Real-world approaches to outpatient treatment of status migrainosus: A survey study.

OBJECTIVES: Identify how the American Headache Society (AHS) membership manages status migrainosus (SM) among outpatients. BACKGROUND: SM is defined as a debilitating migraine attack lasting more than 72 h. There is no standard of care for SM, including whether a 72-h duration is required before the attack can be treated as SM. METHODS: The Refractory Headache Special Interest Group from AHS developed a four-question survey distributed to AHS members enquiring (1) whether they treat severe refractory migraine attacks the same as SM regardless of duration, (2) what their first step in SM management is, (3) what the top three medications they use for SM are, and (4) whether they are United Council for Neurologic Subspecialties (UCNS) certified. The survey was conducted in January 2022. Descriptive statistical analyses were performed. RESULTS: Responses were received from 196 of 1859 (10.5%) AHS members; 64.3% were UCNS certified in headache management. Respondents treated 69.4% (136/196) of patients with a severe refractory migraine attack as SM before the 72-h period had elapsed. Most (76.0%, 149/196) chose "treat remotely using outpatient medications at home" as the first step, 11.2% (22/196) preferred procedures, 6.1% (12/196) favored an infusion center, 6.1% (12/196) sent patients to the emergency department (ED) or urgent care, and 0.5% (1/196) preferred direct hospital admission. The top five preferred medications were as follows: (1) corticosteroids (71.4%, 140/196), (2) nonsteroidal anti-inflammatory drugs (NSAIDs) (50.1%, 99/196), (3) neuroleptics (46.9%, 92/196), (4) triptans (30.6%, 60/196), and (5) dihydroergotamine (DHE) (21.4%, 42/196). CONCLUSIONS: Healthcare professionals with expertise in headache medicine typically treated severe migraine attacks early and did not wait 72 h to fulfill the diagnostic criteria for SM. Outpatient management with one or more medications for home use was preferred by most respondents; few opted for ED referrals. Finally, corticosteroids, NSAIDs, neuroleptics, triptans, and DHE were the top five preferred treatments for home SM management.

Acupoint Sensitivity in Health and Disease: A Systematic Review.

Introduction: The concept of acupoints is a key defining feature of acupuncture, yet the scientific basis of acupoints remains unclear. In recent years, there has been an emerging body of animal studies demonstrating an association between cutaneous sensitivity and visceral pathophysiology, through which acupoints over the skin are sensitized in pathologic conditions. Several studies with humans have also been conducted to assess whether the sensitivity of acupoints is distinct in healthy versus clinical populations. However, no systematic review has been conducted to collate and synthesize the status and quality of human studies on this topic. Methods: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Literature search was performed by combining variations of search terms related to acupoints and pain sensitivity in PubMed, EMBASE, and Alt HealthWatch (EBSCOHost). Screening of titles and abstracts and review of full-text articles for eligibility were performed by two independent investigators. Using a predefined template, information on subject characteristics, pathologic conditions, names of assessed acupoints, and relevant main findings were extracted from the included studies. The methodological quality of included studies was assessed using a modified Newcastle-Ottawa Scale (NOS) for case-control studies. A quality assessment checklist was also developed by the present authors to examine the quality of reporting of experimental variables that were considered important for evaluating acupoint sensitivity. Results: A total of 3453 studies were identified from the database search, of which 11 met the eligibility criteria to be included in this review. Six studies examined the mechanical sensitivity of body acupoints, and the remaining five studies examined the mechanical sensitivity of auricular points. Overall, findings suggest that the sensitivity of acupoints may be distinct in healthy versus clinical populations. However, there were various potential sources of bias and substantial heterogeneity across included studies in clinical conditions and acupoints. Conclusion: There is at present insufficient evidence to support or refute that acupoints in humans are sensitized in pathologic conditions. There were various methodological issues, including small sample size and poor reporting of experimental design and variables, which limit the ability to draw a definitive conclusion on this topic. It is also largely unclear whether it is the general body regions rather than specific acupoints that may be sensitized, as most studies did not include nonacupoint location(s) for comparison. Thus, further rigorous research is warranted.

