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.

Relationship between subjectively-rated and objectively-tested physical function across six different medical diagnoses.

OBJECTIVE: To quantify and compare associations and relationships between self-rated and tested assessments of mainly mobility-related physical function in different diagnoses. DESIGN: Six longitudinal cohort studies before and after inpatient rehabilitation. PATIENTS: Patients with whiplash-associated disorder (n = 71), low back pain (n = 121), fibromyalgia (n = 84), lipoedema (n = 27), lymphoedema (n = 78), and post-acute coronary syndrome (n = 64). METHODS: Physical function was measured with the self-rated Short-Form 36 Physical functioning (SF-36 PF) and with the tested 6-Min Walk Distance (6MWD) and assessed by correlation coefficients. Across the 6 cohorts, the relationship between the 2 scores was compared using the ratio between them. RESULTS: The correlations between the 2 scores were mostly moderate to strong at baseline (up to r = 0.791), and weak to moderate for the changes to follow-up (up to r = 0.408). The ratios SF-36 PF to 6MWD were 1.143-1.590 at baseline and 0.930-3.310 for the changes, and depended on pain and mental health. CONCLUSION: Moderate to strong cross-sectional and moderate to weak longitudinal correlations were found between the 6MWD and the SF-36 PF. Pain and mental health should be considered when interpreting physical function. For a comprehensive assessment in clinical practice and research, the combination of self-rated and tested physical function measures is recommended.

Occipital transcranial direct current stimulation in episodic migraine patients: effect on cerebral perfusion.

Cerebral blood flow differs between migraine patients and healthy controls during attack and the interictal period. This study compares the brain perfusion of episodic migraine patients and healthy controls and investigates the influence of anodal transcranial direct current stimulation (tDCS) over the occipital cortex. We included healthy adult controls and episodic migraineurs. After a 28-day baseline period and the baseline visit, migraine patients received daily active or sham anodal tDCS over the occipital lobe for 28 days. All participants underwent a MRI scan at baseline; migraineurs were also scanned shortly after the stimulation period and about five months later. At baseline, brain perfusion of migraine patients and controls differed in several areas; among the stimulated areas, perfusion was increased in the cuneus of healthy controls. At the first visit, the active tDCS group had an increased blood flow in regions processing visual stimuli and a decreased perfusion in other areas. Perfusion did not differ at the second follow-up visit. The lower perfusion level in migraineurs in the cuneus indicates a lower preactivation level. Anodal tDCS over the occipital cortex increases perfusion of several areas shortly after the stimulation period, but not 5 months later. An increase in the cortical preactivation level could mediate the transient reduction of the migraine frequency.Trial registration: NCT03237754 (registered at clincicaltrials.gov; full date of first trial registration: 03/08/2017).

Assessing the Risk of Developing Delirium on Admission to Inpatient Rehabilitation: A Clinical Prediction Model.

OBJECTIVES: To develop a clinical model to predict the risk of an individual patient developing delirium during inpatient rehabilitation, based on patient characteristics and clinical data available on admission. DESIGN: Retrospective observational study based on electronic health record data. SETTING AND PARTICIPANTS: We studied a previously validated data set of inpatients including incident delirium episodes during rehabilitation. These patients were admitted to ZURZACH Care, Rehaklinik Bad Zurzach, a Swiss inpatient rehabilitation clinic, between January 1, 2015, and December 31, 2018. METHODS: We performed logistic regression analysis using backward and forward selection with alpha = 0.01 to remove any noninformative potential predictor. We subsequentially used the Akaike information criterion (AIC) to select the final model among the resulting "intermediate" models. Discrimination of the final prediction model was evaluated using the C-statistic. RESULTS: Of the 20 candidate predictor variables, 6 were included in the final prediction model: a linear spline of age with 1 knot at 60 years and a linear spline of the functional independence measure (FIM), a measure of the functional degree of patients independency, with 1 knot at 64 points, diagnosis of disorders of fluid, electrolyte, and acid-base balance (E87), use of other analgesic and antipyretics (N02B), use of anti-parkinson drugs (N04B), and an anticholinergic burden score (ACB) of ≥3 points. CONCLUSIONS AND IMPLICATIONS: Our clinical prediction model could, upon validation, identify patients at risk of incident delirium at admission to inpatient rehabilitation, and thus enable targeted prevention strategies.

Guideline on multimodal rehabilitation for patients with post-intensive care syndrome.

