Enhanced audiovisual associative pair learning in migraine without aura in adult patients: An unexpected finding.

BACKGROUND: Altered sensory processing in migraine has been demonstrated by several studies in unimodal, and especially visual, tasks. While there is some limited evidence hinting at potential alterations in multisensory processing among migraine sufferers, this aspect remains relatively unexplored. This study investigated the interictal cognitive performance of migraine patients without aura compared to matched controls, focusing on associative learning, recall, and transfer abilities through the Sound-Face Test, an audiovisual test based on the principles of the Rutgers Acquired Equivalence Test. MATERIALS AND METHODS: The performance of 42 volunteering migraine patients was compared to the data of 42 matched controls, selected from a database of healthy volunteers who had taken the test earlier. The study aimed to compare the groups' performance in learning, recall, and the ability to transfer learned associations. RESULTS: Migraine patients demonstrated significantly superior associative learning as compared to controls, requiring fewer trials, and making fewer errors during the acquisition phase. However, no significant differences were observed in retrieval error ratios, generalization error ratios, or reaction times between migraine patients and controls in later stages of the test. CONCLUSION: The results of our study support those of previous investigations, which concluded that multisensory processing exhibits a unique pattern in migraine. The specific finding that associative audiovisual pair learning is more effective in adult migraine patients than in matched controls is unexpected. If the phenomenon is not an artifact, it may be assumed to be a combined result of the hypersensitivity present in migraine and the sensory threshold-lowering effect of multisensory integration.

Reduced neurovascular coupling of the visual network in migraine patients with aura as revealed with arterial spin labeling MRI: is there a demand-supply mismatch behind the scenes?

BACKGROUND: Although neuroimaging investigations have consistently demonstrated that "hyperresponsive" and "hyperconnected" visual cortices may represent the functional substrate of cortical spreading depolarization in patients with migraine with aura, the mechanisms which underpin the brain "tendency" to ignite the cortical spreading depolarization and, consequently, aura phenomenon are still matter of debate. Considering that triggers able to induce aura phenomenon constrain brain to increase global (such as physical activity, stressors and sleep abnormalities) or local (such as bright light visual stimulations) energy demand, a vascular supply unable to satisfy the increased energy requirement could be hypothesized in these patients. METHODS: Twenty-three patients with migraine with aura, 25 patients with migraine without aura and 20 healthy controls underwent a 3-Tesla MRI study. Cerebral blood flow and local functional connectivity (regional homogeneity) maps were obtained and registered to the MNI space where 100 cortical regions were derived using a functional local-global normative parcellation. A surrogate estimate of the regional neurovascular coupling for each subject was obtained at each parcel from the correlation coefficient between the z-scored ReHo map and the z-scored cerebral blood flow maps. RESULTS: A significantly higher regional cerebral blood flow across the visual cortex of both hemispheres (i.e. fusiform and lingual gyri) was detected in migraine with aura patients when compared to patients with migraine without aura (p < 0.05, corrected for multiple comparisons). Concomitantly, a significantly reduced neurovascular coupling (p < 0.05, false discovery rate corrected) in the primary visual cortex parcel (VIS-4) of the large-scale visual network was observed in the left hemisphere of patients with migraine with aura (0.23±0.03), compared to both patients with migraine without aura (0.32±0.05) and healthy controls (0.29±0.05). CONCLUSIONS: Visual cortex neurovascular "decoupling" might represent the "link" between the exposure to trigger factors and aura phenomenon ignition. While physiological vascular oversupply may compensate neurovascular demand-supply at rest, it becomes inadequate in case of increased energy demand (e.g. when patients face with trigger factors) paving the way to the aura phenomenon ignition in patients with migraine with aura. Whether preventive treatments may exert their therapeutic activity on migraine with aura restoring the energy demands and cerebral blood flow trade-off within the visual network should be further investigated.

Migraine and large artery atherosclerosis in young adults with ischemic stroke.

