Stimuli In Migraine Research Articles

Preventive treatment with CGRP monoclonal antibodies restores brain stem habituation deficits and excitability to painful stimuli in migraine: results from a prospective case-control study

Background & ObjectivesCalcitonin gene-related peptide ligand/receptor (CGRP) antibodies effectively reduce headache frequency in migraine. It is understood that they act peripherally, which raises the question whether treatment merely interferes with the last stage of headache generation or, alternatively, causes secondary adaptations in the central nervous system and might thus possess disease modifying potential. This study addresses this question by investigating the nociceptive blink reflex (nBR), which is closely tied to central disease activity, before and after treatment with CGRP antibodies.MethodsWe enrolled 22 patients suffering episodic migraine (21 female, 46.2 ± 13.8 years of age) and 22 age-/gender-matched controls. Patients received assessments of the nBR (R2 component, 10 trials, 6 stimuli/trial) before (V0) and three months (V3) after treatment with CGRP antibodies started, controls were assessed once. The R2 area (R2a) and habituation (R2h; gradient of R2a against stimulus order) of the stimulated/non-stimulated side (_s/_ns) following repeated supraorbital stimulation provide a direct readout of brainstem excitability and habituation as key mechanisms in migraine.ResultsAll patients showed a substantial reduction of headache days/month (V0: 12.4±3.3, V3: 6.6 ± 4.9). R2a_s (Fglobal=5.86, p<0.001; block 1: R2a_s: -28%, p<0.001) and R2a_ns (Fglobal=8.22, p<0.001, block 1: R2a_ns: -22%, p=0.003) were significantly decreased, and R2h_ns was significantly enhanced (Fglobal=3.07, p<0.001; block 6: R2h_ns: r=-1.36, p=0.007) from V0 to V3. The global test for changes of R2h_s was non-significant (Fglobal=1.46, p=0.095). Changes of R2h significantly correlated with improvement of headache frequency (R2h_s, r=0.56, p=0.010; R2h_ns: r=0.45, p=0.045). None of the nBR parameters assessed at baseline predicted treatment response.DiscussionWe provide evidence that three months of treatment with CGRP antibodies restores brain stem responses to painful stimuli and thus might be considered disease modifying. The nociceptive blink reflex may provide a biomarker to monitor central disease activity. Future studies should evaluate the blink reflex as a clinical biomarker to predict treatment response at baseline and to establish the risk of relapse after treatment discontinuation.Trial registrationThis trial was prospectively registered at clinicaltrials.gov (ID: NCT04019496, date of registration: July 15, 2019).

Dynamic Causal Modelling of the Reduced Habituation to Painful Stimuli in Migraine: An EEG Study.

A consistent finding in migraine is reduced cortical habituation to repetitive sensory stimuli. This study investigated brain dynamics underlying the atypical habituation to painful stimuli in interictal migraine. We investigated modulations in effective connectivity between the sources of laser evoked potentials (LEPs) from a first to final block of trigeminal LEPs using dynamic causal modelling (DCM) in a group of 23 migraine patients and 20 controls. Additionally, we looked whether the strength of dynamical connections in the migrainous brain is initially different. The examined network consisted of the secondary somatosensory areas (lS2, rS2), insulae (lIns, rIns), anterior cingulate cortex (ACC), contralateral primary somatosensory cortex (lS1), and a hidden source assumed to represent the thalamus. Results suggest that migraine patients show initially heightened communication between lS1 and the thalamus, in both directions. After repetitive stimulations, connection strengths from the thalamus to all somatosensory areas habituated in controls whereas this was not apparent in migraine. Together with further abnormalities in initial connectivity strengths and modulations between the thalamus and the insulae, these results are in line with altered thalamo-cortical network dynamics in migraine. Group differences in connectivity from and to the insulae including interhemispheric connections, suggests an important role of the insulae.

Interictal abnormal fMRI activation of visual areas during a motor task cued by visual stimuli in migraine.

ABSTRACTObjective To assess changes in blood-oxygen-level-dependent activity after light deprivation compared to regular light exposure in subjects with migraine in the interictal state and in controls.Methods Ten subjects with migraine and ten controls participated in two sessions of functional magnetic resonance imaging. In each session, they performed a finger-tapping task with the right hand, cued by visual stimuli. They were scanned before and after 30 minutes of light deprivation or light exposure. In subjects with migraine, functional magnetic resonance imaging was performed interictally. Analysis of variance was made with the factors time (before or after), session (light deprivation or exposure), and group (migraine or control).Results There were significant “group” effects in a cluster in the bilateral cuneus encompassing the superior border of the calcarine sulcus and extrastriate cortex. There were no significant effects of “time”, “session”, or interactions between these factors.Conclusion The main result of this study is consistent with aberrant interictal processing of visual information in migraine. Light deprivation did not modulate functional magnetic resonance imaging activity in subjects with or without migraine.

Migraine and functional connectivity: an innovative pathophysiological perspective.

Migraine is a chronic disorder of neuro-vascular origin, characterized by abnormal neuronal excitability and altered processing of multimodal stimuli. Methods able to detect subtle changes of EEG rhythms under painful stimulation may improve the knowledge of mechanisms of pain processing in normal subjects and patients with chronic pain syndromes. The study of the dynamical relationships between signals recorded at different scalp locations can help to confirm and formulate hypotheses on the physiological mechanisms related to stimuli processing. Correlations, spectral coherence and phase synchronization, which allow to understand the extent to which two variables are statistically connected or shared, influenced by a third variable, together with analyses of the directionality of these dynamical interactions, may potentially contribute to understanding the mechanism of pain processing in migraine. Functional and effective connectivity in terms of synchronization and information transfer were able to reveal differences in visual reactivity between migraine patients and controls, so these methods may presumably outline a different way to process nociceptive laser stimuli in migraine, giving further knowledge on how the cortex changes its inter-connections under painful inputs. Thirty-one migraine without aura outpatients (MwoA) were evaluated and compared to 19 controls (CONT). The right hand was stimulated by means of 30 consecutive CO2 laser stimuli. EEG signal was examined by means of Morlet wavelet, synchronization entropy and Granger causality, and the statistic results embedded into a scalp model. The vertex complex of averaged laser evoked responses (LEPs) showed reduced habituation compared to controls. In the pre-stimulus phase enhanced synchronization entropy in the 0, 5-30 Hz range was present in MwoA and CONT between the bilateral temporal parietal and the frontal regions around the midline. Migraine patients showed an anticipation of EEG changes preceding the painful stimulation compared to controls. In the post-stimulus phase, the same cortical areas were more connected in MwoA vs CONT. In the totality of patients and controls, the habituation index was negatively correlated with the Granger Causality scores. A different pattern of cortical activation after painful stimulation was present in migraine. The increase in cortical connections during repetitive painful stimulation may subtend the phenomenon of LEPs reduced habituation. Brain network analysis may give an aid in understanding subtle changes of pain processing under laser stimuli in migraine patients. Written informed consent to publication was obtained from the patient(s).

Interictal Neurocognitive Processing of Visual Stimuli in Migraine: Evidence from Event-Related Potentials

Research has established decreased sensory habituation as a defining feature in migraine, while decreased cognitive habituation has only been found with regard to cognitive assessment of the relative probability of the occurrence of a stimulus event. Our study extended the investigation of interictal habituation in migraine to include cognitive processing when viewing of a series of visually-complex images, similar to those we encounter on the internet everyday. We examined interictal neurocognitive function in migraine from a habituation perspective, using a novel paradigm designed to assess how the response to a series of images changes over time. Two groups of participants--migraineurs (N = 25) and non-migraine controls (N = 25)--were asked to view a set of 232 unfamiliar logos in the context of a target identification task as their brain electrical responses were recorded via event-related potentials (ERPs). The set of logos was viewed serially in each of 10 separate trial blocks, with data analysis focusing on how the ERP responses to the logos in frontal electrodes from 200-600 ms changed across time within each group. For the controls, we found that the amplitude of the late positive potential (LPP) ERP component elicited by the logos had no significant change across trial blocks. In contrast, in migraineurs we found that the LPP significantly increased in amplitude across trial blocks, an effect consistent with a lack of habituation to visual stimuli seen in previous research. Our findings provide empirical support abnormal cognitive processing of complex visual images across time in migraineurs that goes beyond the sensory-level habituation found in previous research.

Overreaction to non noxious vascular stimuli in migraine and effect of NMDA receptor blockade

In ‘94 we enlighten vascular hyperalgesia/allodynia in migraine (M) sufferers [1]. Central pain is defined as “spontaneous pain and painful overreaction to stimulation”. Delayed painful sensation was also described in so called hyperpathia following partial lesions in the CNS. The aim was to stress possible overreaction and its NMDA antagonists blockade after non noxious stimulation of vein walls induced as elsewhere described. Procedure: a sharp stretch of vein walls, innocuous in controls, was induced in M sufferers. Delayed overreaction might be reported and scored on a 0-10 VAS in 189 M sufferers (101 females , 88 males, mean age 32.5 +3.8 SD) reporting 6-10 attacks A3 /month. It was planned to administer ketamine, specific non competitive antagonist at NMDA receptor sites, to M sufferers to observe possible overreaction. Tested M sufferers reported delayed overreaction ranging from 3 to 8 on a 0-1 0 VAS (mean 4.5 + 1.5 SD). Delayed overreaction lasted from 5 min to 4320 min, mean 210.22 min + 623 SD . The majority of sufferers reported overreaction till to 25 min after application of the stimulus revealing their visceral/vascular hyperalgesia/allodynia, 5 reported overreaction lasting 4320 min and 6 were ailed by overreaction for 5 mins. The duration of overreaction was directely related to the severity/ frequency of headache attacks. ANOVA failed in evidencing sex or M duration relationship, whereas a modest significativity (p>0.02) was related to high scores in Wang and Zung tests (cut off = 40). Ten days later the same stimulus was applied after 0,1 mg/Kg/ i.m. administration of ketamine, after a 3 days wash-out period. Patients reported neither allodynia/hyperalgesia or overreaction. The experience indicated the occurrence of overreaction in M. The partial deafferentation condition was inhibited by using a sub-anesthetic dose of ketamine. Thus, the drug likely acted by altering process of neural deafferentation-like related discharge.

Overreaction to non noxious vascular stimuli in migraine and effect of NMDA receptor blockade

Overreaction to non noxious vascular stimuli in migraine and effect of NMDA receptor blockade

Altered processing of emotional stimuli in migraine: An event-related potential study

Migraine patients report psychosocial stress to be among the major triggers for their migraine attacks. The mechanisms underlying the onset of migraine attacks are not yet fully understood. Neuroimaging studies have shown changes in the cortical excitability of migraine patients. Here, we investigated cortical activation related to processing of emotional stimuli in individuals with migraine. Twenty-four participants suffering from migraine attacks and 25 healthy volunteers had to passively observe pictures of emotional facial expressions (angry, happy and neutral). Electro-cortical activity was continuously recorded by means of an electroencephalogram (EEG), and ratings of valence (unpleasant vs. pleasant) and arousal (calm vs. exciting) were collected. The migraine and control group did not differ in their ratings of valence and arousal of the visual stimuli. However, participants with migraine, in contrast to healthy controls, showed larger N170 amplitudes toward angry facial expressions compared to neutral ones. Individuals with migraine may have an altered cortical activity linked to the processing of emotional information. Thus, these individuals may process high arousing and threatening events preferentially, and this facilitated processing may be related to their already high cortical excitability.

Habituation of the nociceptive blink reflex in episodic and chronic cluster headache

Analysis of habituation patterns in patients with primary headache disorders allows the detection of changes to the excitability level of the trigeminal nociceptive system. Previous studies demonstrated a habituation deficit to painful stimuli in migraine and it was suggested that similar observations could be made in cluster headache (CH). Habituation of the "nociceptive" blink reflex (nBR) (R2 response) was studied in 66 CH patients (18 episodic CH inside bout, 28 episodic CH outside bout, 20 chronic CH) as well as in 30 healthy controls in a case-control study design. Habituation behaviour was similar in CH and healthy controls as well as in CH subtypes. No side-to-side differences of habituation between headache side and non-headache side were detected. Our results did not detect an altered habituation in CH patients. Despite clinical similarities, migraine and CH seem not to share the same pathophysiological mechanisms in this regard.

Suggestion and Pain in Migraine: A Study by Laser Evoked Potentials

Belief and expectation are part of placebo effect. Migraine patients are characterized by a dysfunctional modulation of pain processing, though a clear placebo effect emerges in clinical trials. The aim of the study was to evaluate the effect of visual and verbal suggestion on subjective pain sensation and cortical responses evoked by CO2 painful laser stimuli in migraine without aura patients vs healthy controls. Twenty-six patients were recorded during the inter-ictal phase and compared to 26 sex and age-matched controls. The right hand and the right supraorbital zone were stimulated during a not conditioned and a conditioned task, where laser stimuli were delivered after a verbal and visual cues of decreased (D), increased (I) or basal (B) intensity, which was left unmodified during the entire task. In control subjects pain rating changed, according to the announced intensity, while in migraine patients the basal hyper-algesia remained unmodified. The N1 and N2 amplitudes tended to change coherently with the stimulus cue in controls, while an opposite paradoxical increase in decreasing condition emerged in migraine. The P2 amplitude modulation was also reduced in migraine, differently from controls. The altered pattern of pain rating and N2 amplitude modulation concurred with frequency of migraine, disability and allodynia. In controls suggestion influenced cortical pain processing and subjective pain rating, while in migraine a peculiar pattern of cortical activation contrasted external cues in order to maintain the basal hyper-algesia. This scarce influence of induced suggestion on pain experience seemed to characterize patients with more severe migraine and central sensitization.

