Cortical Excitability in Chronic Migraine

A proportion of episodic migraine patients experiences a progressive increase in attack frequency leading to chronic migraine (CM). The most frequent external factor that leads to headache chronification is medication overuse. The neurobiological bases of headache chronification and of the vicious circle of medication overconsumption are not completely elucidated. More recently, the same neurophysiological methods used to study episodic migraine were applied to CM and medication-overuse headache (MOH). Studies of cortical responsivity tend overall to indicate an increase in excitability, in particular of somatosensory and visual cortices, reflected by increased amplitude of evoked responses, decreased activity of inhibitory cortical interneurons reflected in the smaller magnetic suppression of perceptual accuracy, and, at least for visual responses, an increase in habituation. In MOH, overconsumption of triptans or NSAIDs influences cortical excitability differently. Generalized central sensitization is suggested to play an important role in the pathophysiology of headache chronification.     

Brainstem dysfunction in chronic migraine as evidenced by neurophysiological and positron emission tomography studies

BACKGROUND: The pathophysiology of chronic migraine (CM) is not fully understood. We aimed to examine transcranial magnetic stimulation (TMS) indices of cortical excitability in patients with CM and also performed PET studies to ascertain if there were any areas of activation and inhibition for possible correlation. METHODS: Excitability of the cortex was assessed by a reliable parameter of magnetic suppression of perceptual accuracy (MSPA) profiles using transcranial magnetic stimulation in 25 patients with CM. Of these 10 patients were also studied with ((18)F-FDG PET) scans. RESULTS: MSPA demonstrated decreased inhibition in CM compared to normal controls and episodic migraine. The percentage of letters reported correct at 100 ms was 84.37 for CM compared to 19.14 for normal controls and 57.41 for episodic migraine. The PET evaluation in 10 subjects demonstrated increased cerebral metabolism in areas of in the brainstem compared to the global flow. There were also decreased areas of cerebral metabolism in the medial frontal and parietal as well as the somatosensory cortex. CONCLUSIONS: Patients with CM appear to be characterized by reduced visual suppression correlating with high cortical excitability. In a cohort of these subjects there was brainstem activation and inhibition in certain areas of the cortex suggesting a potential dysfunction in the inhibitory pathways.     

Obsessive-Compulsive Disorder and Migraine With Medication-Overuse Headache

Objective.— A strong association has been demonstrated between migraine, particularly in the chronic form and with medication overuse, and either major depression or various anxiety disorders. However, there has been less systematic research on the links between migraine with medication-overuse headache (MOH) and obsessive-compulsive disorder (OCD). A drug-seeking behavior shares with OCD the compulsive quality of the behavior. We investigated the relationship between OCD and MOH in migraineurs.
Methods.— A structured questionnaire was administered to subjects with: episodic migraine (EM) (n = 30), chronic migraine (CM) (n = 24), and MOH with a previous history of EM (n = 33) and 29 control subjects. Psychiatric diagnoses were made by a senior psychiatrist blinded to the diagnosis of migraine. Psychiatric assessment of OCD illness was evaluated by means of The Yale-Brown Obsessive Compulsive Scale (Y-BOCS).
Results.— In the subgroup of patients with MOH, psychiatric comorbidity (anxiety and mood disorders) was prevalent compared with CM, EM, and controls ( P  < .0001). Subclinical OCD was significantly prevalent in MOH patients with respect to other groups ( P  < .0002). Higher scores in Y-BOCS, as a measure of severity of obsessive-compulsive symptoms, were found in both MOH and CM compared with controls and EM.
Conclusions.— The excess of psychiatric comorbidity in patients with MOH can be related either to medication overuse or to chronification of headache. Among anxiety disorders, we observed a high rate of subclinical OCD. However, a direct link between compulsive behavior and medication overuse cannot be established yet. OCD in MOH might be underdiagnosed and undertreated.     

