Cortical Excitability In Migraine Research Articles

TMS-evoked EEG potentials demonstrate altered cortical excitability in migraine with aura

Migraine is associated with altered sensory processing, that may be evident as changes in cortical responsivity due to altered excitability, especially in migraine with aura. Cortical excitability can be directly assessed by combining transcranial magnetic stimulation with electroencephalography (TMS-EEG). We measured TMS evoked potential (TEP) amplitude and response consistency as these measures have been linked to cortical excitability but were not yet reported in migraine.We recorded 64-channel EEG during single-pulse TMS on the vertex interictally in 10 people with migraine with aura and 10 healthy controls matched for age, sex and resting motor threshold. On average 160 pulses around resting motor threshold were delivered through a circular coil in clockwise and counterclockwise direction. Trial-averaged TEP responses, frequency spectra and phase clustering (over the entire scalp as well as in frontal, central and occipital midline electrode clusters) were compared between groups, including comparison to sham-stimulation evoked responses.Migraine and control groups had a similar distribution of TEP waveforms over the scalp. In migraine with aura, TEP responses showed reduced amplitude around the frontal and occipital N100 peaks. For the migraine and control groups, responses over the scalp were affected by current direction for the primary motor cortex, somatosensory cortex and sensory association areas, but not for frontal, central or occipital midline clusters.This study provides evidence of altered TEP responses in-between attacks in migraine with aura. Decreased TEP responses around the N100 peak may be indicative of reduced cortical GABA-mediated inhibition and expand observations on enhanced cortical excitability from earlier migraine studies using more indirect measurements.

Altered brain activity and functional connectivity in migraine without aura during and outside attack

ABSTRACT Background Migraine is commonly seen as a cyclic disorder with variable cortical excitability at different phases. Herein, we investigated the cortical excitability in migraine without aura patients during an attack (MWoA-DA) and interictal period (MWoA-DI) and further explored the functional connectivity (FC) in brain regions with cortical excitability abnormalities in patients. Methods Seven MWoA-DA patients, twenty-seven MWoA-DI patients, and twenty-nine healthy controls (HC) underwent resting-state functional magnetic resonance imaging (rs-fMRI) scan. The amplitude of low-frequency fluctuations (ALFF) was assessed to identify spontaneous brain activity. Then, brain regions showing significant differences across groups were identified as regions of interest (ROI) in FC analysis. Results Compared with MWoA-DI patients and HC, the ALFF in the trigeminocervical complex (TCC) was higher in the MWoA-DA patients. Decreased FC in MWoA-DA patients was found between TCC and left postcentral gyrus compared with MWoA-DI patients. Compared with HC, ALFF was lower in the right cuneus but higher in the right rolandic operculum of MWoA-DI patients. Additionally, the ALFF in the right cuneus was negatively correlated with the Migraine Disability Assessment Scale (MIDAS) in MWoA-DI patients. Conclusions The trigeminovascular system and impairments in descending pain modulatory pathways participate in the pathophysiology of migraine during the ictal period. The defense effect exists in the interictal phase, and the dysfunction in the cuneus may be related to the disease severity. This dynamic change in different brain regions could deepen our understanding of the physiopathology underlying migraine.

Cortical excitability in migraine: Contributions of magnetic resonance imaging.

Migraine is characterized by symptoms related to cortical hyperexcitability such as photophobia, phonophobia, osmophobia and allodynia. One-third of migraineurs experience aura, whose neurophysiological substrate is thought to be cortical spreading depression (CSD). Functional magnetic resonance imaging (MRI) has shown the migraine aura to be characterized by cerebral hyperactivity/hyperperfusion followed by hypometabolism/hypoperfusion spreading along the occipital cortex with the same spatiotemporal organization as the experimentally triggered CSD. The link between migraine aura and headache remains undetermined. Neuroimaging studies have failed to show a leakage of the blood-brain barrier, which was suspected to occur during CSD and to cause the stimulation of trigeminal nociceptive receptors. However, recent studies have highlighted the involvement of neuroglial inflammation and other studies have suggested that a common central network plays a role in the link between CSD and migraine pain. Finally, MRI has made it possible to study the contribution of metabolites such as glutamic acid, γ-amino-butyric acid and sodium in the pathophysiology of hyperexcitability in migraine.

