On the utility of the trail making test in migraine with and without aura: a meta-analysis.

This meta-analytical review assesses the utility of the Trail Making Test (TMT), versions A and B, in detecting migraine-related cognitive deficits. A comprehensive literature search was performed in two electronic databases and other sources to obtain relevant studies administering TMT to migraine patients. Search terms included "migraine" and "Trail Making". Only studies in which the TMT-A, TMT-B or both were administered to adult patients suffering from migraine with and without aura were included. All pooled meta-analyses were based on random effects models. A total of 14 studies for TMT-A and 15 for TMT-B met inclusion criteria and were subjected to meta-analyses. Results showed that performance is worse in migraine patients than in controls for both the TMT-A (Hedges' g = -.28) and TMT-B (g = -.37), with no difference between migraine with and without aura. This study demonstrates the sensitivity of the TMT in detecting cognitive alterations in migraine. This test should be considered for inclusion in cognitive batteries assessing patients with migraine.

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.

Relating excitatory and inhibitory neurochemicals to visual perception: A magnetic resonance study of occipital cortex between migraine events.

Certain perceptual measures have been proposed as indirect assays of brain neurochemical status in people with migraine. One such measure is binocular rivalry, however, previous studies have not measured rivalry characteristics and brain neurochemistry together in people with migraine. This study compared spectroscopy-measured levels of GABA and Glx (glutamine and glutamate complex) in visual cortex between 16 people with migraine and 16 non-headache controls, and assessed whether the concentration of these neurochemicals explains, at least partially, inter-individual variability in binocular rivalry perceptual measures. Mean Glx level was significantly reduced in migraineurs relative to controls, whereas mean occipital GABA levels were similar between groups. Neither GABA levels, nor Glx levels correlated with rivalry percept duration. Our results thus suggest that the previously suggested relationship between rivalry percept duration and GABAergic inhibitory neurotransmitter concentration in visual cortex is not strong enough to enable rivalry percept duration to be reliably assumed to be a surrogate for GABA concentration, at least in the context of healthy individuals and those that experience migraine.

Coping Strategies in Migraine without Aura: A Cross-Sectional Study.

BACKGROUND: In the context of a causal relationship between stress and migraine, coping strategies are aimed at managing stressful life events and reducing the distressing emotions connected to them. METHODS: Sixty-one consecutive patients with migraine without aura (MwoA) and sixty-one healthy controls (HCs) completed three self-report questionnaires assessing a broad range of coping (cognitive and behavioural) strategies: the Coping Orientation to Problems Experienced (COPE), the Coping Inventory for Stressful Situation (CISS), and the Proactive Coping Inventory (PCI). Moreover, the Perceived Stress Scale (PSS), a scale measuring self-perception of stress, global cognitive functioning, depressive symptoms, apathy, state, and trait anxiety, was administered to all participants. RESULTS: No significant difference was found on the scales and subscales of PCI and CISS as well as in the PSS between MwoA patients and HCs. However, the two groups showed different scores in the subscale "turning to religion" of COPE (22.08 ± 5.19 in migraineurs vs. 24.70 ± 4.44 in HCs, p = 0.003). A significant negative correlation of the turning to religion score with the HIT-6 score was found. CONCLUSIONS: The present study revealed that MwoA patients show a significantly reduced use of the "turning to religion" approach, an emotion-focused coping strategy. Although migraine patients appeared to be less oriented to transcendent (that means a reduced utilization of an adaptive coping strategy), they did not perceive daily living as more stressful than HCs. Finally, the reduced utilization of the "turning to religion" coping strategy is associated with a great impact of migraine on ability to function on the job or at school, at home, and in social situations in migraine patients.

Assessment of gray and white matter structural alterations in migraineurs without aura.

