Sex differences in the age-related decrease of spontaneous baroreflex function in healthy individuals.

The baroreflex is a powerful physiological mechanism for rapidly adjusting heart rate in response to changes in blood pressure. Spontaneous baroreflex sensitivity (BRS) has been shown to decrease with age. However, studies of sex differences in these age-related changes are rare. Here we investigated several markers of spontaneous baroreflex function in a large sample of healthy individuals. Cardiovascular signals were recorded in the supine position under carefully controlled resting conditions. After quality control, n = 980 subjects were divided into five age groups [age < 30 yr (n = 612), 30-39 yr (n = 140), 40-49 yr (n = 95), 50-59 yr (n = 61), and >60 yr (n = 72)]. Spontaneous baroreflex function was assessed in the time domain (bradycardic and tachycardic slope) and in the frequency domain in the low- and high-frequency band (LF-α, HF-α) applying the transfer function. General linear models showed a significant effect of factor age (P < 0.001) and an age × sex interaction effect (P < 0.05) on each indicator of the baroreflex function. Simple main effects showed a significantly higher BRS as indicated by tachycardic slope, LF-α and HF-α in middle-aged women compared with men (30-39 yr) and higher LF-α, bradycardic and tachycardic slope in men compared with women of the oldest age group (>60 yr). Changes in BRS over the lifespan suggest that baroreflex function declines more slowly but earlier in life in men than in women. Our findings could be linked to age-related changes in major sex hormone levels, suggesting significant implications for diverse cardiovascular outcomes and the implementation of targeted preventive strategies.NEW & NOTEWORTHY In this study, we demonstrate that the age-related decrease of spontaneous baroreflex sensitivity is different in men and women by analyzing resting state cardiovascular data of a large sample of healthy individuals.

Testing visual self-misperception in anorexia nervosa using a symmetrical body size estimation paradigm.

OBJECTIVE: Individuals diagnosed with anorexia nervosa (AN) often report seeing themselves as overweight. While body size estimation tasks suggest that such individuals overestimate their body size, these tasks have failed to establish whether this misestimation stems from visual misperception. Misestimation might, instead, be due to response bias. We designed a paradigm to distinguish between visual and response bias contributions to body size misestimation: the symmetrical body size estimation (s-BSE) paradigm. METHOD: The s-BSE paradigm involves two tasks. In the conventional task, participants estimate the width of their photographed body by adjusting the size of a rectangle to match. In the transposed task, participants adjust the size of a photograph of their body to match the rectangle. If overestimation stems exclusively from visual misperception, then errors in each task would be equal and opposite. Using this paradigm, we compared the performance of women diagnosed with AN (n = 14) against women without any eating disorder (n = 40). RESULTS: In the conventional task, we replicated previous findings indicating that both women with AN and women without any eating disorder overestimate their body size. In the transposed task, neither group adjusted the bodies to be narrower than the rectangle. Participants with AN set their photographs to be significantly wider. DISCUSSION: While we replicated previous findings of body size overestimation amongst women with AN and those without any eating disorder, our results are inconsistent with the hypothesis that such overestimation stems exclusively from visual misperception and instead suggest a substantial response bias effect. PUBLIC SIGNIFICANCE: Women with anorexia nervosa overestimate their own body size. Research has not yet determined whether this overestimation stems from them seeing themselves as larger or other, non-visual factors. We employ a new method for distinguishing these possibilities and find that non-visual factors influence size estimates for women with and without anorexia nervosa. This method can help future research control for non-perceptual influences on participant responses.

Central Autonomic Network Alterations in Anorexia Nervosa Following Peripheral Adrenergic Stimulation.