Intracortical facilitation within the migraine motor cortex depends on the stimulation intensity. A paired-pulse TMS study

IntroductionConnectivity within the primary motor cortex can be measured using the paired-pulse transcranial magnetic stimulation (TMS) paradigm. This evaluates the effect of a first conditioning stimulus on the motor evoked potential (MEP) elicited by a second test stimulus when different interstimulus intervals are used. Aim of the present study was to provide, in patients suffering from migraine without aura (MwoA), additional information on intracortical facilitation (ICF), short intracortical inhibition (SICI), and long intracortical inhibition (LICI), using different intensities of the test stimulus (TS).MethodsWe enrolled 24 patients with episodic MwoA and 24 age- and sex-matched healthy volunteers. Both patients and controls were randomly assigned to two different experimental groups: the first group underwent evaluation of ICF, while in the second group we assessed SICI and LICI. All these measures were assessed by using three different suprathreshold intensities of the TS (110%, 130% and 150% of the resting motor threshold, RMT). Interstimulus intervals (ISIs) of 10 ms were used for testing ICF, while SICI and LICI were carried out by using 2 ms and 100 ms ISIs respectively. All migraine patients underwent the experimental protocol while in the interictal pain-free state.ResultsA main finding of the study was that an increased ICF could be seen in migraineurs as compared to the healthy subjects only by using a 110% intensity of the TS. Instead, no significant differences were observed between patients and controls as regards both measures of intracortical inhibition.ConclusionWe show that hyperresponsivity of the glutamatergic intracortical circuits can be detected in the migraine motor cortex only by applying a low suprathreshold intensity of stimulation. Our results strengthen the notion that, to be reliable, the assessment of cortical excitability in migraine should always include evaluation of the cortical response to different stimulation intensities.

Cortical excitability in migraine and epilepsy: A common feature?: Erratum

Cortical excitability in migraine and epilepsy: A common feature?: Erratum

Spatial Heterogeneity of Cortical Excitability in Migraine Revealed by Multifrequency Neuromagnetic Signals.

To investigate the spatial heterogeneity of cortical excitability in adolescents with migraine, magnetoencephalography (MEG) recordings at a sampling rate of 6,000Hz were obtained from 35 adolescents with an acute migraine and 35 age- and sex-matched healthy control participants during an auditory-motor task. Neuromagnetic activation from low- to high-frequency ranges (5-1,000Hz) was measured at sensor and source levels. The heterogeneity of cortical excitability was quantified within each functional modality (auditory vs motor) and hemispherical lateralization. MEG data showed that high-frequency, not low-frequency neuromagnetic signals, showed heterogeneous cortical activation in migraine subjects compared with control participants (P<.001). The alteration of the heterogeneity of cortical excitability in migraine subjects was independent of age and sex. The degree of the neuromagnetic heterogeneity of cortical activation was significantly correlated with headache frequency (r=.71, P<.005). The alteration of cortical excitability in migraine subjects was spatially heterogeneous and frequency dependent, which previously has not been reported. The finding may be critical for developing spatially targeted therapeutic strategies for normalizing cortical excitability with the purpose of reducing headache attacks. This article presents a new approach to quantitatively measure the spatial heterogeneity of cortical excitability in adolescents with migraine using MEG signals in a frequency range of 5 to 1,000Hz. The characteristics of the location and degree of cortical excitability may be critical for spatially targeted treatment for migraine.

Correlation between habituation of visual-evoked potentials and magnetophosphene thresholds in migraine: A case-control study.

In migraine most studies report an interictal deficit of habituation of visual-evoked potentials (VEP-hab) and reduced thresholds for phosphene induction (PT) by transcranial magnetic stimulation (TMS). We searched for a possible correlation between VEP-hab and PT in migraine patients and healthy controls to test whether they reflect the same pathophysiological abnormality. We assessed PT and VEP-hab measured as the percentage change of N1/P1 amplitude over six blocks of 100 responses in 15 healthy volunteers (HV) and in 13 episodic migraineurs without aura (MO) between attacks. Results were compared using Mann-Whitney U test. Interrelationships were examined using Spearman's correlation. In MO patients VEP-hab was reduced compared to HV (p = 0.001), while PT were not significantly different between HV and MO. There was no correlation between PT and VEP-hab in either group of participants. We confirm that in interictal migraine VEP habituation is deficient, but magnetophosphene threshold normal. VEP-hab and PT were not correlated with each other in healthy controls or in migraineurs. This finding suggests that they index different facets of cortical excitability in migraine, i.e. a punctual normal measure of the cortical activation threshold for PT and a dynamic response pattern to repeated stimuli for VEP habituation.

