Dysregulation of the autonomic nervous system in adult attention deficit hyperactivity disorder. A systematic review.

Background: Adult Attention Deficit Hyperactivity Disorder (aADHD) is characterised by inattention, hyperactivity, impulsivity, and emotional instability, all of which were linked to altered modulation of the autonomic nervous system. This and the clinical effectiveness of sympathomimetic medication raised the question if autonomic modulation is altered in aADHD patients.Methods: We systematically searched PubMed, Cochrane Library, and Web Of Science for publications investigating autonomic modulation in aADHD and controls during resting-state and/or under task conditions.Results: We reviewed 15 studies involving 846 participants (424 aADHD and 422 controls), including 4 studies on sympathetic tone at rest, 13 studies on sympathetic modulation during tasks, 3 studies on resting state parasympathetic modulation and 3 papers on task-related parasympathetic modulation. Studies comprised measurements of electrodermal activity, heart rate variability, blood pressure variability, blood volume pulse, pre-ejection period, and baroreflex sensitivity. 2 studies reported reduced sympathetic tone in aADHD; 7 papers described lower sympathetic reactivity to task demands in this cohort. One study linked aADHD to impaired vagal tone, while no indications of altered tasks-related parasympathetic reactivity in aADHD patients were reported.Conclusion: The reviewed data revealed impaired cardiovascular autonomic modulation in aADHD patients, predominantly in sympathetic modulation and during stress exposure.

Cardiovascular autonomic regulation correlates with cognitive performance in patients with a history of traumatic brain injury.

BACKGROUND AND OBJECTIVE: Traumatic brain injury (TBI) may afflict brain areas contributing to both cardiovascular autonomic regulation and cognitive performance. To evaluate possible associations between both functions in patients with a history of TBI (post-TBI-patients), we determined correlations between cardiovascular autonomic regulation and cognitive function in post-TBI-patients. METHODS: In 86 post-TBI-patients (33.1 ± 10.8 years old, 22 women, 36.8 ± 28.9 months after injury), we monitored RR intervals (RRI), systolic and diastolic blood pressures (BPsys, BPdia), and respiration (RESP) at rest. We calculated parameters of total cardiovascular autonomic modulation (RRI-standard-deviation (RRI-SD), RRI-coefficient-of-variation (RRI-CV), RRI-total-powers), sympathetic (RRI-low-frequency-powers (RRI-LF), normalized (nu) RRI-LF-powers, BPsys-LF-powers) and parasympathetic modulation (root-mean-square-of-successive-RRI-differences (RMSSD), RRI-high-frequency-powers (RRI-HF), RRI-HFnu-powers), sympathetic-parasympathetic balance (RRI-LF/HF-ratios), and baroreflex sensitivity (BRS). We used the Mini-Mental State Examination and Clock Drawing Test (CDT) to screen the general global and visuospatial cognitive function, and applied the standardized Trail Making Test (TMT)-A assessing visuospatial abilities and TMT-B assessing executive function. We calculated correlations between autonomic and cognitive parameters (Spearman's rank correlation test; significance: P < 0.05). RESULTS: CDT values positively correlated with age (P = 0.013). TMT-A values inversely correlated with RRI-HF-powers (P = 0.033) and BRS (P = 0.043), TMT-B values positively correlated with RRI-LFnu-powers (P = 0.015), RRI-LF/HF-ratios (P = 0.036), and BPsys-LF-powers (P = 0.030), but negatively with RRI-HFnu-powers (P = 0.015). CONCLUSIONS: In patients with a history of TBI, there is an association between decreased visuospatial and executive cognitive performance and reduced parasympathetic cardiac modulation and baroreflex sensitivity with relatively increased sympathetic activity. Altered autonomic control bears an increased cardiovascular risk; cognitive impairment compromises quality of life and living conditions. Thus, both functions should be monitored in post-TBI-patients.

Absenteeism and associated labour costs according to depressive symptom severity in the German general population: why preventive strategies matter.