BACKGROUND: Intensive Care Unit (ICU) survivors often experience several impairments in their physical, cognitive, and psychological health status, which are labeled as post-intensive care syndrome (PICS). The aim of this work is to develop a multidisciplinary and -professional guideline for the rehabilitative therapy of PICS. METHODS: A multidisciplinary/-professional task force of 15 healthcare professionals applied a structured, evidence-based approach to address 10 scientific questions. For each PICO-question (Population, Intervention, Comparison, and Outcome), best available evidence was identified. Recommendations were rated as "strong recommendation", "recommendation" or "therapy option", based on Grading of Recommendations, Assessment, Development and Evaluation principles. In addition, evidence gaps were identified. RESULTS: The evidence resulted in 12 recommendations, 4 therapy options, and one statement for the prevention or treatment of PICS. RECOMMENDATIONS: early mobilization, motor training, and nutrition/dysphagia management should be performed. Delirium prophylaxis focuses on behavioral interventions. ICU diaries can prevent/treat psychological health issues like anxiety and post-traumatic stress disorders. Early rehabilitation approaches as well as long-term access to specialized rehabilitation centers are recommended. Therapy options include additional physical rehabilitation interventions. Statement: A prerequisite for the treatment of PICS are the regular and repeated assessments of the physical, cognitive and psychological health in patients at risk for or having PICS. CONCLUSIONS: PICS is a variable and complex syndrome that requires an individual multidisciplinary, and multiprofessional approach. Rehabilitation of PICS should include an assessment and therapy of motor-, cognitive-, and psychological health impairments.

Effects of Inpatient Rehabilitation in Leg Lymphedema: A Naturalistic Prospective Cohort Study With Intra-individual Control of Effects.

OBJECTIVE: To quantify therapy-attributable effects of a comprehensive inpatient rehabilitation program for lower limb lymphedema (LLL) and to compare the levels of health-related quality of life (HRQL) to population-based norms. DESIGN: Naturalistic prospective cohort study with intra-individual control of effects. SETTING: Rehabilitation hospital. PARTICIPANTS: Patients with LLL (N=67; 46 women). INTERVENTIONS: Comprehensive, multidisciplinary inpatient rehabilitation with 45-60 hours of therapy. MAIN OUTCOME MEASURES: Short Form 36 (SF-36) for HRQL, lymphedema-specific Freiburg Quality of Life Assessment for lymphatic disorders, Short Version (FLQA-lk), knee-specific Knee Outcome Survey Activities of Daily Living Scale (KOS-ADL), and Symptom Checklist-90Standard (SCL-90S). Observed pre/post rehabilitation effects were individually corrected by subtracting the home waiting-time effects and expressed as standardized effect sizes (ESs) and standardized response means (SRMs). Score differences to norms were quantified by standardized mean differences (SMDs). RESULTS: Participants were on average aged 60.5 years, not yet obese, and had 3 comorbidities (n=67). The greatest improvement was in HRQL on the FLQA-lk with ES=0.767/SRM=0.718, followed by improvements in pain and function with ES/SRM=0.430-0.495 on the SF-36, FLQA-lk, and KOS-ADL (all P<.001). Vitality, mental health, emotional well-being, and interpersonal sensitivity improved most by ES/SRM=0.341-0.456 on all 4 measures (all P≤.003). Post rehabilitation scores were significantly higher than population norms on SF-36 bodily pain (SMD=1.140), vitality (SMD=0.886), mental health (SMD=0.815), and general health (SMD=0.444) (all P<.001), and comparable on the other scales. CONCLUSIONS: Those affected by LLL stages II and III benefited substantially from the intervention, attaining equal or higher levels of HRQL than expected compared with the general population norms. Multidisciplinary, inpatient rehabilitation should be recommended for LLL management.

Potential Risk Factors for, and Clinical Implications of, Delirium during Inpatient Rehabilitation: A Matched Case-Control Study.

