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 prevalence of head and face pain decreased from 1997 to 2017 in Switzerland.

BACKGROUND: Pain in the head and the face is highly prevalent but may have changed during the past years. This study aimed to analyze changes in the prevalence of pain in the head and the face in Switzerland from 1997 to 2017. METHODS: This is a secondary analysis of data collected in the Swiss Health Surveys of 1997-2017. Included persons were 15 years and older. Besides studying demographic data, we analyze the item assessing the presence of "headache, pressure in the head, or facial pain" during the past 4 weeks. Percentages with their Wilson confidence intervals are reported for each response option of categorical variables. Moreover, we calculate the age-standardized number of persons affected by the pain. RESULTS: While 41% reported head and face pain in 1997, the proportion dropped to 31% in 2017. There was a decrease of 19.5% in women and 29.4% in men; after age standardization, the decrease was 16.5% in women and 25.4% in men. The most considerable numerical changes in the percentages of women with pain occurred in those aged 55-69 and 85 and above. In men, the changes were not limited to specific age groups. CONCLUSIONS: The proportion of people reporting headaches, pressure in the head, or facial pain has dropped in Switzerland from 1997 to 2017. However, in women, the prevalence diminished more strongly and consistently in the middle-aged and the elderly than in the young.

Impact of family history for endometriosis, migraine, depression and early menopause on endometriosis symptoms, localization and stage: A case control study.

INTRODUCTION: Endometriosis is a common disabling pain condition in women of childbearing age, frequently showing familial clustering. Nevertheless, little is known about whether familial predispositions influence its severity or presentation. In this study, we investigate disease characteristics in endometriosis patients with a family history (FH) for endometriosis or the comorbidities migraine, depression and early menopause (EMP). MATERIALS AND METHODS: We performed an observational case-control study enrolling women with histologically confirmed endometriosis in a tertiary center. Based on surgical findings, patient records and phone interviews, we examined the relations between a FH for endometriosis, migraine, depression or EMP and endometriotic signs and symptoms, such as response to combined hormonal contraceptives (CHC) and analgesics, disease localization, infiltration depth, Enzian- and rASRM-scores. RESULTS: A positive FH for endometriosis, migraine, depression or EMP was reported by 10.2 %, 33.4 %, 32.6 % and 9.9 % of the 344 patients. A positive FH of endometriosis was associated with an increased risk for high rASRM-scores (rASRM 3 + 4: OR 2.74 (95 % CI 1.16-6.49), p = 0.017) and the presence of endometriomas (OR 2.70 (1.22-5.95), p = 0.011). A positive FH for migraine was associated with less response of endometriosis symptoms to CHC (OR 0.469 (0.27-0.82) p = 0.025). Depression in the family was linked to less severe rASRM-scores (rASRM 3 + 4: OR 0.63 (0.39-0.99), p = 0.046) and less endometriomas (OR 0.58 (0.67-0.92), p = 0.02), but increased the risk of both migraine (OR 1.66 (1.01-2.73), p = 0.043) and depression (OR 3.04 (1.89-4.89), p < 0.001) while showing a better response to CHC (OR 2.0 (1.15-3.48, p < 0.001). Patients with EMP in their family reported more current endometriosis symptoms at present (OR 3.72 (1.67-8.30), p = 0.001), more dysmenorrhea (OR 2.13 (1.04-4.35), p = 0.037), more frequent severe dysmenorrhea (OR 2.32 (1.14-4.74), p = 0.019) and suffered significantly more often > 5 days of non-cyclic pain (OR 3.58 (1.72-7.44), p < 0.001). CONCLUSIONS: Around 30% reported a positive FH for migraine or depression. Patients with a positive FH for endometriosis, migraine, depression or EMP differ in symptoms and surgical findings when compared to controls. While a FH for endometriosis is associated with higher rASRM scores and more endometriomas, women with a FH for depression had lower rASRM scores and less endometriomas while responding better to CHC. In contrast, women with a FH for migraine showed less response to CHC.

Endometriosis features and dienogest tolerability in women with depression: a case-control study.