PURPOSE: Depression is a highly prevalent mental health condition with substantial individual, societal and economic consequences. This study focussed on the association of depressive symptom severity with absenteeism duration and employer labour costs. METHODS: Using cross-sectional data from the German Health Update 2014/2015, multivariable zero-inflated Poisson regression (ZIP) models explored the association of depressive symptom severity (8-item depression patient health questionnaire-PHQ-8), with absenteeism weeks during 12 months in men and women working full- or part-time. The predicted sick leave weeks were multiplied by mean average labour costs. RESULTS: The sample consisted of 12,405 persons with an average sick leave of 1.89 weeks (SD 4.26). Fifty-four % were women and 57% were between 40 and 59 years of age. In men and women, mild, moderate, moderately severe and severe depressive symptoms were associated with a significant factor increase in sick leave weeks compared to persons with no or minimal symptoms. Labour costs increased with increasing symptom severity from € 1468.22 for men with no or minimal depressive symptoms to € 7190.25 for men with severe depressive symptoms and from € 1045.82 to € 4306.30 in women, respectively. CONCLUSION: The present results indicate that increasing depressive symptom severity is associated with increasing absenteeism and employer costs. They emphasize the need for implementation, realignment or extension of professional work-site health promotion programmes aiming at the improvement and maintenance of employee health and the reduction of labour costs associated with depression-related sick leave.

Cardiovascular Autonomic Modulation during Metronomic Breathing and Stress Exposure in Patients with Borderline Personality Disorder.

INTRODUCTION: Given the growing evidence of reduced heart rate variability in psychiatric diseases associated with emotional instability, we investigated cardiovascular autonomic modulation in patients with borderline personality disorder (BPD) during resting state, parasympathetic stimulation (metronomic breathing), and sympathetic stimulation (mental arithmetic stress test). METHODS: In 29 BPD outpatients and 30 controls, we recorded RR-intervals (RRI), blood pressure, skin conductance levels, and respiratory frequency during resting state, metronomic breathing, stress anticipation, stress exposure, and stress recovery. We calculated baroreflex sensitivity (BRS) and parameters of heart rate variability, including the root mean square of successive differences (RMSSD), an index of cardiovagal modulation. RESULTS: During resting state, BPD patients showed higher blood pressure and shorter RRI, as well as lower RMSSD and BRS than controls. Metronomic breathing increased RMSSD and BRS in BPD patients. During the stress exposure, BRS significantly decreased in controls, but not in BPD patients. Furthermore, BPD patients showed less cardioacceleration in response to stress exposure than controls. During stress recovery, we found increases in RMSSD and BRS in controls, but not in BPD patients. CONCLUSION: Our data show reduced cardiovascular autonomic modulation in BPD patients during resting state, psychophysiological relaxation, and stress exposure. The results indicate a vagal modulation deficit in this cohort. Breathing techniques, such as metronomic breathing, might be helpful to reduce stress and to increase vagal tone in BPD patients.

Emotional and Autonomic Processing of Olfactory Stimuli Is Compromised in Patients with a History of Mild Traumatic Brain Injury.