INTRODUCTION: Migraine is a risk factor for ischemic stroke, but the mechanisms of stroke associated with migraine are debated. The aim of this study was to investigate the association between migraine and large artery atherosclerosis (LAA) in young adults with ischemic stroke. METHODS: Patients aged between 18 and 54 years consecutively treated for first acute ischemic stroke in a university hospital stroke unit between January 2017 and December 2019 were included in this cross-sectional study. Migraine status was systematically assessed by the same headache specialist. Stenotic and nonstenotic LAA of extracranial and intracranial cerebral arteries were evaluated and graded using the ASCOD (atherosclerosis, small-vessel disease, cardiac pathology, other causes, dissection) criteria. We adjusted the association between migraine and LAA for traditional risk factors. RESULTS: A total of 415 patients were included (mean age [standard deviation], 43.9 [8.7] years; 258/415 [62.2%] men). Migraine with aura (MWA) was diagnosed in 76 patients, and migraine without aura (MWoA) in 68 patients. Patients with migraine had fewer traditional cardiovascular risk factors. Stenotic LAA (10/144 [6.9%] vs. 42/271 [15.5%]; p < 0.001) and LAA of any grade (35/144 [24.3%] vs. 138/271 [50.9%]; p < 0.001) were significantly less frequent in patients with migraine than in patients without migraine, respectively. Multivariable analysis adjusting for age, sex, overweight, tobacco use, hypertension, diabetes, and hyperlipidemia showed a negative association between migraine and LAA of any grade (odds ratio [OR] = 0.44, 95% confidence interval [CI: 0.254-0.78], p = 0.005). This negative association was found for both MWoA (OR = 0.42, 95% CI [0.204-0.88], p = 0.020) and MWA (OR = 0.47, 95% CI [0.228-0.96], p = 0.037) compared to no migraine. CONCLUSION: In this study of young adults with ischemic stroke, migraine had a negative association with LAA. This negative association was independent of traditional vascular risk factors and was found for both MWA and MWoA.

A Resting-State Functional Magnetic Resonance Imaging Study of Abnormal Frontoparietal Network Function in Migraine without Aura.

BACKGROUND This study aimed to investigate frontoparietal network (FPN) dysfunction in participants with migraine without aura (MwoA). MATERIAL AND METHODS We selected 48 age-, sex-, and education level-matched graduate students (24 participants with MwoA [MwoA group] and 24 healthy controls). RS-fMRI and independent component analysis were used to examine the FPN and to compare abnormal encephalic regional homogeneity values. The Mindful Attention Awareness Scale (MAAS), Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), and Self-Rating Scale of Sleep (SRSS) were used to evaluate attention, anxiety, depression, and sleep, respectively. Pearson's correlation was applied to evaluate the association between abnormal brain areas and the scores for each scale. RESULTS Neural function activity in encephalic regions of FPN showed abnormal changes in the MwoA group. The MwoA group had significantly lower MAAS scores (P<0.001), higher SAS scores (P<0.001), and higher SDS (P=0.06) and SRSS scores (P=0.26). In the MwoA group, functional activity of the right parietal lobule in the left FPN was positively correlated with MAAS scores (P=0.01) and negatively correlated with SAS (P=0.02). The orbital part of left inferior frontal gyrus activity in the right FPN was positively correlated with SDS (P=0.04) and SRSS (P<0.001). Right superior marginal gyrus activity in the right FPN was positively correlated with SDS (P=0.02). CONCLUSIONS Abnormal FPN function was correlated with attention, anxiety, depression, and sleep status in the MwoA group. These results offer further insights into the evaluation and treatment of MwoA.

Disrupted Dynamic Functional Connectivity of the Visual Network in Episodic Patients with Migraine without Aura.

Background: Visual symptoms are common in patients with migraine, even in interictal periods. The purpose was to assess the association between dynamic functional connectivity (dFC) of the visual cortex and clinical characteristics in migraine without aura (MwoA) patients. Methods: We enrolled fifty-five MwoA patients as well as fifty gender- and age-matched healthy controls. Regional visual cortex alterations were investigated using regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF). Then, significant regions were selected as seeds for conducting dFC between the visual cortex and the whole brain. Results: Relative to healthy controls, MwoA patients exhibited decreased ReHo and ALFF values in the right lingual gyrus (LG) and increased ALFF values in the prefrontal cortex. The right LG showed abnormal dFC within the visual cortex and with other core brain networks. Additionally, ReHo values for the right LG were correlated with duration of disease and ALFF values of the right inferior frontal gyrus and middle frontal gyrus were correlated with headache frequency and anxiety scores, respectively. Moreover, the abnormal dFC of the right LG with bilateral cuneus was positively correlated with anxiety scores. Conclusions: The dFC abnormalities of the visual cortex may be involved in pain integration with multinetworks and associated with anxiety disorder in episodic MwoA patients.

Brain Energy Deficit as a Source of Oxidative Stress in Migraine: A Molecular Basis for Migraine Susceptibility.

