Altered pain processing in children with migraine: An evoked potential study

In adults, evidence is accumulating that migraine is associated with altered central processing of pain stimuli and, possibly, changes in the allocation of attentional resources to such stimuli. In pediatric migraine, however, little is known about altered pain processing. We examined 15 children with migraine and 15 controls (age 10–15) in an oddball standards task. Children had to respond to rare targets (tones) and ignore frequent painful (pain threshold) or non‐painful mechanical standard stimuli while evoked potentials were obtained. Painful as compared to non‐painful stimuli elicited significantly larger N150, P260 and P300 components of the somatosensory evoked potential in all children. The pain‐evoked N150 and P260 components did not differ significantly between groups. However, in children with migraine, both painful and non‐painful standard stimuli were associated with significantly larger P300 amplitudes at significantly shorter latencies. Perceived intensity of the painful and non‐painful stimuli was comparable in both groups. The evoked potentials and reaction times to the target tones did not differ significantly between groups. Habituation across trials was similar in both groups. Hence, children with migraine may display an automatic attentional bias towards painful and potentially painful somatosensory stimuli. Consistent with the psychobiological perspective of chronic pain, such an attentional bias could constitute an important mechanism for migraine becoming a chronic problem.     

Personality and response to repeated visual stimulation in migraine and tension-type headaches

Migraine sufferers potentiate their visual evoked potentials (VEPs) from a short period of 2 min to a longer period of 15 min. As a lack of habituation is linked to higher level arousal, we thus hypothesized that short-term VEP potentiation might he correlated with an arousal-related personality trait. We therefore carried out short-term VFPs, Plutchik-van Praag's Depression Inventory, Zuckerman's Sensation-Seeking Scales (Form V), and Zuckerman- Kuhlman's Personality Questionnaire in 26 healthy subjects, 22 patients suffering from migraine without aura between attacks, 13 episodic and 20 chronic tension-type headaches. The chronic tension-type headache sufferers showed increased depression compared with other groups, which might be a consequence of the headache itself. Migraines, however, showed steeper habituation slopes of N1-P1 and P1-N2, decreased thrill and adventure-seeking, and general sensation-seeking than healthy controls; in addition, the habituation slope of P1-N2 was positively correlated with experience-seeking in migraine. The short-term VEP potentiation and the decreased thrill and adventure-seeking and general sensation-seeking in migraine might be related to a high level of cortical arousal and a low 5HT neurotransmission. In compliance with the long-term VEP study, the positive correlation between the P1-N2 habituation slope and experience-seeking in migraine suggests a continuous metabolic overload for the brain interictally, which can trigger the activation of a migraine attack.     

Median nerve somatosensory evoked potentials in migraine.

Eur J Neurol. 2002;9:227-232.
In visual evoked potential studies, habituation during stimulus repetition with the same stimulus at a constant intensity has been found to be abnormal in migraineurs between attacks. The purpose of this study was to investigate habituation of somatosensory evoked potentials (SEPs) and the effects of migraine on them. Eighty-five subjects were included in the study: 30 healthy volunteers (HVs) and 55 migraineurs [30 with migraine without aura (MO), 25 with migraine with aura (MA)]. During continuous stimulation at 3 Hz, four blocks of 100 responses were sequentially averaged of Erb's point (N9), cervical (N13), and cortical (N20) median nerve SEPs. Mean amplitude changes in the second, third and fourth blocks are expressed as percentages of the first block. There was habituation to N13 and N20 in the second, third and fourth blocks in HVs. In the migraine groups, there was no habituation; on the contrary, potentiation was found. This potentiation was statistically significant only in the second blocks for N13 (MO P   =  0.007, MA P   =  0.01 versus HVs). However, in both migraineur groups, the rate of N20 potentiations was statistically significant versus that in HVs for all blocks (all P < 0.05). It is concluded that whilst physiological habituation occurs in HVs for cervical and cortical SEPs, in migraine patients there is an interictal deficit of habituation of this sensory modality.
Comment: This interesting study confirms the lack of habituation to repetitive stimuli reported in migraineurs between attacks and extends this finding to somatosensory evoked potentials using median nerve stimulation. One might speculate that migraineurs lack a protective mechanism which modulates both cervical and cortical sensory inputs. DSM     