OBJECTIVE: Primary aim of this study was to investigate endometriosis characteristics of patients with psychiatric conditions or depression. The secondary aim was to study tolerability of dienogest in this context. METHODS: This observational case-control study included endometriosis data from patients visiting our clinic from 2015-2021. We collected information from patient charts and in phone interviews based on a structured survey. Patients with surgical confirmed endometriosis were included. RESULTS: 344 patients fulfilled the inclusion criteria: n = 255 no psychiatric disorder, n = 119 any psychiatric disorder and n = 70 depression. Patients with depression (EM-D, p=.018; p=.035) or psychiatric condition (EM-P, p=.020; p=.048) suffered more often from dyspareunia and dyschezia. EM-P patients had more often primary dysmenorrhoea with higher pain scores (p=.045). rASRM stage or localisation of lesions did not differ. EM-D and EM-P patients discontinued dienogest treatment more often related to worsening of mood (p= .001, p=.002). CONCLUSION: EM-D or EM-P had a higher prevalence of pain symptoms. This could not be attributed to differences in rASRM stage or location of endometriosis lesions. Strong primary dysmenorrhoea might predispose to develop chronic pain-based psychological symptoms. Therefore, early diagnosis and treatment are relevant. Gynaecologist should be aware of the potential impact of dienogest on mood.

Women with endometriosis and psychiatric disorders especially have more dyschezia and dyspareunia, independent from rASRM stage, depth of infiltration and localisation of endometriosis lesions. Dienogest has an impact on mood especially in already prone patients.Trial registration: trial registration number: NCT04816357. https://clinicaltrials.gov/ct2/show/NCT04816357Date of registration: 22.03.2021, date of enrolment of the first subject: 25.03.2021.

Endometriosis Features in Women With and Without Migraine.

Background: This study examines endometriosis (EM) features in women with EM and migraines (MG) (EM-MG) and women with EM alone (EM-O). The comorbidity of MG and EM is well known. However, knowledge about differences in symptoms, clinical manifestations, and severity of EM between EM-MG and EM-O is scarce. Materials and Methods: We conducted a cross-sectional observational study of premenopausal patients with biopsy-confirmed EM treated in our department from 2015 to 2021. All patients underwent surgical treatment for EM. Information about infiltration depth and localization of EM was available. We interviewed patients using a structured questionnaire that includes questions about clinical characteristics, symptoms, and treatment history. We reported categorical variables as frequencies and continuous variables as means with standard deviations. We compared subgroups (EM-MG vs. EM-O) using an independent sample t-test, the Wilcoxon-Mann-Whitney test, chi-square test, and Fisher's exact test. The significance level was 0.05. Results: We included 344 participants: 250 with EM-O and 94 with EM-MG. EM-MG had less severe revised American Society of Reproductive Medicine scores (p = 0.023), more deliveries (p = 0.009), more and higher scores of dysmenorrhea at menarche (p = 0.044; p = 0.036), prolonged heavy menstrual bleeding (p = 0.009), more and prolonged pain during menstrual bleeding (p = 0.011, p = 0.039), and more dyschezia (p < 0.001) compared with EM-O. Conclusion: Migraineurs experienced more intense EM symptoms at lower EM stages. This discrepancy strongly indicates pain sensitizations and a lower pain threshold in patients with EM-MG. Knowledge about EM features allows early diagnosis and treatment of women with potential EM-MG, both highly disabling conditions. Clinical Trials.gov (NCT04816357).

Migraine and Happiness.

Objective: To investigate the association between happiness and migraine. Background: Contemporary operationalizations of happiness include the prevailing positive over negative affect and the satisfaction with life. Generally, extreme events and circumstances influence happiness only temporarily. However, how does periodic cycling between being relatively healthy and relatively disabled-as in migraineurs-affect happiness? Migraine is a primary headache disorder, in which headache attacks intermittently interfere with normal living and cause a significant personal, societal, and potentially irreversible disease burden. Methods: In this cross-sectional observational study, migraineurs completed the satisfaction with life scale (SWLS), the Patient Health Questionnaire, and the Generalized Anxiety Disorder scale and reported their headache frequency as well as recent changes in that frequency. Furthermore, participants answered a free text question on how to remain happy despite migraine attacks. We built a regression model with the SWLS score as the dependent variable. Results: Seventy participants completed the questionnaire. The regression model revealed that happiness increases with headache days, and subsequent analysis showed a U-shaped relationship between headache frequency and happiness. The participants' advice on remaining happy focused on upvaluing the pain-free time or relieving the attacks themselves. The latter was increasingly common with longer disease durations. Conclusions: Both high and low headache frequencies facilitate adaptation to the disorder, while intermediate frequencies resulted in lower life satisfaction. The nonlinear relationship between happiness and headache days may be due to "hedonic habituation" and implies that headache calendars do not necessarily correctly reflect patients' difficulty to feel well despite the disorder. Many patients advised other migraineurs to increase happiness by enjoying pain-free time. However, with increasing disease duration, patients' recommendations focused on coping with attacks.