People with migraine are prone to a brain energy deficit between attacks, through increased energy demand (hyperexcitable brain) or decreased supply (mitochondrial impairment). However, it is uncertain how this precipitates an acute attack. Here, the central role of oxidative stress is adduced. Specifically, neurons' antioxidant defenses rest ultimately on internally generated NADPH (reduced nicotinamide adenine dinucleotide phosphate), whose levels are tightly coupled to energy production. Mitochondrial NADPH is produced primarily by enzymes involved in energy generation, including isocitrate dehydrogenase of the Krebs (tricarboxylic acid) cycle; and an enzyme, nicotinamide nucleotide transhydrogenase (NNT), that depends on the Krebs cycle and oxidative phosphorylation to function, and that works in reverse, consuming antioxidants, when energy generation fails. In migraine aura, cortical spreading depression (CSD) causes an initial severe drop in level of NADH (reduced nicotinamide adenine dinucleotide), causing NNT to impair antioxidant defense. This is followed by functional hypoxia and a rebound in NADH, in which the electron transport chain overproduces oxidants. In migraine without aura, a similar biphasic fluctuation in NADH very likely generates oxidants in cortical regions farthest from capillaries and penetrating arterioles. Thus, the perturbations in brain energy demand and/or production seen in migraine are likely sufficient to cause oxidative stress, triggering an attack through oxidant-sensing nociceptive ion channels. Implications are discussed for the development of new classes of migraine preventives, for the current use of C57BL/6J mice (which lack NNT) in preclinical studies of migraine, for how a microembolism initiates CSD, and for how CSD can trigger a migraine.

Preference for Lighting Chromaticity in Migraine With Aura.

OBJECTIVE: We studied the color of lighting chosen as comfortable for reading by individuals with migraine and controls. We explored the effects of the chosen color on visual performance. BACKGROUND: It has been reported that individuals who experience migraine with aura (MWA) choose, as comfortable for reading, light that is more strongly saturated in color than that chosen by individuals without migraine. METHODS: A convenience sample of 18 individuals who experienced MWA, 18 without aura, and 18 controls without migraine participated in a cross-sectional laboratory study at Anglia Ruskin University. We used an Intuitive Colorimeter that illuminated text with colored light and permitted the separate control of hue (color) and saturation (strength of color) without a change in luminance. We selected individuals with migraine and healthy controls from the general population. They were headache-free in the 48 hours prior to testing. We used a routine that permitted the selection of the most comfortable hue from 12 alternatives and then alternately optimized the saturation and hue using small changes, thereby allowing for color adaptation. Visual performance at a word search task was measured under white light and under light of a color chosen as comfortable, using colored lenses. RESULTS: Healthy individuals chose light with chromaticity close to the Planckian locus, which approximates the chromaticities of daylight and most electric lighting. The distance from the locus averaged 0.029 (SD 0.021). Individuals who experienced MWA chose strongly saturated colors well away from the Planckian locus (average distance 0.056, SD 0.022). Individuals who experienced migraine without aura chose intermediate chromaticities (average distance 0.034, SD 0.022). Overall there was a large statistically significant difference between participant groups that explained 24% variance. Visual search time of individuals with migraine aura decreased from 22.5 to 16.8 s when light of the chosen color was provided using tinted lenses (the average increase in search speed was 45.7%). The lenses had no statistically significant effect on the performance of individuals without migraine aura. CONCLUSIONS: Individuals who experienced MWA selected as comfortable colors that deviated from the lighting typically experienced in everyday life. Possibly, individuals who experience MWA may be more susceptible to photophobia under typical lighting. Visual performance was improved using lenses that provided light of the chosen comfortable color. The spectral power of that choice showed no evident relationship to melanopic energy (energy captured by the intrinsically photosensitive retinal ganglion cells).

Plasma Glucose Levels Increase During Spontaneous Attacks of Migraine With and Without Aura.

OBJECTIVE: To investigate plasma glucose changes during the ictal state of migraine compared to the interictal state. BACKGROUND: Previous studies suggest abnormal glucose metabolism in migraine patients during and outside of attacks. It is not known if plasma glucose levels change during spontaneous migraine attacks. METHODS: Plasma glucose levels were measured during and outside of spontaneous migraine attacks with and without aura. Plasma glucose values were corrected for diurnal variation of plasma glucose by subtracting the difference between the moving average (intervals of 2 hours) and overall mean from the plasma glucose values. RESULTS: This was a sub-study of a larger study conducted at Rigshospitalet Glostrup in the Capital Region of Denmark. Thirty-one patients (24 F, 7 M, 13 with aura, 18 without aura) were included in the study. Mean time from attack onset to blood sampling was 7.6 hours. Mean pain at the time of investigation was 6 on a 0-10 verbal rating scale. Plasma glucose was higher ictally compared to the interictal phase (interictal mean: 88.63 mg/dL, SD 11.70 mg/dL; ictal mean: 98.83 mg/dL, SD 13.16 mg/dL, difference 10.20 mg/dL, 95% CI = [4.30; 16.10]), P = .0014). The ictal increase was highest in patients investigated early during attacks and decreased linearly with time from onset of migraine (-1.57 mg/dL/hour from onset of attack, P = .020). The attack-related increase in blood glucose was not affected by pain intensity or presence of aura symptoms. CONCLUSIONS: We demonstrated higher plasma glucose values during spontaneous migraine attacks, independent of the presence of aura symptoms and not related to pain intensity, peaking in the early phase of attacks. Additional studies are necessary to confirm our findings and explore the possible underlying mechanisms.