BACKGROUND: Migraine constitute a disorder characterized by recurrent headaches, and have a high prevalence, a high socio-economic burden and severe effects on quality of life. Our previous fMRI study demonstrated that some brain regions are functional alterations in migraineurs. As the function of the human brain is related to its structure, we further investigated white and gray matter structural alterations in migraineurs. METHODS: In current study, we used surface-based morphometry, voxel-based morphometry and diffusion tensor imaging analyses to detect structural alterations of the white matter and gray matter in 32 migraineurs without aura compared with 32 age- and gender-matched healthy controls. RESULTS: We found that migraineurs without aura exhibited significantly increased gray matter volume in the bilateral cerebellar culmen, increased cortical thickness in the lateral occipital-temporal cortex, decreased cortical thickness in the right insula, increased gyrification index in left postcentral gyrus, superior parietal lobule and right lateral occipital cortex, and decreased gyrification index in the left rostral middle frontal gyrus compared with controls. No significant change in white matter microstructure was found in DTI analyses. CONCLUSION: The significantly altered gray matter brain regions were known to be associated with sensory discrimination of pain, multi-sensory integration and nociceptive information processing and were consistent with our previous fMRI study, and may be involved in the pathological mechanism of migraine without aura.

The role of attachment insecurity in the emergence of anxiety symptoms in children and adolescents with migraine: an empirical study.

BACKGROUND: It is widely recognised that there are associations between headache, psychiatric comorbidity and attachment insecurity in both adults and children. The aims of this study were: 1) to compare perceived attachment security and anxiety in children and adolescents with migraine without aura and a healthy control group; 2) to test whether the child's perceived security of attachment to the mother and the father mediated the association between migraine and anxiety. METHODS: One hundred children and adolescents with Migraine without Aura were compared with a control group of 100 children without headache. The Security Scale (measures perceived security of attachments) and the Self-Administered Psychiatric Scales for Children and Adolescents, a measure of anxiety symptoms, were administered to all participants. RESULTS: The clinical group had lower attachment security than the control group and higher scores on all anxiety scales. Anxiety was negatively correlated with attachment. Children's attachment to their mother mediated the increase in global anxiety in the clinical group. Insecure paternal attachment was associated with greater insecurity in maternal attachment, suggesting that there is a complex pathway from migraine to anxiety symptoms mediated by perceived insecurity of paternal attachment and hence also by perceived insecurity of maternal attachment. CONCLUSION: These results suggest that insecure parental attachment may exacerbate anxiety in children and adolescents with migraine and point to the importance of multimodal interventions, perhaps taking account of family relationships, for children and adolescents with migraine.

Raven coloured progressive matrices in migraine without aura patients.

Conflicting results emerged from studies investigating cognitive performances in migraine patients. Based on clinical and neuroradiological aspects, the possible involvement of executive functions has been especially taken into consideration. The aim of this study was to evaluate, in a population of subjects affected by migraine without aura (MwoA), frontal lobe cognitive functions. We enrolled all the consecutive patients affected by MwoA referred to our headache centre for a first evaluation. Each patient underwent a neuropsychological evaluation including Raven coloured progressive matrices (CPM). We collected variables as age, education, years of migraine, frequency of attacks and CPM scores. Relationship between continuous variables was explored with multiple regression lines, selecting the best-fitting trendline for each relationship. We obtained a final sample of 36 subjects (females: 62.5%; mean age: 42.25 ± 10.21 years). Patients had mean length of migraine history of 12.25 ± 11.00 years and a mean frequency of attacks of 8.06 ± 7.15 per month. Linear regression underlines a progressive decrease of CPM score with the increase of the migraine history's length (R 2 = 0.8871; p < 0.001), and the frequency of migraine attacks (R 2 = 0.3122; p < 0.05). Our findings suggest that pathological CPM scores can be associated with the severity of migraine. These data seem to confirm the hypothesis of an impairment of executive functions in MwoA. Different hypotheses to explain cognitive impairment in migraine have been postulated including the impact of the typical white matter lesions and a long history of drug abuse. The possible relevant clinical consequence of a full comprehension of this particular aspect related to migraine deserves further attention and consideration.

