Oxygen as an abortive therapy in cluster headache: a narrative review and clinical practice aspects.

Cluster headache (International Classification of Headache Disorders third edition, ICHD-3 3.1) is a primary headache disorder affecting around 0.12% of individuals. It is characterized by severe headache attacks causing significant negative impact on the lives of patients. While administration of 100% oxygen is considered to be the first-choice acute treatment, undertreatment also exists. Reasons for undertreatment may entail problems with the correct prescription of oxygen, reimbursement issues or the practical implementation of home oxygen therapy. The aim of this manuscript is to review the scientific evidence on oxygen therapy for cluster headache and provide a practical guidance for both physicians and patients to optimize its use in an acute setting. The current evidence of the administration of 100% oxygen as a safe and effective treatment for cluster headache is strong. Based on several clinical trials and surveys, the recommended flow rates range between 12 and 15 L/min via a non-rebreathing mask, for at least fifteen minutes. The frequency of cluster headache attacks and thus the need for acute treatment can be very high. Fortunately, the Belgian social security system provides a full and lifetime reimbursement of oxygen therapy for cluster headache if the diagnosis and the need for this therapy has been certified by a neurologist, neurosurgeon or neuropsychiatrist.

Exploring the Therapeutic Potential of Quadripulse rTMS over the Visual Cortex: A Proof-of-Concept Study in Healthy Volunteers and Chronic Migraine Patients with Medication Overuse Headache.

In chronic migraine with medication overuse (CM-MOH), sensitization of visual cortices is reflected by (i) increased amplitude of stimulus-evoked responses and (ii) habituation deficit during repetitive stimulation. Both abnormalities might be mitigated by inhibitory transcranial neurostimulation. Here, we tested an inhibitory quadripulse repetitive transcranial magnetic stimulation (rTMS-QPI) protocol to decrease durably visual cortex excitability in healthy subjects (HS) and explored its therapeutic potential in CM-MOH patients. Pattern-reversal visual evoked potentials (VEP) were used as biomarkers of effect and recorded before (T1), immediately after (T2), and 3 h after stimulation (T3). In HS, rTMS-QPI durably decreased the VEP 1st block amplitude (p < 0.05) and its habituation (p < 0.05). These changes were more pronounced for the P1N2 component that was modified already at T2 up to T3, while for N1P1 they were significant only at T3. An excitatory stimulation protocol (rTMS-QPE) tended to have an opposite effect, restricted to P1N2. In 12 CM-MOH patients, during a four-week treatment (2 sessions/week), rTMS-QPI significantly reduced monthly headache days (p < 0.01). In patients reversing from CM-MOH to episodic migraine (n = 6), VEP habituation significantly improved after treatment (p = 0.005). rTMS-QPI durably decreases visual cortex responsivity in healthy subjects. In a proof-of-concept study of CM-MOH patients, rTMS-QPI also has beneficial clinical and electrophysiological effects, but sham-controlled trials are needed.

Central sensitization mechanisms in chronic migraine with medication overuse headache: a study of thalamocortical activation and lateral cortical inhibition.

BACKGROUND: It is unclear whether cortical hyperexcitability in chronic migraine with medication overuse headache (CM-MOH) is due to increased thalamocortical drive or aberrant cortical inhibitory mechanisms. METHODS: Somatosensory evoked potentials (SSEP) were performed by electrical stimulation of the median nerve (M), ulnar nerve (U) and simultaneous stimulation of both nerves (MU) in 27 patients with CM-MOH and, for comparison, in 23 healthy volunteers (HVs) of a comparable age distribution. We calculated the degree of cortical lateral inhibition using the formula: 100 - [MU/(M + U) × 100] and the level of thalamocortical activation by analyzing the high frequency oscillations (HFOs) embedded in parietal N20 median SSEPs. RESULTS: Compared to HV, CM-MOH patients showed higher lateral inhibition (CM-MOH 52.2% ± 15.4 vs. HV 40.4% ± 13.3; p = 0.005), which positively correlated with monthly headache days, and greater amplitude of pre-synaptic HFOs (p = 0.010) but normal post-synaptic HFOs (p = 0.122). CONCLUSION: Our findings suggest that central neuronal circuits are highly sensitized in CM-MOH patients, at both thalamocortical and cortical levels. The observed changes could be due to the combination of dysfunctional central pain control mechanisms, hypersensitivity and hyperresponsiveness directly linked to the chronic intake of acute migraine drugs.