Enhanced functional connectivity between habenula and salience network in medication-overuse headache complicating chronic migraine positions it within the addiction disorders: an ICA-based resting-state fMRI study

BackgroundMedication-overuse headache (MOH) is a relatively frequently occurring secondary headache caused by overuse of analgesics and/or acute migraine medications. It is believed that MOH is associated with dependence behaviors and substance addiction, in which the salience network (SN) and the habenula may play an important role. This study aims to investigate the resting-state (RS) functional connectivity between the habenula and the SN in patients with MOH complicating chronic migraine (CM) compared with those with episodic migraine (EM) and healthy controls (HC).MethodsRS-fMRI and 3-dimensional T1-weighted images of 17 patients with MOH + CM, 18 patients with EM and 30 matched healthy HC were obtained. The RS-fMRI data were analyzed using the independent component analysis (ICA) method to investigate the group differences of functional connectivity between the habenula and the SN in three groups. Correlation analysis was performed thereafter with all clinical variables by Pearson correlation.ResultsIncreased functional connectivity between bilateral habenula and SN was detected in patients with MOH + CM compared with patients with EM and HC respectively. Correlation analysis showed significant correlation between medication overuse duration and habenula-SN connectivity in MOH + CM patients.ConclusionsThe current study supported MOH to be lying within a spectrum of dependence and addiction disorder. The enhanced functional connectivity of the habenula with SN may correlate to the development or chronification of MOH. Furthermore, the habenula may be an indicator or treatment target for MOH for its integrative role involved in multiple aspects of MOH.     

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.     

Central sensitization of the trigeminal and somatic nociceptive systems in medication overuse headache mainly involves cerebral supraspinal structures

Trigeminal and somatic nociceptive systems were studied in controls (n=15), episodic migraine (n=16), analgesics (n=14) and triptan-induced medication overuse headache (MOH) (n=15) before and after withdrawal. Patients with MOH and comorbid depressive symptoms and depression without headache were studied to investigate the influence of depression. Trigeminal nociception was studied by simultaneous registration of pain-related cortical potentials (PREP) and nociceptive blink reflex (nBR) following nociceptive-specific electrical stimulation of the forehead. Somatic nociception was evaluated using PREP of upper limbs. We found facilitation of both trigeminal and somatic PREP but not of nBR in MOH, which normalized after withdrawal. No differences were found comparing analgesics vs. triptan MOH. No differences were observed between controls and patients with episodic migraine and depression without headache. A transient facilitation was found of trigeminal and somatic nociceptive systems in MOH, which was more pronounced on a supraspinal level.     

Cyclical changes of cortical excitability and metaplasticity in migraine: Evidence from a repetitive transcranial magnetic stimulation study

The primary brain dysfunctions leading to the onset of a migraine attack remain largely unknown. Other important open questions concern the mechanisms of initiation, continuation, and termination of migraine pain, and the changes in brain function underlying migraine transformation. Brief trains of high-frequency repetitive transcranial magnetic stimulation (rTMS), when applied to the primary motor cortex at suprathreshold intensity (?120% of resting motor threshold [RMT]), elicit in healthy subjects a progressive, glutamate-dependent facilitation of the motor evoked potentials (MEP). Conversely, in conditions of increased cortical excitability, the rTMS trains induce inhibitory MEP responses likely mediated by cortical homeostatic mechanisms. We enrolled 66 migraine-without-aura patients, 48 migraine-with-aura patients, 14 patients affected by chronic migraine (CM), and 20 healthy controls. We assessed motor cortical response to 5-Hz rTMS trains of 10 stimuli given at 120% RMT. Patients with episodic migraine were studied in different phases of the migraine cycle: interictal, preictal, ictal, and postictal states. Results showed a facilitatory MEP response during the trains in patients evaluated in the preictal phase, whereas inhibitory responses were observed during and after a migraine attack, as well as in CM patients. In the interictal phase, different responses were observed, depending on attack frequency: facilitation in patients with low and inhibition in those with high attack recurrence. Our findings suggest that changes in cortical excitability and fluctuations in the threshold for inhibitory metaplasticity underlie the migraine attack recurrence, and could be involved in the process of migraine transformation.     

