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.     

The auditory event related potentials in episodic and chronic pain sufferers.

To examine the cognitive processing differences in chronic and episodic pain sufferers, auditory event-related potentials (P300 or P3) were recorded in two consecutive trials from 23 chronic lower back pain patients, 22 episodic tension-type headache sufferers, and from 23 age- and sex-matched healthy persons. P3 latency and amplitude showed no difference between groups at first trial. Considering P3 latency habituation, healthy controls and episodic tension-type headache sufferers showed a significant change of P3 latency whereas lower back pain sufferers failed. Comparing the amount of habituation lower back pain sufferers stood clearly apart from healthy controls. Although there was a remarkable increase of P3 latency in episodic tension-type headache sufferers, the amount of habituation was not statistically different than it was in lower back pain sufferers. Significant P3 amplitude habituation was observed only in healthy controls. Actually, episodic tension-type headache sufferers also showed some degree of habituation, which was not statistically remarkable. The amount of amplitude habituation was not different between groups. No correlation was observed between P3 habituation and age, disease duration and symptom severity. These results may point to a disturbed attentional processing in chronic pain sufferers. Our findings suggest that in spite of a similar cortical information processing, the neurocognitive networks related with decision making and memory processing seem to work differently in chronic pain sufferers from those in episodic pain sufferers in repeating tasks. Taking into consideration the reported P3 habituation abnormalities in chronic migraine patients we can say that not the location of pain but rather its temporal pattern may have a role in disturbed attentional processing.     

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.     

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.     

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.     

Topiramate in migraine progression

Increasing evidence shows that migraine, typically considered as an episodic disease, is a chronic and, in some patients, progressive disorder. Among neuromodulators used for migraine prevention, topiramate has a high level of evidence-based efficacy. Through its wide range of mechanisms of action topiramate increases the activation threshold resulting in neuronal stabilization and thereby reducing cortical neurons hyperexcitability, which is believed to be an important electrophysiological feature underlying the pathogenesis of epilepsy and migraine. Recent studies show that migraineurs have subclinical structural brain changes and persistent alteration of pain perception, in some cases correlated with the duration of the disease and the frequency of attacks that might play a role in the transformation of episodic migraine to chronic forms. An early and prolonged preventive treatment might reduce the risk of such transformation. Recent evidence suggests that topiramate, by reducing migraine frequency and use of acute medication, may prevent the negative progression of migraine. Furthermore, two recently completed multicenter, randomised, placebo-controlled trials have shown that treatment with topiramate 100 mg/day is effective and well tolerated in patients already progressed to chronic migraine and difficult to treat conditions associated with medication-overuse. Topiramate seems to be a preventive treatment, which might be able to act at different levels of the migraine cycle: reduction of frequency in episodic migraine, prevention, and treatment of chronic migraine.     

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.     

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.     

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.     

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.     

Induction of long-lasting changes of visual cortex excitability by five daily sessions of repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers and migraine patients

We have shown that in healthy volunteers (HV) one session of 1 Hz repetitive transcranial magnetic stimulation (rTMS) over the visual cortex induces dishabituation of visual evoked potentials (VEPs) on average for 30 min, while in migraineurs one session of 10 Hz rTMS replaces the abnormal VEP potentiation by a normal habituation for 9 min. In the present study, we investigated whether repeated rTMS sessions (1 Hz in eight HV; 10 Hz in eight migraineurs) on 5 consecutive days can modify VEPs for longer periods. In all eight HV, the 1 Hz rTMS-induced dishabituation increased in duration over consecutive sessions and persisted between several hours (n=4) and several weeks (n=4) after the fifth session. In six out eight migraineurs, the normalization of VEP habituation by 10 Hz rTMS lasted longer after each daily stimulation but did not exceed several hours after the last session, except in two patients, where it persisted for 2 days and 1 week. Daily rTMS can thus induce long-lasting changes in cortical excitability and VEP habituation pattern. Whether this effect may be useful in preventative migraine therapy remains to be determined.     