OBJECTIVES: To investigate the association between a wide set of baseline characteristics (age, sex, rehabilitation discipline), functional scores [Functional Independence Measure (FIM), cumulative Illness Rating Scale (CIRS)], diseases, and administered drugs and incident delirium in rehabilitation inpatients and, furthermore, to assess clinical implications of developing delirium during rehabilitation. DESIGN: Matched case-control study based on electronic health record data. SETTING AND PARTICIPANTS: We studied rehabilitation stays of inpatients admitted between January 1, 2015, and December 31, 2018, to ZURZACH Care, Rehaklinik Bad Zurzach, an inpatient rehabilitation clinic in Switzerland. METHODS: We conducted unconditional logistic regression analyses to estimate adjusted odds ratios (AORs) with 95% CIs of exposures that were recorded in ≥5 cases and controls. RESULTS: Among a total of 10,503 rehabilitation stays, we identified 125 validated cases. Older age, undergoing neurologic rehabilitation, a low FIM, and a high CIRS were associated with an increased risk of incident delirium. Being diagnosed with a bacterial infection (AOR 2.62, 95% CI 1.06-6.49), a disorder of fluid, electrolyte, or acid-base balance (AOR 2.76, 95% CI 1.19-6.38), Parkinson's disease (AOR 5.68, 95% CI 2.54-12.68), and administration of antipsychotic drugs (AOR 8.06, 95% CI 4.26-15.22), antiparkinson drugs (AOR 2.86, 95% CI 1.42-5.77), drugs for constipation (AOR 2.11, 95% CI 1.25-3.58), heparins (AOR 2.04, 95% CI 1.29-3.24), or antidepressant drugs (AOR 1.88, 95% CI 1.14-3.10) during rehabilitation, or an increased anticholinergic burden (ACB ≥ 3) (AOR 2.59, 95% CI 1.41-4.73) were also associated with an increased risk of incident delirium. CONCLUSIONS AND IMPLICATIONS: We identified a set of factors associated with an increased risk of incident delirium during inpatient rehabilitation. Our findings contribute to detect patients at risk of delirium during inpatient rehabilitation.

The longitudinal influence of tDCS on occipital GABA and glutamate/glutamine levels in episodic migraineurs.

This study investigated differences in the concentration of gamma-aminobutyric acid (GABA) and the combination of glutamine and glutamate (as GLX) in the early visual cortex of patients with episodic migraine and the influence of transcranial direct current stimulation (tDCS) on GABA and GLX. In this single-blind, sham-controlled trial, we randomly assigned patients with episodic migraine to receive daily anodal tDCS or sham stimulation. In addition, we included healthy controls. We acquired proton MR spectroscopy data of the visual cortex with 3 Tesla MRI at baseline and from migraine patients directly after the stimulation period and 4 months later. In 22 migraineurs and 25 controls, the GABA and the GLX concentrations did not differ at baseline between the groups. tDCS resulted in reduced concentrations of GABA but not GLX or the migraine frequency directly after the stimulation period, but not 4 months later. The changes in the levels of GABA in the early visual cortex of patients with episodic migraine in the interictal period suggest an effect of tDCS that allowed for subsequent changes in the migraine frequency. However, we might have missed relevant variations in the concentrations of these neurotransmitters during the follow-up period, as changes in migraine frequency appeared after the first MRI and disappeared before the second.

Comparison of Swiss versus Standard Acupuncture in Patients with Chronic Low Back Pain. A Study Protocol for a Randomized, Controlled, Single-Blind, Parallel Trial.

Introduction: Chronic low back pain (CLBP) cannot sufficiently be treated by pharmacological therapy and generates substantial health-care costs worldwide. Acupuncture, a cost-effective, safe and non-pharmacological therapy, has shown promising results in relieving acute low back pain; however, the optimal acupuncture therapy for CLBP remains controversial. This study will compare two acupuncture methods for pain relief in CLBP. Methods and Analysis: This randomized, controlled, single-blind, parallel trial will be conducted in patients with clinically diagnosed CLBP with a disease duration ≥3 months and an average pain intensity of ≥4 points on an 11-point Pain Intensity Numerical Rating Scale (pain-NRS) on the previous 7 days. Patients will be randomized to 9-week acupuncture therapy using Jiu Gong Points (termed Swiss low back acupuncture, SLBA) or standard acupuncture (SA) therapy (weeks 1-6: two sessions/week, weeks 7-9: one session/week, 15 sessions/patient in total). Measurements will be conducted before the first session (T1), at the end of the 9-week therapy (T2) and after 3- and 6-month follow-up (T3 and T4). The primary hypothesis is that 9 weeks of SLBA will be superior in reducing the pain severity assessed by the pain-NRS compared to SA therapy for CLBP. Secondary outcomes will be derived from the Short-Form 36, Oswestry Disability Index, Multidimensional Pain Inventory questionnaire, Symptom Checklist-90 - Revised questionnaire and a daily pain diary. Assuming a minimal clinically important difference in the pain-NRS of 0.39 and an effect size of ≥0.6 between SLBA and SA, 80% power, 0.05 alpha level and 20% dropouts, a total of 55 patients/arm will be required. The primary outcome will be analyzed in the intention-to-treat population using chained linear regression models. Patients, outcome assessors and data analysts will be blinded to the treatment arm. Trial Registration: Clinicaltrials.gov Identifier: NCT05232487.