Dealing with Headache: Sex Differences in the Burden of Migraine- and Tension-Type Headache.

OBJECTIVE: The aim of this study was to investigate sex differences in the burden of migraine and tension-type headache (TTH). BACKGROUND: Migraine and TTH are more common in women than in men, with differences in comorbidities, treatment responses, disease-modifying factors, and ictal and interictal burden of disease. Information about sex-related influences on ictal and interictal burden is limited, and an increased understanding is mandatory to provide tailored individual treatment for female and male patients. METHODS: Participants answered an online survey based on the EUROLIGHT questionnaire. Inclusion criteria were the consent to participate, complete responses to the diagnostic questions, and information about their sex. Sex differences were investigated using the Mann-Whitney U test or Chi-square test. For detecting factors that influence the burden of disease, we built binary regression models. RESULTS: We included 472 (74.6% female) migraineurs and 161 (59.6% female) participants with TTH. Women with migraine reported significantly more problems in their love lives, more self-concealment, less feelings of being understood by family and friends, more interictal anxiety, a higher pain severity, and more depression and anxiety symptoms than men. For TTH, we did not find significant sex-related differences. A higher headache frequency was the factor that increased the burden of disease in female but not in male migraneurs. CONCLUSION: The burden of disease was higher in women than men with migraine in many aspects, but not with TTH. Therefore, according to our results, there is a need for sex-specific precision medicine for migraine but not TTH. Controlling the headache frequency with a proper acute or prophylactic treatment and treating comorbid depression and anxiety symptoms is crucial to ease migraine's burden, especially in women.

Examining Side Effect Variability of Antipsychotic Treatment in Schizophrenia Spectrum Disorders: A Meta-analysis of Variance.

Side effects of antipsychotic drugs play a key role in nonadherence of treatment in schizophrenia spectrum disorders (SSD). While clinical observations suggest that side effect variability between patients may be considerable, statistical evidence is required to confirm this. Here, we hypothesized to find larger side effect variability under treatment compared with control. We included double-blind, placebo-controlled, randomized controlled trials (RCTs) of adults with a diagnosis of SSD treated with 1 out of 14 antipsychotics. Standard deviations of the pre-post treatment differences of weight gain, prolactin levels, and corrected QT (QTc) times were extracted. The outcome measure was the variability ratio of treatment to control for individual antipsychotic drugs and the overall variability ratio of treatment to control across RCTs. Individual variability ratios were weighted by the inverse-variance method and entered into a random-effects model. We included N = 16 578 patients for weight gain, N = 16 633 patients for prolactin levels, and N = 10 384 patients for QTc time. Variability ratios (VR) were significantly increased for weight gain (VR = 1.08; 95% CI: 1.02-1.14; P = .004) and prolactin levels (VR = 1.38; 95% CI: 1.17-1.62; P < .001) but did not reach significance for QTc time (VR = 1.05; 95% CI: 0.98-1.12; P = 0.135). We found marked differences between individual antipsychotics and increased variability in side effects in patients under treatment with antipsychotics suggesting that subgroups of patients or individual patients may benefit from treatment allocation through stratified or personalized medicine.

Treatment effect variability in brain stimulation across psychiatric disorders: A meta-analysis of variance.

Noninvasive brain stimulation methods such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are promising add-on treatments for a number of psychiatric conditions. Yet, some of the initial excitement is wearing off. Randomized controlled trials (RCT) have found inconsistent results. This inconsistency is suspected to be the consequence of variation in treatment effects and solvable by identifying responders in RCTs and individualizing treatment. However, is there enough evidence from RCTs that patients respond differently to treatment? This question can be addressed by comparing the variability in the active stimulation group with the variability in the sham group. We searched MEDLINE/PubMed and included all double-blinded, sham-controlled RCTs and crossover trials that used TMS or tDCS in adults with a unipolar or bipolar depression, bipolar disorder, schizophrenia spectrum disorder, or obsessive compulsive disorder. In accordance with the PRISMA guidelines to ensure data quality and validity, we extracted a measure of variability of the primary outcome. A total of 130 studies with 5748 patients were considered in the analysis. We calculated variance-weighted variability ratios for each comparison of active stimulation vs sham and entered them into a random-effects model. We hypothesized that treatment effect variability in TMS or tDCS would be reflected by increased variability after active compared with sham stimulation, or in other words, a variability ratio greater than one. Across diagnoses, we found only a minimal increase in variability after active stimulation compared with sham that did not reach statistical significance (variability ratio = 1.03; 95% CI, 0.97, 1.08, P = 0.358). In conclusion, this study found little evidence for treatment effect variability in brain stimulation, suggesting that the need for personalized or stratified medicine is still an open question.