P907: Cortical excitability in migraine: new evidence by sound-induced flash illusions and transcranial direct current stimulation of visual cortex

P907: Cortical excitability in migraine: new evidence by sound-induced flash illusions and transcranial direct current stimulation of visual cortex

Cortical Excitability in Migraine and Epilepsy

There is evidence for comorbidity of migraine and epilepsy. We used transcranial magnetic stimulation (TMS) to assess cortical excitability in migraine compared with control subjects and patients with epilepsy. Twenty-six patients drug-naive patients with newly diagnosed migraine were studied. These were compared with 19 healthy control subjects and 50 patients with new onset epilepsy. Motor threshold (MT) and responses to paired pulse stimulation at short (2, 5, 10, and 15 milliseconds) and long (50-400 milliseconds) interstimulus intervals (ISIs) were measured. Compared with control subjects, cortical excitability was higher in migraine only at 250 milliseconds (P < 0.05; effect size 0.7), while in epilepsy, it was higher at 2, 5, 250, and 300 milliseconds. Compared with epilepsy, cortical excitability was lower in migraine only at 250 milliseconds (P < 0.05; effect size 0.6 compared with focal epilepsy and 1.1 compared with idiopathic generalized epilepsy [IGE]). Cortical excitability increases in migraine suggesting the involvement of intracortical inhibitory circuits. This may be a common feature underlying some of the similarities observed in migraine and epilepsy.

Abnormal Changes of Synaptic Excitability in Migraine with Aura

Migraine patients are characterized by altered cortical excitability and information processing between attacks. The relationship between these abnormalities is still poorly understood. In this study, visual evoked potentials (VEP) and proton magnetic resonance spectroscopy were recorded simultaneously in migraineurs and healthy subjects. In order to investigate the homeostatic-like plasticity in the visual cortex, cortical excitability was modified using transcranial direct current stimulation (tDCS). Before any stimulation, migraineurs showed significantly higher glutamate/creatine ratios (Glx/Cr) than healthy subjects. In healthy subjects, excitatory (anodal) tDCS caused an increase and inhibitory (cathodal) tDCS a decrease in the Glx/Cr ratio. Subsequent photic stimulation (PS) reversed the changes in Glx/Cr ratios, which returned back to baseline, demonstrating homeostatic-like metaplasticity in the control group. In migraine patients, both anodal and cathodal tDCS decreased the Glx/Cr ratio, which did not return to baseline after PS. While healthy subjects showed an increase in VEP amplitude under anodal and a reduction under cathodal tDCS, the modifiability of VEP under tDCS was reduced in migraineurs. The results demonstrate a reduced responsiveness of the occipital cortex to interventions that change cortical excitability in migraine. Moreover, altered glutamatergic neurotransmission seems to mediate the relation between abnormal cortical information processing and excitability in migraineurs.

Shortened cortical silent period in facial muscles of patients with migraine

Despite intensive neurophysiological research, evidence is lacking to show whether abnormal cortical excitability in migraine reflects a primary cortical disturbance or reduced control by thalamo-cortical loops. One way to contribute to the scientific discussion on this topic is to deliver transcranial magnetic stimulation (TMS) and test the cortical silent period (SP) recorded in facial muscles. The facial-muscle SP is a purely cortical phenomenon that reflects the excitability of inhibitory interneurons, and can disclose changes in cortical inhibition even in patients without documented primary lesions of the motor cortices. To test the interictal excitability of cortical motor inhibitory interneurons in migraine, we investigated the facial-SP in patients with migraine with and without aura between attacks. In 26 patients and 15 age-matched controls, high-intensity magnetic stimuli were delivered with a round coil centered at the vertex during a maximal muscle contraction. Electromyographic responses were recorded from surface electrodes placed over the subjects’ perioral muscles. Facial SPs were significantly shorter in patients than in controls. The SP shortening provides neurophysiological evidence showing hypoexcitability of cortical inhibitory neurons in patients with migraine between attacks. Despite a possible primary deficit of cortical inhibitory interneurons in migraine, we favor the interpretation of a secondary disfacilitation by hypoactive thalamo-cortical loops. Based on this interpretation, the interictal reduced cortical inhibition documented by the shortened SP could be considered the motor counterpart of the reduced preactivation excitability level in the sensory cortices purported to explain why cortical evoked responses habituate poorly in patients with migraine.