Nociceptive blink reflex and visual evoked potential habituations are correlated in migraine

BACKGROUND: Lack of habituation, as reported in migraine patients between attacks for evoked cortical responses, was also recently found for the nociceptive blink reflex (nBR) mediated by brainstem neurons. It is not known if both brain stem and cortical habituation deficits are correlated in the same patient, which would favor a common underlying mechanism. OBJECTIVE: To search for intraindividual correlations between habituation of pattern reversal-visual evoked potentials and that of the nociception-specific blink reflex in migraineurs and in healthy volunteers (HV). METHODS: We recorded 15 HV and 15 migraine without aura patients between attacks. Habituation for visual evoked potentials was measured by comparing the N1-P1 amplitude change (%) between the first and sixth block of 100 sequential averaged responses. Habituation for the nBR was defined as the percentage change of the R2 response area between the 1st and 10th block of five averaged EMG responses, elicited by stimulating the right side every 2 minutes for 32 minutes. We also calculated the slope of N1-P1 amplitude and R2 response area changes from the first to the last response and the correlation with attack frequency. RESULTS: A significant habituation deficit in both cortical and brain stem evoked activity characterized on average the group of migraineurs compared to controls. In migraine patients, but not in HV, we found a significant positive correlation between habituation of pattern reversal-visual evoked potentials and that of the nociception-specific blink reflex both for the degree of habituation between first and last blocks of averagings (r = 0.703; P = .003) and for the habituation slope (r = 0.751; P = .001). Moreover, nBR habituation was positively correlated with attack frequency (r = 0.548; P = .034). CONCLUSION: The positive correlation between visual evoked potential and nBR habituations is consistent with the idea that in migraine the same neurobiological dysfunction might be responsible for the habituation deficit both in cortex and brain stem. As nBR habituation increases with attack frequency, its interictal deficit is unlikely to be due to trigeminal sensitization.     

Three stages of facial expression processing: ERP study with rapid serial visual presentation

Electrophysiological correlates of the processing facial expressions were investigated in subjects performing the rapid serial visual presentation (RSVP) task. The peak latencies of the event-related potential (ERP) components P1, vertex positive potential (VPP), and N170 were 165, 240, and 240 ms, respectively. The early anterior N100 and posterior P1 amplitudes elicited by fearful faces were larger than those elicited by happy or neutral faces, a finding which is consistent with the presence of a ‘negativity bias.’ The amplitude of the anterior VPP was larger when subjects were processing fearful and happy faces than when they were processing neutral faces; it was similar in response to fearful and happy faces. The late N300 and P300 not only distinguished emotional faces from neutral faces but also differentiated between fearful and happy expressions in lag2. The amplitudes of the N100, VPP, N170, N300, and P300 components and the latency of the P1 component were modulated by attentional resources. Deficient attentional resources resulted in decreased amplitude and increased latency of ERP components. In light of these results, we present a hypothetical model involving three stages of facial expression processing.     

Visual, long-latency auditory and brainstem auditory evoked potentials in migraine: relation to pattern size, stimulus intensity, sound and light discomfort thresholds and pre-attack state

