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.     

Is increased amplitude of contingent negative variation in migraine due to cortical hyperactivity or to reduced habituation?

The aim of this study was to compare the habituation kinetics of contingent negative variation (CNV) between 12 migraineurs without aura and matched healthy controls. CNV was studied with a 3 sec interval between the warning stimulus (WS) and the imperative stimulus (IS). The data from (a) the total interval (WS-IS), (b) early component, and (c) late component were analyzed. During successive trials the habituation kinetics were determined using regression analysis. On CNV averaged over 32 trials, migraine patients had a significantly higher negativity in the total interval compared to controls. When sequential blocks of four trials were analyzed, the most significant finding in migraineurs was lack of habituation of the early CNV component. The present study indicates that a delayed habituation, rather than a general increased cortical activity, is responsible for the CNV abnormalities in migraine without aura. We suggest that migraineurs between attacks not only have a cortical hyperexcitability, but also a lack of cortical inhibition causing delayed habituation.     

Abnormalities of the vestibulo-collic reflex are similar in migraineurs with and without vertigo

The amplitude and habituation of the click-evoked vestibulo-collic reflex (VCR) was found reduced between attacks in migraineurs without complaints of ictal or interictal vertigo or dizziness, compared with healthy subjects. As a next step we recorded VCR in 17 migraine patients (eight with migraine without aura and nine with migraine with aura) who presented ictal migrainous vertigo according to the criteria defined by Neuhauser et al., using a method described previously. Migraineurs with migrainous vertigo have similar VCR abnormalities as patients without vertigo, i.e. a decreased global amplitude and absence of habituation. Potentiation seemed more pronounced in migraineurs with vertigo (7.46 ± 18.6), but the difference was not significant.     

Lack of age-dependent development of the contingent negative variation (CNV) in migraine children?

Increased negativity of contingent negative variation (CNV) in adult migraineurs is thought to reflect cortical hyperexcitability. CNV amplitude changes with age in healthy adults. Recently, evidence emerged that this might not be the case for migraineurs. Our study investigates age-dependency of CNV during childhood age. Seventy-six healthy controls and 61 children with migraine without aura (IHS code 1.1) between 6 and 18 years were examined using an acoustic S1-S2-CNV-paradigm with a 3-s inter-stimulus interval. The amplitude of the late component of CNV, as well as total CNV at the vertex (Cz according to the international 10-20 system), were significantly higher in migraineurs without aura than in controls. Healthy controls showed increasing amplitudes of CNV with age, whereas in migraine children without aura amplitudes did not change. Thus group differences were reduced during adolescence. Increased CNV negativity might reflect a biological vulnerability to migraine, rather than being a result of chronification. Migraineurs seem to lack age-dependent development of CNV also during early age, which supports the hypothesis of migraine as a maturation disorder.     

Effects of fluoxetine on habituation of pattern reversal visually evoked potentials in migraine prophylaxis

OBJECTIVE: To investigate the effects of fluoxetine in migraine prophylaxis on habituation of visually evoked potentials. BACKGROUND: Habituation of pattern reversal visually evoked potentials was found to be abnormal in migraine between attack, and this abnormality was most likely due to serotonergic pathway dysfunction in the brain stem. METHODS: One hundred nineteen subjects were included in the study: 40 healthy volunteers and 79 migraineurs not taking any prophylactic migraine medication (44 without aura and 35 with aura). Visually evoked potentials in migraineurs were recorded in the headache-free interval. Amplitude change of the visually evoked potentials (N1-P1) was measured between the first and fifth block of 50 sequential averagings during continuous stimulation at 3.1 Hz. All migraineurs were placed on fluoxetine 20 mg/day for prophylaxis of migraine. One month later, visually evoked potentials were recorded again. RESULTS: Mean amplitude changes in the fifth block expressed as percentages of the first block were -13.4% +/- 19.2% in healthy volunteers, 9.8% +/- 23.3% in migraine without aura, and 4.4% +/- 8.7% in migraine with aura during the baseline period. The difference was significant between migraineurs and healthy volunteers (both P= 0.0001), but not between migraineur groups. After treatment, amplitude changes were -9.3% +/- 14.5% in migraine without aura and -10.1% +/- 11.5% in migraine with aura. Habituation pattern tended to normalize with prophylactic treatment, and mean amplitude changes were not significant between migraineurs and healthy volunteers (both P = 0.4). CONCLUSIONS: We concluded that the fluoxetine prophylaxis corrects the interictal deficit of habituation in migraineurs.     