Medication overuse headache and chronic migraine in a specialized headache centre: field-testing proposed new appendix criteria

The classification subcommittee of the International Headache Society (IHS) has recently suggested revised criteria for medication overuse headache (MOH) and chronic migraine (CM). We field tested these revised criteria by applying them to the headache population at the Danish Headache Centre and compared the results with those using the current criteria. For CM we also tested two alternative criteria, one requiring > or = 4 migraine days/month and > or = 15 headache days/month, the second requiring > or = 15 headache days/month and > or = 50% migraine days. We included 969 patients with migraine or tension-type headache (TTH) among 1326 patients treated and dismissed in a 2-year period. Two hundred and eighty-five patients (30%) had TTH, 265 (27%) had migraine and 419 (43%) had mixed migraine and TTH. The current criteria for MOH classified 86 patients (9%) as MOH, 98 (10%) as probable MOH and 785 (81%) as not having MOH after a 2-month drug-free period. Using the appendix criteria, 284 patients (29%) were now classified as MOH, no patients as probable MOH and 685 (71%) as not having MOH. For CM only 16 patients (3%) fulfilled the current diagnostic criteria. This increased to 42 patients (7%) when we applied the appendix criteria. Using the less restrictive criteria of > or = 4 migraine days and > or = 15 headache days, 88 patients (14%) had CM, whereas the more restrictive criteria of > or = 15 headache days and > or = 50% migraine days resulted in 24 patients (4%) with CM. Our data suggest that the IHS has succeeded in choosing new criteria for CM which are neither too strict, nor too loose. For MOH, a shift to the appendix criteria will increase the number of MOH patients, but take into account the possibility of permanent changes in pain perception due to medication overuse and the possibility of a renewed effect of prophylactic drugs due to medication withdrawal. We therefore recommend the implementation of the appendix criteria for both MOH and CM into the main body of the International Classification of Headache Disorders.     

Activity in human V1 follows multisensory perception

When a single brief visual flash is accompanied by two auditory bleeps, it is frequently perceived incorrectly as two flashes. Such illusory multisensory perception is associated with increased activation of retinotopic human primary visual cortex (V1) suggesting that such activity reflects subjective perception [Watkins, S., Shams, L., Tanaka, S., Haynes, J.D., Rees, G., 2006. Sound alters activity in human V1 in association with illusory visual perception. Neuroimage. 31, 1247-1256]. However, an alternate possibility is that increased V1 activity reflects either fluctuating attention or auditory-visual perceptual matching on illusion trials. Here, we rule out these possibilities by studying the complementary illusion, where a double flash is accompanied by a single bleep and perceived incorrectly as a single flash. We replicate findings of increased activity in retinotopic V1 when a single flash is perceived incorrectly as two flashes, and now show that activity is decreased in retinotopic V1 when a double flash is perceived incorrectly as a single flash. Our findings provide strong support for the notion that human V1 activity reflects subjective perception in these multisensory illusions.     

Shortened cortical silent period in facial muscles of patients with migraine

Despite intensive neurophysiological research, evidence is lacking to show whether abnormal cortical excitability in migraine reflects a primary cortical disturbance or reduced control by thalamo-cortical loops. One way to contribute to the scientific discussion on this topic is to deliver transcranial magnetic stimulation (TMS) and test the cortical silent period (SP) recorded in facial muscles. The facial-muscle SP is a purely cortical phenomenon that reflects the excitability of inhibitory interneurons, and can disclose changes in cortical inhibition even in patients without documented primary lesions of the motor cortices. To test the interictal excitability of cortical motor inhibitory interneurons in migraine, we investigated the facial-SP in patients with migraine with and without aura between attacks. In 26 patients and 15 age-matched controls, high-intensity magnetic stimuli were delivered with a round coil centered at the vertex during a maximal muscle contraction. Electromyographic responses were recorded from surface electrodes placed over the subjects' perioral muscles. Facial SPs were significantly shorter in patients than in controls. The SP shortening provides neurophysiological evidence showing hypoexcitability of cortical inhibitory neurons in patients with migraine between attacks. Despite a possible primary deficit of cortical inhibitory interneurons in migraine, we favor the interpretation of a secondary disfacilitation by hypoactive thalamo-cortical loops. Based on this interpretation, the interictal reduced cortical inhibition documented by the shortened SP could be considered the motor counterpart of the reduced preactivation excitability level in the sensory cortices purported to explain why cortical evoked responses habituate poorly in patients with migraine.     