Mental and psychosocial health and health related quality of life before and after cardiac rehabilitation: a prospective cohort study with comparison to specific population norms.

BACKGROUND: Data on mental health improvement after cardiac rehabilitation (CR) are contradictory. The aim was to examine the mental and psycho-social health of patients admitted to our rehabilitation center following hospital treatment for acute coronary syndrome, before and after multidisciplinary CR. METHODS: Outcome was measured at admission and discharge by the 36-Item Short Form Survey (SF-36), the Symptom Checklist-90 Revised (SCL-90R), the Coping Strategy Questionnaire (CSQ) and the 6-min-walking distance test. The patients' health status was compared with norms of sex-, age- and comorbidity-matched data from the German general population. Score differences from norms were measured by standardized mean differences (SMDs); health changes were quantified by standardized effect sizes (ESs). Their importance for comprehensive assessment was quantified by explorative factor analysis. RESULTS: Of n = 70 patients followed-up (male: 79%; mean age: 66.6 years), 79% had ≥ 3 comorbidities. At baseline, SF-36 Physical functioning (SMD = - 0.75), Role physical (- 0.90), Social functioning (SMD = - 0.44), and Role emotional (SMD = - 0.45) were significantly worse than the norm. After CR, almost all scores significantly improved by ES = 0.23 (SCL-90R Interpersonal sensitivity) to 1.04 (SF-36 Physical functioning). The strongest factor (up to 41.1% explained variance) for health state and change was the mental health domain, followed by function & pain (up to 26.3%). CONCLUSIONS: Normative deficits in physical and psycho-social health were reported at baseline. After CR, at follow-up, all scores, except phobia, showed significant improvement. The comprehensive measurement of bio-psycho-social health should not be limited to depression and anxiety but include, especially, the somatization and social participation dimensions.

Catastrophizing as a prognostic factor for pain and physical function in the multidisciplinary rehabilitation of fibromyalgia and low back pain.

BACKGROUND: Quantitative data on longitudinal associations between catastrophizing and pain or physical function are patchy. The study aimed to quantify the prognostic value of catastrophizing for pain and function in fibromyalgia and low back pain before and after rehabilitation. METHODS: The associations of state and change on the Multidimensional Pain Inventory (MPI) Pain severity scale, the Short Form 36 (SF-36) Physical functioning scale and the Six-Minute Walking Distance (6MWD) with the Coping Strategies Questionnaire (CSQ) Catastrophizing scale were quantified by multiple regression modelling to adjust for confounders. RESULTS: Sex- and age-matched cohorts (n = 71 each) were compared. Pain and catastrophizing were worse in fibromyalgia than in low back pain, whereas the function levels were comparable. Baseline catastrophizing predicted pain change by adjusted correlations of 0.552 (fibromyalgia) and 0.450 (low back pain), self-rated function by 0.403 and 0.308, and the 6MWD by 0.270 and - 0.072. The change in catastrophizing was associated to the change in pain by 0.440 (fibromyalgia) and 0.614 (low back pain), self-rated function by 0.122 and 0.465, and the 6MWD by 0186 and 0.162. CONCLUSIONS: Catastrophizing (pain-related worrying) was a potential prognostic factor, especially for pain and somewhat less for self-rated physical function but it was only weakly predictive for the walking distance in both conditions, independently of potential confounders, such as sex, age, baseline severity and others. Reduction of maladaptive coping should be integrated into the management of chronic pain. SIGNIFICANCE: Our study showed surprisingly high associations between state and change in catastrophizing to pain relief and functional improvement in chronic pain patients. This is supported by clinical experience and research data, even if the construct and measurement of catastrophizing is under debate. Our findings and those of literature point to more pessimistic self-rating of pain and catastrophizing in fibromyalgia when compared to other conditions. This might obscure positive effects on pain and function achieved by adaptive coping in fibromyalgia.

Cluster Headache and the Comprehension Paradox.