Allodynia in Menstrually Related Migraine: Score Assessment by Allodynia Symptom Checklist (ASC-12).

OBJECTIVE: The aim of this study was to compare the allodynia score in headache attacks related and not related to menstruation in women diagnosed with menstrually related migraine without aura. BACKGROUND: Allodynia is an important symptom in migraine and has been associated with migraine chronification. No study has yet compared prospectively allodynia in menstrual vs non-menstrual attacks within the same cohort of patients. METHODS: This is a prospective cohort study, where participants had the 12-item Allodynia Symptom Checklist (ASC-12) assessed after 1, 2, 4, and 24 hours from the onset of migraine attacks in 2 different conditions, with menstrual migraine attack (MM+) and with non-menstrual migraine attack (MM-). RESULTS: A total of 600 women with headache complaints were screened from March 2013 to July 2014 in a headache outpatient or headache tertiary clinic. From these, 55 participants were recruited, and 32 completed the study. Participants' mean age was 27 years, BMI was 22.1, menarche age 12 years, migraine history was 11.5 years, and most women were young (ranged from 17 to 44 years of age), were in higher school (13/32 = 41%), single (20/32 = 63%), and used contraceptives (22/32 = 69%). Multiple pairwise comparisons of ANCOVA's test showed significant higher ASC-12 scores in MM+ group compared to MM- group at 2 hours [mean, 95% CI of difference: 2.3 (0.31, 4.7), P = .049)]. For the ASC-12 categorical scores (absent, mild, moderate, and severe) MM+ yielded higher scores than MM- at 1 hour (z = -3.08, P = .021) and 4 hours (z = -2.97, P = .03). CONCLUSION: This study demonstrated that in the patents from tertiary headache center assessed, menstrual-related migraine attacks augment allodynia scores in the beginning of attacks compared to non-menstrual migraine attacks.

Sensory Hypersensitivity Symptoms in Migraine With vs Without Aura: Results From the American Registry for Migraine Research.

BACKGROUND AND OBJECTIVES: Migraine with aura (MwA) is associated with increased brain hyper-responsiveness to visual stimuli and increased visual network connectivity relative to migraine without aura (MwoA). Despite this, prior studies have provided conflicting results regarding whether MwA is associated with higher photophobia symptom scores compared to MwoA. The relationships between MwA and other types of sensory hypersensitivity, such as phonophobia and cutaneous allodynia (CA), have not been previously investigated. The purpose of this cross-sectional observational study was to investigate whether MwA is associated with greater symptoms of photophobia, phonophobia, and CA compared to MwoA. METHODS: This analysis included 321 migraine patients (146 MwA; 175 MwoA) who had been enrolled into the American Registry for Migraine Research. The diagnosis of either MwoA or MwA was determined by headache specialists using ICHD diagnostic criteria. Patients completed the Photosensitivity Assessment Questionnaire, the Hyperacusis Questionnaire, and the Allodynia Symptom Checklist. Mean or median values were compared between groups. Regression models were created to analyze the relationship between MwA with photophobia scores, hyperacusis scores, and the presence of interictal CA. RESULTS: Those with MwA had higher mean photophobia scores than those with MwoA (4.1 vs 3.0, P = .0003). MwA was positively associated with photophobia symptom severity (B = 0.50 [SE = 0.14], P = .0003), after controlling for age, patient sex, and headache frequency. Aura was not associated with hyperacusis symptom severity (B = 0.07 [SE = 0.08], P = .346) or the presence of interictal CA (OR 1.33 [95% CI 0.70-2.53], P = .381). CONCLUSION: MwA is associated with higher photophobia symptom scores compared to MwoA. Aura is not associated with greater hyperacusis or interictal allodynia scores. These findings complement prior imaging and neurophysiologic studies that demonstrated MwA to be associated with hyper-responsiveness of brain visual processing regions. The findings suggest that MwA is associated specifically with visual hypersensitivity, as opposed to being associated with a general hypersensitivity to multiple types of sensory stimuli.

The American Registry for Migraine Research: Research Methods and Baseline Data for an Initial Patient Cohort.