Influence of MTHFR genotype on contingent negative variation and MRI abnormalities in migraine

BACKGROUND: The MTHFR C677T genotype has been associated with increased risk of migraine, particularly of migraine with aura (MA) in selected clinical samples and with elevated homocysteine. The hyper-homocysteinemia may favor the vascular and neuronal mechanism underlying migraine, and the risk of stroke. OBJECTIVE: The first aim of the present study was to examine the Contingent Negative Variation (CNV) amplitude and habituation pattern in a migraine sample versus non-migraine subjects, at the light of the MTHFR genotype, according to an unrelated and clinical based case-control panel. The second aim was to compare the frequency of Magnetic Resonance Imaging (MRI) subclinical brain lesions across the different C677 genotypes in the same migraine sample, selected for the young age and the absence of any cardiovascular risk factor. METHODS: One hundred and five 18-45 year old out-patients, 90 affected by migraine without aura (MO) and 15 by MA, and 97 non-migraine healthy subjects, age and sex matched, were selected for the genetic analysis. All subjects had a common ethnic origin from Puglia. Sixty-four migraine subjects and 33 control subjects were submitted to the recording of the CNV. All migraine subjects underwent the MRI evaluation. RESULTS: The frequency of homozygosis was 14.33% in normal subjects, versus 25.7% in MA + MO group (chi2-test: 10.80 P= .001). The frequency of homozygosis in MO patients, was 25.5% (MA versus N: chi2-test: 9 P= .003), in MA group it was 26.6%. Considering the MTHFR genotype in migraine patients and controls, the C677TT subjects exhibited a reduced habituation index of the early CNV (iCNV), in respect with both C677TC and C677CC; in the migraine group, there was a significant decrease of CNV habituation in patients with homozygosis and a positive correlation between the habituation index values and the homocysteine levels. Nineteen migraine patients exhibited subclinical brain lesions (18.05%): patients with C677T homozygosis did not exhibit a higher risk for MRI abnormalities. CONCLUSIONS: This unrelated and clinical based case-control study showed that genetically induced hyper-homocysteinemia may favor the neuronal factors predisposing to migraine, while it does not influence the presence of subclinical vascular brain lesions probably linked with increased risk of stroke.     

Contingent negative variation: methods and potential interest in headache

Contingent negative variation (CNV) is an event-related slow cerebral potential which has been found abnormal in migraine. Its methodology is described. Contrary to other neurophysiological techniques, CNV needs special equipment and expertise. On average, CNV amplitude is increased and its habituation is lacking in migraine without aura between attacks, but not in migraine with aura. The sensitivity of CNV as a diagnostic tool is low, but its specificity is high. CNV amplitude normalizes after treatment with beta-blockers. The CNV abnormalities in migraine might be due to hyperreactivity of central catecholaminergic pathways.     

Contingent negative variation during migraine attack and interval: evidence for normalization of slow cortical potentials during the attack

The contingent negative variation (CNV) amplitudes of 16 subjects with migraine without aura were studied during pain-free intervals and during attacks and the results were compared with those of 22 healthy subjects. In 32 trials the CNV amplitudes were calculated for (a) "total interval", (b) "early CNV component", (c) "late CNV component", and (d) habituation. There was a significantly higher total CNV amplitude in migraine subjects during pain-free intervals compared to that of the healthy subjects and migraine patients during an attack. Healthy subjects as well as subjects studied during the attack showed a significant habituation whereas migraine subjects studied during pain-free intervals did not. This suggests that the higher CNV amplitude in migraine patients studied between pain-free attacks may be due in part to impaired habituation.     

