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Cluster headache is a trigeminal autonomic cephalalgia characterised by extremely painful, strictly unilateral, short-lasting headache attacks accompanied by ipsilateral autonomic symptoms or the sense of restlessness and agitation, or both. The severity of the disorder has major effects on the patient's quality of life and, in some cases, might lead to suicidal ideation. Cluster headache is now thought to involve a synchronised abnormal activity in the hypothalamus, the trigeminovascular system, and the autonomic nervous system. The hypothalamus appears to play a fundamental role in the generation of a permissive state that allows the initiation of an episode, whereas the attacks are likely to require the involvement of the peripheral nervous system. Triptans are the most effective drugs to treat an acute cluster headache attack. Monoclonal antibodies against calcitonin gene-related peptide, a crucial neurotransmitter of the trigeminal system, are under investigation for the preventive treatment of cluster headache. These studies will increase our understanding of the disorder and perhaps reveal other therapeutic targets.

Key Points Chronic migraine is a clearly defined subtype of migraine affecting between 1–2% of the general population, yet it receives little attention Chronic migraine usually develops from episodic migraine at a conversion rate of about 3% a year; the chronification is reversible Risk factors for migraine chronification include overuse of acute migraine medication, ineffective acute treatment, obesity, depression, low educational status and stressful life events The pathophysiology of migraine chronification can be understood as a threshold problem: certain predisposing factors combined with frequent headache pain lower the threshold of migraine attacks, thereby increasing the risk of chronic migraine Treatment options include pharmacological and nonpharmacological options and neuromodulation Prevention of chronification is essential, and requires adequate treatment of individual migraine attacks, early initiation of preventive medication and avoiding analgesic overuse About 2% of the general population and 8% of people with migraine have chronic migraine, defined as ≥15 headache days per month. The condition can be disabling and has a severe impact on quality of life, yet it receives little attention. This Review summarizes the current understanding of the risk factors and pathophysiological mechanisms of migraine chronification, and discusses strategies to prevent and treat the disorder. Chronic migraine has a great detrimental influence on a patient's life, with a severe impact on socioeconomic functioning and quality of life. Chronic migraine affects 1–2% of the general population, and about 8% of patients with migraine; it usually develops from episodic migraine at an annual conversion rate of about 3%. The chronification is reversible: about 26% of patients with chronic migraine go into remission within 2 years of chronification. The most important modifiable risk factors for chronic migraine include overuse of acute migraine medication, ineffective acute treatment, obesity, depression and stressful life events. Moreover, age, female sex and low educational status increase the risk of chronic migraine. The pathophysiology of migraine chronification can be understood as a threshold problem: certain predisposing factors, combined with frequent headache pain, lower the threshold of migraine attacks, thereby increasing the risk of chronic migraine. Treatment options include oral medications, nerve blockade with local anaesthetics or corticoids, and neuromodulation. Well-defined diagnostic criteria are crucial for the identification of chronic migraine. The International Headache Society classification of chronic migraine was recently updated, and now allows co-diagnosis of chronic migraine and medication overuse headache. This Review provides an up-to-date overview of the classification of chronic migraine, basic mechanisms and risk factors of migraine chronification, and the currently established treatment options.

The role of the cerebellum in pathologies of the trigeminal nervous system is still unknown although recently gathered evidence point to a modulatory rather than a passive role. Here we provide evidence for the activation of specific cerebellar areas during nociceptive trigeminal input in the left nostril in a large number of volunteers (54 subjects) and an additional independent group (18 subjects) as measured by functional magnetic resonance imaging (fMRI). Peak voxel activity ipsilateral to the stimulated side can be seen in cerebellar lobules VI, VIIIa and Crus I, and vermal lobule VIIIa, although some activations are also seen in the contralateral side. The individuals’ intensity and unpleasantness ratings are mostly processed in the hemispheric lobules VI stretching to V, representing the face areas of the cerebellar's fractured homunculus. We found a robust functional connectivity during nociception between the cerebellum and the rostral part of the pons as well as the periaqueductal grey and the thalamus, involving the descending antinociceptive network as well as areas known to form close loops with the cerebellum in the motor domain. Cerebellar connectivity with higher cortical areas include most of the known hubs in pain processing which are the insular cortex, operculum and putamen, and the face areas in the precentral gyrus. The current data provide a solid basis for further research of the cerebellar's activity and connectivity in primary headache and facial pain syndromes. •The cerebellum is highly active during nociceptive, trigeminal processing.•The cerebellar's activity is modulated by perceived intensity of pain.•Its functional connectivity to brainstem and cortex is altered by nociception.

