An Analysis of the Determinants of the Health-Related Quality of Life in Asian Patients With Cluster Headaches During Cluster Periods Using the Time Trade-Off Method.

BACKGROUND AND PURPOSE: Patients with cluster headache (CH) exhibit impaired health-related quality of life (HRQoL). However, there have been few studies related to the HRQoL of patients with CH from Asian backgrounds. This study aimed to determine the impact of CH on HRQoL and to identify the factors affecting HRQoL in patients with CH during cluster periods. METHODS: This prospective study enrolled patients with CH from 17 headache clinics in South Korea between September 2016 and February 2021. The study aimed to determine HRQoL in patients with CH using the EuroQol 5 Dimensions (EQ-5D) index and the time trade-off (TTO) method. Age- and sex-matched headache-free participants were recruited as a control group. RESULTS: The study included 423 patients with CH who experienced a cluster period at the time. EQ-5D scores were lower in patients with CH (0.88±0.43, mean±standard deviation) than in the controls (0.99±0.33, p<0.001). The TTO method indicated that 58 (13.6%) patients with CH exhibited moderate-to-severe HRQoL deterioration. The HRQoL states in patients with CH were associated with current smoking patterns, headache severity, frequency, and duration, and scores on the Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health Questionnaire 9-item scale (PHQ-9), 6-item Headache Impact Test, and 12-item Allodynia Symptom Checklist. Multivariable logistic regression analyses demonstrated that the HRQoL states in patients with CH were negatively correlated with the daily frequency of headaches, cluster period duration, and GAD-7 and PHQ-9 scores. CONCLUSIONS: Patients with CH experienced a worse quality of life during cluster periods compared with the headache-free controls, but the degree of HRQoL deterioration varied among them. The daily frequency of headaches, cluster period duration, anxiety, and depression were factors associated with HRQoL deterioration severity in patients with CH.

Guidelines of the International Headache Society for Controlled Clinical Trials in Cluster Headache.

In 1995, a committee of the International Headache Society developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Cluster Headache. These have not been revised. With the emergence of new medications, neuromodulation devices and trial designs, an updated version of the International Headache Society Guidelines for Controlled Clinical Trials in Cluster Headache is warranted. Given the scarcity of evidence-based data for cluster headache therapies, the update is largely consensus-based, but takes into account lessons learned from recent trials and demands by patients. It is intended to apply to both drug and neuromodulation treatments, with specific proposals for the latter when needed. The primary objective is to propose a template for designing high quality, state-of-the-art, controlled clinical trials of acute and preventive treatments in episodic and chronic cluster headache. The recommendations should not be regarded as dogma and alternative solutions to particular methodological problems should be explored in the future and scientifically validated.

Cerebrovascular reactivity and deep white matter hyperintensities in migraine: A prospective CO2 targeting study.

Several studies suggested the association of migraine with deep white matter hyperintensities (WMHs). We aimed to explore the cerebrovascular reactivity (CVR), deep WMH burden, and their association in patients with migraine using a state-of-the-art methodology. A total of 31 patients with migraine without aura and 31 age/sex-matched controls underwent 3T MRI with prospective end-tidal carbon dioxide (CO2) targeting. We quantified deep WMH clusters using an automated segmentation tool and measured voxel-wise CVR by changes in blood oxygen level-dependent signal fitted to subjects' end-tidal CO2. The association of migraine and CVR with the presence of WMH in each voxel and interaction of migraine and CVR on WMH were analysed. Patients had a higher number of deep WMHs than controls (p = 0.015). Migraine and reduced CVR were associated with increased probability of having WMHs in each voxel (adjusted OR 30.78 [95% CI 1.89-500.53], p = 0.016 and adjusted OR 0.30 [0.29-0.32], p < 0.001, respectively). Migraine had an effect modification on CVR on deep WMHs (p for interaction <0.001): i.e. the association between CVR and WMH was greater in patients than in controls. We suggest that the migraine-WMH association can be explained by the effect modification on the CVR.

Characteristics of pre-cluster symptoms in cluster headache: A cross-sectional multicentre study.