Low income and education levels may cause medication overuse and chronicity in migraine patients

BACKGROUND: Frequent analgesic drug intake, especially in migraine patients, may induce the risk of medication overuse headache (MOH). The various conditions that may affect the development and the features of MOH have not been determined yet. AIM: To compare MOH patients with migraine as pre-existing headache and episodic migraine patients according to socioeconomic and educational variables. METHODS: Forty-six MOH patients with migraine as pre-existing headache and 61 migraine patients were included into study. The headache characteristics, socioeconomic and educational variables of MOH and migraine groups and subgroups divided according to the education (low/high education subgroups), and income (low/high income subgroups) levels were evaluated. RESULTS: We found that mean duration of education was shorter in MOH patients than migraine patients. There was a negative correlation between duration of education and duration of MOH. The mean duration of MOH was longer and rate of low-income level was higher in patients with low-education level. The duration of education was lower in MOH patients with low income. The frequency of migraine attacks and low-income rate was also higher in low-educated migraine patients. The duration of education was shorter in migraine patients with low income. CONCLUSION: We report that migraineurs with low socioeconomic status may have risk of developing MOH. A better identification of patients at risk of drug-associated headache may contribute to improved health in a group of patients with MOH.     

Magnetic suppression of perceptual accuracy is not reduced in episodic migraine without aura

Background

Altered cortical excitability is thought to be part of migraine pathophysiology. Reduced magnetic suppression of perceptual accuracy (MSPA) has been found in episodic migraine with aura and in chronic migraine, and has been interpreted as reduced inhibition of the occipital cortex in these migraine subtypes. Results are less clear for episodic migraine without aura. In the present study we compared MSPA between 24 healthy controls and 22 interictally measured episodic migraine patients without aura. In addition, we investigated test-retest reliability in 33 subjects (24 controls, 9 migraine).

Findings

Visual accuracy was assessed by letter recognition and modulated by transcranial magnetic stimulation delivered to the occipital cortex at different intervals to the letter presentation (40, 100 and 190 ms). The results confirm suppression of visual accuracy at the 100 ms interval (p < 0.001), but there were no significant group differences (percentage of correctly recognized letters, control: 36.1 ± 36.2; migraine: 44.0 ± 32.3, p = 0.44). Controls and migraine patients were pooled for assessment of test-retest reliability (n = 33). Levels of suppression at 100 ms were similar at test (percentage of correctly recognized letters: 42.3 ± 32.6) and retest (41.9 ± 33.8, p = 0.90) and test-retest correlations were good (r = 0.82, p < 0.001).

Conclusions

The results demonstrate that occipital cortex inhibition as assessed with MSPA is not reduced in episodic migraine without aura. This suggests a larger role of occipital cortex excitability in episodic migraine with aura and in chronic migraine compared to episodic migraine without aura. Test-retest reliability of MSPA was good.     

Iron deposition in pain-regulatory nuclei in episodic migraine and chronic daily headache by MRI

Background.— Progression of migraine toward a more disabling chronic form of at least 15 days/month is linked with frequency of attacks. Magnetic resonance imaging (MRI) findings of iron accumulation in the brain, especially in periaqueductal gray and red nucleus, have been correlated with both duration of illness and frequency of attacks. Methods.— This study therefore evaluated iron deposition as measured with MRI in basal ganglia and pain regulatory nuclei in neurologically healthy control volunteers and in patients with various migraine subtypes: episodic migraine (n = 10) with (n = 4) or without aura (n = 6), and chronic daily headache (n = 11), including medication overuse headache (MOH, n = 8), chronic tension‐type headache (n = 1), and primary chronic migraine (n = 2). The goal was to assess differences in iron deposition among migraine subtypes and controls in the hopes of linking the by‐products of frequent attacks or long duration of illness with these changes. Results.— The study sought to evaluate the tradeoff between sensitivity and specificity in T2 imaging of patients with migraine, and found that only T2 imaging in the globus pallidus was able to distinguish between episodic and chronic migraine, suggesting that this technique may be the most appropriate to assess migraine frequency. Patients with MOH did not demonstrate T2′ shortening. Conclusions.— Because iron accumulation should cause shortening of both T2 and T2′, although the lack of significance in observed T2′ difference could be due to increased variance in T2′ the measurement, these results suggest that a mechanism other than increased iron deposition may play a role in the genesis or pathophysiology of MOH.     

