Partial pharmacologic blockade shows sympathetic connection between blood pressure and cerebral blood flow velocity fluctuations

Cerebral autoregulation (CA) dampens transfer of blood pressure (BP)-fluctuations onto cerebral blood flow velocity (CBFV). Thus, CBFV-oscillations precede BP-oscillations. The phase angle (PA) between sympathetically mediated low-frequency (LF: 0.03–0.15 Hz) BP- and CBFV-oscillations is a measure of CA quality. To evaluate whether PA depends on sympathetic modulation, we assessed PA-changes upon sympathetic stimulation with and without pharmacologic sympathetic blockade. In 10 healthy, young men, we monitored mean BP and CBFV before and during 120-second cold pressor stimulation (CPS) of one foot (0 °C ice-water). We calculated mean values, standard deviations and sympathetic LF-powers of all signals, and PAs between LF-BP- and LF–CBFV-oscillations. We repeated measurements after ingestion of the adrenoceptor-blocker carvedilol (25 mg). We compared parameters before and during CPS, without and after carvedilol (analysis of variance, post-hoc t-tests, significance: p < 0.05). Without carvedilol, CPS increased BP, CBFV, BP-LF- and CBFV-LF-powers, and shortened PA. Carvedilol decreased resting BP, CBFV, BP-LF- and CBFV-LF-powers, while PAs remained unchanged. During CPS, BPs, CBFVs, BP-LF- and CBFV-LF-powers were lower, while PAs were longer with than without carvedilol. With carvedilol, CPS no longer shortened resting PA. Sympathetic activation shortens PA. Partial adrenoceptor blockade abolishes this PA-shortening. Thus, PA-measurements provide a subtle marker of sympathetic influences on CA and might refine CA evaluation

Neuroanatomic Correlates of Female Sexual Dysfunction in Multiple Sclerosis

OBJECTIVE: This study intended to determine associations between alterations of female sexual arousal as well as vaginal lubrication and the site of cerebral multiple sclerosis (MS) lesions. METHODS: In 44 women with MS (mean age: 36.5 ± 9.9 years), we assessed their medical history and evaluated sexual function using the Female Sexual Function Index scores for arousal and vaginal lubrication. We determined potential confounding factors of sexual dysfunction: age; disease duration; physical disability; depression; bladder or urinary dysfunction; and total volume of cerebral lesions. Arousal and lubrication scores were correlated with one another and with potential confounding factors. Cerebral MS lesions were recorded on imaging scans. A voxel-based lesion symptom mapping (VLSM) analysis adjusted for confounding variables was performed correlating cerebral sites of MS lesions with arousal and lubrication scores. RESULTS: Decreased arousal scores correlated with decreased lubrication scores; decreased lubrication scores were associated with bladder or urinary symptoms. Arousal and lubrication scores were not associated with any other variables. Multivariate VLSM analysis, including arousal and lubrication scores as covariables of interest, showed right occipital lesions associated with impaired arousal and left insular lesions associated with decreased lubrication. Impaired lubrication remained associated with left insular lesions after adjustment for bladder or urinary dysfunction. INTERPRETATION: Our data indicate that impaired female sexual arousal is associated with MS lesions in the occipital region, integrating visual information and modulating attention toward visual input. Impaired lubrication correlated with lesions in the left insular region, contributing to mapping and generating visceral arousal states

Sexual Dysfunction Seems to Trigger Depression in Female Multiple Sclerosis Patients

Background: In women with multiple sclerosis (MS), depression and sexual dysfunction (SD) are common. Whether SD promotes depression or vice versa remains unclear despite therapeutic relevance. Therefore, we aimed to assess whether SD more likely triggers depression or vice versa. Methods: In 83 female MS patients and 21 age-matched healthy women, we assessed depression, using the Beck Depression Inventory-V (BDI-V), and SD using the Female Sexual Function Index (FSFI). We diagnosed depression with BDI-V-scores >35 and SD with FSFI scores < 26.55. We divided patients into groups with and without SD, with and without depression. Between groups, we compared prevalence of SD and depression (Fisher’s-exact-test), age, MS-duration, MS-severity, BDI-V-, and FSFI scores (Mann-Whitney U-test; significance: p < 0.05). Results: A total of 37/83 MS patients and 1/21 controls had SD; 28/83 patients and 3/21 controls had depression; 51.4% patients with SD but only 19.6% without SD had depression (p = 0.003). SD was present in 67.9% depressed and 32.7% non-depressed patients. BDI-V-scores were higher in patients with SD than in patients without SD. FSFI scores were lower in depressed than non-depressed patients. Conclusion: In conclusion, SD was more common than depression. SD afflicted 67.9% depressed MS patients and was also more common in non-depressed MS patients than controls. SD may occur independently from depression while increased depressiveness seems linked to coexistent SD

Fingolimod initiation in multiple sclerosis patients is associated with potential beneficial cardiovascular autonomic effects

Background: Fingolimod slows heart rate (HR) due to vagomimetic effects and might cause additional cardiovascular autonomic changes. While the time course of HR changes is well described, the extent and course of cardiovascular autonomic changes upon fingolimod initiation has not yet been evaluated. This study, therefore, intended to assess cardiovascular autonomic changes during the first 6 h after fingolimod initiation. Methods: In 21 patients with relapsing-remitting multiple sclerosis (RRMS), we recorded respiration (RESP), electrocardiographic RR interval (RRI), systolic and diastolic blood pressure (BPsys, BPdia) at rest, before and 0.5, 1, 2, 3, 4, 5, and 6 h after fingolimod initiation. We calculated parameters of total autonomic modulation [RRI standard deviation (RRI-SD), RRI coefficient of variation (RRI-CV), RRI-total powers], mainly sympathetic cardiac modulation [RRI low frequency (LF) powers], sympathetic BP modulation (BPsys-LF powers), parasympathetic modulation [square root of the mean squared difference of successive RRIs (RMSSD), RRI high frequency (HF) powers], sympatho-vagal cardiac balance (RRI-LF/HF ratios), and baroreflex sensitivity (BRS). We compared parameters between the eight measurements [analysis of variance (ANOVA) or Friedman test with post-hoc analysis; significance: p < 0.05]. Results: After fingolimod initiation, RESP, BPsys, and BPsys-LF powers remained unchanged while RRIs, RRI-CV, RRI-SD, RRI-total powers, RRI-LF powers, RMSSD, RRI-HF powers, and BRS increased after 1 h and rose to peak values occurring after 5, 1, 2, 2, 1, 4, 4, and 4 h, respectively. After 3 h, BPdia had decreased significantly and was lowest after 5 h. RRI-LF/HF ratios decreased to a nadir after 4 h. Conclusions: The increases in parasympathetic and overall cardiac autonomic modulation and in BRS seen with fingolimod initiation are theoretically beneficial for the MS patient’s cardiovascular system. However, long-term studies must show whether these effects persist or are attenuated (e.g. due to S1P1 receptor down-regulation upon continued fingolimod therapy)

Medial gastrocnemius muscle stiffness cannot explain the increased ankle joint range of motion following passive stretching in children with cerebral palsy.

Stretching is often used to increase/maintain joint range of motion (ROM) in children with cerebral palsy (CP) but the effectiveness of these interventions is limited. Therefore, this study aimed to determine the acute changes in muscle-tendon lengthening properties that contribute to increased ROM after a bout of stretching in children with CP. Eleven children with spastic CP (age:12.1(3)y, 5/6 hemiplegia/diplegia, 7/4 GMFCS level I/II) participated in this study. Each child received 3 sets of 5 × 20 s passive, manual static dorsiflexion stretches separated by 30 s rest, and 60 s rest between sets. Pre- and immediately post-stretching, ultrasound was used to measure medial gastrocnemius fascicle lengthening continuously over the full ROM and an individual common ROM pre- to post-stretching. Simultaneously, 3D motion of two marker clusters on the shank and the foot was captured to calculate ankle angle, and ankle joint torque was calculated from manually applied torques and forces on a 6DoF load cell. After stretching, ROM was increased (9.9° (12.0), P = 0.005). Over a ROM common to both pre and post measurements, there were no changes in fascicle lengthening or torque. The maximal ankle joint torque tolerated by the participants increased (2.9(2.4) Nm, P = 0.003) and at this highest passive torque maximal fascicle length was 2.8(2.4) mm greater (P = 0.009) when compared to before stretching. These results indicate that the stiffness of the muscle fascicles in children with CP remain unaltered by an acute bout of stretching. This article is protected by copyright. All rights reserved

Antihyperalgesia by α2-GABAA Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites

Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABAA receptors (GABAARs) containing α2 subunits (α2-GABAARs). Previous work indicates that potentiation of these receptors in the spinal cord evokes profound antihyperalgesia also after systemic administration, but possible synergistic or antagonistic actions of supraspinal α2-GABAARs on spinal antihyperalgesia have not yet been addressed. Here we generated two lines of GABAAR-mutated mice, which either lack α2-GABAARs specifically from the spinal cord, or, which express only benzodiazepine-insensitive α2-GABAARs at this site. We analyzed the consequences of these mutations for antihyperalgesia evoked by systemic treatment with the novel non-sedative benzodiazepine site agonist HZ166 in neuropathic and inflammatory pain. Wild-type mice and both types of mutated mice had similar baseline nociceptive sensitivities and developed similar hyperalgesia. However, antihyperalgesia by systemic HZ166 was reduced in both mutated mouse lines by about 60% and was virtually indistinguishable from that of global point-mutated mice, in which all α2-GABAARs were benzodiazepine insensitive. The major (α2-dependent) component of GABAAR-mediated antihyperalgesia was therefore exclusively of spinal origin, whereas supraspinal α2-GABAARs had neither synergistic nor antagonistic effects on antihyperalgesia. Our results thus indicate that drugs that specifically target α2-GABAARs exert their antihyperalgesic effect through enhanced spinal nociceptive control. Such drugs may therefore be well-suited for the systemic treatment of different chronic pain conditions

Are clinical measures of foot posture and mobility associated with foot kinematics when walking?

Background: There is uncertainty as to which foot posture measures are the most valid in terms of predicting kinematics of the foot. The aim of this study was to investigate the associations of clinical measures of static foot posture and mobility with foot kinematics during barefoot walking. Method: Foot posture and mobility were measured in 97 healthy adults (46 males, 51 females; mean age 24.4 ± 6.2 years). Foot posture was assessed using the 6-item Foot Posture Index (FPI), Arch Index (AI), Normalised Navicular Height (NNHt) and Normalised Dorsal Arch Height (DAH). Foot mobility was evaluated using the Foot Mobility Magnitude (FMM) measure. Following this, a five-segment foot model was used to measure tri-planar motion of the rearfoot, midfoot, medial forefoot, lateral forefoot and hallux. Peak and range of motion variables during load acceptance and midstance/propulsion phases of gait were extracted for all relative segment to segment motion calculations. Hierarchical regression analyses were conducted, adjusting for potential confounding variables. Results: The degree of variance in peak and range of motion kinematic variables that was independently explained by foot posture measures was as follows: FPI 5 to 22 %, NNHt 6 to 20 %, AI 7 to 13 %, DAH 6 to 8 %, and FMM 8 %. The FPI was retained as a significant predictor across the most number of kinematic variables. However, the amount of variance explained by the FPI for individual kinematic variables did not exceed other measures. Overall, static foot posture measures were more strongly associated with kinematic variables than foot mobility measures and explained more variation in peak variables compared to range of motion variables. Conclusions: Foot posture measures can explain only a small amount of variation in foot kinematics. Static foot posture measures, and in particular the FPI, were more strongly associated with foot kinematics compared with foot mobility measures. These findings suggest that foot kinematics cannot be accurately inferred from clinical observations of foot posture alone

Valsalva maneuver unveils central baroreflex dysfunction with altered blood pressure control in persons with a history of mild traumatic brain injury

BACKGROUND: Patients with a history of mild TBI (post-mTBI-patients) have an unexplained increase in long-term mortality which might be related to central autonomic dysregulation (CAD). We investigated whether standardized baroreflex-loading, induced by a Valsalva maneuver (VM), unveils CAD in otherwise healthy post-mTBI-patients. METHODS: In 29 healthy persons (31.3 ± 12.2 years; 9 women) and 25 post-mTBI-patients (35.0 ± 13.2 years, 7 women, 4–98 months post-injury), we monitored respiration (RESP), RR-intervals (RRI) and systolic blood pressure (BP) at rest and during three VMs. At rest, we calculated parameters of total autonomic modulation [RRI-coefficient-of-variation (CV), RRI-standard-deviation (RRI-SD), RRI-total-powers], of sympathetic [RRI-low-frequency-powers (LF), BP-LF-powers] and parasympathetic modulation [square-root-of-mean-squared-differences-of-successive-RRIs (RMSSD), RRI-high-frequency-powers (HF)], the index of sympatho-vagal balance (RRI LF/HF-ratios), and baroreflex sensitivity (BRS). We calculated Valsalva-ratios (VR) and times from lowest to highest RRIs after strain (VR-time) as indices of parasympathetic activation, intervals from highest systolic BP-values after strain-release to the time when systolic BP had fallen by 90 % of the differences between peak-phase-IV-BP and baseline-BP (90 %-BP-normalization-times), and velocities of BP-normalization (90 %-BP-normalization-velocities) as indices of sympathetic withdrawal. We compared patient- and control-parameters before and during VM (Mann-Whitney-U-tests or t-tests; significance: P < 0.05). RESULTS: At rest, RRI-CVs, RRI-SDs, RRI-total-powers, RRI-LF-powers, BP-LF-powers, RRI-RMSSDs, RRI-HF-powers, and BRS were lower in patients than controls. During VMs, 90 %-BP-normalization-times were longer, and 90 %-BP-normalization-velocities were lower in patients than controls (P < 0.05). CONCLUSIONS: Reduced autonomic modulation at rest and delayed BP-decrease after VM-induced baroreflex-loading indicate subtle CAD with altered baroreflex adjustment to challenge. More severe autonomic challenge might trigger more prominent cardiovascular dysregulation and thus contribute to increased mortality risk in post-mTBI-patients