BACKGROUND: Contrary to pre-attack symptoms before an individual cluster headache attack, little is known about the pre-cluster symptoms before the onset of cluster bouts. We previously described pre-attack symptoms before cluster headache attacks. The aim of this study was to investigate characteristics of pre-cluster symptoms in patients with episodic cluster headache. METHODS: In this multicentre study, 184 patients with episodic cluster headache were recruited between October 2018 and December 2020. They were interviewed by investigators and completed a structured questionnaire. To investigate pre-cluster and pre-attack symptoms, we assessed 20 symptoms and signs using the questionnaire. RESULTS: The upcoming cluster bout was predictable in 35.3% (n = 65/184) of the patients. When present, pre-cluster symptoms occurred at a median duration of 7 days (interquartile range, 2.3-14 days) before the onset of the cluster bout. Patients with pre-cluster symptoms showed a higher proportion of women, prevalence of pre-attack symptoms and seasonal rhythmicity, frequency of cluster headache attacks per day, and total number of cluster bouts compared to patients without pre-cluster symptoms. In univariable and multivariable logistic regression analyses, female sex was associated with the predictability of pre-cluster symptoms (odds ratio = 2.297, p = 0.016). CONCLUSIONS: The upcoming cluster bout was predicted in approximately 35% of patients with episodic cluster headache, which may allow for an earlier preventive treatment and help understand the pathophysiology.

Effect of caffeine and caffeine cessation on cerebrovascular reactivity in patients with migraine.

OBJECTIVE: To investigate the effect of chronic caffeine use and caffeine cessation on vasodilatory function in the posterior circulation in patients with migraine. BACKGROUND: Studies regarding cerebrovascular reactivity (CVR) using vasodilatory stimuli in patients with migraine have yielded conflicting results. We postulated that CVR may not be static, and caffeine might negatively affect vasodilatory function via its vasoconstrictive effect. METHODS: In this prospective longitudinal observation study, we recruited patients with episodic migraine who were 18-50 years of age and free of vascular risk factors at the Samsung Medical Center between August 2015 and March 2020. Patients were classified into caffeine users and non-users at baseline, and caffeine users were instructed to discontinue caffeine intake. We measured the mean breath-holding index (BHI) of bilateral posterior cerebral arteries (PCA) using transcranial Doppler in all the included patients at baseline and followed up after 3 months. We compared breath-holding indices cross-sectionally between caffeine users and non-users and analyzed BHI changes according to caffeine cessation. RESULTS: In total, 84 patients completed the study protocol. Cross-sectional analysis showed that the baseline BHI of PCA was lower in caffeine users (n = 56, 1.1 [interquartile range (IQR) 0.8-1.3]) than that in nonusers (n = 28, 1.3 [IQR 1.0-1.5], p = 0.030). In the longitudinal analysis, caffeine quitters showed a significant improvement in BHI in PCA (baseline 1.1 [IQR 0.8-1.2], follow-up 1.3 [IQR 1.0-1.4], p = 0.034), whereas continuous users and non-users did not. Multivariable analysis showed an independent effect of caffeine cessation on the changes in BHI of PCA (unstandardized ß = 0.27, 95% confidence interval 0.01-0.53, p = 0.044). CONCLUSION: In patients with migraine, caffeine use is associated with reduced CVR in the posterior circulation, and caffeine cessation might be beneficial in improving CVR.

Diagnostic Delay and Its Predictors in Cluster Headache.