Patients with a history of mild traumatic brain injury (post-mTBI patients) may have enduring cardiovascular-autonomic dysregulation and emotional problems. Olfactory stimulation (OS) triggers emotional and cardiovascular-autonomic responses that might be compromised in post-mTBI patients. We therefore evaluated these responses to OS in post-mTBI patients. In 17 post-mTBI patients (interval since mTBI: 32.4 ± 6.8 months) and 17 age- and sex-matched controls, we recorded respiration, electrocardiographic RR intervals, and systolic and diastolic blood pressures (BPsys, BPdia) before and during pleasant vanilla stimulation and unpleasant hydrogen sulphide (H2S) stimulation. Participants rated OS-related pleasantness, arousal, intensity, and familiarity on 9-point Likert scales. Analyses of variance (ANOVAs) with post hoc analyses compared parameters within each group before and during OS. To assess associations between pleasantness, arousal, intensity, and familiarity, we correlated OS scores within groups (significance: p < 0.05). Baseline parameters were similar between groups. Only in controls, vanilla stimulation significantly lowered BPsys and BPdia, whereas H2S stimulation lowered RR intervals. Vanilla-related pleasantness scores were lower, intensity scores were higher in patients than controls. During vanilla stimulation, pleasantness scores correlated negatively with arousal scores in controls, whereas familiarity scores correlated positively with intensity scores in patients. During H2S stimulation, familiarity scores correlated negatively with pleasantness scores in controls, whereas pleasantness scores correlated negatively with arousal scores in mTBI patients. Post-mTBI patients could not change BP or RR intervals during OS but perceived vanilla stimuli as less pleasant and more intense than did controls. Associations between pleasantness, arousal, intensity, and familiarity differed between groups suggesting different activation of the olfactory network and the central autonomic network upon OS. Subtle lesions within these networks might cause persistent changes in emotional and cognitive odor perception and cardiovascular responses.

The association of physical activity and depression in patients with, or at risk of, osteoarthritis is captured equally well by patient reported outcomes (PROs) and accelerometer measurements - Analyses of data from the Osteoarthritis Initiative.

OBJECTIVES: Osteoarthritis (OA) patients are at increased risk of depression, and low levels of physical activity (PA) are a potential warning sign of depression. PA can be estimated by patient reported outcomes (PROs) or measured with accelerometers (ACCs). We explored which of these two best captures depression in patients with, or at risk of, OA. METHODS: 48-months data from the Osteoarthritis Initiative were cross-sectionally analysed. The dichotomized Centre for Epidemiological Studies Depression Scale score was used as outcome (depression y/n). The Physical Activity Scale for the Elderly (PASE) was selected as PRO. ACC-data comprised average minutes of daily moderate to vigorous activity. Two multivariable models (PRO-model/ACC-model) were compared directly and indirectly using areas under the curve (AUC) for the predicted probability of depression, penalized model selection criteria (PMSC) and log-likelihood ratio tests. RESULTS: AUCs from the ACC (0.71 [95% CI 0.67; 0.75]) and PRO model (0.72 [95% CI 0.68; 0.76]) were not significantly different (p = 0.28). Differences in PMSC were small (<10). The log-likelihood ratio test for the comparison of the ACC (ll -505.22) with the base model (ll -505.98) was not significant (LR chi2 = 1.52; p = 0.22), but the PRO model (ll -501.55) had a better fit than the base model (LR chi2 = 8.87; p < 0.01). CONCLUSIONS: PRO and ACC data perform similarly in capturing depression. Indirect comparison even pleads for PROs. Costs of accelerometers and the additional burden for patients are in support of the PASE as an appropriate alternative to screen for depression in OA patients.

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.

Eyeball pressure stimulation induces subtle sympathetic activation in patients with a history of moderate or severe traumatic brain injury.

