Circadian functional changes of pain-processing brainstem nuclei and implications for cluster headache: A 7 Tesla imaging study.

BACKGROUND: Pain thresholds and primary headaches, including cluster headache attacks, have circadian rhythmicity. Thus, they might share a common neuronal mechanism. OBJECTIVE: This study aimed to elucidate how the modulation of nociceptive input in the brainstem changes from noon to midnight. Insights into the mechanism of these fluctuations could allow for new hypotheses about the pathophysiology of cluster headache. METHODS: This repeated measure observational study was conducted at the University Hospital Zurich from December 2019 to November 2022. Healthy adults between 18 and 85 years of age were eligible. All participants were examined at noon and midnight. We tested the pain threshold on both sides of the foreheads with quantitative sensory testing, assessed tiredness levels, and obtained high-field (7 Tesla) and high-resolution functional magnetic resonance imaging (MRI) at each visit. Functional connectivity was assessed at the two visits by performing a region-of-interest analysis. We defined nuclei in the brainstem implicated in processing nociceptive input as well as the thalamus and suprachiasmatic nucleus as the region-of-interest. RESULTS: Ten people were enrolled, and seven participants were included. First, we did not find statistically significant differences between noon and midnight of A-delta-mediated pain thresholds (median mechanical pain threshold at noon: left 9.2, right 9.2; at night: left 6.5, right 6.1). Second, after correction for a false discovery rate, we found changes in the mechanical pain sensitivity to have a statistically significant effect on changes in the functional connectivity between the left parabrachial nucleus and the suprachiasmatic nucleus (T = -40.79). CONCLUSION: The MRI data analysis suggested that brain stem nuclei and the hypothalamus modulate A-delta-mediated pain perception; however, these changes in pain perception did not lead to statistically significantly differing pain thresholds between noon and midnight. Hence, our findings shed doubt on our hypothesis that the physiologic circadian rhythmicity of pain thresholds could drive the circadian rhythmicity of cluster headache attacks.

The location of pain in cluster headache: Data from the International Cluster Headache Questionnaire.

OBJECTIVE: To identify the most common locations of cluster headache pain from an international, non-clinic-based survey of participants with cluster headache, and to compare these locations to other cluster headache features as well as to somatotopic maps of peripheral, brainstem, thalamic, and cortical areas. BACKGROUND: Official criteria for cluster headache state pain in the orbital, supraorbital, and/or temporal areas, yet studies have noted pain extending beyond these locations, and the occipital nerve appears relevant, given the effectiveness of suboccipital corticosteroid injections and occipital nerve stimulation. Furthermore, cranial autonomic features vary between patients, and it is not clear if the trigeminovascular reflex is dermatome specific (e.g., do patients with maxillary or V2 division pain have more rhinorrhea?). Finally, functional imaging studies show early activation of the posterior hypothalamus in a cluster headache attack. However, the first somatosensory area to be sensitized is unclear; the first area can be hypothesized based on the complete map of pain locations. METHODS: The International Cluster Headache Questionnaire was an internet-based cross-sectional survey that included a clickable pain map of the face. These data were compared to several other datasets: (1) a meta-analysis of 22 previous publications of pain location in cluster headache (consisting of 6074 patients); (2) four cephalic dermatome maps; (3) participants' survey responses for demographics, autonomic features, and effective medications; and (4) previously published somatotopic maps of the brainstem, thalamus, primary somatosensory cortex, and higher order somatosensory cortex. RESULTS: One thousand five hundred eighty-nine participants completed the pain map portion of the survey, and the primary locations of pain across all respondents was the orbital, periorbital, and temporal areas with a secondary location in the lower occiput; these primary and secondary locations were consistent with our meta-analysis of 22 previous publications. Of the four cephalic dermatomes (V1, V2, V3, and a combination of C2-3), our study found that most respondents had pain in two or more dermatomes (range 85.7% to 88.7%, or 1361-1410 of 1589 respondents, across the four dermatome maps). Dermatomes did not correlate with their respective autonomic features or with medication effectiveness. The first area to be sensitized in the canonical somatosensory pathway is either a subcortical (brainstem or thalamus) or higher order somatosensory area (parietal ventral or secondary somatosensory cortices) because the primary somatosensory cortex (area 3b) and somatosensory area 1 have discontinuous face and occipital regions. CONCLUSIONS: The primary pain locations in cluster headache are the orbital, supraorbital, and temporal areas, consistent with the official International Classification of Headache Disorders criteria. However, activation of the occiput in many participants suggests a role for the occipital nerve, and the pain locations suggest that somatosensory sensitization does not start in the primary somatosensory cortex.

