Positive response to galcanezumab following treatment failure to onabotulinumtoxinA in patients with migraine: post hoc analyses of three randomized double-blind studies.

BACKGROUND AND PURPOSE: Humanized monoclonal antibody galcanezumab, which binds to calcitonin-gene-related peptide, has shown efficacy for episodic and chronic migraine prevention. These analyses evaluated galcanezumab response for migraine headache prevention in patients who previously failed onabotulinumtoxinA ('nonresponse' or 'inadequate response' or safety reasons). METHODS: Post hoc analyses included data from three double-blind, placebo-controlled, phase 3 episodic or chronic migraine studies; 2886 patients randomly received 120 or 240 mg galcanezumab or placebo. During double-blind periods the study drug was administered subcutaneously once a month for 6 months in EVOLVE-1 and -2 and for 3 months in REGAIN. The 120 mg groups received a 240 mg loading dose at month 1. Pooled analyses included 129 patients who failed onabotulinumtoxinA. Using mixed effect model repeat measurements, the least squares mean change from baseline in the number of migraine headache days (MHDs) was calculated for the first 3 months of treatment. RESULTS: For pooled analyses, significant decreases from baseline in the number of MHDs were observed for 120 mg (-3.91) and 240 mg (-5.27) galcanezumab overall versus placebo (-0.88) across 3-month time points for patients who failed onabotulinumtoxinA. Corresponding data for patients with chronic migraine showed significant decreases: 120 mg (-3.18) and 240 mg (-4.26) galcanezumab versus placebo (0.16). Significant reductions in the number of MHDs per month with acute medication use included 120 mg galcanezumab (-4.35) and 240 mg galcanezumab (-4.55) versus placebo (-0.83). Estimates of ≥50% response during months 1-3 were 9.4% for placebo, 41.3% for 120 mg galcanezumab and 47.5% for 240 mg galcanezumab. CONCLUSION: Galcanezumab is an option for prevention of migraine in patients who have previously failed onabotulinumtoxinA preventive therapy.

Efficacy of galcanezumab in patients with episodic migraine and a history of preventive treatment failure: results from two global randomized clinical trials.

BACKGROUND AND PURPOSE: The efficacy of galcanezumab, a monoclonal antibody for migraine prevention, has been demonstrated in two pivotal trials in patients with episodic migraine. METHODS: EVOLVE-1 and EVOLVE-2 were identical phase 3, randomized, double-blind, placebo-controlled studies in patients with episodic migraine. Mean migraine headache days per month at baseline was 9. Patients were randomized 2:1:1 to monthly injections of placebo, galcanezumab 120 mg/240 mg during the 6-month double-blind treatment period. Key efficacy outcomes were assessed in subgroups amongst patients for whom, previously, for efficacy and/or safety/tolerability reasons (i) one or more (≥1) preventives failed, (ii) two or more (≥2) preventives failed and (iii) preventives were never used, or used but not failed (no prior failure). RESULTS: In an integrated analysis of EVOLVE studies, galcanezumab 120 mg/240 mg versus placebo led to larger overall mean (SE) reductions in monthly migraine headache days across 6 months in patients with prior preventive failures (P < 0.001): ≥1 failure: 120 mg: -4.0 (0.4); 240 mg: -4.2 (0.5); placebo: -1.3 (0.4); ≥2 failures: 120 mg: -3.1 (0.7); 240 mg: -3.8 (0.8); placebo: -0.5 (0.6). Similar results were observed amongst patients with no prior failure, but the placebo response was larger: 120 mg: -4.7 (0.2); 240 mg: -4.5 (0.2); placebo: -3.0 (0.2) (P < 0.001 versus placebo). Significant improvements were observed with galcanezumab versus placebo for ≥50% and ≥75% reduction in monthly migraine headache days. CONCLUSION: In patients with episodic migraine treated with galcanezumab, those with ≥1 or ≥2 prior preventive failures had significantly larger improvements, versus placebo, in efficacy outcomes. Similar results were observed in patients with no prior failure, with a larger placebo response.

OnabotulinumtoxinA for chronic migraine: efficacy, safety, and tolerability in patients who received all five treatment cycles in the PREEMPT clinical program.