Stereotyped topography of different elevated contingent negative variation components in children with migraine without aura points towards a subcortical dysfunction

Increased negativity during contingent negative variation (CNV) is thought to reflect abnormal neural activation in adult migraineurs' attention related processing. Findings in childhood and adolescence have yielded less clear results. This study characterizes the age-dependent development of CNV topography in migraine during childhood in order to elucidate the origin and cerebral generators of described CNV elevations. A large sample of children with primary headache (migraine with/without aura, tension type headache) and healthy controls aged 6-18 years was examined in a CNV paradigm using 64-channel high resolution DC-EEG. Patients were tested for diagnose-related topographic group differences of initial CNV (iCNV), late CNV (lCNV) and postimperative negative variation (PINV). All three CNV components of 6-11-year-old migraineurs without aura showed elevated negativity over the supplementary motor area (SMA) and around the vertex. Migraine children lacked age-dependent development of late CNV around Cz as previously reported. However, they showed a normal development of late CNV over pre-/primary motor cortex (MI). There was no marked elevation of iCNV amplitude over frontal areas (orienting reaction) nor specific amplitude elevations over "motor" or "sensory" areas during sustained attention (late CNV). Additional "pre-mature" activation e.g., in the locus coeruleus (leading to diffuse cortical activation summing up to a maximum over the vertex) or the basal ganglia (interacting with SMA) explained the rather stereotyped CNV elevation around the vertex better than a specific implication of the cortical systems responsible for orienting, motor preparation or sensory attention.     

Interictal and postictal contingent negative variation in migraine without aura

Cortical hyperexcitability is thought to explain the more enhanced contingent negative variation (CNV) amplitudes and impaired CNV habituation that have been found during the interictal period in migraine without aura. These CNV characteristics have been shown to normalize to the level of healthy controls during an attack. This study aimed to replicate the interictal findings, and additionally examine whether migraineurs show reduced CNV amplitudes during the postattack period. Of 12 patients with migraine without aura and their sex- and age-matched healthy controls, CNV characteristics were recorded once in an interictal period, once during the postattack period within 30 hours after an attack that was treated with sumatriptan, and once after an attack that was treated with habitual nonvasoactive medication (counterbalanced). The present results did not confirm the enhanced CNV early and late wave amplitudes or impaired habituation, and cortical hyperexcitability that have previously been reported in the interictal period in patients with migraine without aura. During the postattack period, a decrease in CNV early and late amplitudes was found but only after sumatriptan use. This reduction in CNV amplitudes was most prominent over the frontal cortex and could reflect cortical hypoexcitability, possibly related to a suppression of central catecholaminergic activity by sumatriptan.     

Duration of migraine disease correlates with amplitude and habituation of event-related potentials

BACKGROUND: Duration of a migraine disease and hypervigilance are factors which possibly enable the transformation from episodic into chronic migraine. To elucidate this assumption, attentional parameters were measured by recording contingent negative variation (CNV) and correlated with the individual duration of migraine disease. PATIENTS AND METHODS: A total of 28 patients (episodic migraine with or without aura) were compared with 16 healthy controls. CNV analysis included amplitude and habituation calculation. Data were correlated with the individual duration of the migraine disease. The migraine group was divided into two groups based on a median split (short vs long lasting) which were compared by t-tests. RESULTS: Migraine patients produce higher CNV amplitudes than controls. Moreover, migraineurs showed dishabituation while habituation was seen in controls. There was a Pearson correlation coefficient of r = -0.767 between duration of disease and early component of CNV. Patients with long-lasting disease showed lower dishabituation by a higher intercept than patients with short-lasting disease. CONCLUSION: The correlation between duration of disease and attentional parameters and the changing dishabituation can be interpreted as an enhancement in preactivation level in patients with long-lasting migraine. Maybe this change is a prerequisite for transformation into chronic migraine.     