Neural development during human childhood and adolescence involves highly coordinated and sequenced events, characterized by both progressive and regressive processes. Despite a multitude of results demonstrating the age-dependent development of gray matter, white matter, and total brain volume, a reference curve allowing prediction of structural brain maturation is still lacking but would be clinically valuable. For the first time, the present study provides a validated reference curve for structural brain maturation during childhood and adolescence, based on structural MRI data. By employing kernel regression methods, a novel but well-validated BrainAGE framework uses the complex multidimensional maturation pattern across the whole brain to estimate an individual's brain age. The BrainAGE framework was applied to a large human sample (n=394) of healthy children and adolescents, whose image data had been acquired during the NIH MRI study of normal brain development. Using this approach, we were able to predict individual brain maturation with a clinically meaningful accuracy: the correlation between predicted brain age and chronological age resulted in r=0.93. The mean absolute error was only 1.1years. Moreover, the predicted brain age reliably differentiated between all age groups (i.e., preschool childhood, late childhood, early adolescence, middle adolescence, late adolescence). Applying the framework to preterm-born adolescents resulted in a significantly lower estimated brain age than chronological age in subjects who were born before the end of the 27th week of gestation, demonstrating the successful clinical application and future potential of this method. Consequently, in the future this novel BrainAGE approach may prove clinically valuable in detecting both normal and abnormal brain maturation, providing important prognostic information. [Display omitted] ► A sensitive reference curve for structural brain maturation in humans is provided. ► The BrainAGE framework uses structural MRI data and is fully automatic. ► The multidimensional maturation pattern is aggregated to the individual brain age. ► Preterm-born subjects showed a delay in brain maturation of 1.5years in adolescence. ► The novel BrainAGE method proved to detect both normal and abnormal brain maturation.

Background Migraine patients usually report a high prevalence of neck pain preceding or during the migraine attack. A recent investigation of musculoskeletal dysfunctions in migraine patients concluded that neck pain is not simply a symptom of the migraine attack but corresponds to identifiable muscle and joint alterations. Particularly pain provocation using palpation of the joints in the upper cervical spine was significantly more prevalent in patients with migraine than in headache-free participants. Methods One hundred seventy-nine migraineurs (diagnosed according to IHS classification criteria version III beta) and 73 age- and gender-matched healthy controls were examined by a physiotherapist blinded towards the diagnosis, using a palpation technique over the upper cervical spine. The palpation combined oscillating movements and sustained pressure. Findings Using simple palpation of the upper cervical spine, migraine patients can be stratified into three groups: painfree (11%), local pain only (42%), and pain referred to the head during sustained pressure (47%). Combining both test components (palpation and sustained pressure) has a high sensitivity and specificity for migraine. Conclusions The response to palpation of the upper cervical spine may indicate migraine subtypes. The presence of musculoskeletal dysfunctions of the upper cervical spine should be identified and treated to avoid ongoing nociceptive input into the trigeminocervical complex. Trial registration German Clinical Trial Register DRKS-ID: DRKS00009622 .

Recently, activation-dependant structural brain plasticity in humans has been demonstrated in adults after three months of training a visio-motor skill. Learning three-ball cascade juggling was associated with a transient and highly selective increase in brain gray matter in the occipito-temporal cortex comprising the motion sensitive area hMT/V5 bilaterally. However, the exact time-scale of usage-dependant structural changes occur is still unknown. A better understanding of the temporal parameters may help to elucidate to what extent this type of cortical plasticity contributes to fast adapting cortical processes that may be relevant to learning. Using a 3 Tesla scanner and monitoring whole brain structure we repeated and extended our original study in 20 healthy adult volunteers, focussing on the temporal aspects of the structural changes and investigated whether these changes are performance or exercise dependant. The data confirmed our earlier observation using a mean effects analysis and in addition showed that learning to juggle can alter gray matter in the occipito-temporal cortex as early as after 7 days of training. Neither performance nor exercise alone could explain these changes. We suggest that the qualitative change (i.e. learning of a new task) is more critical for the brain to change its structure than continued training of an already-learned task.

Chronic pain appears to be associated with brain gray matter reduction in areas ascribable to the transmission of pain. The morphological processes underlying these structural changes, probably following functional reorganisation and central plasticity in the brain, remain unclear. The pain in hip osteoarthritis is one of the few chronic pain syndromes which are principally curable. We investigated 20 patients with chronic pain due to unilateral coxarthrosis (mean age 63.25±9.46 (SD) years, 10 female) before hip joint endoprosthetic surgery (pain state) and monitored brain structural changes up to 1 year after surgery: 6-8 weeks, 12-18 weeks and 10-14 month when completely pain free. Patients with chronic pain due to unilateral coxarthrosis had significantly less gray matter compared to controls in the anterior cingulate cortex (ACC), insular cortex and operculum, dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex. These regions function as multi-integrative structures during the experience and the anticipation of pain. When the patients were pain free after recovery from endoprosthetic surgery, a gray matter increase in nearly the same areas was found. We also found a progressive increase of brain gray matter in the premotor cortex and the supplementary motor area (SMA). We conclude that gray matter abnormalities in chronic pain are not the cause, but secondary to the disease and are at least in part due to changes in motor function and bodily integration.