Real-world effectiveness of fremanezumab for the preventive treatment of migraine: Interim analysis of the pan-European, prospective, observational, phase 4 PEARL study.

BACKGROUND: The ongoing Pan-European Real Life (PEARL) phase 4 study is evaluating fremanezumab effectiveness and safety for the prevention of episodic and chronic migraine. This interim analysis reports primary, secondary and exploratory endpoints from when 500 participants completed at least six months of treatment. METHODS: Adults with episodic migraine or chronic migraine maintaining daily headache diaries were enrolled upon initiation of fremanezumab. Primary endpoint: proportion of participants with ≥50% reduction in monthly migraine days during the six-month period after fremanezumab initiation. Secondary endpoints: mean change from baseline across months 1-12 in monthly migraine days, acute migraine medication use, and headache-related disability. Exploratory endpoint: mean change in headache severity from baseline across months 1-12. Safety was assessed through adverse events reported. RESULTS: Overall, 897 participants were enrolled and 574 included in the effectiveness analyses (episodic migraine, 25.8%; chronic migraine, 74.2%). Of participants with data available, 175/313 (55.9%) achieved ≥50% monthly migraine days reduction during the six-month period post-initiation. Across months 1-12, there were sustained reductions in mean monthly migraine days, acute medication use, disability scores, and headache severity. Few adverse events were reported. CONCLUSION: PEARL interim results support the effectiveness and safety of fremanezumab for migraine prevention in a real-world population across several European countries.Trial registration: encepp.eu: EUPAS35111.

Skin Temperature of Acupoints in Health and Disease: A Systematic Review.

Introduction: Despite substantial progress made in the field of acupuncture research, the existence and specificity of acupoints remain controversial. In recent years, the concept of acupoint sensitization has emerged as a theoretical framework for understanding acupoints as dynamic functional entities that are sensitized in pathological conditions. Based on this premise, some have claimed that specific acupoints are thermally distinct between healthy and clinical populations, but no systematic review has been conducted to synthesize and evaluate the quality of studies supporting such claims. In this review, we provide a summary and quality assessment of the existing literature addressing the question of whether changes in skin temperature at specific acupoints are indicative of pathological conditions. Methods: A systematic literature search was performed in PubMed, EMBASE, and AltHealthWatch (EBSCO Host), by combining variations of search terms relevant to acupoints and temperature. The search was limited to the English language, and publication dates ranged from database inception to December 2020. Two authors independently screened all resulting abstracts and subsequently read full-text articles for eligibility. Information on study design, sample, acupoints, parameters of skin temperature assessments, and main findings were extracted from included studies. Quality of the thermal sensing methodology was evaluated using a thermal assessment checklist, adapted from the Thermographic Imaging in Sports and Exercise Medicine (TISEM) consensus checklist, and a modified Newcastle-Ottawa Scale (NOS) for case-control studies. Results: The search strategy yielded a total of 1771 studies, of which 10 articles met the eligibility criteria. Eight studies compared skin temperature at acupoints in healthy versus clinical populations, and two studies assessed within-subject changes in temperature of acupoints in relation to changes in health status. There were seven clinical conditions examined in the included studies: chronic bronchial asthma, chronic hepatitis, hyperplasia of mammary glands, infertility, intracranial hypertension, obesity, and primary dysmenorrhea. There were numerous methodological quality issues related to skin temperature measurements. Eight studies with case-control designs reported significant differences between healthy and clinical populations in temperature at certain acupoints. Two studies with pre-post designs reported that changes in health-disease status could be associated with changes in temperature at specific acupoints. Conclusion: A review of the available literature suggests that certain acupoints may be thermally distinct between healthy and unhealthy states. However, given the methodological limitations and heterogeneity across included studies, no definitive conclusion could be drawn as to whether changes in skin temperature at specific acupoints are indicative of pathological conditions.