OBJECTIVE: Cluster headache (CH) is a rare, primary headache disorder, characterized of excruciating, strictly one-sided pain attacks and ipsilateral cranial autonomic symptoms. Given the debilitating nature of CH, delayed diagnosis can increase the disease burden. Thus, we aimed to investigate the diagnostic delay, its predictors, and clinical influence among patients with CH. METHODS: Data from a prospective multicenter CH registry over a 4-year period were analyzed. CH was diagnosed according to the International Classification of Headache Disorders (ICHD)-3 criteria, and diagnostic delay of CH was assessed as the time interval between the year of the first onset and the year of CH diagnosis. Patients were classified into three groups according to the tertiles of diagnostic delay (1st tertile, <1 year; 2nd tertile, 1-6 years; and 3rd tertile, ≥7 years). RESULTS: Overall, 445 patients were evaluated. The mean duration of diagnosis delay was 5.7 ± 6.7 years, (range, 0-36 years). Regarding the age of onset, majority of young patients (age <20 years) belonged to the third tertile (60%), whereas minority of old patients (>40 years) belonged to the third tertile (9.0%). For year of onset, the proportion of patients in the 3rd tertile was the highest for the groups before the publication year of the ICHD-2 (74.7%) and the lowest for the groups after the publication year of the ICHD-3 beta version (0.5%). Compared with the first CH, episodic CH [multivariable-adjusted odds ratio (aOR) = 5.91, 95% CI = 2.42-14.48], chronic CH (aOR = 8.87, 95% CI = 2.66-29.51), and probable CH (aOR = 4.12, 95% CI = 1.48-11.43) were associated with the tertiles of diagnostic delay. Age of onset (aOR = 0.97, 95% CI = 0.95-0.99) and PHQ-9 score (aOR = 0.96, 95% CI = 0.93-0.99) were inversely associated with the tertile of diagnostic delay. The prevalence of suicidal ideation was highest in the patients of the third tertile. The mean HIT-6 score increased significantly with the diagnostic delay (p = 0.041). CONCLUSIONS: Patients with a younger onset of CH have a higher risk of diagnostic delay. Nevertheless, the rate of delayed diagnosis gradually improved over time and with the publication of the ICHD criteria, supporting the clinical significance of diagnostic clinical criteria and headache education to reduce the disease burden of CH.

Smoking History and Clinical Features of Cluster Headache: Results from the Korean Cluster Headache Registry.

BACKGROUND AND PURPOSE: Epidemiologic data suggest that cluster headache (CH) is significantly associated with cigarette smoking. The aim of this study was to determine differences in features between patients with a smoking history and those who are never-smokers, using data from a prospective multicenter registry. METHODS: Data used in this study were obtained from the Korean Cluster Headache Registry that collected data from consecutive patients diagnosed with CH. We compared clinical and demographic features between ever-smokers (current or former smokers) and never-smokers. RESULTS: This study enrolled 250 patients who were diagnosed with CH, of which 152 (60.8%) were ever-smokers and 98 (39.2%) were never-smokers. The age at CH onset was significantly lower in the never-smoker group than in the ever-smoker group [27.1±12.9 years vs. 30.6±10.9 years (mean±standard deviation), p=0.024]. Seasonal rhythmicity (58.1% vs. 44.7%, p=0.038) and triptan responsiveness (100% vs. 85.1%, p=0.001) were higher in never-smokers, while other clinical features such as pain severity, duration, attack frequency, and associated autonomic symptoms did not differ significantly between the groups. The male-to-female ratio was markedly higher in ever-smokers (29.4:1) than in never-smokers (1.7:1). CONCLUSIONS: Most of the clinical features did not differ significantly between patients with a smoking history and never-smokers. However, the age at CH onset, sex ratio, and seasonal rhythmicity were significantly associated with smoking history.

RCVS-TCH score can predict reversible cerebral vasoconstriction syndrome in patients with thunderclap headache.

Reversible cerebral vasoconstriction syndrome (RCVS) is one of the most important differential diagnosis in patients with thunderclap headache (TCH). We aimed to develop a new scoring system for RCVS in patients with TCH. We retrospectively analyzed 72 patients enrolled in the prospective study of TCH conducted in 2015-2016 (derivation set). We identified possible predictors for the diagnosis of RCVS and constructed a prediction model (RCVS-TCH score) using the multivariable logistic regression model. Diagnostic performance was validated to an independent validation set from our headache registry. The derivation set comprised 41 patients with RCVS and 31 with non-RCVS, and the validation set included 253 patients with TCH (165 with RCVS and 88 with non-RCVS). The RCVS-TCH score (range: 0-12) contained four predictors: recurrent TCHs, female sex, triggering factor for TCH (single or multi) and blood pressure surge. The C-index of RCVS-TCH score was 0.929 (95% CI = 0.874-0.984). The RCVS-TCH score ≥ 7 had a sensitivity of 80% and a specificity of 97% in discriminating RCVS from non-RCVS. In the validation set, RCVS-TCH score showed a C-index of 0.861 (95% CI = 0.815-0.908). In our study, the RCVS-TCH showed good performance, which may aid the diagnosis of RCVS among patients with TCH.

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.