Voxel-based morphometry reveals gray matter abnormalities in migraine

BACKGROUND: Migraine is generally considered a functional brain disorder lacking structural abnormalities. Recent magnetic resonance imaging (MRI) studies, however, suggested that migraine may be associated with subtle brain lesions. OBJECTIVE: We evaluated the presence of global or focal gray or white matter alterations in migraine patients using voxel-based morphometry (VBM), a fully automated method of analyzing changes in brain structure. VBM data also were used to evaluate possible differences between episodic and chronic migraine. METHODS: Twenty-seven migraine right-handed patients and 27 healthy controls were selected for the study. Sixteen patients fulfilled the International Headache Society criteria for episodic migraine and 11 for chronic migraine. MRI scans were analyzed with MATLAB 6.5 and SPM2 software, using VBM method. RESULTS: In comparison with controls, migraineurs presented a significant focal gray matter reduction in the Right Superior Temporal Gyrus, Right Inferior Frontal Gyrus, and Left Precentral Gyrus. Chronic migraine patients, compared to episodic, showed a focal gray matter decrease in the bilateral Anterior Cingulate Cortex, Left Amygdala, Left Parietal Operculum, Left Middle and Inferior Frontal Gyrus, Right Inferior Frontal Gyrus, and bilateral Insula. Considering all the migraine patients, a significant correlation between gray matter reduction in anterior cingulate cortex and frequency of migraine attacks was found. CONCLUSIONS: Our study shows that migraine is associated with a significant gray matter reduction in several of the cortical areas involved in pain circuitry. In addition, we found a significant correlation between frequency of migraine attacks and signal alteration in the Anterior Cingulate Cortex. Our data provide new insight into migraine pathophysiology and support the concept that migraine may be a progressive disorder.     

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.     

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.     

Central mechanisms of controlled-release metoprolol in migraine: a double-blind, placebo-controlled study

beta-Blockers are widely used in the prophylaxis of migraine and have been described as very effective drugs in many studies. Some investigators have demonstrated that the clinical improvement of migraine corresponds to the normalization of the contingent negative variation (CNV), a slow cortical potential measuring cortical information processing. However, most of these studies have contained a variety of methodological pitfalls, which we attempted to address in the current study. Twenty patients suffering from migraine without aura were randomly divided into two groups. The groups were treated either with controlled-release metoprolol or placebo for 3 months, using a double-blind design. Twice before and once after each month of the treatment the CNV was recorded. After 3 months, a significant reduction of migraine frequency, duration and intensity was demonstrated for the metoprolol compared with the placebo group. The CNV was characterized by a marked reduction of the amplitude of the total CNV and postimperative negative variation and normalization of the eartly CNV habituation following treatment. Therefore, metoprolol may exert its prophylactic effect in migraine through the influence on cortical information processing and excitability represented by the CNV.     

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.     

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.     

Cortical inhibition is reduced in chronic and episodic migraine and demonstrates a spectrum of illness

BACKGROUND: The pathophysiological relationship between episodic migraine and chronic migraine is not fully understood. We aimed to examine transcranial magnetic stimulation (TMS) indices of cortical excitability in patients with episodic migraine (EM) and probable chronic migraine (PCM), and matched controls. METHODS: Cortical excitability was assessed at baseline with two well-established methods: phosphene thresholds (PT) and magnetic suppression of perceptual accuracy (MSPA) profiles. Five EM patients, five PCM patients, and five normal controls participated in the main study. In addition, two patients were reassessed after 30 days of treatment with topiramate. RESULTS: Both PT and MPSA measures were consistent in indicating a continuum of excitability across the three groups: PCM patients had the highest excitability, followed by EM, then controls. In the two treated patients MPSA profiles appeared to normalize at a 100 mg dosage. CONCLUSIONS: Patients with PCM appear to be characterized by very high cortical excitability. This may contribute to their greatly increased attack frequency. TMS-based methods will be important for future research examining the evolution of chronic migraine from episodic migraine over time.     

Interventional Procedures for Facial Pain

Chronic migraine is a disabling condition which affects a considerable proportion of patients. Several risk factors and lifestyle habits contribute to the transformation of migraine into a chronic form. Behavioral treatments, including relaxation, biofeedback, and cognitive behavioral therapy reduce the risk of episodic into chronic migraine transformation, thus restraining the headache-related disability. The rationale of behavioral therapies is that a medical problem should be recognized and thoroughly examined by the patient to be successfully managed. Being aware of factors which precipitate or aggravate migraine allows patients to progressively modulate the frequency and duration of their attacks. Similarly, the acquisition of healthy habits improves the quality of life and the subjective well-being of patients and contributes to breaking the vicious cycle that leads to migraine chronification. The highest level of care is achieved when behavioral therapies are integrated with other treatments, including physical and pharmacological interventions.