BACKGROUND: Anorexia nervosa (AN) is characterized by low body weight, disturbed eating, body image disturbance, anxiety, and interoceptive dysfunction. However, the neural processes underlying these dysfunctions in AN are unclear. This investigation combined an interoceptive pharmacological probe, the peripheral ß-adrenergic agonist isoproterenol, with resting-state functional magnetic resonance imaging to examine whether individuals with AN relative to healthy comparison participants show dysregulated neural coupling in central autonomic network brain regions. METHODS: Resting-state functional magnetic resonance imaging was performed in 23 weight-restored female participants with AN and 23 age- and body mass index-matched healthy comparison participants before and after receiving isoproterenol infusions. Whole-brain functional connectivity (FC) changes were examined using central autonomic network seeds in the amygdala, anterior insular cortex, posterior cingulate cortex, and ventromedial prefrontal cortex after performing physiological noise correction procedures. RESULTS: Relative to healthy comparison participants, adrenergic stimulation caused widespread FC reductions in the AN group between central autonomic network regions and motor, premotor, frontal, parietal, and visual brain regions. Across both groups, these FC changes were inversely associated with trait anxiety (State-Trait Anxiety Inventory-Trait), trait depression (9-item Patient Health Questionnaire), and negative body image perception (Body Shape Questionnaire) measures, but not with changes in resting heart rate. These results were not accounted for by baseline group FC differences. CONCLUSIONS: Weight-restored females with AN show a widespread state-dependent disruption of signaling between central autonomic, frontoparietal, and sensorimotor brain networks that facilitate interoceptive representation and visceromotor regulation. Additionally, trait associations between central autonomic network regions and these other brain networks suggest that dysfunctional processing of interoceptive signaling may contribute to affective and body image disturbance in AN.

Dynamic changes in the central autonomic network of patients with anorexia nervosa.

Autonomic cardiac dysfunction is a common complication in patients with anorexia nervosa (AN). Despite its high prevalence, physicians often overlook this clinical condition, and little research has been dedicated so far. To probe the functional role of the neurocircuitry underpinning the poorly understood autonomic cardiac dysfunction, we examined dynamic functional differences in the central autonomic network (CAN) between 21 acute AN individuals and 24 age, sex and heart rate-matched healthy controls (HC). We assessed functional connectivity (FC) changes in CAN using seeds in the ventromedial prefrontal cortex, left and right anterior insular cortex, left and right amygdala and dorsal anterior cingulate cortex. The overall FC between the six investigated seeds is reduced in AN individuals compared to HC, although no changes were observed for single connections. Moreover, AN exhibited higher complexity in the FC time series of such CAN regions. Contrary to HC, we found that the degree of complexity between FC and heart rate (HR) series did not correlate in AN, suggesting a shift from central to peripheral control of the heart in AN individuals. Using dynamic FC analysis, we showed that the CAN transits across five functional states with no preference for any. Strikingly, at the state of weakest connectivity, the entropy significantly diverges between healthy and AN individuals, reaching its minimum and maximum values, respectively. Overall, our findings provide evidence that core regions of the CAN engaged in cardiac regulation are functionally affected in acute AN.

Associations of common genetic risk variants of the muscarinic acetylcholine receptor M2 with cardiac autonomic dysfunction in patients with schizophrenia.

OBJECTIVES: Decreased vagal modulation, which has consistently been observed in schizophrenic patients, might contribute to increased cardiac mortality in schizophrenia. Previously, associations between CHRM2 (Cholinergic Receptor Muscarinic 2) and cardiac autonomic features have been reported. Here, we tested for possible associations between these polymorphisms and heart rate variability in patients with schizophrenia. METHODS: A total of three single nucleotide polymorphisms (SNPs) in CHRM2 (rs73158705 A>G, rs8191992 T>A and rs2350782 T>C) that achieved significance (p < 5 * 10-8) in genome-wide association studies for cardiac autonomic features were genotyped in 88 drug-naïve patients, 61 patients receiving antipsychotic medication and 144 healthy controls. Genotypes were analysed for associations with parameters of heart rate variability and complexity, in each diagnostic group. RESULTS: We observed a significantly altered heart rate variability in unmedicated patients with identified genetic risk status in rs73158705 A>G, rs8191992 T>A and rs2350782 T>C as compared to genotype non-risk status. In patients receiving antipsychotic medication and healthy controls, these associations were not observed. DISCUSSION: We report novel candidate genetic associations with cardiac autonomic dysfunction in schizophrenia, but larger cohorts are required for replication.

