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.     

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.     

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.     

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.     

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.     

Contingent negative variation in childhood migraine

Adult migraineurs without aura have an increased amplitude of the Contingent Negative Variation (CNV) between attacks. Given the potential diagnostic importance of this finding and the difficulties associated with diagnosing migraine in childhood it seemed important to assess CNV in children suffering from this disorder. Ninety-seven children aged between 8 and 14 years were recruited. Forty-two suffered from migraine, 34 from tension-type headache. Twenty-one healthy controls were also studied. CNV was recorded from Fz, Cz and Pz referenced to linked earlobes during 20 trials consisting of two tones of moderate intensity with an interstimulus interval (ISI) of 4 sec and an intertrial interval (ITI) of 10 to 14 sec. The second tone of each trial required a button press. EOG was recorded from the left eye. The 10 CNV responses with the least EOG artefact were selected and averaged. Children with migraine had a highly significantly more negative mean CNV amplitude at all three electrode sites than children with tension-type headache and also a more pronounced Post-Imperative-Negative-Variation (PINV). Migrainous children differed from controls only at Cz (ISI). There was also a highly significant increase of mean CNV amplitude and PINV at all three electrode sites in the control group compared to the tension headache group.     

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.     

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.     

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.     

Contingent Negative Variation in Migraine

The Contingent Negative Variation (CNV) is an event-related slow potential. It was recorded in healthy volunteers (n = 8) and in patients suffering from migraine without (n = 12) or with (n = 5) aura, during one (CNV1) and three second (CNV3) foreperiods in a forewarned reaction time task. CNV1 was recorded at the vertex while CNV3 was recorded at multiple electrode sites to assess topographical differences. Seven out of twelve migraine patients without aura had increased CNV1 amplitudes. CNV3 amplitudes were increased as well, but only at electrode positions C3 and C4 and not at Fz. CNV3, which allows for analysis of both an early and a late CNV component, could improve the discrimination of migraine without aura beyond that of CNV1. In migraine with aura all CNV parameters were at control levels, confirming previous results. The data obtained are discussed in terms of arousal, activation and stress and the "biobehavioral model of migraine" (Welch, 1986).     

Contingent negative variation in subjects at risk for migraine without aura.

Migraine is a complex disease with a significant genetic background. One possible strategy to investigate the genetics of migraine is the evaluation of functional vulnerability markers or biological elementary endophenotypes in individuals with the greatest probability of developing the disorder (high-risk design). In this study the contingent negative variation (CNV) was recorded in 35 high-risk subjects with a positive family history of migraine without aura (FHP), 35 low-risk individuals without a positive family history (FHN), and 35 migraineurs (migraine without aura). FHP subjects and migraine patients differed significantly from FHN individuals with regard to amplitude and habituation slope of the early CNV component (initial CNV or iCNV). FHP participants demonstrated the same iCNV abnormalities and distribution among iCNV characteristics as migraineurs. The amplitude of the iCNV correlated significantly with the relative number of subjects suffering from migraine among first- and second-degree relatives. The higher the density of affected individuals in the family, the more pronounced were the CNV abnormalities in relatives. This study provides evidence that the familial factor contributes to the abnormal amplitude, and to a lesser degree, habituation of the iCNV, and that the iCNV may be used as a functional-genetic vulnerability marker in further research of migraine genetics.     

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.     

Electrophysiological studies on headache: the contingent negative variation

The contingent negative variation (CNV) is a slow cortical potential recorded from the scalp. This method allows the pathophysiology of chronic headaches to be elucidated. When assessed during the pain-free interval patients suffering from migraine without aura show significantly more negative amplitudes than healthy controls. This negativity reflects the activity of cerebral noradrenergic systems. Some studies using repeated recordings of the CNV show a periodicity in amplitude change. When migraine patients are assessed a few days before a migraine attack occurs, they show pronounced negativity, which normalized during the attack. Despite these interesting findings that are based on group comparisons, evaluating the CNV on an individual basis does not allow specific conclusions. Thus, assessment of the CNV is an important tool to examine pathophysiological aspects of chronic headaches, but is not suitable as a diagnostic procedure.     