We aimed to estimate primary sensory evoked potential (EP) amplitude, amplitude-intensity functions and habituation in migraine patients compared with healthy control subjects and to investigate the possible relation to check size, sound and light discomfort thresholds, and the time to the next attack. Amplitudes of cortical visual evoked potentials (VEP, check size 8' and 33'), cortical long latency auditory evoked potential (AEP NIP1; 40, 55 and 70 dB SL tones) and brainstem auditory evoked potential (BAEP wave IV-V; 40, 55 and 65 dB SL clicks) were recorded and analysed in a blind and balanced design. The difference between the response to the first and the second half of the stimulus sequence was used as a measure of habituation. Twenty-one migraine patients (16 women and five men, mean age 39.3 years, six with aura, 15 without aura) and 22 sex- and age-matched healthy control subjects were studied (18 women and four men, mean age 39.5 years). Low sound discomfort threshold correlated significantly with low levels of BAEP wave IV-V amplitude habituation (r = -0.30, P = 0.05). VEP an AEP amplitudes, habituation, and amplitude-intensity function (ASF) slopes did not differ between groups when ANOVA main factors were considered. Control group VEP habituation was found for small check stimuli (P = 0.04), while potentiation was observed for medium sized checks (P = 0.02). The eight migraine patients who experienced headache within 24 h after the test tended to have increased BAEP wave IV-V ASF slopes (P = 0.08). This subgroup did also have a significant VEP habituation to small checks (P = 0.04). No correlation was found between different modalities. These results suggest that: (i) VEP habituation/potentiation state and brainstem activatio state may depend on the attack-interval cycle in migraine; (ii) VEP habituation/ potentiation may depend on spatial stimulus frequency; (iii) phonophobia (and possibly photophobia) may depend more on subcortical (brainstem) function than on cortical mechanisms; (iv) low cortical preactivation in migraine could not be confirmed; (v) EP habituation and ASF analysis may reflect sensory modality-specific, not generalized, central nervous system states in migraine and healthy control subjects.     

Passive paradigm single-tone elicited ERPs in tension-type headaches and migraine

The active 'oddball' event-related potential (ERP) P3 is elongated or reduced in migraine and tension-type headaches, indicating a deficit of active attention in these primary headaches. It is then reasonable to study the passive attention function in these headaches through the technology of passive paradigm single-tone elicited ERPs. We invited 32 patients suffering from chronic tension-type headache (CTTH), 17 from frequent episodic tension-type headache (FETH) and 32 from interictal migraine without aura, as well as 28 healthy subjects to undergo passive paradigm single-tone ERPs. There were no statistically significant differences when the mean latencies and amplitudes of N1, P2, N2 or the mean latencies of P3 of the four groups were considered. In contrast, the P3 amplitudes were significantly reduced in the patient groups when compared with healthy controls. However, no further significant difference was found between patient groups when considering P3 amplitude. Our study demonstrated a deficit of passive attention in CTTH, FETH and migraine, but could not separate these headache types in this regard. The reduced P3 in patients might be due to the head pain experienced.     

Slow cortical potentials in migraine families

Amplitude and habituation of event-related potentials are abnormal in migraine. We investigated 43 migraine and 41 healthy families to evaluate the influences of age, sex and familial contribution on the variance of amplitude and habituation of the contingent negative variation (CNV). Analysis of individual differences in relation to the CNV habituation was performed. The study demonstrated that habituation of the early CNV component characterizes migraine considerably better than the CNV amplitudes. Habituation, however, is strongly influenced by age. Migraine adults and children generally showed reduced habituation. Surprisingly, more than 30% of the healthy adults demonstrated a marked loss of habituation. The reduced CNV habituation represented a high sensitivity but low specificity to migraine, especially in children. CNV amplitude and habituation parameters revealed a considerable familial contribution associated with migraine. No familial influence on either morphology or habituation of the CNV in healthy families or between healthy members of migraine families was observed. The low specificity and familial transmission of CNV parameters in members of migraine families suggest that increased amplitudes and reduced habituation of CNV do not constitute a primary risk factor for migraine, but rather represent a predisposition. Genetic components probably affect variation of the CNV amplitude and habituation.     

P300 and contingent negative variation in migraine

We reviewed P300 and contingent negative variation (CNV) studies performed in migraine in order to identify their relevance in migraine and the role of neurophysiology in migraine. Publications available to us were completed by a Medline search. There is experimental and clinical evidence for loss of cognitive habituation in migraine which may serve as a specific diagnostic tool; therefore, we reviewed studies on migraine that analyzed habituation and lack of habituation by P300 and CNV, performing short-term habituation (STH) and long-term habituation (LTH). Finally, we described the two components of P300 (a and b) and of CNV (early and late wave) and the two abnormalities reported from the majority of studies on event-related potential in migraine: increased amplitude of average event-related potential and lack of habituation. These abnormalities are especially related to the early component characterizing orienting activity.     