Occipital transcranial direct current stimulation in episodic migraine patients: effect on cerebral perfusion.

Cerebral blood flow differs between migraine patients and healthy controls during attack and the interictal period. This study compares the brain perfusion of episodic migraine patients and healthy controls and investigates the influence of anodal transcranial direct current stimulation (tDCS) over the occipital cortex. We included healthy adult controls and episodic migraineurs. After a 28-day baseline period and the baseline visit, migraine patients received daily active or sham anodal tDCS over the occipital lobe for 28 days. All participants underwent a MRI scan at baseline; migraineurs were also scanned shortly after the stimulation period and about five months later. At baseline, brain perfusion of migraine patients and controls differed in several areas; among the stimulated areas, perfusion was increased in the cuneus of healthy controls. At the first visit, the active tDCS group had an increased blood flow in regions processing visual stimuli and a decreased perfusion in other areas. Perfusion did not differ at the second follow-up visit. The lower perfusion level in migraineurs in the cuneus indicates a lower preactivation level. Anodal tDCS over the occipital cortex increases perfusion of several areas shortly after the stimulation period, but not 5 months later. An increase in the cortical preactivation level could mediate the transient reduction of the migraine frequency.Trial registration: NCT03237754 (registered at clincicaltrials.gov; full date of first trial registration: 03/08/2017).

Ten open questions in migraine prophylaxis with monoclonal antibodies blocking the calcitonin-gene related peptide pathway: a narrative review.

The monoclonal antibodies (mAbs) blocking the calcitonin-gene related peptide (CGRP) pathway, collectively called here "anti-CGRP/rec mAbs", have dramatically improved preventive migraine treatment. Although their efficacy and tolerability were proven in a number of randomized controlled trials (RCTs) and, maybe even more convincingly, in real world settings, a number of open questions remain. In this narrative review, we will analyze published data allowing insight in some of the uncertainties related to the use of anti-CGRP/rec mAbs in clinical practice: their differential efficacy in migraine subtypes, outcome predictors, switching between molecules, use in children and adolescents, long-term treatment adherence and persistence, effect persistence after discontinuation, combined treatment with botulinum toxin or gepants, added-value and cost effectiveness, effectiveness in other headache types, and potential contraindications based on known physiological effects of CGRP. While recent studies have already provided hints for some of these questions, many of them will not find reliable and definitive answers before larger studies, registries or dedicated RCTs are available.

Burden of migraine in patients attending Belgian headache specialists: real-world evidence from the BECOME study.

INTRODUCTION: Migraine is a primary headache disorder, which imposes a major burden on the sufferers. The BECOME study (Burden of migrainE in specialist headache Centers treating patients with prOphylactic treatMent failurE) attempted to characterize and assess the prevalence, burden and healthcare resource utilization of migraine patients presenting in specialized headache centers in Europe and Israel. In this paper, we will describe the patient characteristics of the Belgian headache centers. METHODS: The BECOME study was a prospective, non-interventional, cross-sectional study consisting of two parts. In the first part of the study, data were collected from subjects with a diagnosis of migraine. Subsequently, patients with ≥ 4 monthly migraine days (MMD) and ≥ 1 prior preventive treatment failure (PPTF) filled out validated questionnaires to assess the burden of disease. RESULTS: In part 1 of the Belgian study population (N = 806), 45% of patients reported ≥ 8 MMD and 25% had failed ≥ 4 preventive treatments. In part 2 (N = 90), more than 90% of patients reported having severe impact of headache on daily life and having severe migraine-related disability. The impact was the highest for patients with ≥ 15 MMD, however, even within the patient population with < 8 MMD, the burden was significant. Almost 40% of the study population suffered from anxiety. CONCLUSIONS: These findings in the Belgian sample of the BECOME study demonstrate the substantial burden and unmet need for the management of difficult-to-treat migraine.