Dose selection for fremanezumab (AJOVY) phase 3 pediatric migraine studies using pharmacokinetic data from a pediatric phase 1 study and a population pharmacokinetic modeling and simulation approach.

BACKGROUND: Potential fremanezumab doses for pediatric patients were evaluated using pharmacokinetic modeling and simulation. An open-label phase 1 pharmacokinetic and safety study was conducted in pediatric patients with migraine. This study's results together with refinement of the adult population pharmacokinetic model were used to determine fremanezumab dose recommendations for phase 3 pediatric studies. METHODS: Initial application of the adult model suggested that a 75 mg dose in pediatric patients would match exposures determined safe and efficacious in adults; thus, in the phase 1 study, 15 patients, aged 6-11 years and weighing 17-45 kg received a single subcutaneous 75 mg fremanezumab dose. The sparse pharmacokinetic data collected were used to refine the adult model and simulate concentration-time profiles for monthly subcutaneous doses (60 to 225 mg) in a virtual pediatric population. RESULTS: In the phase 1 pediatric study, the safety profile was similar to that of adults. A two-compartment model with first-order absorption and elimination and body weight effects on clearance and central volume was found to adequately describe the pediatric pharmacokinetic data. CONCLUSIONS: Using exposure matching to the effective adult fremanezumab dose (225 mg subcutaneous monthly), modeling and simulations predict recommended dose of 120 mg in pediatric patients weighing < 45 kg.Registration: The phase 1 study of this report is registered at EudraCT with the identifier 2018-000734-35.

In Vivo Visualization of the Pericardium Meridian with Fluorescent Dyes.

The anatomical basis of acupuncture meridians continues to be enigmatic. Although much attention has been placed on potential correlations with inter/intramuscular fascia or lower electrical impedance, animal studies performed in the past 40 years have shown that tracer dyes-specifically Tc-99m pertechnetate-injected at strategic skin points generate linear migrations closely aligning with acupuncture meridians. To evaluate whether this phenomenon is also observable in humans, we injected two fluorescent dyes-fluorescein sodium and indocyanine green (ICG)-into the dermal layer both at acupuncture points (PC5, PC6, and PC7) and a nonacupoint control. Fifteen healthy volunteers were enrolled in this study. Of the 19 trials of fluorescein injected at PC6, 15 (79%) were associated with slow diffusion of the dye proximally along a path matching closely with the pericardium meridian. Furthermore, the dye emerged and coalesced proximally at exactly acupoint PC3. Injections of ICG at the acupoints PC5, PC6, or PC7 showed a similar trajectory close to the injection site but diverged when migrating proximally, failing converge on acupoint PC3. Injections of either dye at an adjacent PC6-control did not generate any notable linear pathway. Both ultrasound imaging and vein-locating device did not reveal any corresponding vessels (arterial or venous) at the visualized tracer pathway but did demonstrate correlations with intermuscular fascia.

Dynamic brain-body coupling of breath-by-breath O2-CO2 exchange ratio with resting state cerebral hemodynamic fluctuations.

BACKGROUND: The origin of low frequency cerebral hemodynamic fluctuations (CHF) in the resting state remains unknown. Breath-by breath O2-CO2 exchange ratio (bER) has been reported to correlate with the cerebrovascular response to brief breath hold challenge at the frequency range of 0.008-0.03Hz in healthy adults. bER is defined as the ratio of the change in the partial pressure of oxygen (ΔPO2) to that of carbon dioxide (ΔPCO2) between end inspiration and end expiration. In this study, we aimed to investigate the contribution of respiratory gas exchange (RGE) metrics (bER, ΔPO2 and ΔPCO2) to low frequency CHF during spontaneous breathing. METHODS: Twenty-two healthy adults were included. We used transcranial Doppler sonography to evaluate CHF by measuring the changes in cerebral blood flow velocity (ΔCBFv) in bilateral middle cerebral arteries. The regional CHF were mapped with blood oxygenation level dependent (ΔBOLD) signal changes using functional magnetic resonance imaging. Temporal features and frequency characteristics of RGE metrics during spontaneous breathing were examined, and the simultaneous measurements of RGE metrics and CHF (ΔCBFv and ΔBOLD) were studied for their correlation. RESULTS: We found that the time courses of ΔPO2 and ΔPCO2 were interdependent but not redundant. The oscillations of RGE metrics were coherent with resting state CHF at the frequency range of 0.008-0.03Hz. Both bER and ΔPO2 were superior to ΔPCO2 in association with CHF while CHF could correlate more strongly with bER than with ΔPO2 in some brain regions. Brain regions with the strongest coupling between bER and ΔBOLD overlapped with many areas of default mode network including precuneus and posterior cingulate. CONCLUSION: Although the physiological mechanisms underlying the strong correlation between bER and CHF are unclear, our findings suggest the contribution of bER to low frequency resting state CHF, providing a novel insight of brain-body interaction via CHF and oscillations of RGE metrics.

Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities.

Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.

Attributable risk of all-cause mortality in hypertensive adults based on disease risk prediction model: A Chinese cohort study.

BACKGROUND: The aim of this study was to estimate the attributable risk for all-cause mortality in hypertensive adults living in Beijing, China. METHODS: We conducted a prospective cohort study on the basis of the disease risk prediction model, which included 3006 hypertensive patients aged 50 and over who participated in the annual health examination from thirty-eight community health centers were randomly selected from all 53 community health centers in Dongcheng district of Beijing in China. This cohort study was conducted from January 1, 2013 to June 31, 2018 in these community health centers. Data included age, gender, education level, BMI, smoking and drinking status, renal function, diabetes mellitus (DM), coronary heart disease, levels of blood pressure, use of medications, and blood lipid levels. RESULTS: the follow-up time was 4.90±0.51 years. There were significant survival differences by gender, renal function (eGFR>90 vs. 60-90 vs. <60mL/min per 1.73m2), smoking (smoking vs. No smoking), hypertension severity (SBP≥140 or DBP≥r vs. SBP/DBP<140/90mmHg), education level (<6 vs. 6-12 vs. >12 years), coronary heart disease (CHD) (CHD vs. NO CHD). In the multivariate Cox proportional hazard analysis, the prognostic factors of all-cause mortality in hypertensive patients were male [HR 1.662, 95% CI 1.110-2.489, p=0.014], educational level<6 years [HR 2.044, 95% CI 1.164-3.591, p 0.013], age ≥65 years [HR 3.092, 95% CI 1.717-5.571, p<0.001], smoking [HR 1.885, 95% CI 1.170-3.309, p=0.009], eGFR<60mL/min per 1.73m2 [HR 3.591, 95% CI 2.023-6.371, p<0.001]. CONCLUSIONS: we conclude that decreasing eGFR, increasing age, smoking, low education and gender (male) are significant and independent risk factor for mortality in hypertension for this urban cohort. Recommendations may include protecting renal function, providing patient education, and cessation of smoking. It highlights that early preventive measures are needed to detect kidney impairment and protect renal function. It also suggests that earlier smoking cessation may be important for hypertensive patients.

Cerebrovascular reactivity assessment with O2-CO2 exchange ratio under brief breath hold challenge.