Clinical characteristics of pre-attack symptoms in cluster headache: A large series of Korean patients.

BACKGROUND: Previous studies have reported notable differences in demographic and clinical features of cluster headache between Western and Asian populations, including lower prevalence of the chronic type and in women. Recently, prodromal symptoms of migraine and pre-attack symptoms of cluster headache have drawn attention regarding their potential pathophysiological implications and pre-emptive treatment. However, pre-attack symptoms of cluster headache have not been studied in the Asian population. METHODS: A total of 136 patients with cluster headache (21 first-onset, 110 episodic, and five chronic cases) were recruited in this multi-center study between October 2018 and December 2019. We evaluated the characteristics of pre-attack symptoms in a current bout using a structured questionnaire. Univariable and multivariable logistic regression analyses were performed to evaluate the factors associated with presence of pre-attack symptoms. RESULTS: Pre-attack symptoms were reported in 71.3% of our patients with cluster headache. When present, pre-attack symptoms occurred at a median of 20 minutes (range 1-120) before the attack. The prevalence of local and painful, local and painless sensory, autonomic, and general symptoms was 58.8%, 14.7%, 11.0%, and 30.1%, respectively. Multivariable logistic regression analysis revealed that higher number of bouts was associated with higher prevalence of pre-attack symptoms (OR = 1.464, p = 0.044). CONCLUSIONS: Pre-attack symptoms were frequently observed in Korean patients with cluster headache, which was consistent with previous Western studies.

Whole-brain functional connectivity correlates of obesity phenotypes.

Dysregulated neural mechanisms in reward and somatosensory circuits result in an increased appetitive drive for and reduced inhibitory control of eating, which in turn causes obesity. Despite many studies investigating the brain mechanisms of obesity, the role of macroscale whole-brain functional connectivity remains poorly understood. Here, we identified a neuroimaging-based functional connectivity pattern associated with obesity phenotypes by using functional connectivity analysis combined with machine learning in a large-scale (n ~ 2,400) dataset spanning four independent cohorts. We found that brain regions containing the reward circuit positively associated with obesity phenotypes, while brain regions for sensory processing showed negative associations. Our study introduces a novel perspective for understanding how the whole-brain functional connectivity correlates with obesity phenotypes. Furthermore, we demonstrated the generalizability of our findings by correlating the functional connectivity pattern with obesity phenotypes in three independent datasets containing subjects of multiple ages and ethnicities. Our findings suggest that obesity phenotypes can be understood in terms of macroscale whole-brain functional connectivity and have important implications for the obesity neuroimaging community.

Machine learning-based automated classification of headache disorders using patient-reported questionnaires.

Classification of headache disorders is dependent on a subjective self-report from patients and its interpretation by physicians. We aimed to apply objective data-driven machine learning approaches to analyze patient-reported symptoms and test the feasibility of the automated classification of headache disorders. The self-report data of 2162 patients were analyzed. Headache disorders were merged into five major entities. The patients were divided into training (n = 1286) and test (n = 876) cohorts. We trained a stacked classifier model with four layers of XGBoost classifiers. The first layer classified between migraine and others, the second layer classified between tension-type headache (TTH) and others, and the third layer classified between trigeminal autonomic cephalalgia (TAC) and others, and the fourth layer classified between epicranial and thunderclap headaches. Each layer selected different features from the self-reports by using least absolute shrinkage and selection operator. In the test cohort, our stacked classifier obtained accuracy of 81%, sensitivity of 88%, 69%, 65%, 53%, and 51%, and specificity of 95%, 55%, 46%, 48%, and 51% for migraine, TTH, TAC, epicranial headache, and thunderclap headaches, respectively. We showed that a machine-learning based approach is applicable in analyzing patient-reported questionnaires. Our result could serve as a baseline for future studies in headache research.

The impact of remission and coexisting migraine on anxiety and depression in cluster headache.

BACKGROUND: Our aim was to investigate the relationship between coexisting cluster headache (CH) and migraine with anxiety and depression during active cluster bouts, and how symptoms change during remission. METHODS: We analyzed data from 222 consecutive CH patients and 99 age- and sex-matched controls using a prospective multicenter registry. Anxiety or depression was evaluated using the Generalized Anxiety Disorder-7 (GAD-7) or Patient Health Questionnaire-9 (PHQ-9), respectively. Moderate-to-severe anxiety or depression was defined as a score of ≥10 at baseline (during a cluster bout). We assessed for changes in anxiety and depression during CH remission periods. RESULTS: Among the CH patients, the prevalence of moderate-to-severe anxiety and depression was seen in 38.2% and 34.6%, respectively. Compared with controls, CH patients were associated with moderate-to-severe anxiety and depression (multivariable-adjusted odds ratio [aOR] = 7.32, 95% confidence intervals [CI] = 3.35-15.99 and aOR = 4.95, 95% CI = 2.32-10.57, respectively). CH patients with migraine were significantly more likely to have moderate-to-severe anxiety and depression (aOR = 32.53, 95% CI = 6.63-159.64 and aOR = 16.88, 95% CI = 4.16-68.38, respectively), compared to controls without migraine. The GAD-7 and PHQ-9 scores were significantly reduced between cluster bout and remission periods (from 6.8 ± 5.6 to 1.6 ± 2.8; P < 0.001, and from 6.1 ± 5.0 to 1.8 ± 2.4; P < 0.001, respectively). CONCLUSIONS: Our results indicate that CH patients are at increased risk of anxiety and depression, especially in the presence of coexisting migraine. However, the anxiety and depression can improve during remission periods.

Effect of Sleep Quality on Headache-Related Impact in Primary Headache Disorders.

BACKGROUND AND PURPOSE: Sleep disturbance is common in patients with primary headache disorders. We were interest in whether poor sleep quality affects patients directly or via increases in the frequency and severity of headaches. To that end, we investigated the direct and indirect effects of sleep quality on the headache-related impact among patients with primary headache disorders. METHODS: We analyzed migraine and tension-type headache (TTH) in patients included in the headache registry of our headache clinic from October 2015 to May 2018. We collected information on the headache frequency, severity, and psychological status. Sleep quality and headache-related impact were measured using the Pittsburgh Sleep Quality Index and Headache Impact Test-6, respectively. We performed path analyses with headache frequency and severity as covariates to determine the direct effect of sleep quality on the headache-related impact, and the indirect effects mediated by increases in the headache frequency and severity. RESULTS: This study included 915 patients: 784 with migraine and 131 with TTH. Worse sleep quality was independently associated with greater headache-related impact in both patients with migraine and those with TTH. Path analysis revealed a direct effect (ß=0.207, p<0.001) of sleep quality and an indirect effect mediated by headache frequency and severity (ß=0.067, p=0.004) on the headache-related impact in migraine. In TTH, only direct effects of sleep quality on the headache-related impact were significant (ß=0.224, p=0.004). CONCLUSIONS: We suggest that poor sleep quality can directly increase the headache-related impact in both patients with migraine and TTH as well as indirectly by increasing the headache frequency and severity in patients with migraine.

Temporal Profile of Blood-Brain Barrier Breakdown in Reversible Cerebral Vasoconstriction Syndrome.

Background and Purpose- Reversible cerebral vasoconstriction syndrome (RCVS) has a unique temporal course of vasoconstriction. Blood-brain barrier (BBB) breakdown is part of the pathophysiology of RCVS, but its temporal course is unknown. We aimed to investigate the temporal profile of BBB breakdown and relevant clinical profiles in a large sample size. Methods- In this prospective observatory bicenter study, patients who underwent contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging within 2 months from onset were included. The presence and extent of BBB breakdown were evaluated using contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging. Contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging data were analyzed using a semiautomated segmentation technique to quantitatively measure the area of Gadolinium leakage into cerebrospinal fluid space. The univariable and multivariable linear regressions were performed to investigate the independent effect of time from onset with adjustment for other covariates. Results- In the 186 patients with angiogram-proven RCVS included in this analysis, BBB breakdown was observed in 52.6%, 56.8%, 30.3%, 40.0%, and 23.8% in the first, second, third, fourth, and ≥fifth week after onset. The extent of BBB breakdown peaked at first and second week, whereas the peak of vasoconstriction was observed at the third week after onset. Multivariable analysis showed the second week from onset (ß, 3.35 [95% CI, 0.07-6.64]; P=0.046) and blood pressure surge (ß, 3.84 [95% CI, 1.75-5.92]; P<0.001) were independently associated with a greater extent of BBB breakdown. A synergistic effect of time from onset and blood pressure surge was found (P for interaction=0.006). Conclusions- Frequency and extent of BBB breakdown are more prominent during the early stage in patients with RCVS, with an earlier peak than that of vasoconstriction. The temporal course of BBB breakdown may provide a pathophysiologic background of the temporal course of neurological complications of RCVS.