Synthesis of Long Oxahelicenes by Polycyclization in a Flow Reactor.

A series of oxahelicenes composed of ortho/meta-annulated benzene/pyridine and 2H-pyran rings were synthesized on the basis of the cobalt(I)-mediated (or rhodium(I)- or nickel(0)-mediated) double, triple, or quadruple [2+2+2] cycloisomerization of branched aromatic hexa-, nona-, or dodecaynes, thus allowing the construction of 6, 9, or 12 rings in a single operation. The use of a flow reactor was found to be beneficial for the multicyclization reactions. The stereogenic centers present in some of the oligoynes steered the helical folding in such a way that the final oxa[9]-, [13]-, [17]- and [19]helicenes were obtained in both enantiomerically and diastereomerically pure form. Specifically, the oxa[19]helicenes beat the current record in the length of a helicene backbone. Single-molecule conductivity was studied by the mechanically controllable break-junction method with a pyridooxa[9]helicene.

Stability and Conversion of Tin Zintl Anions in Liquid Ammonia Investigated by NMR spectroscopy.

Homoatomic polyanions of post-transition main-group metals, namely, Zintl anions, are precast in analogous Zintl phases and can react in solution to form new materials. Despite comprehensible reaction approaches, the formed products cannot be planned in advance, as hitherto undetected and therefore disregarded side reactions take place. The outcomes and interpretations of the reactions of Zintl anions are so far based mainly on crystal structures, which only allow characterization of the product that has the lowest solubility. Here we present the results of our investigation of the stability of highly charged tin Zintl anions in liquid ammonia, which is not exclusively based on solution effects but also on the oxidative influence of the solvent. This allows for a deeper understanding of the ongoing processes in solution and opens doors to the directed synthesis of transition metal complexes of Sn4 (4-) , here shown by its reactivity towards MesCu.

Elongated Gilman cuprates: the key to different reactivities of cyano- and iodocuprates.

In the past the long-standing and very controversial discussion about a special reactivity of cyano- versus iodocuprates concentrated on the existence of higher-order cuprate structures. Later on numerous structural investigations proved the structural equivalence of iodo and cyano Gilman cuprates and their subsequential intermediates. For dimethylcuprates similar reactivities were also shown. However, the reports about higher reactivities of cyanocuprates survived obstinately in many synthetic working groups. In this study we present an alternative structural difference between cyano- and iodocuprates, which is in agreement with the results of both sides. The key is the potential incorporation of alkyl copper in iodo but not in cyano Gilman cuprates during the reaction. In the example of cuprates with a highly soluble substituent (R = Me3SiCH2) we show that in the case of iodocuprates during the reaction several copper-rich complexes are formed, which consume additional iodocuprate and provide lower reactivities. To confirm this, a variety of highly soluble copper-rich complexes were synthesized, and their molecular formulas, the position of the equilibriums, their monomers and their aggregation trends were investigated by NMR spectroscopic methods revealing extended iodo Gilman cuprates. In addition, the effect of these copper-rich complexes on the yields of cross-coupling reactions with an alkyl halide was tested, resulting in reduced yields for iodocuprates. Thus, this study gives an explanation for the thus far confusing results of both similar and different reactivities of cyano- and iodocuprates. In the case of small substituents the produced alkyl copper precipitates and similar reactivities are observed. However, iodocuprates with large substituents are able to incorporate alkyl copper units. The resulting copper-rich species have less polarized alkyl groups, i.e. gradually reduced reactivities.

Synthesis of heteroatomic Zintl anions in liquid ammonia--the new highly charged [Sn4Bi4]4- and fully ordered [Sn2Bi2]2-.

The new Zintl anion [Sn(4)Bi(4)](4-), synthesized by dissolving CsSnBi in liquid ammonia, forms a monocapped nortricyclane-like cage. Its electron localization function (ELF) analysis shows evidence for 3-centre bonding. The analogous reaction with KSnBi results in a crystallographically fully ordered tetrahedral [Sn(2)Bi(2)](2-) ion.

Ligand exchange reactions in Cu(III) complexes: mechanistic insights by combined NMR and DFT studies.

NMR studies of (13)C/(12)C isotopic patterns in Cu(iii) intermediates and reaction products together with DFT calculations of possible reaction pathways indicate an intermolecular S(N)2 like substitution mechanism for ligand exchange reactions in square planar Cu(iii) complexes, which is proposed to be slow compared to reductive elimination at synthetic conditions.