OBJECTIVE: After traumatic brain injury (TBI), there may be persistent central-autonomic-network (CAN) dysfunction causing cardiovascular-autonomic dysregulation. Eyeball-pressure-stimulation (EPS) normally induces cardiovagal activation. In patients with a history of moderate or severe TBI (post-moderate-severe-TBI), we determined whether EPS unveils cardiovascular-autonomic dysregulation. METHODS: In 51 post-moderate-severe-TBI patients (32.7 ±â€¯10.5 years old, 43.1 ±â€¯33.4 months post-injury), and 30 controls (29.1 ±â€¯9.8 years), we recorded respiration, RR-intervals (RRI), systolic and diastolic blood-pressure (BPsys, BPdia), before and during EPS (120 sec; 30 mmHg), using an ocular-pressure-device (Okulopressor®). We calculated spectral-powers of mainly sympathetic low (LF: 0.04-0.15 Hz) and parasympathetic high (HF: 0.15-0.5 Hz) frequency RRI-fluctuations, sympathetically mediated LF-powers of BPsys, and calculated normalized (nu) LF- and HF-powers of RRI. We compared parameters between groups before and during EPS by repeated-measurement-analysis-of-variance with post-hoc analysis (significance: p < 0.05). RESULTS: At rest, sympathetically mediated LF-BPsys-powers were significantly lower in the patients than the controls. During EPS, only controls significantly increased RRIs and parasympathetically mediated HFnu-RRI-powers, but decreased LF-RRI-powers, LFnu-RRI-powers, and LF-BPsys-powers; in contrast, the patients slightly though significantly increased BPsys upon EPS, without changing any other parameter. CONCLUSIONS: In post-moderate-severe-TBI patients, autonomic BP-modulation was already compromised at rest. During EPS, our patients failed to activate cardiovagal modulation but slightly increased BPsys, indicating persistent CAN dysregulation. SIGNIFICANCE: Our findings unveil persistence of subtle cardiovascular-autonomic dysregulation even years after TBI.

Insular multiple sclerosis lesions are associated with erectile dysfunction.

Erectile function (EF) is frequently compromised in men with multiple sclerosis (MS). Functional neuroimaging in healthy men identified a network of brain areas, such as the insula, visual and somatosensory association areas, cingulate gyrus, prefrontal cortex, as well as subcortical regions, contributing to EF. This study intended to determine associations between EF deterioration during MS and cerebral MS-associated lesion sites. In 31 men with MS (mean age 38.2 ± 11.2 years), we evaluated MS-related EF deterioration by comparing scores of the 5-item International Index of Erectile Function-5 questionnaire (IIEF5) at the time of study and retrospectively, 3 months prior to MS diagnosis, by calculating score differences as DeltaIIEF5 (DeltaIIEF5 score < 0 indicated EF deterioration). To assess the impact of confounding factors of EF, patient age, disease duration, disease severity, depressiveness, bladder and bowel symptoms, and total cerebral MS lesion volume were correlated with DeltaIIEF5 scores (Spearman rank correlation) and compared between patients with and without EF deterioration (t tests or Mann-Whitney U test). MS lesions were assessed on T2-weighted magnetic resonance imaging (MRI; 1.5 or 3 T). We determined the lesion overlap (prevalence of identical lesion sites among patients), subtracted lesion overlaps in patients without EF deterioration from overlaps in patients with EF deterioration, and compared DeltaIIEF5 scores voxel-wise between patients with and without lesions in a given voxel (t test; significance: p < 0.05). In 14 patients (45.2%), DeltaIIEF5 scores indicated EF deterioration. DeltaIIEF5 scores were not associated with age (ρ = 0.06; p = 0.74), disease duration (ρ = 0.26; p = 0.15), disease severity (ρ = - 0.19; p = 0.31), depressiveness (ρ = 0.07; p = 0.72), bladder symptoms (ρ = - 0.11; p = 0.57), bowel symptoms (ρ = 0.17; p = 0.37), and total lesion volume (ρ = - 0.13; p = 0.47). The voxel-wise analysis showed associations between EF deterioration and MS lesions primarily in the bilateral, and predominantly left juxtacortical insular region. In conclusion, MS lesions particularly in the left insular region, which is activated with sexual arousal, contribute to erectile dysfunction.

Severity of traumatic brain injury correlates with long-term cardiovascular autonomic dysfunction.