BACKGROUND: Hypercapnia during breath holding is believed to be the dominant driver behind the modulation of cerebral blood flow (CBF). However, increasing evidence show that mild hypoxia and mild hypercapnia in breath hold (BH) could work synergistically to enhance CBF response. We hypothesized that breath-by-breath O2-CO2 exchange ratio (bER), defined as the ratio of the change in partial pressure of oxygen (ΔPO2) to that of carbon dioxide (ΔPCO2) between end inspiration and end expiration, would be able to better correlate with the global and regional cerebral hemodynamic responses (CHR) to BH challenge. We aimed to investigate whether bER is a more useful index than end-tidal PCO2 to characterize cerebrovascular reactivity (CVR) under BH challenge. METHODS: We used transcranial Doppler ultrasound (TCD) to evaluate CHR under BH challenge by measuring cerebral blood flow velocity (CBFv) in the middle cerebral arteries. Regional changes in CHR to BH and exogenous CO2 challenges were mapped with blood oxygenation level dependent (BOLD) signal changes using functional magnetic resonance imaging (fMRI). We correlated respiratory gas exchange (RGE) metrics (bER, ΔPO2, ΔPCO2, end-tidal PCO2 and PO2, and time of breaths) with CHR (CBFv and BOLD) to BH challenge. Temporal features and frequency characteristics of RGE metrics and their coherence with CHR were examined. RESULTS: CHR to brief BH epochs and free breathing were coupled with both ΔPO2 and ΔPCO2. We found that bER was superior to either ΔPO2 or ΔPCO2 alone in coupling with the changes of CBFv and BOLD signals under breath hold challenge. The regional CVR results derived by regressing BOLD signal changes on bER under BH challenge resembled those derived by regressing BOLD signal changes on end-tidal PCO2 under exogenous CO2 challenge. CONCLUSION: Our findings provide a novel insight on the potential of using bER to better quantify CVR changes under BH challenge.

Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 3b trial.

BACKGROUND: Antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor have shown efficacy in the prevention of migraine attacks. We investigated the efficacy and tolerability of fremanezumab, a fully humanised CGRP antibody, in patients with migraine who had previously not responded to two to four classes of migraine preventive medications. METHODS: The randomised, double-blind, placebo-controlled, parallel-group, phase 3b FOCUS trial was done at 104 sites (including hospitals, medical centres, research institutes, and group practice clinics) across Belgium, the Czech Republic, Denmark, Finland, France, Germany, Italy, the Netherlands, Poland, Spain, Sweden, Switzerland, the UK, and the USA. We enrolled participants aged 18-70 years with episodic or chronic migraine who had documented failure to two to four classes of migraine preventive medications in the past 10 years. Failure was defined as no clinically meaningful improvement after at least 3 months of therapy at a stable dose, as per the treating physician's judgment; discontinuation because of adverse events that made treatment intolerable; or treatment contraindicated or unsuitable for the preventive treatment of migraine for the patient. Participants were randomly assigned (1:1:1) by electronic interactive response technology to subcutaneously administered quarterly fremanezumab (month 1, 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: 225 mg in episodic migraine and 675 mg in chronic migraine; months 2 and 3: 225 mg in both migraine subgroups), or matched monthly placebo for 12 weeks. The primary outcome was mean change from baseline in the monthly average number of migraine days during the 12-week treatment period. This trial is registered with ClinicalTrials.gov, number NCT03308968, and is now completed. FINDINGS: Between Nov 10, 2017, and July 6, 2018, 838 participants with episodic (329 [39%]) or chronic (509 [61%]) migraine were randomly assigned to placebo (n=279), quarterly fremanezumab (n=276), or monthly fremanezumab (n=283). Reductions from baseline in monthly average migraine days over 12 weeks were greater versus placebo (least-squares mean [LSM] change -0·6 [SE 0·3]) with quarterly fremanezumab (LSM change -3·7 [0·3]; LSM difference vs placebo -3·1 [95% CI -3·8 to -2·4]; p<0·0001) and with monthly fremanezumab (LSM change -4·1 [0·34]; LSM difference vs placebo -3·5 [-4·2 to -2·8]; p<0·0001). Adverse events were similar for placebo and fremanezumab. Serious adverse events were reported in four (1%) of 277 participants with placebo, two (<1%) of 276 with quarterly fremanezumab, and four (1%) of 285 with monthly fremanezumab. INTERPRETATION: Fremanezumab was effective and well tolerated in patients with difficult-to-treat migraine who had previously not responded to up to four classes of migraine preventive medications. FUNDING: Teva Pharmaceuticals.