BACKGROUND: The American Registry for Migraine Research (ARMR) is a multicenter, prospective, longitudinal patient registry, biorepository, and neuroimaging repository that collects clinical data, electronic health record (EHR) data, blood samples, and brain imaging data from individuals with migraine or other headache types. In this manuscript, we outline ARMR research methods and report baseline data describing an initial cohort of ARMR participants. METHODS: Adults with any International Classification of Headache Disorders (ICHD) diagnosis were prospectively enrolled from one of the 8 participating headache specialty centers. At baseline, ARMR participants complete web-based questionnaires, clinicians enter the participant's ICHD diagnoses, an optional blood specimen is collected, and neuroimaging data are uploaded to the ARMR neuroimaging repository. Participants maintain the ARMR daily headache diary longitudinally and follow-up questionnaires are completed by participants every 3 months. EHR data are integrated into the ARMR database from a subset of ARMR sites. Herein, we describe the ARMR methodology and report the summary data from ARMR participants who had, from February 2016 to May 2019, completed at least 1 baseline questionnaire from which data are reported in this manuscript. Descriptive statistics are used to provide an overview of patient's sociodemographics, headache diagnoses, headache characteristics, most bothersome symptoms other than headache, headache-related disability, comorbidities, and treatments. RESULTS: Data were available from 996 ARMR participants, enrolled from Mayo Clinic Arizona, Dartmouth-Hitchcock Medical Center, University of Utah, University of Colorado, Thomas Jefferson University, University of Texas Health Science Center at Houston, Georgetown University Medical Center, and DENT Neurological Institute. Among ARMR participants, 86.7% (n = 864) were female and the mean age at the time of enrollment was 48.6 years (±13.9; range 18-84). The most common provider-reported diagnosis was chronic migraine (n = 622), followed by migraine without aura (n = 327), migraine with aura (n = 196), and medication overuse headache (n = 65). Average headache frequency was 19.1 ± 9.2 days per month (n = 751), with 68% reporting at least 15 headache days per month. Sensitivity to light was the most frequent (n = 222) most bothersome symptom overall, other than headache, but when present, cognitive dysfunction was most frequently (n = 157) the most bothersome symptom other than headache. Average migraine disability assessment (MIDAS) score was 52 ± 49 (n = 760), (very severe headache-related disability); however, 17% of the ARMR population had MIDAS scores suggesting "no" or "mild" disability. The most common non-headache health issues were allergies (n = 364), back pain (n = 296), neck pain (n = 296), depression (n = 292), and anxiety (n = 278). Nearly 85% (n = 695) of patients were using preventive medications and 24.7% were using non-medication preventive therapy (eg, vitamins and neuromodulation). The most common preventive medication classes were neurotoxins, anticonvulsants, antidepressants, vitamins/supplements, and anticalcitonin gene-related peptide ligand or receptor-targeted monoclonal antibodies. Nearly 90% (n = 734) of ARMR participants was taking medications to treat migraine attacks, with the most common classes being triptans, non-steroidal anti-inflammatory drugs, antiemetics, acetaminophen, and combination analgesics. CONCLUSIONS: ARMR is a source of real-world patient data, biospecimens, and brain neuroimaging data that provides comprehensive insight into patients with migraine and other headache types being seen in headache specialty clinics in the United States. ARMR data will allow for longitudinal and advanced analytics that are expected to lead to a better characterization of patient heterogeneity, healthcare resource utilization, identification of endophenotypes, factors that predict treatment outcomes and clinical course, and ultimately advance the field toward precision headache medicine.

Cognitive Networks Disarrangement in Patients With Migraine Predicts Cutaneous Allodynia.