After traumatic brain injury (TBI), central autonomic dysfunction might contribute to long-term increased mortality rates. Central autonomic dysfunction might depend on initial trauma severity. This study was performed to evaluate differences in autonomic modulation at rest and upon standing between patients with a history of mild TBI (post-mild-TBI patients), moderate or severe TBI (post-moderate-severe-TBI patients), and healthy controls. In 20 post-mild-TBI patients (6-78 months after TBI), age-matched 20 post-moderate-severe-TBI patients (6-94 months after TBI) and 20 controls, we monitored respiration, RR intervals (RRI) and systolic blood pressure (BPsys) at supine rest and upon standing. We determined mainly sympathetic low (LF) and parasympathetic high (HF) frequency powers of RRI fluctuations, sympathetically mediated LF-BPsys powers, LF/HF-RRI ratios, normalized (nu) LF-RRI and HF-RRI powers, and compared data between groups, at rest and upon standing (ANOVA with post hoc testing). We correlated autonomic parameters with initial Glasgow Coma Scale (GCS) scores (Spearman test; significance: p < 0.05). Supine BPsys and LFnu-RRI powers were higher while HFnu-RRI powers were lower in post-moderate-severe-TBI patients than post-mild-TBI patients and controls. LFnu-RRI powers were higher and HFnu-RRI powers were lower in post-mild-TBI patients than controls. Upon standing, only post-mild-TBI patients and controls increased LF-BPsys powers and BPsys and decreased HF-RRI powers. GCS scores correlated positively with LFnu-RRI powers, LF/HF-RRI ratios, and inversely with HFnu-RRI powers, at standing position. More than 6 months after TBI, there is autonomic dysfunction at rest and upon standing which is more pronounced after moderate-severe than mild TBI and in part correlates with initial trauma severity.

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).

Lesion mapping of stroke-related erectile dysfunction.

Acute ischaemic stroke in brain areas contributing to male sexual function may impair erectile function depending on the lesion site. This study intended to determine associations between stroke-related erectile dysfunction and cerebral ischaemic lesion sites using voxel-based lesion mapping. In 52 males (mean age 60.5 ± 10.5 years) with first-ever ischaemic strokes, we assessed erectile function after and retrospectively 3 months prior to the stroke using scores of the 5-item International Index of Erectile Function-5 questionnaire. We assessed cardiovascular risk factors and determined clinical stroke severity and infarct volumes as well as total brain volume by neuroimaging. We calculated correlations between patient age, clinical stroke severity, infarct volumes as well as brain volumes and the difference between erectile dysfunction scores before and after stroke. Moreover, we compared patient age, prevalence of cardiovascular risk factors, clinical stroke severity, infarct volumes and brain volumes of patients with unchanged and deteriorated erectile function after stroke. The infarcts were manually outlined and transformed into stereotaxic space. We determined the lesion overlap and performed subtraction analyses of lesions. In a voxel-based lesion analysis, the difference between erectile dysfunction scores before and after stroke was correlated with the lesion site using t-test statistics. Finally, we conducted a region of interest-based multivariate linear regression analysis that was adjusted for potential confounding factors including patient age, clinical stroke severity, imaging modality, lesion size and brain volume. In 32 patients (61.5%) erectile dysfunction scores declined after the stroke and therefore had stroke-related erectile dysfunction. Deterioration of erectile dysfunction scores was not associated with patient age, clinical stroke severity, infarct volume, brain volume, and cardiovascular risk factors. The voxel-wise subtraction analysis showed associations between stroke-related erectile dysfunction and lesion sites in the right occipito-parietal cortex and thalamus, as well as in the left insula and adjacent temporo-parietal areas. Using voxel-wise t-test statistics, we showed associations between deterioration of erectile function and lesion sites in the right occipital and thalamic region, and the left parietal association area. The linear regression analysis showed that stroke-related erectile dysfunction remained associated with lesions of the right occipital and left parietal association areas after adjusting for confounding factors. In conclusion, our voxel-wise analysis indicates that deteriorating erectile function after stroke is associated with lesions in the right occipito-parietal and thalamic areas integrating visual and somatosensory information, as well as lesions in the left insular and adjacent parieto-temporal areas contributing to generating and mapping visceral arousal states.

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. Ann Neurol 2016;80:490-498.

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: 0.03-0.15Hz) 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 (25mg). 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.

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.

Erectile dysfunction (ED) after ischemic stroke: association between prevalence and site of lesion.