Recent advances in diagnosing, managing, and understanding the pathophysiology of cluster headache.

Cluster headache, characterised by attacks of severe, recurrent, unilateral headache and ipsilateral cranial autonomic symptoms, remains a primary headache with an elusive pathophysiology. Recent advances have introduced effective treatments and broadened understanding of the clinical features of cluster headache. These features are similar in patients globally, but regional differences in prevalence and burden exist. International collaborations have led to identification of eight genetic loci associated with cluster headache. The pathophysiological mechanisms are still not fully understood but recent studies show that targeting the trigeminal autonomic reflex by neurostimulation, or targeting the neuropeptide calcitonin gene-related peptide (CGRP), might lessen the attack burden. The US Food and Drug Administration has approved galcanezumab, a monoclonal antibody targeting CGRP, as the first specific preventive treatment for episodic cluster headache. However, a preventive effect was not replicated in chronic cluster headache, and the European Medicines Agency did not approve galcanezumab, restricting its availability in Europe. Owing to the low prevalence of cluster headache, continued collaboration through multicentre clinical trials and data sharing will be imperative for further breakthroughs in understanding and management.

Cluster headache: a single tertiary center study.

OBJECT: The characteristics of cluster headache (CH) patients in many countries and the diagnostic and therapeutic approach have been described in several publications, but so far no clinical data have been published from Turkey. MATERIAL METHODS: This is a cross-sectional retrospective study that includes all patients who were diagnosed with CH and referred to our headache clinic, Dokuz Eylül University Faculty of Medicine, Neurology Department from 1991 to January 2018. RESULTS: We included 114 patients (24 females and 90 males) in our study. The mean age at onset was 31.68 ± 12.72 (range 13-68). Eighty-six (78.18%) patients had episodic cluster headache (ECH) and 24 (21.82%) patients had chronic cluster headache (CCH). The age at onset was significantly higher in the patients with CCH than with ECH (p = 0.002). The most common location was orbitotemporal for both genders. The most common accompanying symptoms were lacrimation (80.73%). The male:female ratio in all patients was 3:7, 3.8:1 in those with CCH and 4:1 in those with ECH. Eighty-nine (87.25%) patients had prophylactic treatment and 60 of them received verapamil. CONCLUSION: In our study, some clinical features of our patients were similar to those of Europe and America or the Asian countries and some of them not. There are regional differences in cluster headache patients. With more awareness of cluster headache and research from many countries, clinical differences can be revealed more objectively in the future.

Enlarging the spectrum of cluster headache: Extracranial autonomic involvement revealed by voice analysis.

