Effect of CGRP inhibitors on interictal cerebral hemodynamics in individuals with migraine.

Introduction: Calcitonin gene-related peptide (CGRP) plays an important role in cerebral vasodilation, so here we aim to quantify the impact of CGRP monoclonal antibody (mAb) therapy on cerebral hemodynamics. Methods: In 23 patients with chronic and episodic migraine, cerebral hemodynamic monitoring was performed (1) prior to and (2) 3-months into CGRP-mAb therapy. Transcranial Doppler monitored cerebral blood flow velocity (CBFv) in the middle cerebral artery (MCA) and posterior cerebral artery (PCA), from which cerebrovascular reactivity (CVR) and cerebral autoregulation (CA; Mx-index) were calculated. Results: CA was similar off and on treatment, in the MCA (p = 0.42) and PCA (p = 0.72). CVR was also unaffected by treatment, in the MCA (p = 0.38) and PCA (p = 0.92). CBFv and blood pressure were also unaffected. The subgroup of clinical responders (>50% reduction in migraine frequency) exhibited a small reduction in MCA-CBFv (6.0 cm/s; IQR: 1.1-12.4; p = 0.007) and PCA-CBFv (8.9 cm/s; IQR: 6.9-10.3; p = 0.04). Discussion: Dynamic measures of cerebrovascular physiology were preserved after 3 months of CGRP-mAb therapy, but a small reduction in CBFv was observed in patients who responded to treatment. Subgroup findings should be interpreted cautiously, but further investigation may clarify if CBFv is dependent on the degree of CGRP inhibition or may serve as a biomarker of drug sensitivity.

A measure of the blink reflex to parametric variation of mechanical stimulation of the trigeminal nerve.

The primary goal of this study was to develop a parametric model that relates variation in stimulation of the trigeminal nerve to properties of the blink response. We measured blink responses in 17 healthy, adult participants to air puffs directed at the lateral canthus of the eye at five different, log-spaced intensities (3.5-60 PSI). Lid position over time was decomposed into amplitude and velocity components. We found that blink amplitude was systematically related to log stimulus intensity, with the relationship well described by a sigmoidal function. The parameters of the model fit correspond to the slope of the function and the stimulus intensity required to produce half of a maximal blink response (the half-response threshold). There was a reliable increase in the half-response threshold for the contralateral as compared to the ipsilateral blink response. This increase was consistent across participants despite substantial individual differences in the half-response threshold and slope parameters of the overall sensitivity function, suggesting that the laterality effect arises in the neural circuit subsequent to individual differences in sensitivity. Overall, we find that graded mechanical stimulation of the somatosensory trigeminal afferents elicits a graded response that is well described by a simple parametric model. We discuss the application of parametric measurements of the blink response to the detection of group differences in trigeminal sensitivity.

Role of Calcitonin Gene-Related Peptide on the Gastrointestinal Symptoms of Migraine-Clinical Considerations: A Narrative Review.

Calcitonin gene-related peptide (CGRP) is involved in several of the pathophysiological processes underpinning migraine attacks. Therapies that target CGRP or its receptor have shown efficacy as preventive or acute treatments for migraine. Two small-molecule CGRP receptor antagonists (rimegepant and ubrogepant) are approved for the acute treatment of migraine, and four monoclonal antibodies (eptinezumab, erenumab, fremanezumab, and galcanezumab) are approved for migraine prevention; erenumab targets the canonical CGRP receptor, the others CGRP ligand. CGRP plays a role in gastrointestinal nociception, inflammation, gastric acid secretion, and motility. Nausea and vomiting are among the gastrointestinal symptoms associated with migraine, but individuals with migraine may also experience functional upper and lower gastrointestinal comorbidities, such as gastroesophageal reflux disease, gastroparesis, functional diarrhea or constipation, and irritable bowel syndrome. Although gastrointestinal symptoms in migraine can be treatment-related, they may also be attributable to increased CGRP. In this review, we summarize the epidemiological evidence for associations between migraine and gastrointestinal disorders, consider the possible physiological role of CGRP in these associations, and review the clinical occurrence of gastrointestinal events in patients with migraine receiving CGRP-based therapies and other migraine treatments. Because patients with migraine are at an increased risk of comorbid and treatment-related gastrointestinal effects, we also propose a patient-management strategy to mitigate these effects.