Whole brain surface-based morphometry and tract-based spatial statistics in migraine with aura patients: difference between pure visual and complex auras.

Background: The migrainous aura has different clinical phenotypes. While the various clinical differences are well-described, little is known about their neurophysiological underpinnings. To elucidate the latter, we compared white matter fiber bundles and gray matter cortical thickness between healthy controls (HC), patients with pure visual auras (MA) and patients with complex neurological auras (MA+). Methods: 3T MRI data were collected between attacks from 20 patients with MA and 15 with MA+, and compared with those from 19 HCs. We analyzed white matter fiber bundles using tract-based spatial statistics (TBSS) of diffusion tensor imaging (DTI) and cortical thickness with surface-based morphometry of structural MRI data. Results: Tract-based spatial statistics showed no significant difference in diffusivity maps between the three subject groups. As compared to HCs, both MA and MA+ patients had significant cortical thinning in temporal, frontal, insular, postcentral, primary and associative visual areas. In the MA group, the right high-level visual-information-processing areas, including lingual gyrus, and the Rolandic operculum were thicker than in HCs, while in the MA+ group they were thinner. Discussion: These findings show that migraine with aura is associated with cortical thinning in multiple cortical areas and that the clinical heterogeneity of the aura is reflected by opposite thickness changes in high-level visual-information-processing, sensorimotor and language areas.

Defining metabolic migraine with a distinct subgroup of patients with suboptimal inflammatory and metabolic markers.

Emerging evidence suggest migraine is a response to cerebral energy deficiency or oxidative stress in the brain. Beta-hydroxybutyrate (BHB) is likely able to circumvent some of the meta-bolic abnormalities reported in migraine. Exogenous BHB was given to test this assumption and, in this post-hoc analysis, multiple metabolic biomarkers were identified to predict  clinical improvements. A randomized clinical trial, involving 41 patients with episodic migraine. Each treatment period was 12 weeks long, followed by eight weeks of washout phase / second run-in phase before entering the corresponding second treatment period. The primary endpoint was the number of migraine days in the last 4 weeks of treatment adjusted for baseline. BHB re-sponders were identified (those with at least a 3-day reduction in migraine days over placebo) and its predictors were evaluated using Akaike's Information Criterion (AIC) stepwise boot-strapped analysis and logistic regression. Responder analysis showed that metabolic markers could identify a "metabolic migraine" subgroup, which responded to BHB with a 5.7 migraine days reduction compared to the placebo. This analysis provides further support for a "metabolic migraine" subtype. Additionally, these analyses identified low-cost and easily accessible biomarkers that could guide recruitment in future research on this subgroup of patients.This study is part of the trial registration: ClinicalTrials.gov: NCT03132233, registered on 27.04.2017, https://clinicaltrials.gov/ct2/show/NCT03132233.

The longitudinal influence of tDCS on occipital GABA and glutamate/glutamine levels in episodic migraineurs.

This study investigated differences in the concentration of gamma-aminobutyric acid (GABA) and the combination of glutamine and glutamate (as GLX) in the early visual cortex of patients with episodic migraine and the influence of transcranial direct current stimulation (tDCS) on GABA and GLX. In this single-blind, sham-controlled trial, we randomly assigned patients with episodic migraine to receive daily anodal tDCS or sham stimulation. In addition, we included healthy controls. We acquired proton MR spectroscopy data of the visual cortex with 3 Tesla MRI at baseline and from migraine patients directly after the stimulation period and 4 months later. In 22 migraineurs and 25 controls, the GABA and the GLX concentrations did not differ at baseline between the groups. tDCS resulted in reduced concentrations of GABA but not GLX or the migraine frequency directly after the stimulation period, but not 4 months later. The changes in the levels of GABA in the early visual cortex of patients with episodic migraine in the interictal period suggest an effect of tDCS that allowed for subsequent changes in the migraine frequency. However, we might have missed relevant variations in the concentrations of these neurotransmitters during the follow-up period, as changes in migraine frequency appeared after the first MRI and disappeared before the second.