BACKGROUND: Two-thirds of patients with migraine without aura (MwoA) complain ictal cutaneous allodynia (CA), clinical sign of central nociceptive pathway sensitization, and independent predictor for migraine chronification. AIM: We aimed to investigate whether functional abnormalities, structural, or microstructural changes of the main cognitive networks (default mode network [DMN], salience network [SN], and central executive network [CEN]) could predict the development of CA in patients with MwoA. METHODS: Baseline 3-Tesla MRI images of 50 patients with MwoA were analyzed between 2009 and 2015. Over a three-year period, patients were then stratified into 2 groups based on CA development and compared with matched healthy controls (HC). Group-level independent components analysis was used to investigate intrinsic functional connectivity (FC) differences within the cognitive resting-state networks. Voxel-based morphometry (VBM) was used to assess whether group differences in cognitive network FC were related to structural differences. Tract-based spatial statistical analyses (TBSS) were conducted to assess the microstructural properties of white matter tracts. We also compared internetwork connectivity between patients. Finally, a logistic regression analysis was used to investigate baseline imaging predictors of CA development. RESULTS AND DISCUSSION: We observed a significantly reduced FC of both DMN and CEN in patients with MwoA developing CA (MwoA d CA) when compared with both patients with MwoA not developing CA (MwoA nd CA) and HC. Within the DMN, the PCC/precuneus is a key hub aimed to anti-nociception and multisensory integration. The reduced intrinsic PCC/precuneus FC observed in patients with MwoA d CA could subtend abnormal inputs integration, from different sensory modalities, allowing the development of CA. On the other hand, within the CEN, a central role in pain modulation as well as in executive functions is played by ACC and MFG. Our finding of reduced ACC and MFG FC in MwoA d CA may represent the neuronal substrate of both subclinical impairment of complex executive functions and dysfunctional anti-nociceptive pathway, making these patients more prone to migraine chronification. TBSS analyses showed a statistically significant reduced corpus callosum (CC) FA in patients with MwoA d CA as previously demonstrated in migraine patients with other chronification factors such as medication overuse or affective disorders. No VBM differences in both global and local volumes were revealed between groups. No significant correlations have been found between the observed functional and microstructural changes and clinical parameters of disease severity. Logistic regression analysis indicated that the full model containing all predictors was statistically significant while the decreased ACC-FC was significantly associated with CA development. CONCLUSION: We suggest that DMN and CEN FC abnormalities as well as CC microstructural changes could represent a prognostic imaging biomarker able to identify migraine patients more prone to experiencing CA and therefore, more inclined to chronic migraine. In the new pharmacological scenario, it would be useful to address therapeutic resources to specific migraine populations with a high risk of more severe clinical phenotype.

Acute sleep deprivation enhances susceptibility to the migraine substrate cortical spreading depolarization.

BACKGROUND: Migraine is a common headache disorder, with cortical spreading depolarization (CSD) considered as the underlying electrophysiological event. CSD is a slowly propagating wave of neuronal and glial depolarization. Sleep disorders are well known risk factors for migraine chronification, and changes in wake-sleep pattern such as sleep deprivation are common migraine triggers. The underlying mechanisms are unknown. As a step towards developing an animal model to study this, we test whether sleep deprivation, a modifiable migraine trigger, enhances CSD susceptibility in rodent models. METHODS: Acute sleep deprivation was achieved using the "gentle handling method", chosen to minimize stress and avoid confounding bias. Sleep deprivation was started with onset of light (diurnal lighting conditions), and assessment of CSD was performed at the end of a 6 h or 12 h sleep deprivation period. The effect of chronic sleep deprivation on CSD was assessed 6 weeks or 12 weeks after lesioning of the hypothalamic ventrolateral preoptic nucleus. All experiments were done in a blinded fashion with respect to sleep status. During 60 min of continuous topical KCl application, we assessed the total number of CSDs, the direct current shift amplitude and duration of the first CSD, the average and cumulative duration of all CSDs, propagation speed, and electrical CSD threshold. RESULTS: Acute sleep deprivation of 6 h (n = 17) or 12 h (n = 11) duration significantly increased CSD frequency compared to controls (17 ± 4 and 18 ± 2, respectively, vs. 14 ± 2 CSDs/hour in controls; p = 0.003 for both), whereas other electrophysiological properties of CSD were unchanged. Acute total sleep deprivation over 12 h but not over 6 h reduced the electrical threshold of CSD compared to controls (p = 0.037 and p = 0.095, respectively). Chronic partial sleep deprivation in contrast did not affect CSD susceptibility in rats. CONCLUSIONS: Acute but not chronic sleep deprivation enhances CSD susceptibility in rodents, possibly underlying its negative impact as a migraine trigger and exacerbating factor. Our findings underscore the importance of CSD as a therapeutic target in migraine and suggest that headache management should identify and treat associated sleep disorders.

Altered lateral geniculate nucleus functional connectivity in migraine without aura: a resting-state functional MRI study.

OBJECTIVES: To investigate the structural and functional connectivity changes of lateral geniculate nucleus (LGN) and their relationships with clinical characteristics in patients without aura. METHODS: Conventional MRI, 3D structure images and resting state functional MRI were performed in 30 migraine patients without aura (MwoA) and 22 healthy controls (HC). The lateral geniculate nucleus volumes and the functional connectivity (FC) of bilateral lateral geniculate nucleus were computed and compared between groups. RESULTS: The lateral geniculate nucleus volumes in patient groups did not differ from the controls. The brain regions with increased FC of the left LGN mainly located in the left cerebellum and right lingual gyrus in MwoA compared with HC. The increased FC of right LGN located in left inferior frontal gyrus in MwoA compared with HC. The correlation analysis showed a positive correlation between VLSQ-8 score and the increased FC of left cerebellum and right lingual gyrus. CONCLUSIONS: Photophobia in MwoA could be mediated by abnormal resting state functional connectivity in visual processing regions, the pain perception regulatory network and emotion regulation network. This result is valuable to further understanding about the clinical manifestation and pathogenesis of migraine.