Auditory Processing in Children with Migraine: A Controlled Study.

Background This study aimed to investigate central auditory processing performance in children with migraine and compared with controls without headache. Methods Twenty-eight children of both sexes, aged between 8 and 12 years, diagnosed with migraine with and without aura, and a control group of the same age range and with no headache history, were included. Gaps-in-noise (GIN), duration pattern test (DPT), synthetic sentence identification (SSI) test, and nonverbal dichotic test (NVDT) were used to assess central auditory processing performance. Results Children with migraine performed significantly worse in DPT, SSI test, and NVDT when compared with controls without headache; however, no significant differences were found in the GIN test. Conclusions Children with migraine demonstrate impairment in the physiologic mechanism of temporal processing and selective auditory attention. In our short communication, migraine could be related to impaired central auditory processing in children.

Acquired equivalence and related memory processes in migraine without aura.

Introduction Interictal deficits of elementary visuo-cognitive functions are well documented in patients with migraine and are mostly explained in terms of neocortical hyperexcitability. It has been suggested that the basal ganglia and the hippocampi might also be affected in migraine. If so, a deterioration of learning and memory processes related to these structures is expected. Methods A visual learning paradigm thought to be capable of dissociating learning/memory processes mediated by the basal ganglia from processes mediated by the hippocampus (the Rutgers Acquired Equivalence Test) was applied to a group of patients with migraine without aura and to age- and sex-matched controls. Results Patients with migraine showed a significantly poorer performance in both main phases of the test and the deficit in the phase considered to be dependent on the hippocampi was especially marked. Conclusions These results can be interpreted as behavioural support for findings that have suggested the involvement of the basal ganglia and the hippocampi in migraine, but further research is needed to clarify these findings.

Cognitive dysfunctions and psychological symptoms in migraine without aura: a cross-sectional study.

BACKGROUND: The occurrence of cognitive dysfunctions and psychological symptoms, as well as their mutual relationships, in migraine patients are still debated. The aim of the study was to characterize the cognitive profile and psychological symptoms (i.e. depression, anxiety and apathy) in drug-naïve migraine without aura (MwoA) patients. METHODS: Seventy-two consecutive MwoA patients, referred to the Italian University Headache Clinic and 72 healthy subjects (HCs) were enrolled. Patients, during an attack-free period, and HCs completed Montreal Cognitive Assessment (MoCA), Beck Depression Inventory-II (BDI-II), Self-version of Apathy Evaluation Scale (AES-S) and State and Trait Anxiety Inventory (STAI-Y-1 and 2). Clinical parameters of disease severity (i.e. disease duration, migraine attacks per month, mean pain intensity during migraine attacks, migraine disability and impact on daily life) were recorded. RESULTS: Although performance of MwoA patients on MoCA was above Italian cut-off threshold (<15.5) suggesting presence of cognitive impairment, MwoA patients achieved significantly lower scores than HCs on total MoCA scale (22.3 ± 2.7 versus 25.4 ± 2.3) and on its attention (4.9 ± 1.1 versus 5.6 ± 0.7), memory (1.8 ± 1.4 versus 3.1 ± 1.3), visuospatial (3.2 ± 0.9 versus 3.6 ± 0.6) and executive subscales (2.6 ± 1.1 versus 3.1 ± 0.8). In addition, we observed significant correlations between MoCA executive domain subscore and the attack-related disability score (MIDAS). As for behavioral profile, the percentage of depressive symptoms (4.2 %), high state and trait anxiety (13.9 and 9.7 %, respectively), and apathy (11.1 %) in MwoA patients were similar to that of HCs. No significant associations of behavioural symptoms with cognitive performance and clinical parameters were found. CONCLUSIONS: Drug-naïve MwoA patients are characterized by subtle cognitive dysfunctions and low percentage of behavioural symptoms. The results support the importance of searching for subclinical cognitive disturbances in patients with MwoA, who deserve to be followed-up to verify whether they develop clinically relevant disorders over time.