Patients with primary headache disorders such as cluster headache cycle between being entirely healthy and almost completely incapacitated. Sick leave or reduced performance due to headache attacks demands flexibility by their social counterparts. The objective of this study is to test the hypothesis that headache patients cause frustration that grows with the times colleagues have to take over their work. In this study, we analysed cluster headache patients' answers to an online questionnaire. Participants self-reported their number of sick days, the number of days on which leisure activities were missed and whether they felt understood by colleagues and family. We then investigated the correlation between the number of sick days and the proportion of patients feeling understood by colleagues and friends. We found that feeling understood by colleagues and friends decreases with a growing number of sick days. However, when sick days accrue further, this proportion increases again. The number of sick days correlates similarly with both colleagues' and friends' understanding. The number of cluster headache patients feeling understood by others decreases with an increasing number of sick days. Their social circles' frustration with the patients' failure to meet obligations and expectations are a likely reason. With a growing number of sick days, however, the portion of patients feeling understood rises again despite patients meeting others' expectations even less. This 'comprehension paradox' implies the influence of other factors. We suspect that growing numbers of sick days foster understanding as the disability of the disease becomes increasingly apparent.

Clinical features of migraine with onset prior to or during start of combined hormonal contraception: a prospective cohort study.

Many studies have described the features of menstrually related migraines but there is a lack of knowledge regarding the features of migraine in combined hormonal contraceptive users (CHC). Hormone-withdrawal migraines in the pill-free period could differ from those in the natural cycle. Gynaecologic comorbidities, like dysmenorrhea and endometriosis, but also depression or a family history might modify the course of migraine. A better understanding of migraine features linked to special hormonal situations could improve treatment. For this prospective cohort study, we conducted telephone interviews with women using a CHC and reporting withdrawal migraine to collect information on migraine frequency, intensity, triggers, symptoms, pain medication, gynaecologic history and comorbidities (n = 48). A subset of women agreed to also document their migraines in prospective diaries. The mean number of migraine days per cycle was 4.2 (± 2.7). Around 50% of these migraines occurred during the hormone-free interval. Migraine frequency was significantly higher in women who suffered from migraine before CHC start (5.0 ± 3.1) (n = 22) in comparison to those with migraine onset after CHC start (3.5 ± 2.1) (n = 26). Menstrually related attacks were described as more painful (57.5%), especially in women with migraine onset before CHC use (72%) (p < 0.02). Comorbidities were rare, except dysmenorrhea. The majority of migraine attacks in CHC users occur during the hormone-free interval. Similar as in the natural cycle, hormone-withdrawal migraines in CHC users are very intense and the response to acute medication is less good, especially in those women, who developed migraine before CHC use.

Detecting Incident Delirium within Routinely Collected Inpatient Rehabilitation Data: Validation of a Chart-Based Method.

BACKGROUND: Delirium is a brain condition associated with poor outcomes in rehabilitation. It is therefore important to assess delirium incidence in rehabilitation. PURPOSE: To develop and validate a chart-based method to identify incident delirium episodes within the electronic database of a Swiss rehabilitation clinic, and to identify a study population of validated incident delirium episodes for further research purposes. DESIGN: Retrospective validation study. SETTINGS: Routinely collected inpatient clinical data from ZURZACH Care. PARTICIPANTS: All patients undergoing rehabilitation at ZURZACH Care, Rehaklinik Bad Zurzach between 2015 and 2018 were included. METHODS: Within the study population, we identified all rehabilitation stays for which ≥2 delirium-predictive key words (common terms used to describe delirious patients) were recorded in the medical charts. We excluded all prevalent delirium episodes and defined the remaining episodes to be potentially incident. At least two physicians independently confirmed or refuted each potential incident delirium episode by reviewing the patient charts. We calculated the positive predictive value (PPV) with 95% confidence interval (95% CI) for all potential incident delirium episodes and for specific subgroups. RESULTS: Within 10,515 rehabilitation stays we identified 554 potential incident delirium episodes. Overall, 125 potential incident delirium episodes were confirmed by expert review. The PPV of the chart-based method varied from 0.23 (95% CI 0.19-0.26) overall to 0.69 (95% CI 0.56-0.79) in specific subgroups. CONCLUSIONS: Our chart-based method was able to capture incident delirium episodes with low to moderate accuracy. By conducting an additional expert review of the medical charts, we identified a study population of validated incident delirium episodes. Our chart-based method contributes towards an automated detection of potential incident delirium episodes that, supplemented with expert review, efficiently yields a validated population of incident delirium episodes for research purposes.