Relationship of locus of control in women with migraine and healthy volunteers

OBJECTIVE: To investigate potential differences in various aspects of personality in women with migraine with aura, without aura, and in healthy volunteers. METHODS: The following instruments were used to evaluate a sample of 35 women with migraine with aura, 35 women with migraine without aura, and 35 healthy women: Locus of Control and Competence Questionnaire, Health Locus of Control Questionnaire, Trait scale of the State-Trait Anxiety Inventory, and the depression scale by von Zerssen. RESULTS: There were no significant differences in generalized locus of control beliefs among the 3 groups. Migraineurs with aura were found to score very low on the social locus of control scale. Statistically significant differences were found regarding anxiety in migraineurs with aura as opposed to migraineurs without aura and healthy control subjects. As for depression, migraineurs with aura were significantly more likely to indicate feelings of worthlessness and lack of self-confidence. CONCLUSIONS: Our results suggest that migraineurs with aura differ from migraineurs without aura and healthy control subjects in terms of anxiety and depression. With regard to health-related locus of control, there was no correlation among mean number of migraine attacks per year, duration of disease, time of last migraine attack, and number of aura symptoms.     

Contingent negative variation in patients with chronic daily headache

The aim of this study was the investigation of amplitude and habituation of contingent negative variation (CNV) in migraine and chronic daily headache (CDH) patients in order to describe possible neurophysiological features responsible for the clinical transformation and worsening of the headache. Fifteen females suffering from migraine without aura and 15 females diagnosed with CDH evolved from migraine without aura with interparoxysmal chronic tension-type headache (transformed migraine), underwent CNV recording. Fifteen healthy females matched for age served as controls. CNV was obtained from C3 and C4 using the standard reaction time paradigm and 3 sec ISI. The amplitudes and habituation of total CNV, early and late components, and of post-imperative negative variation (PINV) were calculated. The migraine patients were characterized by significantly more pronounced negativity of the early component and total CNV, compared to CDH sufferers and controls. CDH patients demonstrated significantly reduced negativity of the late component and pronounced PINV compared to the other groups. The early component of CNV did not habituate in migraine or CDH patients. However, the impaired habituation in CDH was related to significantly lower amplitudes. These results support the diagnostic and scientific value of habituation in migraine research and therapy. Late components of CNV and PINV can be considered as predictive variables for transformation of migraine. The results are discussed in terms of the relationship between late CNV, PINV, environment control abilities and susceptibility for development of depression.     

Migräne

Background

Duration of a migraine disease and hypervigilance are factors which possibly enable the transformation from episodic into chronic migraine. To elucidate this assumption, attentional parameters were measured by recording contingent negative variation (CNV) and correlated with the individual duration of migraine disease.

Patients and methods

A total of 28 patients (episodic migraine with or without aura) were compared with 16 healthy controls. CNV analysis included amplitude and habituation calculation. Data were correlated with the individual duration of the migraine disease. The migraine group was divided into two groups based on a median split (short vs long lasting) which were compared by t-tests.

Results

Migraine patients produce higher CNV amplitudes than controls. Moreover, migraineurs showed dishabituation while habituation was seen in controls. There was a Pearson correlation coefficient of r = ?0.767 between duration of disease and early component of CNV. Patients with long-lasting disease showed lower dishabituation by a higher intercept than patients with short-lasting disease.

Conclusion

The correlation between duration of disease and attentional parameters and the changing dishabituation can be interpreted as an enhancement in preactivation level in patients with long-lasting migraine. Maybe this change is a prerequisite for transformation into chronic migraine.     

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.     

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     

Interictal abnormalities of gamma band activity in visual evoked responses in migraine: an indication of thalamocortical dysrhythmia?

Between attacks, migraineurs lack habituation in standard visual evoked potentials (VEPs). Visual stimuli also evoke high-frequency oscillations in the gamma band range (GBOs, 20-35 Hz) assumed to be generated both at subcortical (early GBOs) and cortical levels (late GBOs). The consecutive peaks of GBOs were analysed regarding amplitude and habituation in six successive blocks of 100 averaged pattern reversal (PR)-VEPs in healthy volunteers and interictally in migraine with (MA) or without aura patients. Amplitude of the two early GBO components in the first PR-VEP block was significantly increased in MA patients. There was a significant habituation deficit of the late GBO peaks in migraineurs. The increased amplitude of early GBOs could be related to the increased interictal visual discomfort reported by patients. We hypothesize that the hypofunctioning serotonergic pathways may cause, in line with the thalamocortical dysrhythmia theory, a functional disconnection of the thalamus leading to decreased intracortical lateral inhibition, which can induce dishabituation.     