Effects of Botulinum Toxin Type A on the Nociceptive and Lemniscal Somatosensory Systems in Chronic Migraine: An Electrophysiological Study.

(1) Background: OnabotulinumtoxinA (BoNT-A) is a commonly used prophylactic treatment for chronic migraine (CM). Although randomized placebo studies have shown its clinical efficacy, the mechanisms by which it exerts its therapeutic effect are still incompletely understood and debated. (2) Methods: We studied in 15 CM patients the cephalic and extracephalic nociceptive and lemniscal sensory systems using electrophysiological techniques before and 1 and 3 months after one session of pericranial BoNT-A injections according to the PREEMPT protocol. We recorded the nociceptive blink reflex (nBR), the trigemino-cervical reflex (nTCR), the pain-related cortical evoked potential (PREP), and the upper limb somatosensory evoked potential (SSEP). (3) Results: Three months after a single session of prophylactic therapy with BoNT-A in CM patients, we found (a) an increase in the homolateral and contralateral nBR AUC, (b) an enhancement of the contralateral nBR AUC habituation slope and the nTCR habituation slope, (c) a decrease in PREP N-P 1st and 2nd amplitude block, and (d) no effect on SSEPs. (4) Conclusions: Our study provides electrophysiological evidence for the ability of a single session of BoNT-A injections to exert a neuromodulatory effect at the level of trigeminal system through a reduction in input from meningeal and other trigeminovascular nociceptors. Moreover, by reducing activity in cortical pain processing areas, BoNT-A restores normal functioning of the descending pain modulation systems.

Guidelines of the International Headache Society for Controlled Clinical Trials in Cluster Headache.

In 1995, a committee of the International Headache Society developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Cluster Headache. These have not been revised. With the emergence of new medications, neuromodulation devices and trial designs, an updated version of the International Headache Society Guidelines for Controlled Clinical Trials in Cluster Headache is warranted. Given the scarcity of evidence-based data for cluster headache therapies, the update is largely consensus-based, but takes into account lessons learned from recent trials and demands by patients. It is intended to apply to both drug and neuromodulation treatments, with specific proposals for the latter when needed. The primary objective is to propose a template for designing high quality, state-of-the-art, controlled clinical trials of acute and preventive treatments in episodic and chronic cluster headache. The recommendations should not be regarded as dogma and alternative solutions to particular methodological problems should be explored in the future and scientifically validated.

Bimodal sensory integration in migraine: A study of the effect of visual stimulation on somatosensory evoked cortical responses.

BACKGROUND: Merging of sensory information is a crucial process for adapting the behaviour to the environment in all species. It is not known if this multisensory integration might be dysfunctioning interictally in migraine without aura, where sensory stimuli of various modalities are processed abnormally when delivered separately. To investigate this question, we compared the effects of a concomitant visual stimulation on conventional low-frequency somatosensory evoked potentials and embedded high-frequency oscillations between migraine patients and healthy volunteers. METHODS: We recorded somatosensory evoked potentials in 19 healthy volunteers and in 19 interictal migraine without aura patients before, during, and 5 min after (T2) simultaneous synchronous pattern-reversal visual stimulation. At each time point, we measured amplitude and habituation of the N20-P25 low-frequency-somatosensory evoked potentials component and maximal peak-to-peak amplitude of early and late bursts of high-frequency oscillations. RESULTS: In healthy volunteers, the bimodal stimulation significantly reduced low-frequency-somatosensory evoked potentials habituation and tended to reduce early high-frequency oscillations that reflect thalamocortical activity. By contrast, in migraine without aura patients, bimodal stimulation significantly increased low-frequency-somatosensory evoked potentials habituation and early high-frequency oscillations. At T2, all visual stimulation-induced changes of somatosensory processing had vanished. CONCLUSION: These results suggest a malfunctioning multisensory integration process, which could be favoured by an abnormal excitability level of thalamo-cortical loops.

Cluster Headache and the Comprehension Paradox.

Patients with primary headache disorders such as cluster headache cycle between being entirely healthy and almost completely incapacitated. Sick leave or reduced performance due to headache attacks demands flexibility by their social counterparts. The objective of this study is to test the hypothesis that headache patients cause frustration that grows with the times colleagues have to take over their work. In this study, we analysed cluster headache patients' answers to an online questionnaire. Participants self-reported their number of sick days, the number of days on which leisure activities were missed and whether they felt understood by colleagues and family. We then investigated the correlation between the number of sick days and the proportion of patients feeling understood by colleagues and friends. We found that feeling understood by colleagues and friends decreases with a growing number of sick days. However, when sick days accrue further, this proportion increases again. The number of sick days correlates similarly with both colleagues' and friends' understanding. The number of cluster headache patients feeling understood by others decreases with an increasing number of sick days. Their social circles' frustration with the patients' failure to meet obligations and expectations are a likely reason. With a growing number of sick days, however, the portion of patients feeling understood rises again despite patients meeting others' expectations even less. This 'comprehension paradox' implies the influence of other factors. We suspect that growing numbers of sick days foster understanding as the disability of the disease becomes increasingly apparent.

Tolerability and safety of galcanezumab in patients with chronic cluster headache with up to 15 months of galcanezumab treatment.

OBJECTIVE: The objective of the study was to assess the tolerability and safety of galcanezumab in patients with chronic cluster headache (CH) with up to 15 months of treatment. BACKGROUND: Chronic CH is a highly debilitating disease with a substantial and unmet medical need. METHODS: Patients were randomized to receive placebo or galcanezumab (300 mg) monthly for 12 weeks, followed by an optional 52-week open-label extension and 16-week posttreatment follow-up (washout). This is a secondary analysis and long-term follow-up of a previously conducted clinical trial. The safety analysis included patients who received galcanezumab at any time during the study. Outcomes included adverse events (AEs), discontinuations, laboratory values, vital signs, electrocardiograms (ECGs), and suicidality ratings. RESULTS: A total of 233 patients received at least one galcanezumab dose. The mean exposure was 341 days. Galcanezumab-treated patients were mostly male (n = 169/233; 72.5%) with a mean age of 44.9 (±10.9) years. Treatment-emergent adverse events (TEAEs) were reported by 185 patients (n = 185/233; 79.4%), 23 patients (n = 23/233; 9.9%) reported serious adverse events (SAEs), and 18 patients (n = 18/233; 7.7%) discontinued due to AEs. The SAE CH was reported by three patients. The most common TEAEs (>10%) were nasopharyngitis (n = 41/233; 17.6%) and injection site pain (n = 33/233; 14.2%). 27.5% of patients (n = 64/233) had TEAEs related to injection sites. Likely hypersensitivity events, including injection site rash, injection site urticaria, and injection site hypersensitivity were reported (n = 14/233; 6.0%). There were past histories of suicidal ideation (n = 55/237; 23.2%) and suicidal behavior (n = 9/236; 3.8%). During the study, 15 patients (n = 15/230; 6.5%), seven with previous history, reported suicidal ideation. One patient had a nonfatal suicide attempt during the open-label extension and an aborted attempt during the washout. There were no new safety findings compared with the placebo-controlled treatment period in laboratory values, vital signs, or ECGs. CONCLUSIONS: Galcanezumab 300 mg monthly had a favorable tolerability and safety profile in patients with chronic CH with up to 15 months of treatment.

