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In past years, several studies evidenced neurophysiologic dysfunctions in sporadic episodic (during both the ictal and the interictal period), and chronic migraine patients. These dysfunctions could reflect a genetic susceptibility that exposes patients to recurrence of migraine attacks. Recently, several studies were performed in order to explore the role of genetic polymorphisms on neurophysiologic dysfunctions that were already known to be related to migraine. These studies evidenced that neurophysiologic features, such as interictal habituation deficit and ictal response sensitization, are influenced by genetic polymorphisms involved in neural plasticity (brain derived neurotrophic factor [BDNF]), in vascular homeostasis (angiotensin converting enzyme [ACE] and methylenetetrahydrofolate reductase [MTHFR]), and in monoaminergic modulation (monoamine oxidase type A [MAO-A]). Moreover, we have recently found that a glutamatergic polymorphism, Glutamate receptor ionotropic AMPA 3 (GRIA3), already known to be related to central sensitization mechanism and then to migraine pathophysiology, can also influence neurophysiologic features of chronic migraine due to medication overuse. The study of the influence of genetic polymorphisms on migraine-related neurophysiological dysfunctions could be regarded as an “in vivo” human experimental model in which the different genetic background could predict different neurophysiologic “endophenotypes”. This experimental model could lead to understand, for instance, the way different drugs act on migraine, or to unveil in which way some risk factors, such as for instance drug overuse, induce transformation from episodic to chronic migraine.

The molecular and cellular mechanisms of the primary brain dysfunction leading to the onset of a migraine attack and to susceptibility to cortical spreading depression (CSD), the neurophysiological correlate of migraine aura and a likely trigger of the headache mechanisms, remain largely unknown and major open issues in the neurobiology of migraine. Our approach to these open questions is the study of the functional consequences of mutations causing familial hemiplegic migraine type 1 and type 2 (FHM1 and FHM2). FHM1 is caused by gain-of-function mutations in the neuronal CaV2.1 channel, a voltage-gated calcium channel that plays a dominant role in controlling neurotransmitter release at brain excitatory and inhibitory synapses. FHM2 is caused by loss-of-function mutations in the glial alpha2 Na/K-ATPase, an isoform that is thought to have specific roles in K+ and glutamate clearance by astrocytes and in astrocyte Ca2+ homeostasis. Knockin (KI) mouse models carrying FHM1 or FHM2 mutations show a lower threshold for CSD induction and a higher velocity of CSD propagation. We have investigated the cortical mechanisms underlying the facilitation of experimental CSD in FHM1 and FHM2 KI mice by studying synaptic transmission at cortical excitatory and inhibitory synapses and the rate of glutamate and K+ clearance by cortical astrocytes in acute cortical slices. Our findings are consistent with the conclusion that increased activation of NMDA receptors due to enhanced cortical glutammatergic synaptic transmission in FHM1 and to reduced rate of glutamate clearance at cortical excitatory synapses in FHM2 contributes to the facilitation of CSD in FHM KI mice. The data from FHM mouse models support the view of migraine as a disorder of brain excitability characterized by dysregulation of the excitatory-inhibitory E/I balance, and point to episodic disruption of the E/I balance and neuronal hyperactivity due to excessive recurrent glutammatergic transmission as the basis for vulnerability to CSD ignition in FHM.

Chronic migraine (CM), a highly disabling condition affecting 2-3% of the general population, represents a difficult-to-treat disorder for its unclear pathophysiology, complex comorbidities, and disappointing response to available pharmacological treatments[1]. High quality evidence (≥2 RCTs) recommends the prophylactic use of onabotulinum toxin A (155-195 IU) and topiramate (100 mg) in CM, while lower quality evidence (1 RCT) supports the treatment with sodium valproate (800-1500 mg), gabapentin (2400 mg) and tizanidine (18 mg)[2]. Amitriptyline, memantine, zonisamide and pregabalin may also be of help in CM but their use has been suggested only in open studies[2]. CM patients may show poor or no response to preventative therapies. The consensus statement of the European Headache Federation (EHF) defines CM refractory to treatment (rCM) when it does not respond to adequate dosages of at least 3 drugs from the classes of beta-blockers, anticonvulsants, tricyclics, onabotulinum toxin A and others (e.g., flunarizine, candesartan) for at least 3 months each, in absence of medication overuse[3]. This rCM definition has been questioned by some authors who stressed the need of using drugs from different classes, not limited to 3, before making rCM diagnosis[4]. Labeling a patient as affected by rCM may profoundly modify his/her life with heavy psychological, social, work and medico-legal consequences, potentially leading to expensive and still unsatisfying surgical procedures such as occipital nerve stimulation[5]. We point out the risk that the current rCM EHF definition could indeed also include pseudo-refractory CM patients, due to potential bias: firstly, a significant proportion of CM patients may spontaneously reverse to episodic migraine, as clearly evidenced in population-based study[6]; secondly, rCM patients may present underlying psychiatric disturbances (e.g., personality disorders) not easily recognized, classified and treated by headache specialists; thirdly, rCM diagnosis could be biased by unproven evidence as current rCM criteria do not specify who should attest patient's previous headache history (theoretically self-reported or stated by unqualified physicians). We suggest that 1) rCM is probably more rare than presently stated; 2) before formulating a diagnosis of rCM, psychiatric disorders should be carefully ruled out by appropriate and thorough psychiatric investigations; 3) when assessing CM patient's past medical history, only clinical data coming from certified headache centers should be considered; 4) CM patients should be followed up for an adequate period of time before making a definite rCM diagnosis.