Autonomic impairment in patients with migraine.

OBJECTIVE: Heart rate variability analysis of electrocardiogram is becoming an increasingly common method to non-invasively evaluate autonomic nervous function. The aim of the study was to investigate cardiac autonomic function in subjects with and without migraine by using 24-hour ambulatory electrocardiographic recordings. PATIENTS AND METHODS: We investigated 27 subjects with migraine (10 with migraine with aura and 17 without aura) during headache free periods and 10 age-matched healthy control subjects. The migraine was diagnosed using the International Classification of Headache Disorders 2nd Edition criteria. Beck Depression and Beck Anxiety Inventory forms were completed by all subjects. Time and frequency-domain of HRV was analyzed for two periods: diurnal and nocturnal. RESULTS: We found an increased frequency of anxiety and depressive symptoms in migraine patients, especially in migraine with aura group. The heart rate variability parameters SDNN, RMSSD, high frequency were decreased and low frequency was increased in migraine patients during night period compared with normal subjects, most affected were migraine with aura patients. During day period we found modification for SDNN, RMSSD and high frequency parameters only in migraine with aura group. CONCLUSIONS: Reduced parasympathetic activity with sympathetic predominance was found in migraine patients during the night period, most affected being migraine with aura patients.

Genetic contribution of catechol-O-methyltransferase in hippocampal structural and functional changes of female migraine sufferers.

Physiological and emotional stressors are associated with or provoke each migraine attack and cause structural and functional changes in the central nervous system. The hippocampus, a limbic structure important in anxiety-related behavior, is vulnerable to long-term stress. Given that catechol-O-methyltransferase (COMT) is widely distributed in the hippocampus and its genetic variation is thought to contribute to the interindividual variability in pain perception and anxiety regulation, whether or not migraine and COMT val(158) met genotype have an interactive effect in the key brain area related to maladaptive stress, the hippocampus, is still poorly understood. Using T1-weighted and resting functional MRI, we evaluated the effect of COMT genetic variations on migraine and possible interactions between COMT and the disease in brain structure and function in 135 females with migraine without aura (MWoA) and 111 matched health controls (HC). Optimized voxel-based morphometry (VBM) and functional connectivity (FC) analyses were applied. From the whole brain VBM analysis, we found a significant disease × genotype interaction in the hippocampus, which overlapped with disease-related increase of gray matter (GM) in val homozygote migraineurs. In our results, increased GM in the hippocampus was only found in val homozygote MWoA compared to val homozygote HC. Moreover, FC between the hippocampus and the medial prefrontal cortex was significantly decreased in val homozygotes, and it was negatively correlated with self-rating anxiety scale values.Our results indicated that brain structure and function of the hippocampus are differentially affected by migraine in val homozygotes compared with met carriers.

Health state utilities for migraine based on attack frequency: a time trade-off study.

This study aims to evaluate health state utilities for migraine based on attack frequency from a mixed population sample consisting of migraineurs and non-migraineurs. A cross-sectional questionnaire survey was designed to measure health-related quality of life (HRQOL) in migraine without aura by time trade-off method (TTO). A convenience sample of university students and staff was recruited regardless of having ever experienced migraine or not. Subjects were asked to elicit two hypothetical health states characterised by different migraine frequencies ('m': two migraines lasting 4 h each month and 'w': each week) within two hypothetical lifetime frames (20 years left to live/lives until the age of 80 years). Utilities were calculated for the four tasks (U20m, U80m, U20w, U20w) and compared amongst subgroups. Overall 180 respondents were included in the analysis. Mean age was 25.6 years (SD 6.4), 128 (71%) were female and 110 (61%) were self-reported migraineurs. Mean utilities for two migraines each month were U20m = 0.84 (SD 0.26) and U80m = 0.89 (SD 0.14), and for each week were U20w = 0.79 (SD 0.27) and U80w = 0.83 (SD 0.17), respectively. Self-reported migraineurs and females attached higher mean utilities for U80m and older respondents for U20m, respectively (p < 0.05). To our knowledge, this is the first study that provides HRQOL results measured by TTO methodology for migraine. Utility loss ranged from 0.1 to 0.2 depending on attack frequency. HRQOL impairment of having two migraine attacks per week was found similar to living with low back pain (0.77-0.79).