Old Habits Die Hard: Dietary Habits of Migraine Patients Challenge our Understanding of Dietary Triggers.

Introduction: Migraine is a multifactorial neurological disorder with a major metabolic facet. Dietary approaches represent a commonly implemented lifestyle modifying strategy in headache clinics, yet the precise relationship between diet and migraine is still a matter of debate. Materials and Methods: The study consisted of two parts: first, in a cross-sectional design, we compared alimentary habits of migraine subjects and a control group of healthy volunteers. For the second part, we prospectively evaluated patients' daily consumption of various potentially migraine-triggering foods over a two-month period in order to examine their possible association with the occurrence of a migraine attack. Results: Most migraine patients reported avoiding at least one potentially migraine-triggering food/drink from their diet. In spite of that, with the sole exemption of citrus fruits, there were no statistically significant differences with respect to consumption patterns between migraine patients and controls (including wine and chocolate). Consumption frequency over time was proportional to intake of potentially migraine-triggering foods the day before a migraine attack. Conclusion: Our results underline the need of performing trigger challenges in order to avoid falling into an association-causation fallacy when attempting to identify possible alimentary migraine triggers. Indeed, it is possible that intake of certain foods like chocolate before attacks is a consequence of pre-attack cravings or a simple coincidence facilitated by previously established dietary habits.

Erenumab for Migraine Prevention in a 1-Year Compassionate Use Program: Efficacy, Tolerability, and Differences Between Clinical Phenotypes.

During a 1-year compassionate use program, 156 patients with migraine self-administered a monthly dose of erenumab 140 mg with a subcutaneous autoinjector. Main inclusion criteria were: ≥ 4 migraine days/month and ≥two prior prophylactic treatment failures. The patients covered the migraine severity spectrum from episodic migraine (EM) (n = 80) to chronic migraine (CM) (n = 76). During the 3rd month of treatment, monthly headache days decreased by 45.7% in EM and 35.5% in CM. The 50% responder rate for reduction in monthly headache days was significantly higher in EM (55%) than in CM (43%) (p = 0.05). In both the migraine subgroups, the clinical improvement vs. baseline was already significant during the 1st month of treatment (p < 0.001). There were also significant reductions in mean headache severity, duration, and monthly days with acute drug intake. The 30% responder rate at 3 months was 60% in CM and 54.1% of patients reversed from CM to EM. The therapeutic effect was maintained at 12 months when 50% responder rates, considering discontinuation for lack of efficacy or adverse effects as 0% response, still were 51% in EM and 41% in CM. A total of 10 patients with EM (12.5%) and 23 patients with CM (30.3%) had discontinued treatment, considering the treatment as ineffective. At 3 months, 48% of patients reported non-serious adverse events among which the most frequent was constipation (20.5%); corresponding figures at 12 months were 30 and 15%. Discontinuation due to an adverse effect for the entire 12 month period was rare (3.8%). The lower efficacy in CM than in EM was mainly due to a very low 50% responder rate in patients with CM with continuous pain (13%) as compared to CM with pain-free periods (58%) (p < 0.001). Similarly, the 50% responder rate was lower in patients with ≥two prior prophylactic treatment failures (40.5%) compared to those with two failures (70%) (p < 0.05). There was no significant efficacy difference between low (4-7 migraine days/month, n = 22) and high frequency (8-14 days, n = 59) EM nor between patients with CM with (n = 50) or without (n = 26) acute medication overuse. Erenumab had no effect on the frequency of auras. Taken together, erenumab 140 mg monthly was highly effective for migraine prophylaxis over the whole severity spectrum of the disease, except in patients with continuous headaches. Its effect is significant after the first injection, quasi-maximal after the second injection, and does not wear off after 12 months. The most frequent adverse effect was constipation. These results are compared to those published for erenumab in the pivotal randomized placebo-controlled trials and to those reported in several recent real-world studies.

CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs.