Trial of Galcanezumab in Prevention of Episodic Cluster Headache.

BACKGROUND: Episodic cluster headache is a disabling neurologic disorder that is characterized by daily headache attacks that occur over periods of weeks or months. Galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, may be a preventive treatment for cluster headache. METHODS: We enrolled patients who had at least one attack every other day, at least four total attacks, and no more than eight attacks per day during a baseline assessment, as well as a history of cluster headache periods lasting at least 6 weeks, and randomly assigned them to receive galcanezumab (at a dose of 300 mg) or placebo, administered subcutaneously at baseline and at 1 month. The primary end point was the mean change from baseline in the weekly frequency of cluster headache attacks across weeks 1 through 3 after receipt of the first dose. The key secondary end point was the percentage of patients who had a reduction from baseline of at least 50% in the weekly frequency of cluster headache attacks at week 3. Safety was also assessed. RESULTS: Recruitment was halted before the trial reached the planned sample size of 162 because too few volunteers met the eligibility criteria. Of 106 enrolled patients, 49 were randomly assigned to receive galcanezumab and 57 to receive placebo. The mean (±SD) number of cluster headache attacks per week in the baseline period was 17.8±10.1 in the galcanezumab group and 17.3±10.1 in the placebo group. The mean reduction in the weekly frequency of cluster headache attacks across weeks 1 through 3 was 8.7 attacks in the galcanezumab group, as compared with 5.2 in the placebo group (difference, 3.5 attacks per week; 95% confidence interval, 0.2 to 6.7; P = 0.04). The percentage of patients who had a reduction of at least 50% in headache frequency at week 3 was 71% in the galcanezumab group and 53% in the placebo group. There were no substantial between-group differences in the incidence of adverse events, except that 8% of the patients in the galcanezumab group had injection-site pain. CONCLUSIONS: Galcanezumab administered subcutaneously at a dose of 300 mg once monthly reduced the weekly frequency of attacks of episodic cluster headache across weeks 1 through 3 after the initial injection, as compared with placebo. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT02397473.).

Complexity-Based Measures of Heart Rate Dynamics in Older Adults Following Long- and Short-Term Tai Chi Training: Cross-sectional and Randomized Trial Studies.

Measures characterizing the complexity of heart rate (HR) dynamics have been informative in predicting age- and disease-related decline in cardiovascular health, but few studies have evaluated whether mind-body exercise can impact HR complexity. This study evaluated the effects of long-term Tai Chi (TC) practice on the complexity of HR dynamics using an observational comparison of TC experts and age- and gender-matched TC-naïve individuals. Shorter-term effects of TC were assessed by randomly assigning TC-naïve participants to either TC group to receive six months of TC training or to a waitlist control group. 23 TC experts (age = 63.3 ± 8.0 y; 24.6 ± 12.0 y TC experience) and 52 TC-naïve (age = 64.3 ± 7.7 y) were enrolled. In cross-sectional analyses, TC experts had a higher overall complexity index (CI, p = 0.004) and higher entropy at multiple individual time scales (p < 0.05); these findings persisted in models accounting for age, gender, body mass index (BMI), and physical activity levels. Longitudinal changes in complexity index did not differ significantly following random assignment to six months of TC vs. a waitlist control; however, within the TC group, complexity at select time scales showed statistically non-significant trends toward increases. Our study supports that longer-term TC mind-body training may be associated with increased complexity of HR dynamics.

5-HT1D receptors inhibit the monosynaptic stretch reflex by modulating C-fiber activity.