Changes in visual-evoked potential habituation induced by hyperventilation in migraine

Hyperventilation is often associated with stress, an established trigger factor for migraine. Between attacks, migraine is associated with a deficit in habituation to visual-evoked potentials (VEP) that worsens just before the attack. Hyperventilation slows electroencephalographic (EEG) activity and decreases the functional response in the occipital cortex during visual stimulation. The neural mechanisms underlying deficient-evoked potential habituation in migraineurs remain unclear. To find out whether hyperventilation alters VEP habituation, we recorded VEPs before and after experimentally induced hyperventilation lasting 3 min in 18 healthy subjects and 18 migraine patients between attacks. We measured VEP P100 amplitudes in six sequential blocks of 100 sweeps and habituation as the change in amplitude over the six blocks. In healthy subjects, hyperventilation decreased VEP amplitude in block 1 and abolished the normal VEP habituation. In migraine patients, hyperventilation further decreased the already low block 1 amplitude and worsened the interictal habituation deficit. Hyperventilation worsens the habituation deficit in migraineurs possibly by increasing dysrhythmia in the brainstem-thalamo-cortical network.     

Effects of noise from functional magnetic resonance imaging on auditory event-related potentials in working memory task

The effects of functional magnetic resonance imaging (fMRI) acoustic noise were investigated on the parameters of event-related responses (ERPs) elicited during auditory matching-to-sample location and pitch working memory tasks. Stimuli were tones with varying location (left or right) and frequency (high or low). Subjects were instructed to memorize and compare either the locations or frequencies of the stimuli with each other. Tape-recorded fMRI acoustic noise was presented in half of the experimental blocks. The fMRI noise considerably enhanced the P1 component, reduced the amplitude and increased the latency of the N1, shortened the latency of the N2, and enhanced the amplitude of the P3 in both tasks. The N1 amplitude was higher in the location than pitch task in both noise and no-noise blocks, whereas the task-related N1 latency difference was present in the no-noise blocks only. Although the task-related differences between spatial and nonspatial auditory responses were partially preserved in noise, the finding that the acoustic gradient noise accompanying functional MR imaging modulated the auditory ERPs implies that the noise may confound the results of auditory fMRI experiments especially when studying higher cognitive processing.     

Lack of cold pressor test-induced effect on visual-evoked potentials in migraine

In patients with migraine, the various sensory stimulation modalities, including visual stimuli, invariably fail to elicit the normal response habituation. Whether this lack of habituation depends on abnormal activity in the sub-cortical structures responsible for processing incoming information as well as nociception and antinociception or on abnormal cortical excitability per se remains debateable. To find out whether inducing tonic pain in the hand by cold pressure test (CPT) alters the lack of visual-evoked potential (VEP) habituation in migraineurs without aura studied between attacks we recorded VEPs in 19 healthy subjects and in 12 migraine patients during four experimental conditions: baseline; no-pain (hand held in warm water, 25°C); pain (hand held in cold water, 2–4°C); and after-effects. We measured P100 amplitudes from six blocks of 100 sweeps, and assessed habituation from amplitude changes between the six sequential blocks. In healthy subjects, the CPT decreased block 1 VEP amplitude and abolished the normal VEP habituation (amplitude decrease to repeated stimulation) in patients with migraine studied between attacks; it left block 1 VEP amplitude and abnormal VEP habituation unchanged. These findings suggest that the interictal cortical dysfunction induced by migraine prevents the cortical changes induced by tonic painful stimulation both during pain and after pain ends. Because such cortical changes presumably reflect plasticity mechanisms in the stimulated cortex, our study suggests altered plasticity of sensory cortices in migraine. Whether this abnormality reflects abnormal functional activity in the subcortical structures subserving tonic pain activation remains conjectural.     

Habituation of single CO2 laser–evoked responses during interictal phase of migraine

A reduced habituation of averaged laser–evoked potential (LEP) amplitudes was previously found in migraine patients. The aim of the present study was to assess the habituation of single LEP responses and pain sensation during the interictal phase in migraine patients. Fourteen migraine patients were compared with ten control subjects. The pain stimulus was laser pulses, generated by CO₂ laser, delivered to right supraorbital zone. Patients were evaluated during attack–free conditions. The LEP habituation was studied by measuring the changes of LEP amplitudes across and within three consecutive repetitions of 21 non–averaged trials. In migraine patients the N2–P2 wave amplitudes did not show a tendency toward habituation across and, above all, within the three repetitions. Anomalous behaviour of nociceptive cortex during the interictal phase of migraine may predispose patients to headache occurrence and persistence.     