Effects of pregnancy on slow cortical potentials in migraine patients and healthy controls

Increased negative amplitudes and lack of habituation of contingent negative variation (CNV) in migraine are well established and are supposed to reflect an altered cortical excitability level. Migraine attacks occur less during pregnancy but often relapse after delivery. We investigated the effect of pregnancy on slow cortical potentials and reaction time in migraine patients and healthy controls. Four groups were examined: 14 pregnant migraine patients, 12 non-pregnant migraine patients, 15 pregnant healthy women and 16 non-pregnant healthy women aged 19-38 years. Two recordings were performed in the pregnant subjects: in the 36th week of gestation and 4 weeks after delivery. The non-pregnant subjects were recorded at the same time interval of 8 weeks. Pregnant migraine patients showed significantly fewer migraine days during the third trimester of pregnancy and returned to nearly the former level 4 weeks post delivery. Non-pregnant migraine patients demonstrated a significant reduction of migraine days at the second measurement. There was no effect of pregnancy on CNV amplitudes, but there was an effect of pregnancy on the habituation coefficient and reaction time of migraine patients. Faster habituation from a higher preactivation level was found. As an explanation for the changed habituation level we favour the model of correlation between preactivation level and habituation level, the so-called law of initial value. We found a correlation between preactivation level and habituation. Our study confirms a specific effect of pregnancy on slow cortical potentials in migraine patients.     

Migräne als Reizverarbeitungsstörung?

Several studies of contingent negative variation (CNV) examined whether this method provides a suitable basis for research on pathogenetic processes in chronic headaches-especially migraine. In the present study, the CNV amplitudes and CNV course of 23 migraine patients were compared with those of 22 healthy subjects. CNV was calculated for (a) "total interval", (b) "early CNV component", and (c) "late CNV component". In 32 trials with an interstimulus interval of 3 s results showed a significant higher CNV in the migraine group. While the amplitude of healthy subjects diminished quickly, the amplitudes of migraine patients remained stable during the session. The results allow the assumption that the higher level of CNV amplitude in migraine patients is not only due to higher cortical noradrenergic or serotoninergic activation. This study shows that migraine patients cannot decrease their CNV amplutides. This is probably due to defective processing of sensory imput.     

The International Headache Society (IHS) Headache Classification as applied to a headache clinic population

Four hundred patients attending a headache clinic were classified using the IHS criteria. The majority required more than two, often three or four, diagnoses. Even though migraine was the most common diagnosis, only 1/4 of those with a migraine diagnosis had it as the only diagnosis. Seventy-five percent of migraine patients had coexistent chronic tension-type headache (CTTH), drug-induced headache or both. Ninety-six percent of patients diagnosed as having migraine with aura also suffered from migraine without aura. More than 1/3 of patients (37.7%) attending the clinic suffered from chronic daily headache (CDH) (chronic cluster headache excluded), which is not included as a separate entity in the IHS classification. Pure CTTH formed only a small minority of CDH, whereas 86.6% of CDH had migraine as one of the diagnoses. Drug-induced headache was a prominent second or third diagnosis. The advantages and disadvantages of multiple verses single diagnosis in CDH and the need to recognize the natural history of headache disorders in the classification are discussed.     

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.     

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.     

Interictal potentiation of passive "oddball" auditory event-related potentials in migraine

We have studied habituation of the P3a component of the passive "oddball" auditory event-related potential which reflects automatic processing of a "novel" stimulus in 24 patients suffering from migraine without aura and in 21 healthy volunteers. Three blocks of responses to 160 standard and to 40 novel tones were sequentially averaged at Cz and analyzed for latencies and peak-to-peak amplitudes. Latencies of components N1 and P2 elicited by standard tones and of components N1, P2, N2, and P3a elicited by novel tones were not significantly different between sequential blocks or between subject groups, nor were mean N1-P2 amplitudes. The N2-P3a amplitude tended to be lower in migraine, but not significantly so. The most striking result in migraineurs was a significant potentiation of N2-P3a in successive blocks, contrasting with an habituation in controls. Our previous evoked- and event-related potential studies and the present one suggest that deficient habituation, or even potentiation, represents interictally a fundamental dysfunction of cortical information processing in migraine, which might increase energy demands and play a role in etiopathogenesis.