Analysis of CACNA1C and KCNH2 Risk Variants on Cardiac Autonomic Function in Patients with Schizophrenia.

BACKGROUND: Cardiac autonomic dysfunction (CADF) is a major contributor to increased cardiac mortality in schizophrenia patients. The aberrant function of voltage-gated ion channels, which are widely distributed in the brain and heart, may link schizophrenia and CADF. In search of channel-encoding genes that are associated with both CADF and schizophrenia, CACNA1C and KCNH2 are promising candidates. In this study, we tested for associations between genetic findings in both genes and CADF parameters in schizophrenia patients whose heart functions were not influenced by psychopharmaceuticals. METHODS: First, we searched the literature for single-nucleotide polymorphisms (SNPs) in CACNA1C and KCNH2 that showed genome-wide significant association with schizophrenia. Subsequently, we looked for such robust associations with CADF traits at these loci. A total of 5 CACNA1C SNPs and 9 KCNH2 SNPs were found and genotyped in 77 unmedicated schizophrenia patients and 144 healthy controls. Genotype-related impacts on heart rate (HR) dynamics and QT variability indices (QTvi) were analyzed separately in patients and healthy controls. RESULTS: We observed significantly increased QTvi in unmedicated patients with CADF-associated risk in CACNA1C rs2283274 C and schizophrenia-associated risk in rs2239061 G compared to the non-risk allele in these patients. Moreover, unmedicated patients with previously identified schizophrenia risk alleles in KCNH2 rs11763131 A, rs3807373 A, rs3800779 C, rs748693 G, and 1036145 T showed increased mean HR and QTvi as compared to non-risk alleles. CONCLUSIONS: We propose a potential pleiotropic role for common variation in CACNA1C and KCNH2 associated with CADF in schizophrenia patients, independent of antipsychotic medication, that predisposes them to cardiac arrhythmias and premature death.

Central autonomic network alterations in male endurance athletes.

Physical exercise causes marked adjustments in brain function and the cardiovascular system. Brain regions of the so-called central autonomic network (CAN) are likely to show exercise-related alterations due to their involvement in cardiac control, yet exercise-induced CAN changes remain unclear. Here we investigate the effects of intensive exercise on brain regions involved in cardiac autonomic regulation using resting-state functional connectivity (rsFC). We explored rsFC of six core regions within CAN, namely ventromedial prefrontal cortex, dorsolateral anterior cingulate cortex, left/right amygdala, and left/right anterior insula, in 20 endurance athletes and 21 non-athletes. We showed that athletes had enhanced rsFC within CAN and sensorimotor areas compared to non-athletes. Likewise, we identified two networks with increased rsFC encompassing autonomic and motor-related areas using network-based statistics analysis. In addition, rsFC displayed an inverse relationship with heart rate, where the stronger rsFC in athletes correlates with their slower heart rate. Despite this significant relationship, mediation analysis revealed that heart rate is a weak mediator of the effect of intensive physical training on rsFC. Our findings prove that physical exercise enhances brain connectivity in central autonomic and sensorimotor networks and highlight the close link between brain and heart.

Depressive rumination and heart rate variability: A pilot study on the effect of biofeedback on rumination and its physiological concomitants.

Objective: Recent studies suggest that lower resting heart rate variability (HRV) is associated with elevated vulnerability to depressive rumination. In this study, we tested whether increases in HRV after HRV-biofeedback training are accompanied by reductions in rumination levels. Materials and methods: Sixteen patients suffering from depression completed a 6-week HRV-biofeedback training and fourteen patients completed a control condition in which there was no intervention (waitlist). The training included five sessions per week at home using a smartphone application and an ECG belt. Depressive symptoms and autonomic function at rest and during induced rumination were assessed before and after each of the two conditions. We used a well-established rumination induction task to provoke a state of pervasive rumination while recording various physiological signals simultaneously. Changes in HRV, respiration rate, skin conductance, and pupil diameter were compared between conditions and time points. Results: A significant correlation was found between resting HRV and rumination levels, both assessed at the first laboratory session (r = -0.43, p < 0.05). Induction of rumination led to an acceleration of heart rate and skin conductance increases. After biofeedback training, resting vagal HRV was increased (p < 0.01) and self-ratings of state anxiety (p < 0.05), rumination (p < 0.05), perceived stress (p < 0.05), and depressive symptoms (QIDS, BDI; both p < 0.05) were decreased. In the control condition, there were no changes in autonomic indices or depressive symptomatology. A significant interaction effect group x time on HRV was observed. Conclusion: Our results indicate that a smartphone-based HRV-biofeedback intervention can be applied to improve cardiovagal function and to reduce depressive symptoms including self-rated rumination tendencies.