The monosynaptic stretch reflex (MSR) plays an important role in feedback control of movement and posture but can also lead to unstable oscillations associated with tremor and clonus, especially when increased with spinal cord injury (SCI). To control the MSR and clonus after SCI, we examined how serotonin regulates the MSR in the sacrocaudal spinal cord of rats with and without a chronic spinal transection. In chronic spinal rats, numerous 5-HT receptor agonists, including zolmitriptan, methylergonovine, and 5-HT, inhibited the MSR with a potency highly correlated to their binding affinity to 5-HT1D receptors and not other 5-HT receptors. Selective 5-HT1D receptor antagonists blocked this agonist-induced inhibition, although antagonists alone had no action, indicating a lack of endogenous or constitutive receptor activity. In normal uninjured rats, the MSR was likewise inhibited by 5-HT, but at much higher doses, indicating a supersensitivity after SCI. This supersensitivity resulted from the loss of the serotonin transporter SERT with spinal transection, because normal and injured rats were equally sensitive to 5-HT after SERT was blocked or to agonists not transported by SERT (zolmitriptan). Immunolabeling revealed that the 5-HT1D receptor was confined to superficial lamina of the dorsal horn, colocalized with CGRP-positive C-fibers, and eliminated by dorsal rhizotomy. 5-HT1D receptor labeling was not found on large proprioceptive afferents or α-motoneurons of the MSR. Thus serotonergic inhibition of the MSR acts indirectly by modulating C-fiber activity, opening up new possibilities for modulating reflex function and clonus via pain-related pathways. NEW & NOTEWORTHY Brain stem-derived serotonin potently inhibits afferent transmission in the monosynaptic stretch reflex. We show that serotonin produces this inhibition exclusively via 5-HT1D receptors, and yet these receptors are paradoxically mostly confined to C-fibers. This suggests that serotonin acts by gating of C-fiber activity, which in turn modulates afferent transmission to motoneurons. We also show that the classic supersensitivity to 5-HT after spinal cord injury results from a loss of SERT, and not 5-HT1D receptor plasticity.

Posttraumatic Headache: Classification by Symptom-Based Clinical Profiles.

There are currently no accepted therapies for posttraumatic headache (PTH). In order to meet the urgent need for effective therapies for PTH, we must continue to address fundamental gaps in our understanding of the clinical course and impact of PTH. Here we examine the existing schema used to characterize the clinical characteristics of PTH, including the International Classification of Headache Disorders (ICHD). There remain unresolved questions about whether to classify patients based on the extent of brain injury or on clinical symptom profiles. There also remain problematic issues of definition such as continuous headache, and chronic daily headache with features of "embedded" migraine-type within these headaches, which will need to be studied further. We make the case that a symptom-based classification is needed to begin an examination of these unresolved questions, and to establish clinically relevant endpoints for research and clinical trials for effective therapies.

Can Tai Chi training impact fractal stride time dynamics, an index of gait health, in older adults? Cross-sectional and randomized trial studies.