Disrupted functional connectivity between sub-regions in the sensorimotor areas and cortex in migraine without aura.

BACKGROUND: Migraine is a severe and disabling brain disorder, and the exact neurological mechanisms remain unclear. Migraineurs have altered pain perception, and headache attacks disrupt their sensory information processing and sensorimotor integration. The altered functional connectivity of sub-regions of sensorimotor brain areas with other brain cortex associated with migraine needs further investigation. METHODS: Forty-eight migraineurs without aura during the interictal phase and 48 age- and sex-matched healthy controls underwent resting-state functional magnetic resonance imaging scans. We utilized seed-based functional connectivity analysis to investigate whether patients exhibited abnormal functional connectivity between sub-regions of sensorimotor brain areas and cortex regions. RESULTS: We found that patients with migraineurs without aura exhibited disrupted functional connectivities between the sensorimotor areas and the visual cortex, temporal cortex, posterior parietal lobule, prefrontal areas, precuneus, cingulate gyrus, sensorimotor areas proper and cerebellum areas compared with healthy controls. In addition, the clinical data of the patients, such as disease duration, pain intensity and HIT-6 score, were negatively correlated with these impaired functional connectivities. CONCLUSION: In patients with migraineurs without aura, the functional connectivities between the sensorimotor brain areas and other brain regions was reduced. These disrupted functional connectivities might contribute to abnormalities in visual processing, multisensory integration, nociception processing, spatial attention and intention and dysfunction in cognitive evaluation and modulation of pain. Recurrent headache attacks might lead to the disrupted network between primary motor cortex and temporal regions and between primary somatosensory cortex and temporal regions. Pain sensitivity and patient quality of life are closely tied to the abnormal functional connectivity between sensorimotor regions and other brain areas.

Headache Outcomes After Treatment of Unruptured Intracranial Aneurysm: A Systematic Review and Meta-Analysis.

Background and Purpose- While unruptured intracranial aneurysms may be discovered incidentally in the workup of chronic headache, it remains unclear whether their treatment ultimately impacts headache severity. We aim to conduct a systematic review and meta-analysis assessing headache severity after treatment of unruptured intracranial aneurysm. Methods- MEDLINE and EMBASE were systematically reviewed. Results- Data from 7 studies met inclusion criteria (309 nonduplicated patients). The standard mean difference in pre- and post-intervention headache severity was estimated at -0.448 (95% CI, -0.566 to -0.329) under a random effects model. No significant heterogeneity was noted nor was any significant publication bias demonstrated. Conclusions- This is the first systematic review assessing postoperative headache severity following treatment of unruptured intracranial aneurysm. While a significant reduction in headache severity was observed, further investigation into this phenomenon is recommended before it influences clinical practice. Future study should stratify headache outcomes by aneurysm size, location, and treatment modality.

Current understanding of premonitory networks in migraine: A window to attack generation.

AIM: To describe neuronal networks underlying commonly reported migraine premonitory symptoms and to discuss how these might precipitate migraine pain. BACKGROUND: Migraine headache is frequently preceded by a distinct and well characterized premonitory phase including symptoms like yawning, sleep disturbances, alterations in appetite and food intake and hypersensitivity to certain external stimuli. Recent neuroimaging studies strongly suggest the hypothalamus as the key mediator of the premonitory phase and also suggested alterations in hypothalamic networks as a mechanism of migraine attack generation. When looking at the vast evidence from basic research within the last decades, hypothalamic and thalamic networks are most likely to integrate peripheral influences with central mechanisms, facilitating the precipitation of migraine headaches. These networks include sleep, feeding and stress modulating centers within the hypothalamus, thalamic pathways and brainstem centers closely involved in trigeminal pain processing such as the spinal trigeminal nucleus and the rostral ventromedial medulla, all of which are closely interconnected. CONCLUSION: Taken together, these networks represent the pathophysiological basis for migraine premonitory symptoms as well as a possible integration site of peripheral so-called "triggers" with central attack facilitating processes.

Postural instability during attacks of migraine without aura.