Are the periodic changes of neurophysiological parameters during the pain-free interval in migraine related to abnormal orienting activity?

OBJECTIVE AND METHODS: Migraine patients are characterized by increased amplitude and reduced habituation of contingent negative variation (CNV). Furthermore, the CNV underlies periodic changes during the pain-free interval, being maximal before attack. The periodicity of CNV is related to periodic changes in habituation, probably due to variation of orienting activity during the pain-free interval. CNV and orienting response (OR) were studied in 20 females suffering from migraine without aura and in 12 matched healthy females. The neurophysiological recordings in the group of patients were performed 1-4 days before and 4 days after a migraine attack. The amplitudes and habituation of early and late components and total CNV were calculated. The OR was assessed using the habituation of the skin conductance response (SCR) and alpha blocking (AB). The non-parametric tests were employed for statistical analysis. RESULTS: There were no differences between the two groups for habituation of all CNV components and of SCR following an attack. However, the habituation of AB was significantly reduced in migraine. Before attack we observed a significantly reduced habituation of the early and total CNV and of the AB compared to controls and recordings performed after an attack. The habituation of the late component and of SCR remained unchanged. CONCLUSIONS: The abnormal habituation could be explained by the periodic changes of physiological parameters during the pain-free interval. The impaired habituation of early CNV in migraine is associated with increased orienting activity seen only in the central component (AB) of OR.     

Search for correlations between genotypes and electrophysiological patterns in migraine: the MTHFR C677T polymorphism and visual evoked potentials

Interictally, migraineurs have on average a reduction in habituation of pattern-reversal visual evoked potentials (PR-VEP) and in mitochondrial energy reserve. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and its C677T polymorphism may be more prevalent in migraine. The aim of this study was to search in migraineurs for a correlation between the MTHFR C677T polymorphism and the PR-VEP profile. PR-VEP were recorded in 52 genotyped migraine patients: 40 female, 24 without (MoA), 28 with aura (MA). Among them 21 had a normal genotype (CC), 18 were heterozygous (CT) and 13 homozygous (TT) for the MTHFR C677T polymorphism. Mean PR-VEP N1-P1 amplitude was significantly lower in CT compared with CC, and tended to be lower in TT with increasing age. The habituation deficit was significantly greater in CC compared with TT subjects. The correlation between the cortical preactivation level, as reflected by the VEP amplitude in the first block of averages, and habituation was stronger in CC than in CT or TT. The MTHFR C677T polymorphism could thus have an ambiguous role in migraine. On one hand, the better VEP habituation which is associated with its homozygosity, and possibly mediated by homocysteine derivatives increasing serotoninergic transmission, may protect the brain against overstimulation. On the other hand, MTHFR C677T homozygosity is linked to a reduction of grand average VEP amplitude with illness duration, which has been attributed to brain damage.     

An analysis of the factors associated with visual field deficits measured with flickering stimuli in-between migraine

We have previously demonstrated that perimetric performance measured with flickering stimuli is not normal in some individuals who experience migraine with aura in the period between their attacks. In this study, flicker perimetric performance is measured in a broad group of migraineurs to determine whether the existence of such visual field deficits is dependent on the presence of visual aura, is correlated with the duration of migraine history, or frequency of attacks. Twenty-eight migraine with aura, 25 migraine without aura, and 24 non-headache control subjects participated. The performance of the migraine groups was not significantly different from each other. The migraine groups showed significantly lower general sensitivity across the visual field and higher incidence of localized visual field deficits relative to controls. Both length of migraine history and frequency of migraine occurrence over the past 12 months were significantly correlated with lower general sensitivity to flickering visual stimuli.