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.

Comprehensiveness and validity of a multidimensional assessment in patients with chronic low back pain: a prospective cohort study.

BACKGROUND: Chronic low back pain is a multidimensional syndrome affecting physical activity and function, health-related quality of life and employment status. The aim of the study was to quantify the cross-sectional and longitudinal validity of single measurement scales in specific construct domains and to examine how they combine to build a comprehensive outcome, covering the complex construct of chronic low back pain before and after a standardized interdisciplinary pain program. METHODS: This prospective cohort study assessed 177 patients using the Short Form 36 (SF-36), the Multidimensional Pain Inventory (MPI), the Symptom Checklist-90-Revised (SCL-90-R), the Oswestry Disability Index (ODI), and 2 functional performance tests, the Back Performance Scale (BPS) and the 6-Minute Walking Distance (6MWD). The comprehensiveness and overlap of the constructs used were quantified cross-sectionally and longitudinally by bivariate correlations, exploratory factor analysis, and effect sizes. RESULTS: The mean age of the participants was 48.0 years (+/- 12.7); 59.3% were female. Correlations of baseline scores ranged from r = - 0.01 (BPS with MPI Life control) to r = 0.76 (SF-36 Mental health with MPI Negative mood). SF-36 Physical functioning correlated highest with the functional performance tests (r = 0.58 BPS, 0.67 6MWD) and ODI (0.56). Correlations of change scores (difference of follow-up - baseline score) were consistent but weaker. Factor analysis revealed 2 factors: "psychosocial" and "pain & function" (totally explained variance 44.0-60.9%). Psychosocial factors loaded strongest (up to 0.89 SCL-90-R) on the first factor, covering 2/3 of the explained variance. Pain and function (ing) loaded more strongly on the second factor (up to 0.81 SF-36 Physical functioning at follow-up). All scales showed improvements, with effect sizes ranging from 0.16-0.67. CONCLUSIONS: Our results confirm previous findings that the chronic low back pain syndrome is highly multifactorial and comprises many more dimensions of health and quality of life than merely back-related functioning. A comprehensive outcome measurement should include the predominant psychosocial domain and a broad spectrum of measurement constructs in order to assess the full complexity of the chronic low back syndrome. Convergence and divergence of the scales capture the overlapping contents and nuances within the constructs.

Structural brain network characteristics in patients with episodic and chronic migraine.

BACKGROUND: Migraine is a primary headache disorder that can be classified into an episodic (EM) and a chronic form (CM). Network analysis within the graph-theoretical framework based on connectivity patterns provides an approach to observe large-scale structural integrity. We test the hypothesis that migraineurs are characterized by a segregated network. METHODS: 19 healthy controls (HC), 17 EM patients and 12 CM patients were included. Cortical thickness and subcortical volumes were computed, and topology was analyzed using a graph theory analytical framework and network-based statistics. We further used support vector machines regression (SVR) to identify whether these network measures were able to predict clinical parameters. RESULTS: Network based statistics revealed significantly lower interregional connectivity strength between anatomical compartments including the fronto-temporal, parietal and visual areas in EM and CM when compared to HC. Higher assortativity was seen in both patients' group, with higher modularity for CM and higher transitivity for EM compared to HC. For subcortical networks, higher assortativity and transitivity were observed for both patients' group with higher modularity for CM. SVR revealed that network measures could robustly predict clinical parameters for migraineurs. CONCLUSION: We found global network disruption for EM and CM indicated by highly segregated network in migraine patients compared to HC. Higher modularity but lower clustering coefficient in CM is suggestive of more segregation in this group compared to EM. The presence of a segregated network could be a sign of maladaptive reorganization of headache related brain circuits, leading to migraine attacks or secondary alterations to pain.

Mitochondrial function and oxidative stress markers in higher-frequency episodic migraine.

Increasing evidence points towards the role of mitochondrial functioning, energy metabolism, and oxidative stress in migraine. However not all previous research has been conclusive and some mitochondrial function/oxidative stress markers have not yet been examined. To this end, alpha-lipoic acid (ALA), total thiols, total plasma antioxidant capacity (TAC), lipid peroxide (PerOx), oxidised LDL (oxLDL), HbA1c and lactate were determined in the serum of 32 higher frequency episodic migraineurs (5-14 migraine days/ months, 19 with aura, 28 females) in this cross-sectional study. The majority of patients had abnormally low ALA and lactate levels (87.5% and 78.1%, respectively). 46.9% of the patients had abnormally high PerOx values, while for thiols and TAC over one third of patients had abnormally low values (31.2% and 37.5%, respectively). 21.9% of patients had abnormally low HbA1c and none had an HbA1c level above 5.6%. oxLDL was normal in all but one patient. This study provides further evidence for a role of oxidative stress and altered metabolism in migraine pathophysiology, which might represent a suitable therapeutic target. ALA, being too low in almost 90% of patients, might represent a potential biomarker for migraine. Further research is needed to replicate these results, in particular a comparison with a control group.This study is part of the trial registration: ClinicalTrials.gov: NCT03132233, registered on 27.04.2017, https://clinicaltrials.gov/ct2/show/NCT03132233 .

Green Flags and headache: A concept study using the Delphi method.

OBJECTIVE: The aim of this study was to collect and rate Green Flags, that is, symptoms or pieces of information indicating that a patient is more likely to suffer from a primary than from a secondary headache. BACKGROUND: When assessing headaches, a central question to be answered is whether the pain is primary or secondary to another disorder. To maximize the likelihood of a correct diagnosis, relevant signs and symptoms must be sought, identified, and weighed against each other. METHODS: The project was designed as a Delphi study. In the first round, an expert panel proposed green flags that were rated anonymously in two subsequent rounds. Proposals with an average rating of 4.0 and higher on a scale from 0 to 5 reached consensus. RESULTS: Five Green Flags reached consensus: (i) "The current headache has already been present during childhood"; (ii) "The headache occurs in temporal relationship with the menstrual cycle"; (iii) "The patient has headache-free days"; (iv) "Close family members have the same headache phenotype"; and (v) "Headache occurred or stopped more than one week ago." CONCLUSIONS: We propose five Green Flags for primary headache disorders. None being a pathognomonic sign, we recommend searching for both Green Flags and Red Flags. If both are present, a secondary headache should be suspected. Overall, the application of the Green Flag concept in clinical practice is likely to increase diagnostic accuracy and improve diagnostic resource allocation. Prospective studies in clinical populations should be conducted to validate these Green Flags.

Long-Term Effects of Self-Administered Transcranial Direct Current Stimulation in Episodic Migraine Prevention: Results of a Randomized Controlled Trial.

BACKGROUND: Migraine is a multifactorial neurovascular disorder, which affects about 12% of the general population. In episodic migraine, the visual cortex revealed abnormal processing, most likely due to decreased preactivation level. Transcranial direct current stimulation (tDCS) is able to modify cortical excitability and might result in an alleviation of migraine occurrence if used repetitively. OBJECTIVE: To test the hypothesis that self-administered anodal tDCS over the visual cortex significantly decreases the number of monthly migraine days in episodic migraine. MATERIALS AND METHODS: The study was single-blind, randomized, and sham-controlled. Inclusion criteria were age 18-80 years and an ICHD-3 diagnosis of episodic migraine. Exclusion criteria were pregnancy, presence of a neurodegenerative disorder, a contraindication against MRI examinations, and less than two migraine days during the 28-day baseline period. Patients in whom the baseline period suggested chronic migraine were excluded. After baseline, participants applied daily either verum (anodal-1 mA to 20 min) or sham tDCS (anodal-1 mA to 30 sec) at Oz (reference Cz electrode) for 28 days. Headache diaries were used to record the number of migraine days at baseline, during the stimulation period, and during four subsequent 28-day periods. RESULTS: Twenty-eight patients were included; two were excluded after the baseline period because less than two migraine days occurred; three were excluded because their headache diaries suggested the diagnosis of chronic migraine. Twenty-three datasets were taken for further analysis. Compared to sham tDCS (n = 12), verum tDCS (n = 11) resulted in a lower number of migraine days (p = 0.010) across all follow-up periods. We found no significant change in total headache days (p = 0.165), anxiety (p = 0.884), or depression scores (p = 0.535). No serious adverse events occurred; minor side effects were similar in both groups. CONCLUSIONS: This study provides Class II evidence that self-administered anodal tDCS over the visual cortex in episodic migraine results in a significantly lower number of monthly migraine days. However, it has neither an immediate nor a long-term effect.