Interictal lack of habituation of mismatch negativity in migraine

The aim was to study mismatch negativity features and habituation during the interictal phase of migraine. In migraine patients, a strong negative correlation has been found between the initial amplitude of long latency auditory-evoked potentials and their amplitude increase during subsequent averaging. We studied 12 outpatients with a diagnosis of migraine without aura recorded in a headache-free interval and 10 gender- and age-matched healthy volunteers not suffering from any recurrent headache. The experiment consisted of two sequential blocks of 2000 stimulations, during which 1800 (90%) recordings for standard tones and 200 (10%) for target tones were selected for averaging. The latency of the N1 component was significantly increased in migraine patients in respect of controls in both the first and second repetitions; the MMN latency was increased in the second repetition. In the control group the MMN amplitude decreased on average by 3.2 +/- 1.4 microV in the second trial, whereas in migraine patients it showed a slight increase of 0.21 +/- 0.11 microV in the second repetition. The MMN latency relieved in the second trial was significantly correlated with the duration of illness in the migraine patients (Spearman correlation coefficient: 0.69; P < 0.05). The increases in N1 latency and MMN latency and amplitude, the latter correlated with duration of illness, seemed to be due to a reduced anticipatory effect of stimulus repetition in migraine patients. This suggests that such hypo-activity of automatic cortical processes, subtending the discrimination of acoustic stimuli, may be a basic abnormality in migraine, developing in the course of the disease.     

Pattern-Shift Visual Evoked Responses and EEG in Migraine

SYNOPSIS
Visual evoked responses (VERs) and spectral analysis of background EEG were obtained from 20migraine patients and their age-matched controls. Full- and half-field reversing checkerboardstimulus presentations elicited no substantial differences between the subject groups for any of themajor component (N75, P100, N145) latencies or amplitudes. No VER differences were found forpatient subcategories based on side of headache, symptom history, or age. However, migrainepatients demonstrated slight but significantly higher mean frequency in their background EEG in the4–8 Hz frequencies in leads C 3 -P 3 and C 4 -P 4 , and a lower mean frequency in the 8–12 Hz band inleads F 3 -C 3 and F 4 -C 3 relative to controls. The results are discussed and compared to previousstudies of visual evoked potentials and EEG in migraine patients.     

Developmental changes of the contingent negative variation in migraine and healthy children

It has been hypothesized that abnormalities of information processing in migraine may be attributed to impairment of cerebral maturation. However, the most evidences for this hypothesis have come from cross-sectional studies during childhood. We performed a longitudinal study and recorded contingent negative variation (CNV), an event-related slow cortical potential, in migraine children (n = 27) and age-matched healthy individuals (n = 23) in 1998 and 8 years later (2006). Amplitudes of all CNV components were reduced and habituation of the initial CNV (iCNV) increased in the observed time. However, the reduction of the iCNV amplitude was more pronounced in migraine patients who were in remission in 2006 and in healthy subjects and less pronounced in migraineurs with persisting headaches. Patients with the worsened migraine demonstrated the most pronounced loss of iCNV habituation in 1998 and significantly increased iCNV amplitudes in 2006. This longitudinal study supports the hypothesis of impaired cerebral maturation in migraine and shows that migraine manifestation is a key factor interfering with the natural maturation process of central information processing.     

Cognitive processing in headache associated with sexual activity

Cognitive processing in headache associated with sexual Cognitive processing as measured by event-related potentials (ERP) in patients suffering from the explosive subtype of headache associated with sexual activity (HSA type 2) was investigated. Visual ERP were measured in 24 patients with HSA type 2 outside the headache period. The differences of the first and the second part of measurement were evaluated separately to determine the amount of cognitive habituation. Twenty-four sex- and age-matched healthy subjects and 24 patients with migraine without aura served as controls. A missing increase of P3 latency during the second part of the measurement was found in 79% of patients with HSA type 2 and in 75% with migraine, but only in 17% of the healthy controls (P < 0.001). The P3 amplitude was increased during the second part in 71% of patients with HSA type 2 and in 79% with migraine, but only in 33% of the healthy controls (P = 0.02). Mean P3 latency was decreased and mean P3 amplitude was increased during the second part of the measurement in HSA type 2 and in migraine but not in the healthy control group. Patients with HSA type 2 have a loss of cognitive habituation as measured by ERP. This specific information processing is very similar to that in migraine observed in previous studies.     