BACKGROUND: People with cluster headache (CH) are frequently burdened by misdiagnosis or diagnostic delay. The peculiar somatic and behavioral changes characterizing patients with CH are not useful to improve diagnostic accuracy. In our clinical experience, we noticed a typical voice quality with low and croaking tone in patients with CH. In this cross-sectional study, we evaluated, by digital voice analysis, whether it is possible to identify typical voice quality characterizing patients with CH compared with healthy controls (HCs). Furthermore, to investigate whether putative differences in voice characteristics could be underpinned by constitutional aspects or pathological processes of vocal cords, subjects underwent a videolaryngostroboscopy. Smoking habits and alcohol consumption were specifically investigated. METHODS: After conducting digital recording of the voices from both patients with CH and HCs in a soundproof insulated cabin in the laboratory of the Audiology Department, a set of voice parameters was analyzed. We included the measures of fundamental frequency, calculations of jitter and shimmer, and noise-to-harmonics ratios as well as quantities related to the spectral tilt (i.e., H1-H2, H1-A1, H1-A2, and H1-A3) in 20 patients with CH and in 13 HCs. A videolaryngostroboscopy was performed in all subjects. RESULTS: Patients with CH, explored during the cluster bout period, showed significantly lower second harmonic (H1-H2) values compared with HCs (-6.9 ± 7.6 vs. 2.1 ± 6.7, p = 0.002), usually characterizing the so-called creaky voice. By using a laryngoscopy investigation, a significantly higher prevalence of mild to moderate vocal cord edema and laryngopharyngeal reflux signs were found in patients with CH (100% of patients with CH vs. 15% of HC, p < 0.001). CONCLUSION: Creaky phonation is a "physiological mode of laryngeal operation" usually underpinned by shortened and thickened vocal folds. Creaky voice phonation can be due to a vocal fold's reduced capability to become slack or flaccid secondary to vocal cord edema underpinned by laryngopharyngeal reflux affecting the phonatory mechanisms in patients with CH. The laryngopharyngeal reflux may represent a dysautonomic sign related to the increased parasympathetic tone during in-bout period, reinforcing the hypothesis of an extracranial autonomic dysfunction as part of CH clinical picture.

Cluster headache in children and adolescents: a systematic review of case reports.

AIM: To describe the clinical characteristics and therapeutic options available to paediatric patients with cluster headache. METHOD: Based on a literature search of the medical databases PubMed, LILACS, and Web of Science and using selected descriptors, we carried out a systematic review of case reports on cluster headache in paediatric patients published from 1990 to 2020. RESULTS: Fifty-one patients (29 males, 22 females) with a mean (SD) age of 9 years 7 months (3y 10mo; range 2-16y) were diagnosed with cluster headache. The mean (SD) diagnosis was made 27.8 months (26.2mo) after the onset of cluster headache. Pain occurred at night or on waking up (76.5%) and consisted of 1 to 3 attacks per day (62.7%) lasting 30 to 120 minutes (68.6%). Headaches were unilateral (90.2%), had a pulsatile character (64.7%), and severe intensity (100%). There were autonomic manifestations (90.2%) predominantly ipsilateral to pain, in this order: lacrimation; conjunctival injection; nasal congestion; ptosis; eyelid oedema; and rhinorrhoea. Sumatriptan and oxygen inhalation were the most effective treatments for acute manifestation. Prophylaxis, corticosteroids, verapamil, and gabapentin were the most effective drugs. INTERPRETATION: Due to the small number of published studies, this review could not provide reliable data; however, it appears that cluster headache in children and adolescents is similar to adults, both in clinical characteristics and treatment. What this paper adds Cluster headache in children and adolescents is poorly studied. Cluster headache is uncommon before 10 years of age and diagnosis is difficult in the first few years of life. Treatment of cluster headache in children and adolescents is similar to that used in adults. The notion of the effectiveness of prophylactic treatment is based only on authors' experience.

Clinical features of cluster headache without cranial autonomic symptoms: results from a prospective multicentre study.

Although cranial autonomic symptoms (CAS) are typical in cluster headache (CH), some individuals with CH show no CAS during their headache attacks. Probable cluster headache (PCH) is a subtype of CH that fulfils all but one criterion of CH. This study aimed to investigate the frequency and clinical features of CH and PCH without CAS in comparison to those with CAS. We analysed data from the Korea Cluster Headache Registry, a prospective multicentre registry involving data from 16 hospitals. Of the 216 participants with CH and 26 with PCH, 19 (8.8%) and 7 (26.9%), respectively, did not have CAS. Participants with CH without CAS exhibited less severe anxiety (General Anxiety Disorder-7 score, median [interquartile range], 2.0 [1.0-6.0] vs 8.0 [3.0-12.0], p = 0.001) and depression (Patient Health Questionnaire-9 score, 3.0 [1.0-7.0] vs 7.0 [3.0-11.0], p = 0.042) than those with CAS. Among participants with PCH, headache intensity was less severe in participants without CAS than in those with CAS (numeric rating scale, 8.0 [7.0-8.0] vs 9.5 [8.0-10.0], p = 0.015). In conclusion, a significant proportion of participants with CH and PCH did not have CAS. Some clinical features of CH and PCH differed based on the presence of CAS.