Objective Assessment of Cortical Excitability in Migraine With and Without Aura

Recent progress in the genetics of migraine has refocused attention on cortical dysfunction as an important component of the pathophysiology of this disorder. In previous work, we have demonstrated functional changes in the visual cortex of migraine patients, using an objective transcranial magnetic stimulation technique, termed magnetic suppression of perceptual accuracy (MSPA). This study aimed to replicate previous findings in migraine with aura (MA) and to use the technique to examine migraine without aura (MoA). Eight MA patients, 14 MoA patients and 13 migraine-free controls participated. MSPA assessments were undertaken using a standardized protocol in which computer-presented letter targets were followed at a variable delay interval by a single magnetic pulse delivered over the occiput. MSPA performance is expressed as a profile of response accuracy across target-pulse delay intervals. The profiles of migraine-free controls exhibited a normal U-shape. MA patients had significantly shallower profiles, showing little or no suppression at intermediate delay intervals. MoA patients had profiles that were similar to controls. Recent animal evidence strongly indicates that the U-shape of the normal MSPA function is caused by preferential activation of inhibitory neurons. Shallower MPSA profiles in MA patients are therefore likely to indicate a functional hyperexcitability caused by impaired inhibition. The finding of normal MPSA profiles in MoA patients is novel and will require further investigation.

Assessing Cortical Excitability in Migraine: Reliability of Magnetic Suppression of Perceptual Accuracy Technique Over Time

To examine test-retest reliability of magnetic suppression of perceptual accuracy (MSPA) prior to its use as a marker of cortical excitability in a trial of migraine prophylactic agents. MSPA is a relatively novel avenue of research in headache, providing an opportunity to study cortical responsiveness objectively and noninvasively. However, little is known about the reliability of magnetic stimulation protocols such as MSPA in longitudinal research designs. We tested 10 healthy headache-free volunteers who had no family history of migraine. In 54 trials, they were briefly presented different three-letter combinations, flashed on a computer screen for 24 ms (target). After a brief interval, each target was followed by a single magnetic pulse through a 90-mm circular coil centered 7 cm above inion in the midline. The interval between target and magnetic pulse was systematically varied. Volunteers were requested to report as many letters as they had possibly identified. After 2 weeks, all volunteers were retested using identical methods. MSPA performance is expressed as a profile of response accuracy (ie, percentage of correctly identified letters) across target-pulse intervals. Profiles were characteristic of normal headache-free subjects at the first test. Analysis of variance revealed no significant difference in profiles between test and retest (F= 2.05; P= .136): the retest profiles are almost coincidental with the test profiles. MSPA is a safe and objective measure of cortical excitability, which is reliable over time. MSPA, therefore, shows excellent promise as a biological marker of cortical response in trials of migraine prophylactics.

Lack of habituation of nociceptive evoked responses and pain sensitivity during migraine attack

Objective The aim of the present study was to investigate the habituation of subjective pain sensation to CO 2 laser stimulus, in relation to the amplitude modifications of the cortical evoked responses (LEPs), during both the migraine attack and the not symptomatic phase. Methods Fourteen migraine patients were selected and compared with 10 healthy controls. Eight patients were evaluated during both the pain-free and the attack phases. Three following series of 20 averaged LEPs were recorded, stimulating the hands and the supraorbital zones: during the attack, two consecutive series of 20 averaged LEPs were carried out. The subjective sensation was requested for each laser stimulus, using a 0–10 points Verbal Rating Scale (VRS). Results In normal subjects the N2–P2 waves amplitude showed habituation across the three repetitions, which correlated with the habituation of the subjective rating of the stimulus. During the not symptomatic phase, patients showed a lack of habituation of the N2–P2 amplitude when the hand and the face was stimulated, with a pattern of increase of the pain rating across the three repetitions; in addition there was a lack of correlation between the LEPs amplitude and the subjective sensation. During the attack, the LEPs amplitude and the pain rating were increased when the face was stimulated, but they did not habituate across the two repetitions, likely the pain-free condition. The percent LEPs amplitude variation across the three repetitions correlated with the main indices of migraine severity, mainly when the supraorbital zone was stimulated. Conclusions The abnormal cortical excitability in migraine could condition an anomalous behavior of nociceptive cortex during the interictal phase of migraine: it persists during the acute phase, and correlates with the frequency and duration of migraine. Significance The reduced habituation of the nociceptive cortex may concur with the onset and evolution of headache.