Migraine with (MA) and without aura (MO) is a common brain disorder that affects 15% of the general population. Genetic studies on twins have shown that MA and MO heritability spans between 50% and 60%[1]. Despite the high degree of heritability the genetic basis of MA and MO has not been elucidated and on the whole their etiology is far from being resolved. Several years ago it has been hypothesized that also epigenetic mechanisms such as DNA methylation, miRNA and histone modifications could play a relevant role in MA and MO. In particular epigenetic mechanisms have the potential to link early life events, neuro-inflammation and estrogen activities in the etiology of migraine and in its chronification[2] and pharmaco-epigenetics could be implicated in the wide spectra of different drug treatment responses[3]. In recent years the technologies for studying nucleic acids have literally exploded, opening to new possibilities for study of genetics and epigenetics of MA and MO[4]. One of the most significant results is the sharp cost decrease for the whole genome DNA sequencing, since the psychological threshold of 1000$ for a 30X genome is about to be achieved. This cost reduction is fostering a wealth of large sequencing campaigns that will allow overcoming all the limitations due to the poor knowledge of human genetic variability that has plagued the ability of identifying the genetic basis of all sporadic diseases including MA and MO[5]. The reduction of nucleic acids sequencing costs and the availability of cost effective microarray solutions for the analysis of DNA methylation has favored the implementation of epigenomic studies, in particular DNA methylation microarray has been thoroughly used providing new insight regarding the variability and the role of such epigenetic agent. DNA methylation, miRNA and histone modifications have proven to be a potential source of powerful and robust biomarkers. Taken together both the new genetic and epigenetic omic approaches have the potential to provide new molecular insight in the etiology of MA and MO. Moreover from such approaches we expect to obtain tools to improve migraine diagnosis, patient stratification, and therapy.

Neurostimulation has been used in pain management for a long time. Several neuromodulatory surgical techniques were developed to manage headaches unresponsive to medical treatment, in particular for preventive treatment. Recently, novel non invasive neurostimulation approaches have been used successfully for different forms of headache: they represent a promising opportunity in headache management useful for acute and preventive treatment of migraine. Among the different non invasive approaches, transcutaneous supraorbital electrostimulation device (Cefaly), transcutaneous magnetic stimulation (TMS), transcranial electrical stimulation (t DCS), and non-invasive vagus nerve stimulation device (n VNS) have shown efficacy in a consistent number of pilot studies (lack of placebo condition). Vagus Nerve Stimulation (VNS) was a well known surgical procedure approved for treatment of refractory epilepsy and depression, with a peripheral mechanism of action. It has been used in selected intractable migraine cases if associated with comorbid depression, with promising results. A hand-held patient controlled non-invasive vagus nerve stimulation device (Gammacore) has been developed to treat migraine attack and has contributed to an easier treatment of migraine episodes. Goadsby et al reported significant results from treatment of migraine attacks by non-invasive transcutaneous vagal nerve stimulation in a population of 30 patients with a 2-hour pain-free rate of 22%. In our open-label, single arm, multiple attack, 27 patients, 18-65 years old, with a diagnosis of migraine without aura according to the IHS beta 2013 classification, with a high frequency, were enrolled and participated in the study with 112 attacks treated. Treatment consisted of one stimulation, 90-second dose, delivered to the right cervical branch of the vagus nerve. In forty-four attacks (39.2%) 9 resolved within 30 minutes; 50 attacks (44.6%) did not resolve in the first 2 hours, so patients used rescue medication; in 18 attacks (16.2%) there was no complete resolution of pain, but a significant relief in the first 2 hours (40% in the VAS scale) and patients did not use any rescue medication. No adverse events were recorded, the therapy was well tolerated. Non-invasive vagus nerve stimulation (nVNS) offers a novel approach to acute migraine attack. For patients with high frequency of migraine attacks, nVNS may represent a suitable tool to decrease the risk of medication overuse. The variety of non-invasive neuromodulatory approaches has opened new strategies for treatment of patients suffering from drug-refractory forms of headache. Randomized sham controlled studies and larger and multicentre trials are needed in order to determine the optimal dosage and to clarify the mode of action.

The use of diagnostic imaging in the evaluation of patients with headache is an almost mandatory step. Although there are specific conditions (the so-called red flags) indicating the need of diagnostic imaging, daily experience shows that a study of the brain and, often, of the intracranial vessels, is part of the routine of many of these patients. The most common and appropriate study is the MRI integrated with the angiographic evaluation (MRA). An MRI and MRA, properly performed, are able to exclude most of the organic pathologies potentially causing headache. The list of these conditions is long and not useful in this context. It is important to remember that significant MRI changes are found in about 4% of patients with chronic headache but this percentage can rise up to 14% in the atypical forms. The MRI evaluation also allows to define whether the patients, especially the young ones, have a condition of brain signal alterations (multiple bright spots). Some studies reported that these are more frequent in patients with migraine especially with aura and mostly in females. The clinical significance and role of these changes remains to be proven. Another approach of imaging is related to the possibility of assessing, by means of functional studies, the pathophysiological moments responsible for the symptoms. These studies are based mainly on functional MRI which includes cerebral perfusion, cortical activation (induced or by means of resting state techniques) and metabolic studies with spectroscopy. The last approach is the one that assesses the consequences of long standing symptom analyzing morpho-volumetric brain “in toto” or inside the cerebral cortex. These are techniques like computed voxel based morphometry (VBM) or Free Surfer able to evaluate small volumetric changes between groups of healthy subjects and patients.