Cluster headache pathophysiology - insights from current and emerging treatments.

Cluster headache is a debilitating primary headache disorder that affects approximately 0.1% of the population worldwide. Cluster headache attacks involve severe unilateral pain in the trigeminal distribution together with ipsilateral cranial autonomic features and a sense of agitation. Acute treatments are available and are effective in just over half of the patients. Until recently, preventive medications were borrowed from non-headache indications, so management of cluster headache is challenging. However, as our understanding of cluster headache pathophysiology has evolved on the basis of key bench and neuroimaging studies, crucial neuropeptides and brain structures have been identified as emerging treatment targets. In this Review, we provide an overview of what is known about the pathophysiology of cluster headache and discuss the existing treatment options and their mechanisms of action. Existing acute treatments include triptans and high-flow oxygen, interim treatment options include corticosteroids in oral form or for greater occipital nerve block, and preventive treatments include verapamil, lithium, melatonin and topiramate. We also consider emerging treatment options, including calcitonin gene-related peptide antibodies, non-invasive vagus nerve stimulation, sphenopalatine ganglion stimulation and somatostatin receptor agonists, discuss how evidence from trials of these emerging treatments provides insights into the pathophysiology of cluster headache and highlight areas for future research.

Cognitive performance in patients with episodic cluster headache outside and inside the active cluster.

BACKGROUND: Previous studies have shown worse cognitive performance in cluster headache (CH) patients compared to healthy controls; however, little is known about cognitive performance in episodic CH (ECH) patients outside and inside the active cluster (AC). OBJECTIVE: Our aim is to compare cognitive function in ECH patients outside and inside the AC. METHODS: In this cross-sectional, observational study, four neuropsychological tests (Trail Making Test [TMT], Stroop Test [ST], verbal fluency [VF], and Symbol Digit Modalities Test [SDT]) were completed by 21 ECH patients at two different points in time: outside and inside the AC. We also assessed self-reported sleep quality and the presence of anxiety or depressive symptoms. Scores were compared. RESULTS: There was not any difference between the scores of the neuropsychological tests performed outside and inside the AC (TMT-A: 23 vs. 23.5; p = 0.984; TMT-B: 96.5 vs. 85.9; p = 0.104; ST word reading: 101.0 vs. 101.2; p = 0.938; ST color naming: 73.0 vs. 73.4; p = 0.858; ST color word: 44.0 vs. 46.0; p = 0.498; SDMT: 44.0 vs. 44.6; p = 0.961; VF phonemic: 29.5 vs. 30.2; p = 0.714; VF semantic: 20 vs. 21; p = 0.489). We found a worsening in the sleep quality component of the Pittsburgh Sleep Quality Index median scores in patients outside the AC (2 vs. 1; p = 0.046). CONCLUSIONS: Our findings suggest that patients with ECH have a similar cognitive performance outside and during the AC.

Cluster headache is one of the most intensely painful human conditions: Results from the International Cluster Headache Questionnaire.

OBJECTIVE: To determine the pain intensity of cluster headache through a large survey by comparing it to other painful disorders. Furthermore, to investigate the relationship between maximal pain, autonomic, and other clinical symptoms, as well as demographic attributes of cluster headache. BACKGROUND: The pain of cluster headache is anecdotally considered to be one of the worst pains in existence. The link between pain and autonomic features of cluster headache is understood mechanistically through the trigeminovascular reflex, though it is not clear if this is a graded response. Links between pain and other features of cluster headache are less well understood. METHODS: This Internet-based cross-sectional survey included questions on cluster headache diagnostic criteria, which were used as part of the inclusion/exclusion criteria for the study. Respondents were asked to rate a cluster headache attack on the 0-10 numerical rating scale. Additionally, they were asked if they had experienced a list of other painful conditions such as labor pain or nephrolithiasis; if so they were asked to rate that pain as well. The survey also included demographics, mood scores, and treatment responses. RESULTS: A total of 1604 cluster headache respondents were included in the analysis. Respondents rated cluster headache as significantly (p < 0.001) more intense than every other pain condition examined. Cluster headache attacks were rated as 9.7 ± 0.6 (mean ± standard deviation) on the numerical rating scale, followed by labor pain (7.2 ± 2.0), pancreatitis (7.0 ± 1.5), and nephrolithiasis (6.9 ± 1.9). The majority of cluster headache respondents rated a cluster headache attack at maximal or 10.0 pain (72.1%, 1157/1604). Respondents with maximal pain were statistically significantly more likely to have cranial autonomic features compared to respondents with less pain: conjunctival injection or lacrimation 91% (1057/1157) versus 85% (381/447), eyelid edema 77% (887/1157) versus 66% (293/447), forehead/facial sweating 60% (693/1157) versus 49% (217/447), fullness in the ear 47% (541/1157) versus 35% (155/447), and miosis/ptosis 85% (1124/1157) versus 75% (426/447) (all p values <0.001). Respondents with maximal pain also had other statistically significant findings: more frequent attacks (4.0 ± 2.0 attacks per day vs. 3.5 ± 2.0 attacks per day), higher Hopelessness Depression Symptom Questionnaire scores (24.5 ± 16.9 vs. 21.1 ± 15.2), decreased overall effectiveness from calcium channel blockers (on a 5-point Likert scale), and more likely female: 34% (389/1157) versus 24% (108/447) (all p values <0.001). Pain intensity was not associated with restlessness, headache duration, age of onset, episodic/chronic status, or the effectiveness of any acute or preventive medication other than calcium channel blockers. CONCLUSIONS: Cluster headache is an intensely painful disorder, even in the context of other disorders considered intensely painful. Maximal pain intensity is associated with more cranial autonomic features, suggesting a graded response between pain and autonomic features. Maximal pain intensity is also associated with headache frequency but not duration, suggesting a relationship between pain intensity and mechanisms controlling headache onset, but not between pain intensity and mechanisms controlling headache offset.

Cluster headache: state of the art of pharmacological treatments and therapeutic perspectives.

Cluster headache (CH) is the most common form of trigeminal autonomic cephalalgia. Current treatments have several limitations, and new drugs are required. This article first briefly reviews present acute and preventive treatments in CH, their mechanism of action and limitations, then describes the state of the art in recent clinical drug trials since 2015, and ends with a critique of trials in the CH field. Research is limited by lack of knowledge of pathophysiology and lack of animal models. In the past 5 years, no brand-new treatment has emerged, but promising drugs, such as CGRP(R) antibodies, are under study. According to the literature and guidelines, clinicians and researchers should be aware of many limitations in study protocols: concomitant medication, patient sample size, patients' protocol compliance, and study designs that tend to restrict patient recruitment.

Chronic Cluster Headache Update and East-West Comparisons: Focusing on Clinical Features, Pathophysiology, and Management.

PURPOSE OF REVIEW: This review provides an update on chronic cluster headache (CH) focusing on clinical features, pathophysiology, and management as well as comparisons between Eastern and Western populations. RECENT FINDINGS: Chronic CH in Eastern populations was relatively rare, compared to that in Western populations. Lacrimation and/or conjunctival injection is the most frequently reported cranial autonomic symptom, and visual aura is predominant in chronic CH patients. Neuroimaging evidence in both ethnic groups suggests that CH pathophysiology involves the hypothalamus and pain-modulatory areas, with dynamic alternations between CH episodes. Recent evidence indicates that midbrain dopaminergic systems may participate in CH chronicity. Noteworthy advances have emerged in neuromodulatory therapies for chronic CH, but treatment with calcitonin gene-related peptide (CGRP) monoclonal antibodies has been unsuccessful. Recent evidence shows divergence of chronic CH between Eastern and Western populations. Neuromodulatory therapies but not CGRP inhibition is effective in this intractable patient group.