Gender differences of cognitive function in migraine patients: evidence from event-related potentials using the oddball paradigm

Background

Migraine shows gender-specific incidence and has a higher prevalence in females. Gender plays an important role in the prevalence of migraine, but few studies have investigated the effect of gender on the cognitive functions of migraine patients. This study investigated gender differences in the cognitive function of migraine patients without aura.

Methods

We recruited 29 migraine patients (15 females; mean age 25.4 y) during the interictal period and 28 healthy age-matched participants (14 females; mean age 24.8 y). We used an auditory oddball paradigm to analyze target processing using event-related potentials.

Results

We investigated the N2 and P3 components. The P3 amplitude was decreased in patients compared with the control, and this reduction was not modulated by gender. These results of the P3 provided a new evidence for the dysfunction of cognitive function in migraine patients. The N2 amplitude was larger for male than female migraine patients, and this gender effect was not found in the control group.

Conclusions

These results of the P3 provided a new evidence for the dysfunction of cognitive function in migraine patients. And those of N2 may explain that male patients have the super-sensitivity of cerebral function relevant to the early target-selection and response preparation. Our findings emphasize the importance of considering gender when researching the cognitive function of migraine patients.     

Maturation of early visual processing investigated by a pattern-reversal habituation paradigm is altered in migraine

Evidence for a disturbed maturation of information processing in migraine came recently from evoked and event-related potential studies during childhood. In adult migraineurs, deficient habituation is proposed as principal interictal abnormality and was found inter alia for Visual Evoked Potentials (VEPs). This study investigated response and habituation to pattern-reversal VEPs and its maturation in 102 children with primary headache (migraine with and without aura, tension-type headache) and 79 healthy controls from 6 to 18 years. A reduction of N180 latency from pre- to postpubertal age reflects maturation and was clearly present in controls but lessened in migraineurs. N180 latency was prolonged in migraineurs without aura from 12 years onwards. Habituation did not differ between groups. In conclusion, diminished N180 latency reduction with age in migraineurs gives further evidence that maturation of visual information processing is altered in migraine. Deficient habituation to pattern-reversal VEPs could not be confirmed during childhood migraine.     

Influence of colors on habituation of visual evoked potentials in patients with migraine with aura and in healthy volunteers

OBJECTIVE: To investigate whether colored glasses influence the habituation of visual evoked potentials. BACKGROUND: We have previously shown that during pattern-reversal stimulations lasting 2 minutes the amplitude of the visual evoked potential increases in migraine with and without aura between attacks, whereas it decreases in healthy volunteers. Red light was found to increase visually evoked EEG fast activity only in children with migraine with aura. Wearing rose-tinted glasses for 4 months decreased attack frequency in parallel with a reduction of the visually evoked EEG fast activity. METHODS: We compared the change in amplitude of the visual evoked potential using five different tinted glasses in 12 patients with migraine with aura and in 10 healthy volunteers. During continuous stimulation at 3.1 Hz, five blocks of 50 responses were sequentially averaged using red, yellow, green, blue, and grey glasses and without glasses in a random order and analyzed in terms of latencies and N1-P1 amplitudes. Amplitude changes were calculated for each block by comparison with the first block in every condition and analyzed statistically using Zerbe's method. RESULTS: In healthy volunteers, the visual evoked potential amplitude increased with red glasses compared to without glasses (P = .05) or with green glasses (P = .03). In patients with migraine with aura, no significant difference was detected using colored glasses. Our findings in healthy volunteers are in line with earlier reports of increased excitability of the human visual cortex when exposed to red light. The lack of such a pattern in patients with migraine with aura suggests that the visual cortex is interictally hypoexcitable rather than hyperexcitable, which is consistent with studies of transcranial magnetic stimulation.