Medication‐Overuse Headache and Personality: A Controlled Study by Means of the MMPI‐2

(Headache 2010;50:198‐209) Objective.— The main aim of this study involves comparing the personality profiles of patients with medication‐overuse headache (MOH) and episodic headaches, in order to elucidate the role of personality characteristics, according to one of the most widely used and validated personality assessment tool: Minnesota Multiphasic Personality Inventory (MMPI‐2). Background.— Many studies have assessed the personality of headache patients by means of MMPI‐2 only using clinical and content scales. In this study the supplementary scales were also used as they evaluate different aspects of personality, particularly broad personality characteristics, generalized emotional distress and behavioral dyscontrol. Methods.— We recruited 219 subjects (151 women and 68 men) who were grouped in the following categories: MOH group (n = 82); episodic headache group (n = 82; 58 migraine aura; 6 migraine with aura; 6 frequent episodic tension‐type headache; 12 migraine+infrequent episodic tension‐type headache) and 1 group of 55 healthy controls. MMPI‐2 was employed. Data were computed with one‐way anova and post hoc analyses. Results.— Medication‐overuse headache and episodic headache patients (EH) showed a very similar pattern, differentiating each other only in the Hypochondriasis (Hs) (P = .007; MOH: mean 14.18 [SD 5.53]; EH: mean 11.93 [SD 5.88] and Health Concerns [HEA]) (P = .005; MOH: mean 14.06 [SD 5.38]; EH: mean 11.81 [SD 5.59]) scales. Surprisingly, no differences were found between the 3 groups in the scales measuring dependence‐related behavior such as Addiction Potential Scale (Aps) and Addiction Admission Scale (Aas). MOH and episodic headache patients scored significantly higher in the so‐called neurotic scales Hs (P < .0001; MOH: mean 14.18 [SD 5.53]; EH: mean 11.93 [SD 5.88]; Controls: mean 5.91 [SD 3.57]), Depression (D) (P < .0001; MOH: mean 26.44 [SD 7.01]; EH: mean 26.09 [SD 5.85]; Controls: mean 21.47 [SD 4.90]), and Hysteria (Hy) (P < .0001; MOH: mean 27.33 [SD 5.51]; EH: mean 26.81 [SD 5.68]; Controls: mean 21.95 [3.85]) and in many other scales such as Paranoia (Pa), Psychasthenia (Pt), Schizophrenia (Sc) while they scored significantly lower on Ego Strength (Es) and Dominance (Do) scales when compared with controls. Conclusions.— Patients with MOH and episodic headache showed very similar patterns, differentiating only in the Hypochondriasis and Health Concerns scales. Surprisingly, there were no significant differences in the scores of the scales measuring dependence‐related behavior. The clinical role of MMPI‐2 in discriminating MOH patients with dependency from drugs is discussed, in order to implement a complete tests' battery for headache patients' assessment.     

Salivary cortisol, dehydroepiandrosteronesulphate (DHEA–S) and testosterone in women with chronic migraine

Hypothalamus–pituitaryadrenal (HPA) axis activity was monitored in 20 women with chronic migraine (CM), previously affected by medication overuse headache (MOH), in comparison to healthy women (20 subjects) by measuring salivary cortisol, testosterone, dehydroepiandrosterone–sulphate (DHEA–S) levels, and their ratios, one week after the end of the MOH rehabilitation procedure. The participants were instructed how to collect saliva samples at home, a procedure that was performed twice a day (08:00 a.m. and 8:00 p.m.). Morning and evening levels of cortisol were significantly increased in CM patients with respect to controls. With regard to the cortisol/DHEA–S ratio, an inverse marker of psycho–physical wellbeing, CM women showed significantly higher values than controls. Moreover, testosterone/cortisol ratios (anabolic/catabolic index of physical performance) were significantly lower in CM patients than in controls. In the present study, CM appears not to be associated with an impairment of cortisol and DHEAS circadian fluctuation; however, CM patients present alterations in HPA axis function that might contribute to metabolic and psychological alterations that have also been associated with CM.     

Chronic migraine plus medication overuse headache: two entities or not?