BACKGROUND: Several drugs are available for the preventive treatment of both episodic and chronic migraine. The choice of which therapy to initiate first, second, or third is not straightforward and is based on multiple factors, including general efficacy, tolerability, potential for serious adverse events, comorbid conditions, and costs. Recently, a new class of migraine preventive drugs was introduced, i.e. monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor. METHODS: The present article summarizes the evidence gathered with this new migraine preventive drug class from randomized placebo-controlled clinical trials. It further puts this into perspective next to the evidence gained by the most widely used agents for the prevention of episodic and chronic migraine with an emphasis on efficacy and the robustness with which this efficacy signal was obtained. RESULTS: Although being a relatively new class of migraine preventive drugs, monoclonal antibodies blocking the CGRP pathway have an efficacy which is at least comparable if not higher than those of the currently used preventive drugs. Moreover, the robustness of this efficacy signal is substantiated by several randomized clinical trials each including large numbers of patients. In addition, because of their excellent tolerability and with long-term safety data emerging, they seem to have an unprecedented efficacy over adverse effect profile, clearly resulting in an added value for migraine prevention. CONCLUSIONS: Balancing the data presented in the current manuscript with additional data concerning long term safety on the one hand and cost issues on the other hand, can be of particular use to health policy makers to implement this new drug class in the prevention of migraine.

Thalamo-cortical networks in subtypes of migraine with aura patients.

BACKGROUND: We searched for differences in resting-state functional connectivity (FC) between brain networks and its relationship with the microstructure of the thalamus between migraine with pure visual auras (MA), and migraine with complex neurological auras (MA+), i.e. with the addition of at least one of sensory or language symptom. METHODS: 3T MRI data were obtained from 20 patients with MA and 15 with MA + and compared with those from 19 healthy controls (HCs). We collected resting state data among independent component networks. Diffusivity metrics of bilateral thalami were calculated and correlated with resting state ICs-Z-scores. RESULTS: As compared to HCs, both patients with MA and MA + disclosed disrupted FC between the default mode network (DMN) and the right dorsal attention system (DAS). The MA + subgroup had lower microstructural metrics than both HCs and the MA subgroup, which correlated negatively with the strength of DMN connectivity. Although the microstructural metrics of MA patients did not differ from those of HCs, these patients lacked the correlation with the strength of DAS connectivity found in HCs. CONCLUSIONS: The present findings suggest that, as far as MRI profiles are concerned, the two clinical phenotypes of migraine with aura have both common and distinct morpho-functional features of nodes in the thalamo-cortical network.

Mitochondrial function and oxidative stress markers in higher-frequency episodic migraine.

Increasing evidence points towards the role of mitochondrial functioning, energy metabolism, and oxidative stress in migraine. However not all previous research has been conclusive and some mitochondrial function/oxidative stress markers have not yet been examined. To this end, alpha-lipoic acid (ALA), total thiols, total plasma antioxidant capacity (TAC), lipid peroxide (PerOx), oxidised LDL (oxLDL), HbA1c and lactate were determined in the serum of 32 higher frequency episodic migraineurs (5-14 migraine days/ months, 19 with aura, 28 females) in this cross-sectional study. The majority of patients had abnormally low ALA and lactate levels (87.5% and 78.1%, respectively). 46.9% of the patients had abnormally high PerOx values, while for thiols and TAC over one third of patients had abnormally low values (31.2% and 37.5%, respectively). 21.9% of patients had abnormally low HbA1c and none had an HbA1c level above 5.6%. oxLDL was normal in all but one patient. This study provides further evidence for a role of oxidative stress and altered metabolism in migraine pathophysiology, which might represent a suitable therapeutic target. ALA, being too low in almost 90% of patients, might represent a potential biomarker for migraine. Further research is needed to replicate these results, in particular a comparison with a control group.This study is part of the trial registration: ClinicalTrials.gov: NCT03132233, registered on 27.04.2017, https://clinicaltrials.gov/ct2/show/NCT03132233 .