BACKGROUND AND PURPOSE: Migraine has long been associated with unsteadiness and dizziness but postural control has not been studied in the ictal state. Here, the stability of upright stance during migraine attacks was measured. METHODS: Static balance was assessed prospectively in migraine patients (n = 30) during quiet stance for 40 s on a posturographic force platform. Recordings were performed both ictally and in the pain-free interval. Subjects were assessed under four different conditions yielding different visual and proprioceptive feedback environments. Both ictal and interictal data were compared with age-matched healthy controls (n = 30). RESULTS: Postural instability increased significantly under all experimental conditions during migraine attacks. Whilst standing on a foam pad with eyes closed, median sway area was 353 mm2 in control subjects, 318 mm2 in migraineurs in the pain-free period and 618 mm2 in the ictal state. However, Romberg and vestibular Romberg quotients were not altered during migraine attacks. Spectral analyses of postural sway also showed similar profiles in migraineurs and controls. The severity of headache was inversely correlated to Romberg quotients. CONCLUSIONS: The demonstrated pattern of balance disorder during migraine attacks suggests a transient cerebellar dysfunction. Our findings also indicate that intense headache induces a re-weighting of sensory processing toward less dependence on visual and proprioceptive information.

Evaluation of Electroencephalogram Using Exact Low-Resolution Electromagnetic Tomography During Photic Driving Response in Patients with Migraine.

BACKGROUND: Photophobia is a common feature of migraine, which may involve abnormal cortical information processing. In electroencephalograms (EEG), photic driving is known as a reaction to visual stimulation. Both photophobia and photic driving response are present during light stimulation. We hypothesized that cortical response to photic stimulation would differ between migraine patients with and without aura. METHODS: We recruited 50 migraine patients (migraine with aura [MWA] = 21; migraine without aura [MWOA] = 29). Spontaneous eyes-closed resting EEG from 20 electrodes on the scalp during the interictal phase was recorded. After recording, each photic stimulation was separately selected. We analyzed EEG by fast Fourier transform and observed the spectrum frequency peaks and topographies in response to photic stimulation. Exact low-resolution electromagnetic tomography (eLORETA) was used to compute the 3-dimensional intracerebral distribution of EEG activity. RESULTS: Photic stimulation at frequencies 5, 8, 15, and 20 Hz showed significant differences between migraine patients with and without aura. MWOA patients consistently had a stronger response to photic stimulation than MWA patients. In all patients, the differential response was located in the visual cortex, except for the stimulation at 20 Hz, where the difference at subharmonic 10 Hz was located in the parietal cortex (Brodmann Area 7). CONCLUSION: We confirmed high incidences of photic hypersensitivity and photic driving responses in migraine patients. We suggest that repeated occurrences of cortical spreading depression in MWA may suppress cortical function, thus contributing to a weaker visual cortical response to photic stimulation in MWA patients compared with MWOA patients.

rs2651899 variant is associated with risk for migraine without aura from North Indian population.

Recently a GWAS study had identified 38 genomic variants commonly found in humans that influence migraine risk. For further replicate these findings, we selected two SNPs; rs2651899 on chromosome 1p36.32 in PRDM16 gene and rs10166942 on chromosome 2q37.1 close to TRPM8 gene for their associations with migraine in the North Indian population as much work has not been done on these variants before from this population. In this case-control association study, 300 unrelated subjects, including 150 migraineurs (43 migraine with aura and 107 migraine without aura) and 150 healthy controls were selected to collect genomic DNA. Polymerase chain reaction and restriction-fragment-length polymorphism methods were performed for genotyping of these variants. Univariate and multivariate analyses were done to find the association of different genotypes and alleles of these SNPs with migraine and its subgroups. We found a statistically significant difference in migraineurs with control for PRDM16 rs2651899 polymorphism at genotypic (p < 0.05), allelic (p = 0.022; OR 1.462; 95% CI 1.058-2.022) and for dominant model (p = 0.011; OR 1.957; 95% CI 1.169-3.276). A similar trend was observed both on subgroup and gender analysis in migraine without aura (MO) and females respectively for rs2651899 variant. For the other SNP (rs10166942), statistically non-significant differences were reported in the allelic/genotypic frequencies between migraineurs and controls as p > 0.05. However, on subgroup analysis we found statistically significant differences at genotypic (p < 0.05) and dominant models in migraine with aura (MA) and in males with that of entire controls. But no significant association was found at allelic level in both subgroup and gender analysis for rs10166942. This research study showed that rs2651899 is a potential genetic marker for migraine susceptibility in MO and female subgroup at both genotypic and allelic level in the North Indian population and found that rs10166942 variant may be a potential marker for MA and male subgroup. Further work with large sample size is required for these SNPs to understand their functional mechanisms and to strengthen our results.