Clinical factors influencing the impact of cluster headache from a prospective multicenter study.

Although many patients with cluster headaches (CH) are disabled by their condition, few studies have examined this in detail. This cross-sectional, multicenter observational study prospectively collected demographic and clinical questionnaire data from 224 consecutive patients with CH. We assessed headache impact using the six-item Headache Impact Test (HIT-6) and evaluated the factors associated with the impact of CH. Participants with a HIT-6 score ≥ 60 were classified into a severe impact group. The majority (190, 84.8%) of the participants were classified into the severe impact group. These patients were characterized by younger age, earlier onset of CH, longer duration of each headache attack, higher pain intensity, more cranial autonomic symptoms, a higher proportion of depression or anxiety, higher score of stress, and lower score of quality of life. The anxiety (OR = 1.19, 95% CI: 1.08-1.31, p = 0.006), greater pain intensity (OR = 1.06, 95% CI: 1.02-1.10, p = 0.002), and age (OR = 0.99, 95% CI: 0.99-1.00, p = 0.008) were significant predictors for a severe impact of CH patients. According to the HIT-6 results, most of the CH patients were significantly affected by CH. As well as pain intensity, anxiety and age modulated CH's impact on their lives.

Two-step deep neural network for segmentation of deep white matter hyperintensities in migraineurs.

BACKGROUND AND OBJECTIVE: Patients with migraine show an increased presence of white matter hyperintensities (WMHs), especially deep WMHs. Segmentation of small, deep WMHs is a critical issue in managing migraine care. Here, we aim to develop a novel approach to segmenting deep WMHs using deep neural networks based on the U-Net. METHODS: 148 non-elderly subjects with migraine were recruited for this study. Our model consists of two networks: the first identifies potential deep WMH candidates, and the second reduces the false positives within the candidates. The first network for initial segmentation includes four down-sampling layers and four up-sampling layers to sort the candidates. The second network for false positive reduction uses a smaller field-of-view and depth than the first network to increase utilization of local information. RESULTS: Our proposed model segments deep WMHs with a high true positive rate of 0.88, a low false discovery rate of 0.13, and F1 score of 0.88 tested with ten-fold cross-validation. Our model was automatic and performed better than existing models based on conventional machine learning. CONCLUSION: We developed a novel segmentation framework tailored for deep WMHs using U-Net. Our algorithm is open-access to promote future research in quantifying deep WMHs and might contribute to the effective management of WMHs in migraineurs.

Accurate neuroimaging biomarkers to predict body mass index in adolescents: a longitudinal study.

Obesity is often associated with cardiovascular complications. Adolescent obesity is a risk factor for cardiovascular disease in adulthood; thus, intensive management is warranted in adolescence. The brain state contributes to the development of obesity in addition to metabolic conditions, and hence neuroimaging is an important tool for accurately assessing an individual's risk of developing obesity. Here, we aimed to predict body mass index (BMI) progression in adolescents with neuroimaging features using machine learning approaches. From an open database, we adopted 76 resting-state functional magnetic resonance imaging (rs-fMRI) datasets from adolescents with longitudinal BMI scores. Functional connectivity analyses were performed on cortical surfaces and subcortical volumes. We identified baseline functional connectivity features in the prefrontal-, posterior cingulate-, sensorimotor-, and inferior parietal-cortices as significant determinants of BMI changes. A BMI prediction model based on the identified fMRI biomarkers exhibited a high accuracy (intra-class correlation = 0.98) in predicting BMI at the second visit (1~2 years later). The identified brain regions were significantly correlated with the eating disorder-, anxiety-, and depression-related scores. Based on these results, we concluded that these functional connectivity features in brain regions related to eating disorders and emotional processing could be important neuroimaging biomarkers for predicting BMI progression.

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.