Chronic migraine (CM) represents migraine natural evolution from its episodic form. It is realized through a chronicization phase that may require months or years and varies from patient to patient. The transition to more frequent attacks pattern is influenced by lifestyle, life events, comorbid conditions and personal genetic terrain, and it often leads to acute drugs overuse. Medication overuse headache (MOH) may complicate every type of headache and all the drugs employed for headache treatment can cause MOH. The first step in the management of CM complicated by medication overuse must be the withdrawal of the overused drugs and a detoxification treatment. The goal is not only to detoxify the patient and stop the chronic headache but also to improve responsiveness to acute or prophylactic drugs. Different methods have been suggested: gradual or abrupt withdrawal; home treatment, hospitalization, or a day-hospital setting; re-prophylaxes performed immediately or at the end of the wash-out period. Up to now, only topiramate and local injection of onabotulinumtoxinA have shown efficacy as therapeutic agents for re-prophylaxis after detoxification in patients with CM with and without medication overuse. Although the two treatments showed similar efficacy, onabotulinumtoxinA is associated with a better adverse events profile. Recently, the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program proved that patients with CM, even those with MOH, are the ones most likely to benefit from onabotulinumtoxinA treatment. Furthermore, it provided an injection paradigm that can be used as a guide for a correct administration of onabotulinumtoxinA.     

Assessment of peripheral biomarkers potentially involved in episodic and chronic migraine: a case-control study with a focus on NGF,BDNF, VEGF,and PGE2

BackgroundSeveral inflammatory and vascular molecules, and neurotrophins have been suggested to have a possible role in the development of migraine. However, pathophysiological events leading to migraine onset and transformation of episodic migraine (EM) to chronic migraine (CM) are not fully understood. Thus, we aimed to assess peripheral levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and prostaglandin E2 (PGE2) in EM and CM patients, and controls.MethodsFrom September 2017 to June 2020, 89 subjects were enrolled in a case-control study; 23 and 36 EM and CM patients, respectively, and 30 age and sex-matched controls. Demographic data and medical history were obtained from all patients. Headache characteristics were recorded at baseline visit and ensuing 30 days for persons with migraine disease. Serum levels of NGF, BDNF, VEGF, and PGE2 were measured once for controls and EM and CM patients, and adjusted for age, sex, and body mass index.ResultsSerum levels of NGF were significantly lower in EM patients compared to controls and CM patients (P-value=0.003 and 0.042, respectively). Serum levels of BDNF were significantly lower in EM and CM patients as opposed to controls (P-value<0.001), but comparable between EM and CM patients (P-value=0.715). Peripheral blood levels of VEGF were significantly higher in EM and CM patients as opposed to controls (P-value<0.001), but not different between EM and CM patients (P-value=0.859). Serum levels of PGE2 were significantly lower in EM patients compared to controls (P-value=0.011), however similar between EM and CM patients (P-value=0.086). In migraine patients, serum levels of NGF and PGE2 positively correlated with headache frequency (NGF: ρ = 0.476 and P-value<0.001; PGE2: ρ = 0.286 and P-value=0.028), while corresponding levels of BDNF and VEGF did not correlate with headache frequency (BDNF: ρ = 0.037 and P-value=0.778; VEGF: ρ= -0.025 and P-value=0.850).ConclusionsOur findings suggest that NGF, BDNF, PGE2, and VEGF may play a significant role in migraine pathogenesis and/or chronification, and therefore might bear potential value for novel targeted abortive and prophylactic migraine therapy. Further prospective cohort studies with larger sample sizes can more robustly evaluate the implications of these findings.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01377-6.     

Eptinezumab improved patient-reported outcomes in patients with migraine and medication-overuse headache: Subgroup analysis of the randomized PROMISE-2 trial

Objective

To evaluate the effect of eptinezumab on patient-reported outcomes in patients with chronic migraine (CM) and medication-overuse headache (MOH).

Background

MOH is a secondary headache disorder commonly occurring in patients with CM and associated with functional and psychological impairments. Medication overuse and monthly headache and migraine days were reduced with eptinezumab compared with placebo as published previously; however, these outcomes do not fully capture the burden of migraine and treatment effect.

Methods

PROMISE-2 was a phase 3, randomized, double-blind, placebo-controlled trial in adults with CM. Patients were randomized (1:1:1) to receive eptinezumab 100 mg, eptinezumab 300 mg, or placebo (up to 2 doses, 12 weeks apart). Patients completed the following patient-reported outcomes: 6-item Headache Impact Test (HIT-6), Patient Global Impression of Change (PGIC), patient-identified most bothersome symptom (PI-MBS), and 36-item Short-Form Health Survey (SF-36).