Altered Cardiovascular Reactivity to Mental Stress But Not to Cold Pressure Test in Migraine

This study assessed cardiovascular reactivity to mental stress and cold pressure test in migraineurs and controls. It compared the cardiovascular reactivity between patients with migraine with aura and patients with migraine without aura. Several studies have assessed the autonomic nervous system functioning and cardiovascular responses to stressor stimuli in migraine. Cold pressure test and sustained attention tasks are distinct forms of induced stress. It is still unknown if patients with migraine have distinct patterns of response to sustained attention tasks and cold pressure test, since no previous studies have evaluated the cardiovascular responses to these 2 distinct types of stress in the same population of migraine patients. Two distinct protocols were used to induce cardiovascular reactivity. Mental stress was induced by using a Stroop test card, a procedure involving the maintenance of the attention control. The other protocol was the cold pressure test. The blood pressure and heart rate were digitally recorded in rest and test phases. The mean elevation and the variance of blood pressure and heart rate were compared between groups. Patients with migraine had higher rest systolic blood pressure and lower heart rate induced by mental stress than controls. There were no differences between migraineurs and controls with cold pressure test. There were no differences between migraineurs with and without aura. There was a significantly different pattern of cardiovascular reactivity between migraineurs and controls with mental stress but not with cold pressure test. Distinct central nervous system structures are involved in these 2 types of stress. A distinct pattern of activation of the prefrontal cortex-periaqueductal gray matter circuit in migraine may explain a singular autonomic reactivity to mental stress in this disease.

Cerebrovascular Response to Repetitive Visual Stimulation in Interictal Migraine with Aura

Cortical hypersensitivity and absent habituation to different stimuli have been observed in migraine patients. These features might also be transmitted to the cerebral vasoreactivity, but results are conflicting so far. Transcranial Doppler ultrasound (TCD) was used to assess cerebral blood flow velocity (CBFV) changes in the middle (MCA) and posterior cerebral arteries (PCA) in relation to repetitive checkerboard visual stimulation. Stimulation consisted of 10 consecutive cycles, each comprising 10 s stimulation and 10 s rest. TCD recordings were analysed using stimulus-related averaging algorithm. Data of 19 interictal migraineurs with aura were compared to those of 19 headache-free healthy volunteers. The CBFV increase in PCA and in MCA during visual stimulation was significantly larger and steeper in migraineurs than in controls (P = 0.017 and P = 0.005). The response in PCA remained stable over the 10 stimulation cycles, both in migraineurs and in controls. The response in MCA was stable only in migraineurs. In controls it decreased over the last 5 stimulation cycles compared with the first 5 cycles (P = 0.04). Migraineurs with aura exhibit a larger cerebrovascular response to repetitive visual stimulation compared to headache-free subjects. A reduced adaptation to environmental stimuli in migraine is suggested, since there was no habituation in migraineurs in contrast to healthy controls.

Pattern-reversal visual-evoked potentials in children with migraine and other primary headache: evidence for maturation disorder?

Recently, evidence for a disturbed maturation of cerebral information processing in migraine came from studies investigating the auditory-evoked contingent negative variation and the auditory-evoked potential from childhood to adulthood. This study is to clarify whether age-dependent development is altered also for the processing of visual stimuli in migraine. Components of pattern-reversal visual-evoked potentials at four different spatial frequencies (which can preferentially activate the magno- and the parvocellular visual system) were compared between children aged 6 and 18 years with primary headache ( N=123; 67 migraine without aura, MO; 32 migraine with aura, MA; 24 tension-type headache, TH) in the headache-free interval and healthy controls ( N=82). Children were divided into two age groups: 6–11 years (pre- and early puberty) and 12–18 years (late and post-puberty). Age-dependent development was normal for N80 and P100 latency in children with primary headache, but altered for N135 latency as indicated by a significant interaction among the factors diagnosis, spatial frequency and age group ( P<0.01). In headache-free controls, N135 latency reduction between pre- and post-puberty age was most pronounced at high spatial frequency. The main ‘decline’ of N135 latency with increasing age was shifted to lower spatial frequencies in the headache subgroups. The results give evidence that maturation of visual processing is partly disturbed in migraineurs.