Visual cortex excitability in migraine before and after valproate prophylaxis: a pilot study using TMS.

Eur J Neurol. 2002 Jan;9(1):35‐40We examined the effect of standard migraine prophylaxis with sodium valproate on repeated measures of occipital excitability using transcranial magnetic stimulation (TMS). We predicted that, comparing pre‐ and post‐treatment assessments, a reduction in clinical migraine parameters would be paralleled by a decrease in excitability measurements.A total of 31 migraine patients enrolled in the study, for assessment prior to and 1 month after commencement of sodium valproate prophylaxis. At each assessment, we used a standardized protocol to stimulate the occipital cortex with a 90‐mm circular (coil A) and 70 mm figure‐of‐eight (coil B) coil. We recorded the threshold stimulation intensity at which subjects just perceived phosphenes. Subjects kept detailed records of headache parameters 1 month before and also during the study period.Valproate therapy significantly improved headache indexes, as expected. In MA subjects assessed with coil B, phosphene thresholds were significantly higher post‐treatment than pre‐treatment, but those for MO did not change. Modest correlations were observed in MA patients between increase in phosphene threshold and decrease in headache index. Although preliminary, the findings with coil B lend some support to the notion that effective migraine prophylaxis may be achieved through lowering cortical excitability by gamma‐aminobutyric acid (GABA)‐ergic intervention. Further investigation of the effect of sodium valproate or other similarly acting substances on cortical excitability in migraine is warranted.Comment: This paper provides a useful noninvasive human model in which to study the potential development of prophylactic treatments for migraine with aura. It will be important to standardize experimental conditions and to establish a rigorous experimental protocol for simulation parameters. However, this promises to be an important technique for use in future drug development. DSM

Visual cortex excitability in migraine before and after valproate prophylaxis: a pilot study using TMS

We examined the effect of standard migraine prophylaxis with sodium valproate on repeated measures of occipital excitability using transcranial magnetic stimulation (TMS). We predicted that, comparing pre- and post-treatment assessments, a reduction in clinical migraine parameters would be paralleled by a decrease in excitability measurements.A total of 31 migraine patients enrolled in the study, for assessment prior to and 1 month after commencement of sodium valproate prophylaxis. At each assessment, we used a standardized protocol to stimulate the occipital cortex with a 90-mm circular (coil A) and 70 mm figure-of-eight (coil B) coil. We recorded the threshold stimulation intensity at which subjects just perceived phosphenes. Subjects kept detailed records of headache parameters 1 month before and also during the study period. Valproate therapy significantly improved headache indexes, as expected. In MA subjects assessed with coil B, phosphene thresholds were significantly higher post-treatment than pre-treatment, but those for MO did not change. Modest correlations were observed in MA patients between increase in phosphene threshold and decrease in headache index. Although preliminary, the findings with coil B lend some support to the notion that effective migraine prophylaxis may be achieved through lowering cortical excitability by gamma-aminobutyric acid (GABA)-ergic intervention. Further investigation of the effect of sodium valproate or other similarly acting substances on cortical excitability in migraine is warranted.

Cortical excitability in migraine

Cortical hyperexcitability in migraine has been suggested to play a pivotal role in triggering migraine attacks, possibly via generation of spreading depression. Low levels of plasma, intracellular and brain magnesium as well as increased amplitudes of visual evoked potentials support this theory. More recent data on evoked and even related potentials, i. e. lack of habituation and low initial amplitudes during repetitive stimulation, however, may indicate reduced levels of cortical excitability. Transcranial magnetic stimulations of motor and visual cortices, a direct method to assess cortical excitability, yielded contradictory results. Lower or elevated motor threshold, amplitudes and/or phosphene prevalence or even no significant differences at all were demonstrated suggesting also cortical hypo- rather than hyperexcitability in migraine. Methodological differences, selection of subjects, and timing of investigations might partly explain these marked differences. Clinical and genetic heterogeneity of migraine, for instance via opposite influence on neuronal excitability caused by recently described ion-channel mutations, might provide further explanation.