Results

A total of 431 CM patients (139, 147, and 145 patients in the eptinezumab 100 mg, eptinezumab 300 mg, and placebo groups, respectively) had MOH diagnosed at screening (40.2% of the total PROMISE-2 population [n = 1072]). In CM with MOH patients, both doses of eptinezumab were associated with clinically meaningful improvements in mean HIT-6 total scores by week 4 and remained improved throughout the 24-week study. Responder rates for individual HIT-6 items were greater with eptinezumab than with placebo at all time points. At week 12, almost twice as many eptinezumab-treated patients indicated the PGIC was “much” or “very much” improved (58.5% [79/135, 100 mg] and 67.4% [95/147, 300 mg] vs. 35.8% [48/134, placebo]). Patients in the eptinezumab groups showed numerically greater improvements over placebo in the PI-MBS and SF-36 scores.

Conclusions

This subgroup analysis in patients with CM/MOH at baseline suggests that eptinezumab treatment is associated with early, sustained, and clinically meaningful improvements in patient-reported outcomes.     

Sound alters activity in human V1 in association with illusory visual perception

When a single brief visual flash is accompanied by two auditory bleeps, it is frequently perceived incorrectly as two flashes. Here, we used high field functional MRI in humans to examine the neural basis of this multisensory perceptual illusion. We show that activity in retinotopic visual cortex is increased by the presence of concurrent auditory stimulation, irrespective of any illusory perception. However, when concurrent auditory stimulation gave rise to illusory visual perception, activity in V1 was enhanced, despite auditory and visual stimulation being unchanged. These findings confirm that responses in human V1 can be altered by sound and show that they reflect subjective perception rather than the physically present visual stimulus. Moreover, as the right superior temporal sulcus and superior colliculus were also activated by illusory visual perception, together with V1, they provide a potential neural substrate for the generation of this multisensory illusion.     

Analysis of leukocytes in medication-overuse headache, chronic migraine, and episodic migraine

(Headache 2011;51:1228‐1238) Objective.— To evaluate the number of immune cells in the peripheral blood of medication‐overuse headache (MOH), chronic migraine (CM), and migraine without aura (MWA) patients, as well as from controls. Background.— Migraine has been linked to immunologic disturbances, but the role of the immune system in chronic forms of headache that evolve from migraine has not been studied. Psychiatric co‐morbidity has been related to both headache chronification and immunologic alterations. Methods.— This cross‐sectional study comprised 68 subjects divided in 4 groups: MOH, CM, MWA, control. Subjects were gender‐matched, had no physical co‐morbidity, and were taking only acetaminophen. Clinical and psychological data were recorded in a standardized protocol. Samples of peripheral blood for hematological analysis were obtained in the morning during the ictal (MOH, CM, and MWA groups) and interictal periods (MWA group), as well from control group. Results.— A higher lymphocyte count was measured in MOH patients relative to the MWA patients (mean ± standard deviation: 2448.7/mm³ ± 775.8 vs 1859.7/mm³ ± 564.7; P = .027). The numbers of blood lymphocytes for CM and control subjects were 2086.1/mm³ ± 540.5 and 1961.7/mm³ ± 385.6, respectively. Multiple linear regression analysis demonstrated that only MOH and MWA groups remained associated with lymphocyte count (B = 540.7; CI 95%: 55.2‐1026.1; P = .03; R² = 19.2%). Analysis for linearity of variables in the spectrum control/MWA/CM/MOH resulted positive for body mass index (from 23.5 ± 3.25 in controls to 26.5 ± 4.49 in MOH patients; P = .034), scores on Beck Depression Inventory (from 3.29 ± 3.05 to 14.65 ± 11.21; P < 0.001) and Hamilton Anxiety Scale (from 4.29 ± 3.93 to 23.24 ± 11.01; P < 0.001), hemoglobin (from 13.7 ± 0.79 to 14.6 ± 1.31; P = .022), and lymphocyte count (from 1961.7 ± 385.6 to 2448.7 ± 775.8; P = .01), but negative for CD8+ T lymphocytes (from 34.0 ± 8.82 to 30.0 ± 6.64; P = .046). Conclusions.— A higher lymphocyte count in the MOH group relative to the MWA group may indicate a chronic inflammatory state. Several clinical and laboratorial characteristics have a range along a spectrum extending from healthy subjects to patients suffering from chronic forms of migraine.