Cognitive dysfunction during migraine attacks: a study on migraine without aura.

BACKGROUND: Cognitive difficulties contribute to patients' disability during migraine attacks and have been overlooked in migraine research. Neuropsychological studies performed during attacks have produced inconsistent findings due to design differences and limitations. OBJECTIVE: Our objective is to document changes in cognitive performance of migraine patients during migraine attacks with a comprehensive battery of cognitive/behavioral tests, while controlling for potential confounders. METHOD: A prospective two-period, randomized, cross-over study compared within-subject neuropsychological evaluation in two conditions-during a naturally occurring untreated migraine attack and a headache-free period. RESULTS: Thirty-nine patients with episodic migraine (37 females, average 38 years old) were included and 24 completed the study. Participants performed worse during the attack in the majority of cognitive tests, compared to the headache-free status, and significantly so in word reading speed (p = 0.013), verbal learning (p = 0.01), short-term verbal recall with (p = 0.01) and without (p = 0.013) semantic cueing and delayed recall with (p = 0.003) and without (p = 0.05) semantic cues. Differences found were unrelated to age, gender, literacy, condition order, interval between evaluations, anxiety, pain intensity or duration of the attack. DISCUSSION: Cognitive performance decreases during migraine attacks, especially in reading and processing speed, verbal memory and learning, supporting patients' subjective complaints. These findings suggest the existence of a reversible brain dysfunction during attacks of migraine without aura, which can relate specifically to migraine or be a consequence of acute pain processing by the brain.

Higher burden of migraine compared to other neurological conditions: results from a cross-sectional study.

Headache disorders are prevalent, burdensome and costly. However, it is difficult to get an idea of how much of a burden do they cause if they are not compared with other conditions. Using data from PARADISE project, we compared 80 migraineurs and 80 patients similar for age, gender and work condition. Our results showed that the amount of psycho-social difficulties was higher among patients with migraine than among patients with epilepsy, stroke, multiple sclerosis or Parkinson's disease.

Migraine trait symptoms in migraine with and without aura.

OBJECTIVES: The aim of the study was to determine whether various transient sensory and neuropsychological symptoms (SNS) were associated with migraine using a custom questionnaire. METHODS: In this hypothesis-generating case-control study, the frequencies of transient SNS in 219 patients with migraine (149 without aura and 70 with aura) were compared with 161 age- and sex-matched healthy controls using a custom questionnaire. Patients from a tertiary academic headache center in Hamburg were contacted by regular mail. Healthy controls without a history of migraine were recruited by means of a screening questionnaire and consecutively approached by e-mail. RESULTS: The presence of both migraine and aura was associated with significantly higher frequencies of autokinesis, metamorphopsia, dyschromatopsia, cinematographic vision, illusionary visual spread, and synesthesia (for all comparisons: corrected p < 0.05). Double vision, inverted 2- and 3-dimensional vision, and altered perception of body weight and size were found more often in patients with migraine without aura than in those with aura. In contrast, aura was associated with the occurrence of visual splitting and corona phenomenon (for all comparisons: corrected p < 0.05). No relevant association with migraine was found for micropsia and macropsia, teleopsia and pelopsia, inverted vision, out-of-body experience, Doppelgänger phenomenon, complex visual hallucinations, and altered perception of body position in space. CONCLUSIONS: The observed SNS seem to belong to a physiologic spectrum of multisensory phenomena. Some of these phenomena were significantly accentuated in patients with migraine and may therefore be termed migraine trait symptoms. However, these results will have to be confirmed in a prospective study with face-to-face interviews.