Monoclonal antibodies (mAbs) against calcitonin gene-related peptides (CGRP) are novel treatments for migraine prevention. Based on a previous functional imaging study which investigated the CGRP receptor mAb (erenumab), we hypothesized that (i) the CGRP ligand mAb galcanezumab would alter central trigeminal pain processing; (ii) responders to galcanezumab treatment would show specific hypothalamic modulation in contrast to non-responders; and (iii) the ligand and the receptor antibody differ in brain responses. Using an established trigeminal nociceptive functional magnetic imaging paradigm, 26 migraine patients were subsequently scanned twice: before and 2-3 weeks after administration of galcanezumab. We found that galcanezumab decreases hypothalamic activation in all patients and that the reduction was stronger in responders than in non-responders. Contrasting erenumab and galcanezumab showed that both antibodies activate a distinct network. We also found that pre-treatment activity of the spinal trigeminal nucleus (STN) and coupling between the STN and the hypothalamus covariates with the response to galcanezumab. These data suggest that despite relative impermeability of the blood-brain barrier for CGRP mAb, mAb treatment induces certain and highly specific brain effects which may be part of the mechanism of their efficacy in migraine treatment. This work was supported by the German Ministry of Education and Research (BMBF) of ERA-Net Neuron under the project code BIOMIGA (01EW2002 to AM) and by the German Research Foundation (SFB936-178316478-A5 to AM). The funding sources did not influence study conduction in any way. The basic science study was preregistered in the Open Science Framework (https://osf.io/m2rc6).

Due to the clinical picture and also based on early imaging data (Weiller et al. Nat Med 1:658–660, 1995 ), the brainstem and midbrain structures have been intensely discussed as possible driving or generating structures in migraine. The fact that the brainstem activation persisted after treatment makes it unlikely that this activation was only due to increased activity of the endogenous anti-nociceptive system. It was consequently (and somewhat simplifying) coined the “migraine generator”. Since then several studies have focussed on this region when investigating episodic, but also chronic migraine. Denuelle et al. were the first to not only demonstrate significant activations in the midbrain and pons but also in the hypothalamus, which, just like the brainstem activation in the first study, persisted after headache relief with sumatriptan. Expanding these studies into f-MRI studies, refined the involvement of rostral parts of the pons in acute migraine attacks. However, they also focused on the preictal stage of NO-triggered and native human migraine attacks and suggested a predominant role of the hypothalamus shortly before the beginning of migraine headaches as well as alterations in hypothalamic functional connectivity. Additionally, changes in resting-state functional connectivity of the dorsal pons and the hypothalamus in interictal migraineurs has recently been found. The pathophysiology and genesis of migraine attacks is probably not just the result of one single “brainstem generator”. Spontaneous oscillations of complex networks involving the hypothalamus, brainstem, and dopaminergic networks lead to changes in activity in certain subcortical and brainstem areas, thus changing susceptibility thresholds and not only starting but also terminating headache attacks.

Background Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptides (CGRP) are established therapies for migraine. There are currently four CGRP-mAbs available on the market: one targets the CGRP receptor, and the other three target the CGRP ligand. Despite the initial comparability of the two groups regarding efficacy, real-life data demonstrate that up to 30% of non-responders to one class exhibit a positive response to switching classes, indicating different mechanisms. The ligand-mAb, galcanezumab, has previously demonstrated a trigeminal dermatome-specific pain modulatory effect. The present study aims to evaluate the sensory modulatory effect of the receptor-mAb, erenumab. Methods Migraine patients were recruited in two phases. In the first phase of the study, 40 patients were included and randomly assigned to receive either erenumab 70 mg (21 patients) or a placebo (19 patients) in a double-blind manner. In the second phase of the study, 46 patients were included and received erenumab 140 mg in an open-label manner. Quantitative sensory testing (QST) parameters were measured on the right forehead (V1 dermatome) and on the forearm prior to and after treatment. A repeated-measures analysis of variance (ANOVA) was used for the statistical analysis. Results All three study cohorts (placebo, erenumab 70 mg, and erenumab 140 mg) were comparable in terms of demographics, including age, sex ratio, and baseline headache frequency, and showed no statistically significant differences in QST parameters. Subsequent to the administration of the treatment, no changes or discernible trends were observed in any of the QST parameters in any study cohort. Conclusions The findings of this study suggest that the receptor-mAb, erenumab, did not modify the sensory thresholds following treatment. This finding is in contrast with the results of galcanezumab in the literature, which demonstrated a trigeminal sensory modulatory effect after treatment. This outcome indicates a different mechanism of action between the anti-CGRP receptor versus ligand mAbs and provides a scientific basis for the rationale of class switching, which aims to achieve additional clinical benefits in patients who are non-responders to anti-CGRP treatment. Preregistration The study was preregistered at the Open Science Framework ( https://osf.io/ygf3t ).