OBJECTIVE: Chronic migraine (CM) is a prevalent and disabling neurological disorder. Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program assessed efficacy and safety of onabotulinumtoxinA (BOTOX(®)) for prophylaxis of headaches in adults with CM. This secondary analysis assessed patients who received all five treatment cycles and completed the study. MATERIALS AND METHODS: PREEMPT (two phase III studies: 24-week double-blind, placebo-controlled [DBPC], parallel-group phase, followed by 32-week open-label [OL] phase) evaluated the efficacy and safety of onabotulinumtoxinA in CM (≥15 days/month with headache lasting ≥4 h a day). Patients were randomized (1:1) to onabotulinumtoxinA or placebo every 12 weeks for two cycles, followed by onabotulinumtoxinA for three cycles. Multiple headache symptom measures were evaluated. Results for the completer (five cycles) subgroup of patients are reported. RESULTS: Of 1384 total PREEMPT patients, 1005 received all five treatment cycles (513 received onabotulinumtoxinA only [onabotulinumtoxinA/onabotulinumtoxinA (O/O)] and 492 received two cycles of placebo then three cycles of onabotulinumtoxinA [placebo/onabotulinumtoxinA (P/O)]). Demographics were similar between treatment groups. At Week 56, after all patients were treated with onabotulinumtoxinA, there continued to be significant between-group differences favoring the O/O vs P/O group for the following headache symptom measures: LS mean change from baseline in frequencies of headache days (-12.0 O/O, -11.1 P/O; P = 0.035), migraine days (-11.6 O/O, -10.7 P/O; P = 0.038), and moderate/severe headache days (-11.0 O/O, -10.1 P/O; P = 0.042). For other measures (cumulative hours of headache on headache days, frequency of headache episodes, and percentage with severe Headache Impact Test (HIT)-6 score, and total HIT-6 and Migraine-Specific Quality of Life Questionnaire scores), there were also large mean improvements from baseline. The percent of patients with a ≥50% reduction from baseline in frequency of headache days was significantly greater for the onabotulinumtoxinA-only group at Week 56 (69.6% O/O, 62.8% P/O; P = 0.023). The treatment-related adverse event rate was 28.5% for onabotulinumtoxinA vs 12.4% for placebo in the DBPC phase and 34.8% for patients treated with onabotulinumtoxinA for all five cycles throughout the 56-week trials. CONCLUSIONS: This subgroup analysis demonstrated improvements with onabotulinumtoxinA treatment (five cycles) vs placebo (two cycles)/onabotulinumtoxinA (three cycles) for multiple headache symptom measures and suggests that at Week 56, patients treated earlier with onabotulinumtoxinA had better outcomes. These findings demonstrate the continued need and cumulative benefit over time with continued prophylaxis, an important and clinically pragmatic observation for clinicians and patients.

Topiramate modulates excitability of the occipital cortex when measured by transcranial magnetic stimulation.

The aim of this study was to measure differences in occipital cortex excitability in migraineurs before and after administration of topiramate. We have previously demonstrated occipital cortex hyperexcitability in migraine using an objective technique of magnetic suppression of perceptual accuracy (MSPA). We hypothesized that a neuromodulator such as topiramate would demonstrate differences in MSPA in migraine compared with baseline. Ten migraine patients were recruited. To assess inhibitory function MSPA was measured using the following protocol. Timed transcranial magnetic stimulation were delivered at interstimulus intervals (ISI) varying from 40 to 190 ms (eight stimulations at each ISI) at 60% stimulus intensity. Subjects were asked to report letters projected at a fixed luminance on the screen. Visual suppression was calculated based on the number of errors the subjects made using automated analysis. This procedure was repeated at a minimum of two different dosages of topiramate when it was titrated for optimal migraine control. The interim dose was that at which an improvement in headache frequency was first observed, and the optimal dose was that at which the patient had a ≥ 50% reduction in headache frequency, or had reached a 100-mg dose. The mean [standard error (s.e.)] level of letters reported correct at baseline at 100-ms ISI was 91.6 (3.4) compared with 48.5 (6.0) (P = 0.001) at an optimal dose of topiramate. Dose ranged from 50 to 100 mg; the average dose was 75 mg. The interim dose for most patients was 50 mg; the mean (s.e.) percentage of letters reported correct at interim was 75.9 (6.2) compared with baseline (P = 0.01). Mean number of headaches at baseline was 27 per month, compared with eight headaches per month at interim dose and four headaches per month at optimal dose. There was no significant correlation between mean change in frequency of headache and mean change in inhibition from baseline to optimal dose (0.04, P = 0.89). Topiramate modulates occipital cortex excitability in chronic migraine possibly via mechanisms of cortical inhibition. Since there was not a strong correlation between the degree of inhibition and reduction of migraine frequency, it would appear that topiramate did have an independent effect on cortical excitability that was not dependent on reduction in migraine frequency.

OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial.

OBJECTIVES: This is the second of a pair of studies designed to evaluate the efficacy and safety of onabotulinumtoxinA (BOTOX) for prophylaxis of headaches in adults with chronic migraine. METHODS: PREEMPT 2 was a phase 3 study, with a 24-week, double-blind, placebo-controlled phase, followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections of onabotulinumtoxinA (155U-195U; n = 347) or placebo (n = 358) every 12 weeks for two cycles. The primary efficacy endpoint was mean change in headache days per 28 days from baseline to weeks 21-24 post-treatment. RESULTS: OnabotulinumtoxinA was statistically significantly superior to placebo for the primary endpoint, frequency of headache days per 28 days relative to baseline (-9.0 onabotulinumtoxinA/-6.7 placebo, p < .001). OnabotulinumtoxinA was significantly favoured in all secondary endpoint comparisons. OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few patients (3.5% onabotulinumtoxinA/1.4% placebo) discontinued due to adverse events. CONCLUSIONS: The results of PREEMPT 2 demonstrate that onabotulinumtoxinA is effective for prophylaxis of headache in adults with chronic migraine. Repeated onabotulinumtoxinA treatments were safe and well tolerated.

OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial.

OBJECTIVES: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX) as headache prophylaxis in adults with chronic migraine. METHODS: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U-195 U; n = 341) or placebo (n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24. RESULTS: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (-5.2 vs. -5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days (p = .006) and migraine days (p = 0.002). OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events. CONCLUSIONS: There was no between-group difference for the primary endpoint, headache episodes. However, significant reductions from baseline were observed for onabotulinumtoxinA for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.

Is chronic migraine one end of a spectrum of migraine or a separate entity?

Chronic migraine is associated with abnormalities in the periaqueductal grey that may be progressive. The condition is also associated with a greater degree of impairment in cortical processing of sensory stimuli than episodic migraine, perhaps due to more pervasive or persistent cortical hyperexcitability. These findings fit with the model of migraine as a spectrum disorder, in which the clinical and pathophysiological features may progress over time. This progression may result from changes in nociceptive thresholds and ensuing central sensitization caused by recurrent migraine in susceptible individuals. This may lead to changes in baseline neurological function between headaches, evident not only in electrophysiological and functional imaging studies, but also as psychological and somatic complaints that occur after years of episodic migraine. From current research and migraine models, a conceptualization of chronic migraine is emerging in which relatively permanent and pervasive central changes have occurred that warrant novel and tolerable treatments.

A double-blind, randomized, placebo-controlled, single-dose study of the cyclooxygenase-2 inhibitor, GW406381, as a treatment for acute migraine.

The objective of the present study was to explore the clinical efficacy and tolerability of GW406381, a cyclooxygenase-2 (COX-2) inhibitor with relatively high CNS penetration, in acute migraine. This was a double-blind, single-dose study of GW406381 compared with placebo and naproxen sodium compared with placebo (protocol number CXA20008). Three hundred and thirty-seven subjects were randomized 1:1:1 to GW406381 (70 mg), naproxen sodium (825 mg), or placebo for the treatment of one migraine headache of moderate or severe intensity in a potential 8-week period. The primary end-point was the proportion of subjects with headache relief [reduction in headache severity score from pre-dose 2 (moderate) or 3 (severe) to 0 (no pain) or 1 (mild)] at 2 h post-dose for GW406381 compared with placebo. Significantly higher proportions of subjects treated with GW406381 (50%, P = 0.032) or naproxen sodium (56%, P = 0.005) than with placebo (35%) reported headache relief at 2 h post-dose. Additional significant benefits were observed on many secondary outcomes, including proportions of subjects pain-free, for both GW406381 and naproxen sodium treatment compared with placebo. Both active treatments were well tolerated. Single-dose GW406381 (70 mg) and naproxen sodium (825 mg) were effective and well tolerated in the treatment of acute migraine.

The brain is hyperexcitable in migraine.

Migraine is a very common disorder occurring in 20% of women and 6% of men. Central neuronal hyperexcitability is proposed to be the putative basis for the physiological disturbances in migraine. Since there are no consistent structural disturbances in migraine, physiological and psychophysical studies have provided insight into the underlying mechanisms. This is a review of the neurophysiological studies which have provided an insight to migraine pathogenesis supporting the theory of hyperexcitability.

Transcranial magnetic stimulation confirms hyperexcitability of occipital cortex in migraine.

OBJECTIVES: We hypothesized that the hyperexcitability of occipital cortex neurons may predispose migraine subjects to develop spreading depression, the putative basis of migraine with aura (MwA). To date there is no direct physiologic correlate confirming this in patients. Accordingly, we evaluated the differences in the threshold of occipital cortex excitation between MwA patients and normal controls (C) using transcranial magnetic stimulation (TMS). METHODS: TMS was performed using the Cadwell MES 10 stimulator. A circular coil 9.5 cm in diameter was applied to the occipital scalp (7 cm above the inion). Stimulator intensity was increased in 10% increments until subjects reported visual phenomena or 100% intensity was reached. Stimulation intensity was then fine-tuned to determine the threshold at which phosphenes were just visualized. RESULTS: Eleven MwA patients, mean age 37 +/- 7 years, were compared with 11 C, mean age 37.7 +/- 7 years. The difference in the proportion of subjects with phosphene generation between MwA patients and C was significant (MwA patients 100% versus C 27.3%, p = 0.001). The mean threshold level for MwA patients was 44.2 +/- 8.6 versus 68.7 +/- 3.1 for C (p = 0.0001). All threshold levels for MwA patients were lower than the lowest threshold for C; the MwA patient with the lowest threshold had an aura after stimulation. CONCLUSIONS: The threshold for excitability of occipital cortex is lower in MwA patients compared with C. This is a direct neurophysiologic correlate for clinical observations that have indicated hyperexcitability of the occipital cortex in migraineurs.

Functional MRI-BOLD of brainstem structures during visually triggered migraine.

BACKGROUND: Previously, hyperoxia and blood volume increase were reported in the red nucleus and substantia nigra during spontaneous migraine with aura. OBJECTIVE: To further understand the pathophysiologic role of these centers, activation of brainstem structures was investigated in patients with visually triggered migraine. METHODS: Twenty-six patients with migraine (23 with aura and 3 without aura), and 10 normal control subjects were studied with blood oxygen level-dependent (BOLD) fMRI during repeated checkerboard visual stimulation. Three axial image sections, which covered the occipital cortex and brainstem, were acquired 224 times with a temporal resolution of 3.5 seconds. RESULTS: Repetitive visual stimulation triggered symptoms in 12 patients; four who had migraine with aura developed both visual symptoms and headaches, and six who had migraine with aura and two who had migraine without aura had headaches only. Four patients who had migraine with aura experienced the onset of their usual aura or onset of their typical headache either during the experiment or immediately after. In the remaining 10 patients with migraine, and all control subjects, visual stimulation failed to trigger symptoms at any time. In 75% of the patients who developed symptoms during stimulation, baseline T2*-weighted MR signal intensities increased in the red nucleus and substantia nigra before occipital cortex signal elevation or the onset of visually triggered symptoms. CONCLUSION: Activation (hyperoxia and blood volume increase) of the red nucleus and substantia nigra in association with visually triggered symptoms of migraine suggest that these brainstem structures are a part of a neuronal network activated during an attack.

OnabotulinumtoxinA improves quality of life and reduces impact of chronic migraine.

OBJECTIVE: To assess the effects of treatment with onabotulinumtoxinA (Botox, Allergan, Inc., Irvine, CA) on health-related quality of life (HRQoL) and headache impact in adults with chronic migraine (CM). METHODS: The Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program (PREEMPT 1 and 2) included a 24-week, double-blind phase (2 12-week cycles) followed by a 32-week, open-label phase (3 cycles). Thirty-one injections of 5U each (155 U of onabotulinumtoxinA or placebo) were administered to fixed sites. An additional 40 U could be administered "following the pain." Prespecified analysis of headache impact (Headache Impact Test [HIT]-6) and HRQoL (Migraine-Specific Quality of Life Questionnaire v2.1 [MSQ]) assessments were performed. Because the studies were similar in design and did not notably differ in outcome, pooled results are presented here. RESULTS: A total of 1,384 subjects were included in the pooled analyses (onabotulinumtoxinA, n = 688; placebo, n = 696). Baseline mean total HIT-6 and MSQ v2.1 scores were comparable between groups; 93.1% were severely impacted based on HIT-6 scores ≥60. At 24 weeks, in comparison with placebo, onabotulinumtoxinA treatment significantly reduced HIT-6 scores and the proportion of patients with HIT-6 scores in the severe range at all timepoints including week 24 (p < 0.001). OnabotulinumtoxinA treatment significantly improved all domains of the MSQ v2.1 at 24 weeks (p < 0.001). CONCLUSIONS: Treatment of CM with onabotulinumtoxinA is associated with significant and clinically meaningful reductions in headache impact and improvements in HRQoL. CLASSIFICATION OF EVIDENCE: This study provides Class 1A evidence that onabotulinumtoxinA treatment reduces headache impact and improves HRQoL.

High prevalence of somatic symptoms and depression in women with disabling chronic headache.

OBJECTIVE: To better define, in women with headache, the relationship of depression and somatic symptoms to headache, characterized by diagnoses, frequency, and disability. METHODS: At six headache specialty clinics, women with headache were classified using ICHD-II criteria, and frequency was recorded. A questionnaire addressing demographics, age at onset of headache, headache-related disability, somatic symptom, and depression severity was completed. Logistic regression was performed to measure the associations of headache frequency and headache-related disability with somatic symptom and depression severity. RESULTS: A total of 1,032 women with headache completed the survey, 593 with episodic (96% with migraine) and 439 with chronic headache (87% with migraine). Low education and household income was more common in chronic headache sufferers and in persons with severe headache disability. Somatic symptom prevalence and severity was greater in persons with chronic headache and with severe headache-related disability. Significant correlation was observed between PHQ-9 and PHQ-15 scores (r = 0.62). Chronic headache, severe disability, and high somatic symptom severity were associated with major depressive disorder (OR = 25.1, 95% CI: 10.9 to 57.9), and this relationship was stronger in the subgroup with a diagnosis of migraine (OR = 31.8, 95% CI: 12.9 to 78.5). CONCLUSIONS: High somatic symptom severity is prevalent in women with chronic and severely disabling headaches. Synergistic relationship to major depression exists for high somatic symptom severity, chronic headache, and disabling headache, suggesting a psychobiological underpinning of these associations.

History of childhood maltreatment is associated with comorbid depression in women with migraine.

BACKGROUND: A bidirectional relationship between migraine and depression suggests a neurobiological link. Adverse experiences, particularly childhood maltreatment, may alter neurobiological systems, and predispose to a multiplicity of adult chronic disorders. Our objective is to determine, within a headache clinic population of women, if depression moderates the abuse-migraine relationship. METHODS: At six headache specialty clinics, women with migraine were diagnosed using ICHD-II criteria, and frequency was recorded. A questionnaire regarding maltreatment history, headache characteristics, current depression, and somatic symptoms was completed. RESULTS: A total of 949 women with migraine completed the survey: 40% had chronic headache (> or =15 headache days/month) and 72% had "very severe" headache-related disability. Major depression was recorded in 18%. Physical or sexual abuse was reported in 38%, and 12% reported both physical and sexual abuse in the past. Migraineurs with current major depression reported physical (p < 0.001) and sexual (p < 0.001) abuse in higher frequencies compared to those without depression. Women with major depression were more likely to report sexual abuse occurring before age 12 years (OR = 2.30, 95% CI: 1.14 to 4.77), and the relationship was stronger when abuse occurred both before and after age 12 years (OR = 5.08, 95% CI: 2.15 to 11.99). Women with major depression were also twice as likely to report multiple types of maltreatment (OR = 2.07, 95% CI: 1.27 to 3.35) compared to those without depression. CONCLUSIONS: Childhood maltreatment was more common in women with migraine and concomitant major depression than in those with migraine alone. The association of childhood sexual abuse with migraine and depression is amplified if abuse also occurs at a later age.

Pathophysiology of migraine headache.

The underlying mechanism of migraine and pain has been unraveled recently with the advent of neuroimaging. In this article mechanism of migraine aura and the pain of migraine are discussed. In addition, interictal studies demonstrating hyperexcitability in migraine are reviewed.

Migraine: imaging the aura.

We currently conceive of a migraine attack as originating in the brain. Triggers of an attack initiate a depolarizing neuroelectric and metabolic event likened to the spreading depression of Leao. This event activates the headache and associated features of the attack by mechanisms that remain to be determined, but appear to involve either peripheral trigeminovascular or brainstem pathways, or both. The excitability of cell membranes, perhaps partly genetically determined, is the brain's susceptibility to attacks. Factors that increase or decrease neuronal excitability constitute the threshold for triggering attacks. Using a model of visual stress-induced migraine or by studying spontaneous attacks and applying advanced imaging and neurophysiological methods, results have been obtained that support spreading neuronal inhibition as the basis of aura. This neuroelectric event is accompanied by hyperoxia of the brain, possibly associated with vasodilation. Evidence has also been obtained that the spreading cortical event can activate the subcortical centers possibly involved in nociception and associated symptoms of the migraine attack. Susceptibility to migraine attacks appears to be related to brain hyperexcitability. These newer techniques of functional neuroimaging have confirmed the primary neural basis of the migraine attack with secondary vascular changes, reconciling previous theories into a neurovascular mechanism.

Brain excitability in migraine: evidence from transcranial magnetic stimulation studies.

Central neuronal hyperexcitability is proposed to be the putative basis for the physiologic disturbances in migraine. Because there are no structural disturbances in migraine, only physiologic studies can provide insight into the underlying mechanisms. Recently, transcranial magnetic stimulation has been developed as a valuable research tool and can be used to study brain function noninvasively. This article is a review of the studies done in migraine using transcranial magnetic stimulation.

Vertebrobasilar artery ectasia presenting as hydrocephalus.

Symptomatic hydrocephalus in association with basilar artery ectasia is a rare occurrence. We report an 81-year-old woman with progressive dementia, gait disturbance, and sphincter incontinence. Brain computed tomography (CT) and magnetic resonance imaging (MRI) scans showed obstructive hydrocephalus with compression of the fourth ventricle by a large ectatic basilar artery. After ventriculoperitoneal shunting, the patient showed rapid resolution of symptoms. This case illustrates that ventricular obstruction due to basilar artery ectasia can mimic the classical triad of normal pressure hydrocephalus.

The cortical silent period is shortened in migraine with aura.

OBJECTIVES: Central neuronal hyperexcitability may be the physiological disturbance that predisposes subjects to migraine attacks. To test this hypothesis, we studied the cortical stimulation silent period (CSSP) elicited by transcranial magnetic stimulation (TMS), which is in part a measure of central inhibition of motor pathways in migraine with aura (MwA) patients and normal controls. METHODS: In nine MwA patients (mean age 35.9 +/- 7) and 9 controls (mean age 37.6 +/- 7), we carried out transcranial stimulation using a 95 mm circular coil and Caldwell MES 10 stimulator to determine resting motor threshold (MT) for bilateral FDI muscles. All subjects performed isometric voluntary contraction of bilateral FDI maintained at 20% of maximal effort, during which we measured bilateral CSSP at (i) the stimulus intensity (SI) determined for the MT and (ii) an SI of 1.5 x MT. RESULTS: Although the mean MT was higher in MwA compared with controls (63.1 +/- 14.4 vs 58.1 +/- 8.9), the difference was not significant. At an SI of 1.5 x MT the mean CSSP did not differ between the groups (MwA 141.7 +/- 31.9 vs controls 162.4 +/- 36.6). At the SI of the MT, however, the CSSP was shorter in MwA patients than in controls (62.9 +/- 27.3 vs 106.3 +/- 19.6, p = 0.001). There was an inverse correlation between the duration of CSSP and an increased frequency of headache (p = 0.02). CONCLUSIONS: The shortened CSSP that we measured in MWA patients compared to normal with low intensity magnetic stimulation suggests reduced central inhibition resulting in increased excitability of cortical neurons in migraine subjects. The association of CSSP reduction with increased frequency of migraine is further suggestive that brain excitability is the basis of susceptibility to migraine attacks.