Gender Minority Stress, Psychiatric Comorbidities, and the Experience of Migraine in Transgender and Gender-Diverse Individuals: a Narrative Review.

PURPOSE OF REVIEW: This review aims to discuss the experience of migraine in transgender and gender-diverse individuals as it relates to other psychiatric comorbidities such as anxiety, depression, PTSD, and others. As this population faces stigma and discrimination, literature posits that gender minority stress can also contribute to the experience of pain in these individuals. RECENT FINDINGS: Though there is little explicit data on these topics, more recent studies have explored the concept of gender minority stress and how stigma and discrimination can affect health outcomes and overall perception of health. These findings, as well as data on psychiatric comorbidities in cisgender individuals with migraine, can be extrapolated to understand how gender minority individuals may experience migraine. Research has demonstrated that stigma and discrimination can affect health outcomes in the transgender and gender-diverse community. A recent study has shown that sexual minority stress associated with stigma, discrimination, and barriers to care can exacerbate migraine. It is known that psychiatric comorbidities such as anxiety, depression, and PTSD can affect migraine frequency and severity in cisgender individuals. Though there are no specific studies in the transgender and gender-diverse patient population, these highly prevalent mental health conditions could potentially contribute to their migraine experience. Hormones, as well, may affect mood in those on gender-affirming hormone therapy, with some studies exploring how this may have both a direct and indirect relationship with migraine. There are clear knowledge gaps that can be addressed by future research in these areas to better understand the migraine experience in transgender and gender-diverse individuals and improve overall care.

Reflexive Eye Closure in Response to Cone and Melanopsin Stimulation: A Study of Implicit Measures of Light Sensitivity in Migraine.

BACKGROUND AND OBJECTIVES: To quantify interictal photophobia in migraine with and without aura using reflexive eye closure as an implicit measure of light sensitivity and to assess the contribution of melanopsin and cone signals to these responses. METHODS: Participants were screened to meet criteria for 1 of 3 groups: headache-free (HF) controls, migraine without aura (MO), and migraine with visual aura (MA). MO and MA participants were included if they endorsed ictal and interictal photophobia. Exclusion criteria included impaired vision, inability to collect usable pupillometry, and history of either head trauma or seizure. Participants viewed light pulses that selectively targeted melanopsin, the cones, or their combination during recording of orbicularis oculi EMG (OO-EMG) and blinking activity. RESULTS: We studied 20 participants in each group. MA and MO groups reported increased visual discomfort to light stimuli (discomfort rating, 400% contrast, MA: 4.84 [95% confidence interval 0.33, 9.35]; MO: 5.23 [0.96, 9.50]) as compared to HF controls (2.71 [0, 6.47]). Time course analysis of OO-EMG and blinking activity demonstrated that reflexive eye closure was tightly coupled to the light pulses. The MA group had greater OO-EMG and blinking activity in response to these stimuli (EMG activity, 400% contrast: 42.9%Δ [28.4, 57.4]; blink activity, 400% contrast: 11.2% [8.8, 13.6]) as compared to the MO (EMG activity, 400% contrast: 9.9%Δ [5.8, 14.0]; blink activity, 400% contrast: 4.7% [3.5, 5.9]) and HF control (EMG activity, 400% contrast: 13.2%Δ [7.1, 19.3]; blink activity, 400% contrast: 4.5% [3.1, 5.9]) groups. DISCUSSION: Our findings suggest that the intrinsically photosensitive retinal ganglion cells (ipRGCs), which integrate melanopsin and cone signals, provide the afferent input for light-induced reflexive eye closure in a photophobic state. Moreover, we find a dissociation between implicit and explicit measures of interictal photophobia depending on a history of visual aura in migraine. This implies distinct pathophysiology in forms of migraine, interacting with separate neural pathways by which the amplification of ipRGC signals elicits implicit and explicit signs of visual discomfort.

Headache in transgender and gender-diverse patients: A narrative review.

OBJECTIVE: To summarize the unique aspects of managing headache in gender minorities and current research in this area including the potential relationship between gender-affirming hormone therapy (GAHT) and headache. BACKGROUND: The study of headache in gender minorities is intrinsically important. Gender minorities are medically underserved, and their medical care to date has been limited by socioeconomic disadvantages including stigma and an unsupportive clinical environment. Despite the rising population of transgender and gender-diverse adults and youth, headache research has also been limited. Knowledge of hormonal effects on headache in cisgender patients raises the question of possible effects of GAHT on transgender patients. METHODS/RESULTS: The manuscript is a narrative review of current best practices in treating transgender patients, including the use of appropriate terminology and ways to create a supportive environment. It also contains current guidelines on GAHT and reviews drug-drug interactions and secondary headache related to hormone therapy. We also review transgender headache research and related research on hormonal effects on headache in cisgender individuals. CONCLUSION: Creating a supportive environment for transgender and gender-diverse patients and being knowledgeable about GAHT are key to providing quality headache care. This review identifies further research needs for this population including the epidemiology of headache disorders in sexual minorities and the potential effects of GAHT on headache disorders in transgender patients.

Selective amplification of ipRGC signals accounts for interictal photophobia in migraine.

Second only to headache, photophobia is the most debilitating symptom reported by people with migraine. While the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to play a role, how cone and melanopsin signals are integrated in this pathway to produce visual discomfort is poorly understood. We studied 60 people: 20 without headache and 20 each with interictal photophobia from migraine with or without visual aura. Participants viewed pulses of spectral change that selectively targeted melanopsin, the cones, or both and rated the degree of visual discomfort produced by these stimuli while we recorded pupil responses. We examined the data within a model that describes how cone and melanopsin signals are weighted and combined at the level of the retina and how this combined signal is transformed into a rating of discomfort or pupil response. Our results indicate that people with migraine do not differ from headache-free controls in the manner in which melanopsin and cone signals are combined. Instead, people with migraine demonstrate an enhanced response to integrated ipRGC signals for discomfort. This effect of migraine is selective for ratings of visual discomfort, in that an enhancement of pupil responses was not seen in the migraine group, nor were group differences found in surveys of other behaviors putatively linked to ipRGC function (chronotype, seasonal sensitivity, presence of a photic sneeze reflex). By revealing a dissociation in the amplification of discomfort vs. pupil response, our findings suggest a postretinal alteration in processing of ipRGC signals for photophobia in migraine.

A web-based, branching logic questionnaire for the automated classification of migraine.

OBJECTIVE: To identify migraineurs and headache-free individuals with an online questionnaire and automated analysis algorithm. METHODS: We created a branching-logic, web-based questionnaire - the Penn Online Evaluation of Migraine - to obtain standardized headache history from a previously studied cohort. Responses were analyzed with an automated algorithm to assign subjects to one of several categories based on ICHD-3 (beta) criteria. Following a pre-registered protocol, the primary outcome was sensitivity and specificity for assignment of headache-free, migraine without aura, and migraine with aura labels, as compared to a prior classification by neurologist interview. RESULTS: Of 118 subjects contacted, 90 (76%) completed the questionnaire; of these 31 were headache-free controls, 29 migraine without aura, and 30 migraine with aura. Mean age was 41 ± 6 years and 76% were female. There were no significant demographic differences between groups. The median time to complete the questionnaire was 2.5 minutes (IQR: 1.5-3.4 minutes). Sensitivity of the Penn Online Evaluation of Migraine tool was 42%, 59%, 70%, and 83%, and specificity was 100%, 84%, 93%, and 90% for headache-free controls, migraine without aura, migraine with aura, and migraine overall, respectively. CONCLUSIONS: The Penn Online Evaluation of Migraine web-based questionnaire, and associated analysis routine, identifies headache-free and migraine subjects with good specificity. It may be useful for classifying subjects for large-scale research studies. Research study pre-registration: https://osf.io/sq9ef The following research study is a not a clinical trial.

Lyme myelopathy: Case report and literature review of a rare but treatable disorder.

The differential diagnosis for transverse myelitis is extensive, and the prognosis is highly variable depending on the etiology. We describe a rare case of a 56-year-old previously healthy male who presented with thoracic paresthesias and hyperesthesias involving the T6-11 dermatomes several weeks after a febrile illness. A thoracic MRI demonstrated a T7-10 transverse myelitis, and an exhaustive evaluation revealed neuroborreliosis. His symptoms improved significantly after an initial steroid course and 21 day course of ceftriaxone. We review neuroborreliosis and summarize the features of 23 previously reported cases of Lyme myelopathy. Although Lyme myelopathy is rare, including Lyme in the differential diagnosis of an acute transverse myelitis work up is important in endemic regions, as it is a potentially reversible disorder with a generally good prognosis when appropriately treated with antibiotics.

Sociodemographic Factors Associated With Hospital Care for Pediatric Migraine: A National Study Using the Kids' Inpatient Dataset.

BACKGROUND: Although migraine often starts in childhood or adolescence, hospital care for migraine in children is not well described. We examined patient and hospital characteristics associated with hospital care for migraine among children in the United States. METHODS: We queried the Kids' Inpatient Database (2003 to 2009) for hospitalizations of children aged 3-20. Sociodemographic and hospital characteristics were compared between hospitalizations for migraine and for other common medical conditions. Multivariate logistic regression models estimated the associations between patient, hospital, and socioeconomic characteristics and inpatient migraine care. RESULTS: We identified 11,696 pediatric migraine hospitalizations, the majority (68.7%) occurring at teaching hospitals, involving a female (68.8%) child, ages 13-20 (71%, mean age: 14.6 years). As compared to the overall inpatient sample, migraine hospitalizations were less likely to involve children who were Black (adjusted odds ratio [AOR] 0.54, 95% confidence interval [CI] 0.49 to 0.60), Hispanic (AOR = 0.58, 95% CI 0.50 to 0.68), or Asian (AOR = 0.42, 95% CI 0.32 to 0.55), and more likely to involve females (AOR = 1.49, 95% CI 1.40 to 1.59). Migraine inpatients were more likely to live in higher income postal ZIP code areas (versus lowest ZIP code income quartile: AOR = 1.32, 95% CI 1.18 to 1.48). The average length of stay for migraine was 2.54 (SEM 0.6) days. CONCLUSIONS: Children who are hospitalized for migraines have distinct sociodemographic characteristics and a short length of stay. Understanding the reasons for these variations will inform the design of interventions aimed at reducing the need for pediatric migraine hospitalization.

CGRP Monoclonal Antibodies for Migraine: Rationale and Progress.

Calcitonin gene-related peptide (CGRP), a neuropeptide abundant in the trigeminal system and widely expressed in both the peripheral and central nervous systems, has recently emerged as a promising target for migraine management. While known as a potent arterial vasodilator, the role of CGRP in migraine is likely mediated by modulating nociception and sustaining neurogenic inflammation that leads to further peripheral and central pain sensitization. Functional blockade of CGRP, which involves either CGRP receptor antagonists or monoclonal antibodies (mAbs) to CGRP or its receptor, has recently shown clinical efficacy in migraine management. The site of action, although still being studied, is likely in nervous system structures outside the blood-brain barrier. To date, four CGRP function-blocking mAbs (three target CGRP and one targets the CGRP receptor) are under clinical investigation for migraine prophylaxis. Phase II and III studies were promising with favorable safety profiles. CGRP function-blocking mAbs may potentially revolutionize the management of migraine. This review discusses in depth the fundamental role of CGRP in migraine pathogenesis as well as the clinical efficacy of CGRP function-blocking mAbs.

Induction of Migraine-Like Photophobic Behavior in Mice by Both Peripheral and Central CGRP Mechanisms.

The neuropeptide calcitonin gene-related peptide (CGRP) is a key player in migraine. Although migraine can be treated using CGRP antagonists that act peripherally, the relevant sites of CGRP action remain unknown. To address the role of CGRP both within and outside the CNS, we used CGRP-induced light-aversive behavior in mice as a measure of migraine-associated photophobia. Peripheral (intraperitoneal) injection of CGRP resulted in light-aversive behavior in wild-type CD1 mice similar to aversion seen previously after central (intracerebroventricular) injection. The phenotype was also observed in C57BL/6J mice, although to a lesser degree and with more variability. After intraperitoneal CGRP, motility was decreased in the dark only, similar to motility changes after intracerebroventricular CGRP. In addition, as with intracerebroventricular CGRP, there was no general increase in anxiety as measured in an open-field assay after intraperitoneal CGRP. Importantly, two clinically effective migraine drugs, the 5-HT1B/D agonist sumatriptan and a CGRP-blocking monoclonal antibody, attenuated the peripheral CGRP-induced light aversion and motility behaviors. To begin to address the mechanism of peripheral CGRP action, we used transgenic CGRP-sensitized mice that have elevated levels of the CGRP receptor hRAMP1 subunit in nervous tissue (nestin/hRAMP1). Surprisingly, sensitivity to low light was not seen after intraperitoneal CGRP injection, but was seen after intracerebroventricular CGRP injection. These results suggest that CGRP can act in both the periphery and the brain by distinct mechanisms and that CGRP actions may be transmitted to the CNS via indirect sensitization of peripheral nerves. SIGNIFICANCE STATEMENT: The neuropeptide calcitonin gene-related peptide (CGRP) is a central player in migraine pathogenesis, yet its site(s) of action remains unknown. Some preclinical studies have pointed to central sites in the brain and brainstem. However, a peripheral site of action is indicated by the ability of intravenous CGRP to trigger migraine in humans and the efficacy of CGRP receptor antagonists that evidently do no penetrate the CNS in effective amounts. Resolving this issue is particularly important given recent clinical trials showing that anti-CGRP monoclonal antibodies can reduce and even prevent migraine attacks. In this study, we report that CGRP can act in both the brain and the periphery of the mouse to cause migraine-like photophobia by apparently distinct mechanisms.

Anti-CGRP antibodies block CGRP-induced diarrhea in mice.

The multifunctional neuropeptide calcitonin gene-related peptide (CGRP) and its receptor are expressed throughout the gastrointestinal tract. Previous studies have shown that CGRP has roles in intestinal motility, water secretion, and inflammation. Furthermore, animal studies have demonstrated CGRP involvement in diarrhea secondary to C. difficile and food allergies. Diarrhea thus provides a convenient bioassay of CGRP activity in the GI system. In this proof of principle study, we report that prophylactic administration of an anti-CGRP antibody is able to block CGRP-induced diarrhea in mice. As a control, the CGRP-receptor antagonist olcegepant also attenuated the diarrhea response to CGRP. This preclinical study indicates that anti-CGRP antibodies may provide a new preventative therapy for gastrointestinal disorders involving CGRP.

CGRP and migraine: could PACAP play a role too?

Migraine is a debilitating neurological disorder that affects about 12% of the population. In the past decade, the role of the neuropeptide calcitonin gene-related peptide (CGRP) in migraine has been firmly established by clinical studies. CGRP administration can trigger migraines, and CGRP receptor antagonists ameliorate migraine. In this review, we will describe multifunctional activities of CGRP that could potentially contribute to migraine. These include roles in light aversion, neurogenic inflammation, peripheral and central sensitization of nociceptive pathways, cortical spreading depression, and regulation of nitric oxide production. Yet clearly there will be many other contributing genes that could act in concert with CGRP. One candidate is pituitary adenylate cyclase-activating peptide (PACAP), which shares some of the same actions as CGRP, including the ability to induce migraine in migraineurs and light aversive behavior in rodents. Interestingly, both CGRP and PACAP act on receptors that share an accessory subunit called receptor activity modifying protein-1 (RAMP1). Thus, comparisons between the actions of these two migraine-inducing neuropeptides, CGRP and PACAP, may provide new insights into migraine pathophysiology.

Modulation of CGRP-induced light aversion in wild-type mice by a 5-HT(1B/D) agonist.

The neuropeptide calcitonin gene-related peptide (CGRP) plays a critical role in the pathophysiology of migraine. We have focused on the role of CGRP in photophobia, which is a common migraine symptom. We previously used an operant-based assay to show that CGRP-sensitized transgenic (nestin/hRAMP1), but not control, mice exhibited light aversion in response to an intracerebroventricular CGRP injection. A key question was whether the transgenic phenotype was due to overexpression of the CGRP receptor at endogenous or novel expression sites. We reasoned that if endogenous receptor sites were sufficient for light-aversive behavior, then wild-type mice should also show the phenotype when given a sufficiently strong stimulus. In this study, we report that mice with normal levels of endogenous CGRP receptors demonstrate light avoidance following CGRP administration. This phenotype required the combination of two factors: higher light intensity and habituation to the testing chamber. Control tests confirmed that light aversion was dependent on coincident exposure to CGRP and light and cannot be fully explained by increased anxiety. Furthermore, CGRP reduced locomotion only in the dark, not in the light. Coadministration of rizatriptan, a 5-HT(1B/D) agonist anti-migraine drug, attenuated the effects of exogenous CGRP on light aversion and motility. This suggests that triptans can act by mechanisms that are distinct from inhibition of CGRP release. Thus, we demonstrate that activation of endogenous CGRP receptors is sufficient to elicit light aversion in mice, which can be modulated by a drug commonly used to treat migraine.

Induction of multiple photophobic behaviors in a transgenic mouse sensitized to CGRP.

Migraine is a complex neurological disorder with a significant impact on patients and society. Clinical and preclinical studies have established the neuropeptide calcitonin gene-related peptide (CGRP) as a key player in migraine and other neurovascular headaches. To study the role of CGRP in these disorders, we have characterized the photophobic phenotype of nestin/hRAMP1 mice, a transgenic model with genetically engineered increased sensitivity to CGRP. These mice have increased nervous system expression of a regulatory subunit of the CGRP receptor, human receptor activity-modifying receptor (hRAMP1). We have previously demonstrated that nestin/hRAMP1 mice display a light-aversive behavior that is greatly enhanced by CGRP and blocked by a CGRP receptor antagonist used to treat migraine. Here we have compared their behavior in two different experimental setups with testing chambers of different sizes and light intensities as well as in complete darkness. We demonstrated similar degrees of light aversion in nestin/hRAMP1 mice with 1000 and 50 lux. To control for other possible factors driving nestin/hRAMP1 mice to the dark zone, we tested them in the absence of any light, and they showed identical behavior as littermates. Furthermore, both nestin/hRAMP1 and control mice have decreased motility in response to CGRP in the dark, but not the light side of the chamber. Our findings confirm the robust CGRP-induced light-aversive phenotype of nestin/hRAMP1 mice, which can be a surrogate of photophobia, and validates its usefulness as a model of migraine and other disorders associated with photophobia.

A Potential Preclinical Migraine Model: CGRP-Sensitized Mice.

The neuropeptide calcitonin gene-related peptide (CGRP) plays a key role in migraine. However, a major challenge for studying CGRP actions is the lack of animal models for migraine. Clinical studies suggested that migraineurs are more sensitive to CGRP than people who do not suffer from migraine. We therefore generated a transgenic mouse that is sensitized to CGRP (nestin/hRAMP1 mice). The mice have elevated expression of a subunit of the CGRP receptor, human receptor activity-modifying protein 1 (hRAMP1). Nestin/hRAMP1 mice have two symptoms of migraine: photophobia and mechanical allodynia. The light aversion was greatly enhanced by intracerebroventricular administration of CGRP. CGRP had little effect on motility in the light zone, but once in the dark, the mice moved less than controls. The CGRP-induced light aversion was attenuated by co-administration of the CGRP receptor antagonist olcegepant. These findings suggest that CGRP acts as a neuromodulator to increase sensory responses and that regulation of a single gene, hRAMP1, could potentially contribute to migraine susceptibility.