Executive dysfunctions in migraine with and without aura: what is the role of white matter lesions?

OBJECTIVE/BACKGROUND: Executive dysfunctions and white matter lesions on magnetic resonance imaging have been reported in migraine. The aim of this study was to determine whether any correlation between these 2 variables exists. MATERIALS AND METHODS: Forty-four subjects affected by migraine with or without aura were compared with 16 healthy subjects. A battery of neuropsychological tests assessing executive functions was administered to all subjects. Number and total volume of white matter lesions were assessed in the whole brain and in the frontal lobe. RESULTS: The performances of both groups of migraineurs, with and without aura, were significantly worse when compared with controls on Boston Scanning Test. Moreover, we found lower performances compared with controls respectively on Frontal Assessment Battery in patients with migraine with aura and on Controlled Oral Word Association Test in patients with migraine without aura. Nineteen patients (43.2%) and one control subject (6.2%) had white matter lesions. We did not find any significant correlation between white matter lesions load and neuropsychological performances. CONCLUSIONS: On the basis of our results, white matter lesions load on magnetic resonance imaging do not seem to contribute to neuropsychological performances deficit in migraineurs.

Disrupted default mode network connectivity in migraine without aura.

BACKGROUND: Resting-state functional magnetic resonance imaging (RS-fMRI) has demonstrated disrupted default mode network (DMN) connectivity in a number of pain conditions, including migraine. However, the significance of altered resting-state brain functional connectivity in migraine is still unknown. The present study is aimed to explore DMN functional connectivity in patients with migraine without aura (MwoA) and investigate its clinical significance. METHODS: To calculate and compare the resting-state functional connectivity of the DMN in 20 patients with MwoA, during the interictal period, and 20 gender- and age-matched HC, Brain Voyager QX was used. Voxel-based morphometry was used to assess whether between-group differences in DMN functional connectivity were related to structural differences. Secondary analyses explored associations between DMN functional connectivity, clinical and neuropsychological features of migraineurs. RESULTS: In comparison to HC, patients with MwoA showed decreased connectivity in prefrontal and temporal regions of the DMN. Functional abnormalities were unrelated to detectable structural abnormalities or clinical and neuropsychological features of migraineurs. CONCLUSIONS: Our study provides further evidence of disrupted DMN connectivity in patients with MwoA. We hypothesize that a DMN dysfunction may be related to behavioural processes such as a maladaptive response to stress which seems to characterize patients with migraine.

Regional homogeneity abnormalities affected by depressive symptoms in migraine patients without aura: a resting state study.

BACKGROUND: Bidirectional relationship between migraine and depression suggests that there might be some etiological risk factors shared. However, few studies investigated resting state abnormalities affected by depressive symptoms in migraine patients without aura (MWoA). MATERIALS AND METHODS: According to their self-rating depression scale (SDS) score, MWoA were divided into twenty in the SDS (+) (SDS > 49) group and 20 in the SDS (-) (SDS ≤ 49) group. Regional homogeneity (ReHo) method were employed to assess local features of spontaneous brain activity between 1) all MWoA and healthy controls, 2) each subgroup and healthy controls, and 3) SDS (-) group and SDS (+) group. RESULTS: Compared with healthy controls, decreased ReHo in similar regions were shown in the MWoA group and subgroups. It is noteworthy that the caudate showed increased ReHo in the SDS (-) group compared with healthy controls and the SDS (+) group. Moreover, the average ReHo values of the caudate in SDS (-) group were significantly positively correlated with duration of migraine. CONCLUSIONS: Our results suggested that ReHo patterns in migraine patients may be affected by depressive symptoms and serve as a biomarker to reflect depression severity in MWoA.