Association of dynamic and widespread mechanical sensitivity in cluster headache.

We investigated if dynamic pressure pain sensitivity in the symptomatic area is associated with pressure sensitivity in local and distant pain-free areas in cluster headache (CH). A pressure algometry set consisting of 8 rollers with fixed pressure levels ranging from 500 to 5300 g was used to assess dynamic pressure pain sensitivity in men with episodic CH. Each roller was moved from an anterior-to-posterior direction over the temporalis muscle. The load level of the first painful roller was considered the dynamic pain threshold (DPT). Further, pain elicited during DPT (roller evoked pain) was also assessed. We used a pressure algometer to determine pressure pain thresholds (PPTs) over the temporalis muscle, C5/C6 joint, second metacarpal, and tibialis anterior. Patients were assessed in an asymptomatic (remission) phase, at least 6 months after their last cluster period and without taking pharmacological treatment. Forty men with episodic CH (mean age 42 years) were included. Both outcomes, DPTs (r = 0.781, P < 0.001) and roller-evoked pain (r = 0.586; P < 0.001) were bilaterally correlated. Further, DPT, but not roller-evoked pain, was moderately associated with PPTs measured at the symptomatic (temporalis: r = 0.665, P < 0.001) and distant pain-free (C5-C6 joint: r = 0.389, P = 0.013; second metacarpal: r = 0.551, P < 0.001; and, tibialis anterior: r = 0.308, P = 0.035) points. Dynamic pressure sensitivity in the trigeminal area was correlated to pressure pain sensitivity at both symptomatic and distant pain-free areas in men with CH supporting the use of roller pressure algometry. Dynamic pressure algometry may be a new tool for assessing the status of sensitization in primary headaches.

Cluster headache therapies: pharmacology and mode of action.

INTRODUCTION: Cluster headache (CH) is the most common trigeminal autonomic cephalalgia with a significant need for novel treatment options. While the use of most of the acute CH medications is supported by clinical trials and based on a pathophysiological concept for the generation of pain, the scientific evidence for preventive CH medications is very limited. AREAS COVERED: This article reviews acute and preventive substances for the pharmacological treatment of CH with a focus on the mode of action of these drugs. We also summarized the clinical trial evidence and discuss future research directions. EXPERT OPINION: Recommendations for current pharmacological CH therapies, in particular for CH prevention, are often based on small open label studies with inconclusive results. Larger trials are missing. A shared pathophysiological mechanism of action of these preventatives does not exist. Future studies with CGRP(R) antibodies and novel substances with specific actions are needed and will thereby help to understanding the pathophysiology of CH.

Phase dependent hypothalamic activation following trigeminal input in cluster headache.

BACKGROUND: Task-free imaging approaches using PET have shown the posterior hypothalamus to be specifically activated during but not outside cluster headache attacks. Evidence from task related functional imaging approaches however is scarce. METHODS: Twenty-one inactive cluster headache patients (episodic cluster headache out of bout), 16 active cluster headache patients (10 episodic cluster headache in bout, 6 chronic cluster headache) and 18 control participants underwent high resolution brainstem functional magnetic resonance imaging of trigeminal nociception using gaseous ammonia as a painful stimulus. RESULTS: Following trigeminonociceptive stimulation with ammonia there was a significantly stronger activation within the posterior hypothalamus in episodic cluster headache patients out of bout when compared to controls. When contrasting estimates of the pain contrast, active cluster headache patients where in between the two other groups but did not differ significantly from either. CONCLUSION: The posterior hypothalamus might thus be hyperexcitable in cluster headache patients outside the bout while excitability to external nociceptive stimuli decreases during in bout periods, probably due to frequent hypothalamic activation and possible neurotransmitter exhaustion during cluster attacks.