PURPOSE: Stroke may cause or worsen erectile dysfunction (ED). Post-stroke ED prevalence and association with stroke location are not well established. Therefore, we assessed post-stroke ED prevalence in relation to ischemic lesion locations and stroke severity. METHODS: In 57 men (62.6 ± 10.5 years) who had ischemic stroke within 24 months prior to evaluation, we used the five-item International Index of Erectile Function questionnaire (IIEF5) to evaluate ED prevalence after stroke and retrospectively 3 months prior to stroke. IIEF5 scores range from 5 to 25; scores below 22 indicate ED. We estimated stroke severity upon hospital admission, using the National Institute of Health Stroke Scale (NIHSS), and determined stroke location from cranial computed tomography or magnetic resonance imaging. We compared pre- and post-stroke results with those of 22 control persons (61.7 ± 11.2 years), calculated correlations between IIEF5 scores and NIHSS scores, and compared ED prevalence with stroke locations (significance: p < 0.05). RESULTS: ED was reported by 45/57 patients after stroke, 26/57 patients before stroke, and 6/22 control persons. Patients' IIEF5 values were significantly lower [median 16 interquartile range (IQR) 3.5-20.5] after than before stroke (median 23, IQR 19.0-24.0) and lower than in controls (median 24, IQR 19.8-25.0). Pre- and post-stroke IIEF5 scores did not correlate with the patients' NIHSS scores at stroke onset (p > 0.05). ED was associated with middle cerebral artery infarction in 27/34, posterior cerebral artery infarction in 4/5, anterior cerebral artery infarction in 1/1, basal ganglia infarction in 3/3, brain stem infarction in 8/10, cerebellar infarction in 2/5, and lesions in more than one region in 1/1 patients. CONCLUSIONS: Disruption of the central network assuring erection might contribute to increased ED severity and prevalence after stroke. Anti-erectile effects of functional and psychological impairment or medication added after stroke may also contribute to ED but must be evaluated in larger patients groups.

Eyeball Pressure Stimulation Unveils Subtle Autonomic Cardiovascular Dysfunction in Persons with a History of Mild Traumatic Brain Injury.

After mild traumatic brain injury (mTBI), patients have increased long-term mortality rates, persisting even beyond 13 years. Pathophysiology is unclear. Yet, central autonomic network dysfunction may contribute to cardiovascular dysregulation and increased mortality. Purely parasympathetic cardiovascular challenge by eyeball pressure stimulation (EP), might unveil subtle autonomic dysfunction in post-mTBI patients. We investigated whether mild EP shows autonomic cardiovascular dysregulation in post-mTBI patients. In 24 patients (34 ± 12 years; 5-86 months post-injury) and 27 controls (30 ± 11 years), we monitored respiration, electrocardiographic RR intervals (RRI), systolic and diastolic blood pressure (BPsys, BPdia) before and during 2 min of 30 mm Hg EP, applied by an ophthalmologic ocular pressure device (Okulopressor(®)). We calculated spectral powers of RRI in the mainly sympathetic low frequency (LF; 0.04-0.15 Hz) and parasympathetic high frequency (HF; 0.15-0.5 Hz) ranges, and of BP in the sympathetic LF range, the RRI-LF/HF ratio as index of the sympathetic-parasympathetic balance, normalized (nu) RRI-LF- and HF-powers, and LF- and HF-powers after natural logarithmic transformation (ln). Parameters before and during EP in post-mTBI patients and controls were compared by repeated measurement analysis of variance with post hoc analysis (p < 0.05). During EP, BPsys and BPdia increased in post-mTBI patients. Only in controls but not in post-mTBI patients, EP increased RRI-HFnu-powers and decreased RRI-LF-powers, RRI-LFnu-powers, BPsys-LF-powers, BPsys-lnLF-powers and BPdia-lnLF-powers. RRI-LF/HF ratios slightly increased in post-mTBI patients but slightly decreased in controls upon EP. Even with only mild EP, our controls showed normal EP responses and shifted sympathetic-parasympathetic balance towards parasympathetic predominance. In contrast, our post-mTBI patients could not increase parasympathetic heart rate modulation but increased BP upon EP, indicating a paradox sympathetic activation. The findings support the hypothesis that central autonomic dysfunction might contribute to an increased cardiovascular risk, even years after mTBI.

