The Migrainous Brain: What You See Is Not All You Get?

Goadsby discusses a new study published inPLoS Medicine of the visual motion-processing network in migraine

N-Methyl-d-aspartate receptor open-channel blockers memantine and magnesium modulate nociceptive trigeminovascular neurotransmission in rats

Experimental and clinical studies suggest that the low-affinity N-methyl-D-aspartate (NMDA) receptor open-channel blockers Mg(2+) and memantine are effective in reducing trigeminal nociceptive activation. The aim of the present study was to investigate the apparent effectiveness of these channel blockers using a model of trigeminal activation in vivo. Rats were anesthetized before electrically stimulating the dura mater adjacent the middle meningeal artery. Neurons responding to stimulation were recorded extracellularly using electrophysiological methods while L-glutamate or NMDA and Mg(2+), memantine, or sodium controls were applied locally using microiontophoresis. Microiontophoretic application of Mg(2+) or memantine into the trigeminocervical complex inhibited mechanically and electrically-stimulated craniovascular afferent, L-glutamate, or NMDA-evoked neuronal activity at the second order trigeminal synapse of craniovascular afferents. By contrast, intravenous administration of MgSO4 (100 mg/kg) or memantine (10 mg/kg) did not significantly affect electrically-stimulated afferent-evoked activity within the trigeminocervical complex. The Mg(2+) and memantine concentrations achieved after systemic administration may not effectively inhibit activation of the trigeminocervical complex, perhaps providing an explanation for the relatively poor efficacy of these NMDA receptor open-channel blockers for headache treatment in clinical studies. Nevertheless, the present results suggest blocking of NMDA-receptor open channels inhibits nociceptive activation of the trigeminocervical complex. Further exploration of such channel blockers as a therapeutic strategy for primary head pain is warranted

Revisiting dose-finding of monoclonal antibodies in migraine

Migraine is a debilitating disorder, and while the introduction of monoclonal antibodies (mAbs) has led to efficacious and tolerable responses, a substantial number of patients are so-called “non-responders”. We introduce reasons for this insufficient response, including insufficient blockade of Calcitonin Gene-Related Peptide (CGRP) or its receptor. We present a clinical case, i.e. a female migraine patient who mistakenly administered supratherapeutic (three-fold higher) doses of erenumab leading to more efficacious clinical responses without any side-effects. This example illustrates that the initial dosages might have been too low, resulting in a remaining undesired increased effect of CGRP. While a capsaicin forearm model has repeatedly been used to evaluate the pharmacokinetic-pharmacodynamic relationship of mAbs, we provide directions to revisit or reconsider dose-finding and dose-ranging of these drugs. These directions include (i) refinement and application of a capsaicin forehead model (instead of a forearm model) to study trigeminovascular activity and improve dosing, and (ii) reconsideration of trial populations. Indeed, the dose-finding studies were mainly performed in relatively young and normal-weight males, while most phase III/IV trials are marked by a high female-to-male ratio, mainly consisting of overweight to obese females. Considering these aspects in future trials could optimize healthcare for a larger proportion of migraine patients.</p

The migraine postdrome:An electronic diary study

OBJECTIVE: To report migraine postdrome symptoms in patients who report nonheadache symptoms as part of their attacks. METHODS: A prospective daily electronic diary study was conducted over 3 months in 120 patients with migraine. Nonheadache symptoms before, during, and after headache were collected on a daily basis. Visual analogue scales were used to capture the overall level of functioning and the severity of the headache. The postdrome was defined as the time from resolution of troublesome headache to return to normal. RESULTS: Of 120 evaluable patients, 97 (81%) reported at least one nonheadache symptom in the postdrome. Postdrome symptoms, in order of frequency, included feeling tired/weary and having difficulty concentrating and stiff neck. Many patients also reported a mild residual head discomfort. In most attacks (93%), there was return to normal within 24 hours after spontaneous pain resolved. There was no relationship between medication taken for the headache and the duration of the postdrome. The severity of the migraine was not associated with the duration of the postdrome. Overall state of health scores remained low during the postdrome. CONCLUSION: Nonheadache symptoms in the postdrome were common and may contribute to the distress and disability in the patients studied. Postdrome symptoms merit larger observational studies and careful recording in clinical trials of acute and preventive migraine treatments

Natural course of visual snow syndrome: a long-term follow-up study.

Visual snow syndrome is characterized by a continuous visual disturbance resembling a badly tuned analogue television and additional visual and non-visual symptoms causing significant disability. The natural course of visual snow syndrome has not hitherto been studied. In this prospective longitudinal study, 78 patients with the diagnosis of visual snow syndrome made in 2011 were re-contacted in 2019 to assess symptom evolution using a semi-structured questionnaire. Forty patients (51% of 78) were interviewed after 84 ± 5 months (mean ± SD). In all patients, symptoms had persisted. Visual snow itself was less frequently rated as the most disturbing symptom (72 versus 42%, P = 0.007), whereas a higher proportion of patients suffered primarily from entopic phenomena (2 versus 17%, P = 0.024). New treatment was commenced in 14 (35%) patients, of whom in seven, visual snow syndrome was ameliorated somewhat. Three (7%) experienced new visual migraine aura without headache, and one (2%) had new migraine headache. There were no differences in the levels of anxiety and depression measured by the Patient Health Questionnaire 8 and the Generalized Anxiety Disorder Scale 7. Thirty-eight patients (49%) were lost to follow-up. In visual snow syndrome, symptoms can persist over 8 years without spontaneous resolution, although visual snow itself might become less bothersome

Implications for migraine

Funding Information: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Margarida Martins-Oliveira is grateful to the Portuguese Fundação para a Ciência e Tecnologia (FCT) for its support with an individual PhD grant (SFRH/BD/77127/2011). The conduct of the research was financially supported by the EUROHEADPAIN European Union FP7 (PJG & PRH: 602633), the Wellcome Trust (PJG: 104033) and the Medical Research Council (PRH: MR/P006264/1). Publisher Copyright: © International Headache Society 2022.Background: Imaging migraine premonitory studies show increased midbrain activation consistent with the ventral tegmental area, an area involved in pain modulation and hedonic feeding. We investigated ventral tegmental area pharmacological modulation effects on trigeminovascular processing and consequent glycemic levels, which could be involved in appetite changes in susceptible migraine patients. Methods: Serotonin and pituitary adenylate cyclase-activating polypeptide receptors immunohistochemistry was performed in ventral tegmental area parabrachial pigmented nucleus of male Sprague Dawley rats. In vivo trigeminocervical complex neuronal responses to dura mater nociceptive electrical stimulation, and facial mechanical stimulation of the ophthalmic dermatome were recorded. Changes in trigeminocervical complex responses following ventral tegmental area parabrachial pigmented nucleus microinjection of glutamate, bicuculline, naratriptan, pituitary adenylate cyclase-activating polypeptide-38 and quinpirole were measured, and blood glucose levels assessed pre- and post-microinjection. Results: Glutamatergic stimulation of ventral tegmental area parabrachial pigmented nucleus neurons reduced nociceptive and spontaneous trigeminocervical complex neuronal firing. Naratriptan, pituitary adenylate cyclase-activating polypeptide-38 and quinpirole inhibited trigeminovascular spontaneous activity, and trigeminocervical complex neuronal responses to dural-evoked electrical and mechanical noxious stimulation. Trigeminovascular sensory processing through modulation of the ventral tegmental area parabrachial pigmented nucleus resulted in reduced circulating glucose levels. Conclusion: Pharmacological modulation of ventral tegmental area parabrachial pigmented nucleus neurons elicits changes in trigeminovascular sensory processing. The interplay between ventral tegmental area parabrachial pigmented nucleus activity and the sensory processing by the trigeminovascular system may be relevant to understand associated sensory and homeostatic symptoms in susceptible migraine patients.publishersversioninpres

Disrupted connectivity within visual, attentional and salience networks in the visual snow syndrome.

Here we investigate brain functional connectivity in patients with visual snow syndrome (VSS). Our main objective was to understand more about the underlying pathophysiology of this neurological syndrome. Twenty-four patients with VSS and an equal number of gender and age-matched healthy volunteers attended MRI sessions in which whole-brain maps of functional connectivity were acquired under two conditions: at rest while watching a blank screen and during a visual paradigm consisting of a visual-snow like stimulus. Eight unilateral seed regions were selected a priori based on previous observations and hypotheses; four seeds were placed in key anatomical areas of the visual pathways and the remaining were derived from a pre-existing functional analysis. The between-group analysis showed that patients with VSS had hyper and hypoconnectivity between key visual areas and the rest of the brain, both in the resting state and during a visual stimulation, compared with controls. We found altered connectivity internally within the visual network; between the thalamus/basal ganglia and the lingual gyrus; between the visual motion network and both the default mode and attentional networks. Further, patients with VSS presented decreased connectivity during external sensory input within the salience network, and between V5 and precuneus. Our results suggest that VSS is characterised by a widespread disturbance in the functional connectivity of several brain systems. This dysfunction involves the pre-cortical and cortical visual pathways, the visual motion network, the attentional networks and finally the salience network; further, it represents evidence of ongoing alterations both at rest and during visual stimulus processing

Fremanezumab for the Preventive Treatment of Chronic Migraine.

BACKGROUND: Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being investigated as a preventive treatment for migraine. We compared two fremanezumab dose regimens with placebo for the prevention of chronic migraine. METHODS: In this phase 3 trial, we randomly assigned patients with chronic migraine (defined as headache of any duration or severity on ≥15 days per month and migraine on ≥8 days per month) in a 1:1:1 ratio to receive fremanezumab quarterly (a single dose of 675 mg at baseline and placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline and 225 mg at weeks 4 and 8), or matching placebo. Both fremanezumab and placebo were administered by means of subcutaneous injection. The primary end point was the mean change from baseline in the average number of headache days (defined as days in which headache pain lasted ≥4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine-specific medication [triptans or ergots] was used to treat a headache of any severity or duration) per month during the 12 weeks after the first dose. RESULTS: Of 1130 patients enrolled, 376 were randomly assigned to fremanezumab quarterly, 379 to fremanezumab monthly, and 375 to placebo. The mean number of baseline headache days (as defined above) per month was 13.2, 12.8, and 13.3, respectively. The least-squares mean (±SE) reduction in the average number of headache days per month was 4.3±0.3 with fremanezumab quarterly, 4.6±0.3 with fremanezumab monthly, and 2.5±0.3 with placebo (P CONCLUSIONS: Fremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo in this 12-week trial. Injection-site reactions to the drug were common. The long-term durability and safety of fremanezumab require further study. (Funded by Teva Pharmaceuticals; ClinicalTrials.gov number, NCT02621931 .)