PURPOSE: To determine if Tai Chi (TC) has an impact on long-range correlations and fractal-like scaling in gait stride time dynamics, previously shown to be associated with aging, neurodegenerative disease, and fall risk. METHODS: Using Detrended Fluctuation Analysis (DFA), this study evaluated the impact of TC mind-body exercise training on stride time dynamics assessed during 10 minute bouts of overground walking. A hybrid study design investigated long-term effects of TC via a cross-sectional comparison of 27 TC experts (24.5 ± 11.8 yrs experience) and 60 age- and gender matched TC-naïve older adults (50-70 yrs). Shorter-term effects of TC were assessed by randomly allocating TC-naïve participants to either 6 months of TC training or to a waitlist control. The alpha (α) long-range scaling coefficient derived from DFA and gait speed were evaluated as outcomes. RESULTS: Cross-sectional comparisons using confounder adjusted linear models suggest that TC experts exhibited significantly greater long-range scaling of gait stride time dynamics compared with TC-naïve adults. Longitudinal random-slopes with shared baseline models accounting for multiple confounders suggest that the effects of shorter-term TC training on gait dynamics were not statistically significant, but trended in the same direction as longer-term effects although effect sizes were very small. In contrast, gait speed was unaffected in both cross-sectional and longitudinal comparisons. CONCLUSION: These preliminary findings suggest that fractal-like measures of gait health may be sufficiently precise to capture the positive effects of exercise in the form of Tai Chi, thus warranting further investigation. These results motivate larger and longer-duration trials, in both healthy and health-challenged populations, to further evaluate the potential of Tai Chi to restore age-related declines in gait dynamics. TRIAL REGISTRATION: The randomized trial component of this study was registered at ClinicalTrials.gov (NCT01340365).

Sex differences in mouse Transient Receptor Potential Cation Channel, Subfamily M, Member 8 expressing trigeminal ganglion neurons.

The detection of cool temperatures is thought to be mediated by primary afferent neurons that express the cool temperature sensing protein Transient Receptor Potential Cation Channel, Subfamily M, Member 8 (TRPM8). Using mice, this study tested the hypothesis that sex differences in sensitivity to cool temperatures were mediated by differences in neurons that express TRPM8. Ion currents from TRPM8 expressing trigeminal ganglion (TRG) neurons in females demonstrated larger hyperpolarization-activated cyclic nucleotide-gated currents (Ih) than male neurons at both 30° and 18°C. Additionally, female neurons' voltage gated potassium currents (Ik) were suppressed by cooling, whereas male Ik was not significantly affected. At the holding potential tested (-60mV) TRPM8 currents were not visibly activated in either sex by cooling. Modeling the effect of Ih and Ik on membrane potentials demonstrated that at 30° the membrane potential in both sexes is unstable. At 18°, female TRPM8 TRG neurons develop a large oscillating pattern in their membrane potential, whereas male neurons become highly stable. These findings suggest that the differences in Ih and Ik in the TRPM8 TRG neurons of male and female mice likely leads to greater sensitivity of female mice to the cool temperature. This hypothesis was confirmed in an operant reward/conflict assay. Female mice contacted an 18°C surface for approximately half the time that males contacted the cool surface. At 33° and 10°C male and female mice contacted the stimulus for similar amounts of time. These data suggest that sex differences in the functioning of Ih and Ik in TRPM8 expressing primary afferent neurons leads to differences in cool temperature sensitivity.

Cardiac Autonomic Alteration and Metabolic Syndrome: An Ambulatory ECG-based Study in A General Population.

Metabolic syndrome (MetS) has been associated with chronic damage to the cardiovascular system. This study aimed to evaluate early stage cardiac autonomic dysfunction with electrocardiography (ECG)-based measures in MetS subjects. During 2012-2013, 175 subjects with MetS and 226 healthy controls underwent ECG recordings of at least 4 hours starting in the morning with ambulatory one-lead ECG monitors. MetS was diagnosed using the criteria defined in the Adult Treatment Panel III, with a modification of waist circumference for Asians. Conventional heart rate variability (HRV) analysis, and complexity index (CI1-20) calculated from 20 scales of entropy (multiscale entropy, MSE), were compared between subjects with MetS and controls. Compared with the healthy controls, subjects with MetS had significantly reduced HRV, including SDNN and pNN20 in time domain, VLF, LF and HF in frequency domain, as well as SD2 in Poincaré analysis. MetS subjects have significantly lower complexity index (CI1-20) than healthy subjects (1.69 ± 0.18 vs. 1.77 ± 0.12, p < 0.001). MetS severity was inversely associated with the CI1-20 (r = -0.27, p < 0.001). MetS is associated with significant alterations in heart rate dynamics, including HRV and complexity.