CNS BOLD fMRI effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal - a pilot study.

BACKGROUND: It has recently been shown that electrical stimulation of sensory afferents within the outer auditory canal may facilitate a transcutaneous form of central nervous system stimulation. Functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) effects in limbic and temporal structures have been detected in two independent studies. In the present study, we investigated BOLD fMRI effects in response to transcutaneous electrical stimulation of two different zones in the left outer auditory canal. It is hypothesized that different central nervous system (CNS) activation patterns might help to localize and specifically stimulate auricular cutaneous vagal afferents. METHODOLOGY: 16 healthy subjects aged between 20 and 37 years were divided into two groups. 8 subjects were stimulated in the anterior wall, the other 8 persons received transcutaneous vagus nervous stimulation (tVNS) at the posterior side of their left outer auditory canal. For sham control, both groups were also stimulated in an alternating manner on their corresponding ear lobe, which is generally known to be free of cutaneous vagal innervation. Functional MR data from the cortex and brain stem level were collected and a group analysis was performed. RESULTS: In most cortical areas, BOLD changes were in the opposite direction when comparing anterior vs. posterior stimulation of the left auditory canal. The only exception was in the insular cortex, where both stimulation types evoked positive BOLD changes. Prominent decreases of the BOLD signals were detected in the parahippocampal gyrus, posterior cingulate cortex and right thalamus (pulvinar) following anterior stimulation. In subcortical areas at brain stem level, a stronger BOLD decrease as compared with sham stimulation was found in the locus coeruleus and the solitary tract only during stimulation of the anterior part of the auditory canal. CONCLUSIONS: The results of the study are in line with previous fMRI studies showing robust BOLD signal decreases in limbic structures and the brain stem during electrical stimulation of the left anterior auditory canal. BOLD signal decreases in the area of the nuclei of the vagus nerve may indicate an effective stimulation of vagal afferences. In contrast, stimulation at the posterior wall seems to lead to unspecific changes of the BOLD signal within the solitary tract, which is a key relay station of vagal neurotransmission. The results of the study show promise for a specific novel method of cranial nerve stimulation and provide a basis for further developments and applications of non-invasive transcutaneous vagus stimulation in psychiatric patients.

Subtype-selective GABAA receptor mimetics--novel antihyperalgesic agents?

Agonists at the benzodiazepine-binding site of ionotropic gamma-aminobutyric acid (GABA(A)) receptors are in clinical use as hypnotics, anxiolytics, and anticonvulsants since the early 1960. Analgesic effects of classical benzodiazepines have occasionally been reported in certain subgroups of patients suffering from chronic pain or after spinal delivery through intrathecal catheters. However, these drugs are generally not considered as analgesics but should in fact be avoided in patients with chronic pain. Recent evidence from genetically modified mice now indicates that agents targeting only a subset of benzodiazepine (GABA(A)) receptors should provide pronounced antihyperalgesic activity against inflammatory and neuropathic pain. Several such compounds have been developed recently, which exhibit significant antihyperalgesia in mice and rats and appear to be devoid of the typical side-effects of classical benzodiazepines.

Reversal of pathological pain through specific spinal GABAA receptor subtypes.

Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology. Facilitation of spinal gamma-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA(A) receptors should be able to compensate for this loss. With the use of GABA(A)-receptor point-mutated knock-in mice in which specific GABA(A) receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA(A) receptors containing the alpha2 and/or alpha3 subunits. We show that their selective activation by the non-sedative ('alpha1-sparing') benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics.