially frontal and parietal sections with great connectivity. This complex network, often referenced as the “pain matrix,” is regarded as the activity characterized by the intensity and unpleasant nature of the perception caused by a nociceptive stimulus, including headache.[11],[12]

As a legitimization of the contention that this system is especially engaged with the impression of pain, researchers often raise the following arguments:

  1. The intensity of the pain perceived is in strong correlation with the magnitude of the neural responses in the “pain matrix;” the question still lies in headache attacks like migraine?[12],[13]
  2. The factors adjusting pain likewise curve the size of the neural reactions in the “pain matrix.” In this manner, the activity of that network shall introduce itself as a “representation” or a “stamp” of pain in the brain, and therefore, shall shed light on the researches in the fields of neural processes, fundamental pain function, and dysfunction or comorbidities in humans. The question still lies in chronic headache disorders, for example, chronic migraine (CM).[12],[13]


Chronic pain disorders like CM or fibromyalgia predominantly elude aberrant salient systems in the processing of sense in the process of cognitive interpretation, integration, and modulatory processing.[14],[15],[16],[17] There are several clues for changed activation of salience network in CM compared to episodic migraine (EM) attacks[2],[18] [Table 2].
Table 2: Putative regions activation in chronic migraine[2],[18]

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CM patients displayed the enhanced activations of key salience regions particularly in the anterior insula and orbitofrontal cortex-related circuits. It is essential to highlight the fact that these patients were not in pain during the scan and were subject only to visual (not to somatosensory) stimuli, focusing on the multisensory parts of dysregulated salience processing in CM specifically.[19] In an ongoing report about gender-related factors in headache patients, various circuits were found in people (matched for age, disease, duration of headache, and management).[20] This could be interpreted that such alteration may tamper with the functioning of their salience networks. Indeed, these changes that were found in women entail the regions associated with salience such as the insula and precuneus highlighting the importance of pain matrix.[20] [Figure 3].
Figure 3: (a) Main networks of lateral orbitofrontal circuit loop. (b) Main networks of medial orbitofrontal circuit loop. Note. Blue lines represent orbitofrontal circuit loop and red lines represent pain matrix including chronic migraine

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It has been detected that an changed glucose metabolism before medication withdrawal in the territories identified with the pain network is in accordance with the research on imaging conducted in the other pain disorders including CM with or without medication-overuse headache (MOH).[21] In addition, its role in motor control and procedural memory cerebellum is known to have impacts on cognitive performances of patients with CM. The cerebellar vermis is also activated in patients with negative mood and has a potential role of having MO in migraine sufferers.[21]

Clinical aspect of migraine and psychiatric comorbidities on the road of frontostriatal circuit dysfunction

Migraine can be defined as significantly common as well as debilitating neurological disruption associated with a wide scope of psychiatric comorbidities far from being circumstantial such as migraine with aura, CM and in females.[22] There are clues which are apparently multifactorial, including either unidirectional causal explanations, though environmental and/or genetically negative elements can pose a threat in the formation of such disease as well as the reciprocal interactivity of the aforementioned factors with one another.[22] Furthermore, in accordance with a newly conducted extensive research on the genome-wide association, migraine displayed significant genetic correlation with psychiatric derangements highlighting common genetic bases or pathways supported by neurophysiological and neuroimaging studies.[22] All of the features mentioned above should be diligently scrutinized when taken into account diagnostic and therapeutic implications associated with migraine comorbidity using a specific practical tool, such as a comorbidity index for a patient-based specific definition.[22],[23],[24]

Migraine and depression

Given the previous reports on the connection of comorbidity among headache disorders including migraine and major depression, the presence of a bidirectional connection including 40%–50% genetic inheritance was indicated as a result of a polygenic foundation and several epigenetic triggers such as ecological changes, rest abnormality, and dietary or hormonal alterations.[22] Among the common neurochemical changes of migraine and depression comorbidity or casual relationship, 5-HT system plays a significant role, and a polymorphism in the 5-HT transporter gene has been associated with migraine in addition to depression, as supported by comprehensive data. On the other hand, migraine attacks management tools, namely triptans or lasmiditan, generally functions as 5-HT agonists. Without a doubt, selective serotonin reuptake inhibitors (SSRIs) may be used for prevention of migraine, especially in comorbidity cases, although the first-line preventive treatment does not cover those and is not recommended at all in the existing guidelines.[25] A secondary potential driver in the association between migraine and depression is the dopaminergic system as a dopamine D2 receptor genotype is fundamentally connected with comorbid migraine with aura, depression, and anxiety disorders including obsessive–compulsive disorder (OCD) and suicidal behavior, although D1 receptors are potentially linked to cognitive dysfunction.[26] Another potential neurotransmitter is lower GABA cerebrospinal fluid (CSF) levels in CM patients suffering from depression when compared to those without. It has likewise a significant role on the FSCs' internal neurons.[27]

All of the mentioned data supported a potential association between depression and CM is evident in the shared involvement of the hypothalamic–pituitary–adrenal (HPA) axis. Data obtained from various researches indicate a discrepancy between pro-inflammatory and anti-inflammatory cytokines leading to the unexpected increase of pro-inflammatory cytokines levels, which can be interpreted as a potential relationship between depression, migraine, atopic disorders, fibromyalgia, irritable bowel syndrome, obesity, and the progression from EM to CM, with primary disorders in tryptophan metabolism and serotonergic activation of the HPA axis.[25],[28],[29]

Current functional neuroimaging studies have suggested that increased activity of mOFC and ventromedial prefrontal cortex together with ventral striatum, amygdala, and hypothalamus showed not only in major depressive brains but also CM sufferers with or without suicide intention because of decreased quality of life.[30],[31],[32]

Migraine and bipolar affective disorder bipolar disorder

Bipolar disorder (BD) is described as a cyclical course of depressive and elevated mood swings. It is generally classified as BD Type I (at least one manic or mixed episodes) and BD Type II (at least one hypomanic, yet not reaching any full-blown mania).[33] In addition, the current information recommended that BD has an increasingly serious course when there is comorbidity with migraine supporting some shared genetic vulnerabilities and multifactorial polygenetic mechanisms have proved to verify the existence of such comorbidity.[33] It likewise focuses on a dysfunction in serotonergic, dopaminergic, and glutamatergic pathways in FSCs as well as in pain matrix, along with the cellular level, changes in specific sodium and calcium ion channels, and alterations in findings which may clarify the common action of antiepileptic drugs such as valproate and lamotrigine in both the disruptions.[33],[34] Another point is the possibility of pro-inflammatory cytokines playing a role in the migraine-BD comorbidity recommending that the comorbidity is not just a coincidence.[22],[33],[34]

Migraine and anxiety disorders including obsessive–compulsive disorders

Wide reported data conclude the fact that anxiety disorders including OCD, panic disorders (PDs), phobic disorders, and generalized anxiety disorder trigger migraine frequency, causing “dose-response” effect; the comorbidity between migraine and anxiety disorders is also reinforced through the overuse of medication.[22] When contrasted with people not suffering from migraine, patients with migraine are 1.2–9.6 times more likely to be diagnosed with PD, 0.11–1.1 more likely to be diagnosed with OCD, 1–2.3 more likely to be diagnosed with posttraumatic stress disorder, 0–0.8 more likely to be diagnosed with eating disorders, and 0–2.4 more likely to be diagnosed with recreational substance abuse.[22],[35]

Anatomical conclusions propose that variations from the norm in FSCs including the orbitofrontal cortex, anterior cingulate cortex, and striatum may lead to the advancement of OCD. Longitudinal study reports of child- and adult-onset OCD serve to understand the developmental trajectories which lead to these unique morphological findings in frontostriatal pathways in the research about children and adults with OCD.[36],[37] Supporting data suggested that inverse correlations of symptom severity with activity in the right orbitofrontal and dorsal anterior cingulate cortices during response inhibition on a go/no-go task support the fact that the patients who activated these regions most were better at suppressing their unwanted thoughts and compulsions.[36],[37],[38]

Migraine and PD potentially share an adjusted autonomic regulation in different terms.[22] A further means of association is somatization, which is ordinarily found in patients with PD and is likely to escalate the prevalence of somatic symptoms, including migraine headaches with or without MOH.[39] Other potential factors incorporate ovarian hormone variances, HPA axis dysregulation, and shared genetic influences.[40]

It is realized that OCD is a specific disorder of orbitofrontal circuits (OFCs) and associated with dACC and dorsal medial prefrontal cortex pathways and there are a significant number of connections with amygdala and OFC or mPFC recommending functional neuroimaging data. STN and ventral caudate have specific connections with the medial and lateral OFC; however, further neurochemical and supranuclear associations are yet to be completely revealed. These functional and chemical common pathways and receptor points also explain why SSRIs, serotonin noradrenergic reuptake inhibitors, TADs, lamotrigine, topiramate, and valproate additionally specific D2 receptor antagonists work both of anxiety disorders and CM with or without MOH. This is additionally a potential clarification for the potential action of cognitive–behavioral therapy (CBT) works for referenced disorders.[40],[41],[42]

Chronic migraine and medication overuse

The mechanism which leads to the progression from EM to CM remains unclear. Nonetheless, dysfunctions in endogenous pain modulation, changed cortical hyperexcitability, central sensitization, and MO have been suggested as factors which have an impact on this progression.[43],[44] It is closely related to a dysfunction of central sensitization or neurotransmitter changes supporting specific functional neuroimaging changes (changes in OFC and pain matrix) far from a coincidence. It is not only an issue for analgesic drugs but is also related to triptans, ergot drugs, or opioids.[43],[44] It is an issue since CM had a higher rate of somatic indications suggesting medication overuse rather than the intensity of headache, combined with headache frequency, probability of generating a psychiatric comorbidity.[22] There is supportive evidence about changed metabolic pathways between OFC and limbic cortex and pain matrix as well.[43]

MOH patients generally indicated less intense pain-related action over the primary somatosensory cortex, inferior parietal lobule, and supramarginal gyrus, in addition to the parts of the lateral pathway of the pain matrix. This movement activity returned to practically typical a half year after medication withdrawal.[11] This hypothesis has been supported by substantiating neuroimaging data which CM with MO patients, compared to CM without MO patients, had lower gray matter volume (GMV) in the orbitofrontal cortex and occipital lobe and higher GMV in the temporal pole/parahippocampus. This information was also upheld by positron-emission tomography (PET) examinations revealing that glucose metabolism was aberrant in the medial orbitofrontal cortex. Then again, the continuation of orbitofrontal cortex hypometabolism following medication withdrawal is obviously revealed, recommending that this change may support constant overuse of medical drugs and predispose some patients to a relapse of MOH.[21] The low GMV of the orbitofrontal cortex might mean atrophy and dysfunction of neurons resulting in poor and defective decision making and dependence behavior related to MO on account of other substance abuses.[21],[44],[45],[46]

Migraine and tic disorders

Tourette's syndrome (TS) (the most widely recognized clinical picture of tic disorder) and OCD are the most commonly researched disorders of self-regulation referenced to FSCs dysfunction. Tics in TS are commonly short, nonintentional, or semi-purposeful behavioral fragments frequently instituted in light of inner or outer tactile signals.[36] Actually, patients with TS also are influenced by OCD and migraine-like headache disorders. The distinctively compartmentalized cortical inputs and outputs of cortico-striato-thalamo-cortical circuits can indicate a neuroanatomical basis for the divergent discharge of either tics or compulsions from regulatory control in individuals with TS or OCD, respectively.[47],[48] Comprehensive neuroimaging-based evidence suggests that the pathophysiology of the two issues includes disruptions in the FSCs which imply the capacity for self-regulation. This dysfunction is likewise identified with some kind of dietary problem (for example, anorexia and bulimia) and migraine-like headache disorders.[36],[47],[48]

Attention-deficit/hyperactivity disorder (ADHD) and TS s are specific disorders with different operators significantly affecting the noradrenergic system and dopaminergic system, both alleviating at least some features of executive dysfunction related to dorsolateral prefrontal cortex dysfunction.[3],[49] Studies on PET and single-photon emission computed tomography claim that dopamine D2 receptors can be extremely perceptive in Tourette's disorder.[50] The above-mentioned results in line with the scientific journals indicating the administration of dopamine antagonists that alleviate tic severity reveal that hyperinnervation of the striatum by dopaminergic neurons can lead to the stimulation of the direct pathways.[36],[49] On the other hand, not only the diminished 5-HT levels of the CSF but also plasma measurements of TS with migraine is prominent than without migraine. There are additionally supported data about changed dopaminergic, GABAergic, noradrenergic, or opioidergic reactions in patients with TS along with migraine.[51],[52]

Epidemiological and clinical reports upheld that 45% of patients with TS have parents with headaches commonly migraine phenotype.[53] Despite the fact that hereditary linkage examination excluded 5-HT receptor gene abnormalities in patients with TS, a situation of migraine, OCD, and other potential comorbidities are unclear. Anyway, there are subtle areas on the mechanism and we know about the positive effect of the topiramate, botulinum toxin injections, and cognitive–behavioral therapies not only on isolated migraine or tic disorders but also on additional comorbidity.[53],[54]

Migraine and attention-deficit/hyperactivity disorder

ADHD is a developmental disorder characterized by excessive impulsive, hyperactive, and off-task (“inattentive”) behaviors causing either individually or in combination with or without additional medical problems like headache. Both of migraine and ADHD are multifactorial disorders genetical bases along with some known and unknown triggers potentially taken into consideration. Despite the fact that the neuronal basis of ADHD remains unclear, essential speculations recommend that ADHD is secondary to abnormalities in frontal–subcortical circuits.[55] Numerous specialists emphasized that the behavioral phenotype of impaired allocation of attention and inadequate inhibitory control can indicate the dysfunction of frontal–striatal–cerebellar circuits similar to the ones encountered in adult patients with gained lesions restricted to these regions.[55],[56] Likewise, volumetric magnetic resonance imaging (MRI) exhibits that the clinical portrait of ADHD exemplifies such malfunction stemming from bizarre advancement of both premotor and prefrontal cortices including nuc caudatus asymmetry, low ratio of GMV cerebellum, and increased GMV of posterior parietal cortex. Proofs from neuroimaging researches have reinforced these hypotheses revealing abnormalities at both subcortical and cortical levels and dysregulation of the dopaminergic neurotransmitter system in ADHD.[36],[55],[56]

In the light of the most current reports, migraine-type headache disorders were altogether progressively normal among children with ADHD and their mothers including high recurrence of intermittent abdominal pain disorders and motion sickness proposed a shared genetical basis.[57]

Aspect of cognitive–behavioral therapy

CBT is the most significant nonpharmachological approach for migraine and other primary headache disorders. CBT changes the remarks of well-established realities and stress conditions. These behavioral and psychological factors that increase or trigger the headache attacks are detected and changed.[58] Behavioral interventions in pain management help patients in understanding their cognitive reaction systems. Patients learn about the factors which trigger pain and stress. In addition, they learn to observe their intellectual, emotional, behavioral, and physical conditions and to test the positive and negative implications of their thoughts and behaviors while experiencing pain and stress.[58],[59] Consequently, by applying new thoughts and behaviors, the patient can prevent the formation of pain and the dysfunctions caused by the pain. There are multi-origin studies which report that behavioral therapy significantly reduces the duration, severity, and frequency of attacks in adult migraine headaches.[59],[60]

The mechanism of action in CBT is based on the pain-matrix theory. According to this theory, cortex, limbic system, basal ganglia, thalamus, hypothalamus, and brainstem are interconnected and they have an inter-modulating effect mentioned before.[61] Another aspect, neuromatrix theory is the developed version of the gate-control theory and was discovered by Melzack.[62] When the headache signal is processed in the brain, the emotions in the limbic system are activated with certain thoughts and memories in the somatosensory cortex. In this way, the person reacts emotionally when having a headache and experience certain feelings and/or thoughts during or after the pain.[63] Similarly, thoughts and emotions can activate the area of the brain which modulates the pain signal. In other words, patients can influence their pain experience with thoughts, memories, and emotions. That is how they can modify the peripheral and central nervous system physiology.[63],[64]

According to preliminary results of the functional MRI study, structural changes occur in the prefrontal cortex after an effective CBT therapy, and secretion of inhibitory neurotransmitters increases.[62],[63],[64]

Headache is a complex biopsychosocial experience that is affected by neurological processes and psychosocial factors. The attempt to define the biopsychosocial headache model required a multidisciplinary approach. CBT will be beneficial, particularly in treatment-resistant migraine cases.

Aspect of neuromodulation

Medications which focus on the orbitofrontal cortex, for example, repetitive transcranial magnetic stimulation have been successfully performed in patients with OCD.[65] Congruent methodologies might be applied on the patients with CM with or without MOH. Further researches combining imaging and interventions shall enable us to comprehend the neuroplasticity and pathogenesis of related headache disorders and the prospective role of pain matrix.[47],[65]


  Conclusions Top


Neuropsychiatric signs of neurodegenerative disorders, just as headache-related neurochemical changes, are closely associated with FSC dysfunctions. A variety of other neuropsychiatric disorders including CM comorbidities and MOH risk factors may be caused by the issues which have a direct or indirect influence on the integrity or functionality of frontal–subcortical circuits. Clinical evidence suggests the hypothesis of common neurochemical and neurophysiological dysfunctions as indicators of migraine and FSC disorders. The conclusion is drawn from neurophysiological, functional imaging, and neurochemical studies as described above. What should be taken into account is that the number of patients in some of these studies was rather low and experimental studies on OFC-pain matrix and migraine are limited. This hypothesis entirely supports the clinical studies that have been widely carried out. Through a multidisciplinary biopsychosocial approach, we believe that more effective solutions shall be obtained if prophylaxis is targeted rather than the attack relief. More evidence gathered through real-life experience; prospective data and comprehensive multidisciplinary extrapolation of findings are required.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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