Peptides, MAbs, Molecules, Mechanisms, and More: Taking a Stab at Cluster Headache.

BACKGROUND: Cluster headache is a highly disabling neurological disorder. PURPOSE: The purpose of this review is to highlight recent therapeutic advances in the treatment of cluster headache such as monoclonal antibodies as well as non-invasive vagus nerve stimulation, and examine future potential therapeutic targets. DISCUSSION: Several therapeutic agents currently in use may have underlying mechanisms important to cluster headache pathophysiology and have yet to be completely elucidated. The psychobiological aspects of cluster headache have a significant impact on patients, as well as pose limitations for treatment. Neuropeptides may play a role in underlying mechanisms in why cluster headache patients are frequent tobacco smokers. Alterations in the hypothalamic-pituitary-adrenal axis and neuroinflammation may play a role in suicidality. The circadian nature of cluster headache may generate the development of future treatment options. New understanding of mechanisms underlying post-traumatic headache may also provide insights into cluster headache pathophysiology. CONCLUSION: Molecular targets and neuromodulation advances have paved the way for a new generation of therapeutic agents in cluster headache. There are several other potential targets.

Changes in grey matter volume and functional connectivity in cluster headache versus migraine.

Cluster headache (CH) shows a more severe clinical picture than migraine (Mig). We tested whether brain changes can explain such difference. Multimodal MRI was acquired in attack-free patients with CH (n = 12), Mig (n = 13) and in normal controls (NC, n = 13). We used FSL for MRI data analysis and nonparametric permutation testing for voxelwise analyses (p < 0.01, corrected). CH showed lower grey matter (GM) volume, compared to Mig and NC, in frontal cortex regions (inferior frontal gyrus and frontal pole [FP], respectively) and, only compared to Mig, in lateral occipital cortex (LOC). Functional connectivity (FC) of CH was higher than Mig and NC within working memory and executive control networks and, only compared to Mig, between cerebellar and auditory language comprehension networks. In the attack-free state, the CH brain seems to be characterized by: (i) GM volume decrease, compared to both Mig and NC, in pain modulation regions (FP) and, only with respect to Mig, in a region of visual processing modulation during pain and working memory (LOC); (ii) increased FC at short range compared to both Mig and NC and at long range only with respect to Mig, in key cognitive networks, likely due to maladaptation towards more severe pain experience.

Temporal changes of circadian rhythmicity in cluster headache.

OBJECTIVE: To investigate the temporal changes of circadian rhythmicity in relation to the disease course in patients with cluster headache. METHODS: In this multicenter study, patients with cluster headache were recruited between September 2016 and July 2018. We evaluated the patients for circadian rhythmicity and time of cluster headache attacks in the current bout and any experience of bout-to-bout change in circadian rhythmicity. We analyzed the patterns of circadian rhythmicity in relation to the disease progression (the number of total lifetime bouts, grouped into deciles). RESULTS: Of the 175 patients in their active, within-bout period, 86 (49.1%) had circadian rhythmicity in the current bout. The prevalence of circadian rhythmicity in the active period was overall similar regardless of disease progression. Sixty-three (46.3%) out of 136 patients with ≥2 bouts reported bout-to-bout changes in circadian rhythmicity. The most frequent time of cluster headache attacks was distributed evenly throughout the day earlier in the disease course and dichotomized into hypnic and midday as the number of lifetime bouts increased (p = 0.037 for the homogeneity of variance). When grouped into nighttime and daytime, nighttime attacks were predominant early in the disease course, while daytime attacks increased with disease progression (up to 7th deciles of total lifetime bouts, p = 0.001) and decreased in patients with the most advanced disease course (p = 0.013 for the non-linear association). CONCLUSIONS: Circadian rhythmicity is not a fixed factor, and changes according to the disease course. Our findings will be valuable in providing a new insight into the stability of functional involvement of the suprachiasmatic nucleus in the pathophysiology of cluster headache.