Autonomic aging - A dataset to quantify changes of cardiovascular autonomic function during healthy aging.

Autonomic regulation of blood pressure and cardiac rhythm progressively declines with increasing age. Impaired cardiovascular control promotes a variety of age-related cardio-vascular conditions. This study aims to provide a database of high-resolution biological signals to describe the effect of healthy aging on cardiovascular regulation. Electrocardiogram and continuous non-invasive blood pressure signals were recorded simultaneously at rest in 1,121 healthy volunteers. With this database, we provide raw signals as well as basic demographic information such as gender and body mass index. To demonstrate validity of the acquired data, we present the well-known decline of heart rate variability with increasing age in this database.

Using machine learning to estimate the calendar age based on autonomic cardiovascular function.

Introduction: Aging is accompanied by physiological changes in cardiovascular regulation that can be evaluated using a variety of metrics. In this study, we employ machine learning on autonomic cardiovascular indices in order to estimate participants' age. Methods: We analyzed a database including resting state electrocardiogram and continuous blood pressure recordings of healthy volunteers. A total of 884 data sets met the inclusion criteria. Data of 72 other participants with an BMI indicating obesity (>30 kg/m²) were withheld as an evaluation sample. For all participants, 29 different cardiovascular indices were calculated including heart rate variability, blood pressure variability, baroreflex function, pulse wave dynamics, and QT interval characteristics. Based on cardiovascular indices, sex and device, four different approaches were applied in order to estimate the calendar age of healthy subjects, i.e., relevance vector regression (RVR), Gaussian process regression (GPR), support vector regression (SVR), and linear regression (LR). To estimate age in the obese group, we drew normal-weight controls from the large sample to build a training set and a validation set that had an age distribution similar to the obesity test sample. Results: In a five-fold cross validation scheme, we found the GPR model to be suited best to estimate calendar age, with a correlation of r=0.81 and a mean absolute error of MAE=5.6 years. In men, the error (MAE=5.4 years) seemed to be lower than that in women (MAE=6.0 years). In comparison to normal-weight subjects, GPR and SVR significantly overestimated the age of obese participants compared with controls. The highest age gap indicated advanced cardiovascular aging by 5.7 years in obese participants. Discussion: In conclusion, machine learning can be used to estimate age on cardiovascular function in a healthy population when considering previous models of biological aging. The estimated age might serve as a comprehensive and readily interpretable marker of cardiovascular function. Whether it is a useful risk predictor should be investigated in future studies.

Estimating Resting HRV during fMRI: A Comparison between Laboratory and Scanner Environment.

Heart rate variability (HRV) is regularly assessed in neuroimaging studies as an indicator of autonomic, emotional or cognitive processes. In this study, we investigated the influence of a loud and cramped environment during magnetic resonance imaging (MRI) on resting HRV measures. We compared recordings during functional MRI sessions with recordings in our autonomic laboratory (LAB) in 101 healthy subjects. In the LAB, we recorded an electrocardiogram (ECG) and a photoplethysmogram (PPG) over 15 min. During resting state functional MRI, we acquired a PPG for 15 min. We assessed anxiety levels before the scanning in each subject. In 27 participants, we performed follow-up sessions to investigate a possible effect of habituation. We found a high intra-class correlation ranging between 0.775 and 0.996, indicating high consistency across conditions. We observed no systematic influence of the MRI environment on any HRV index when PPG signals were analyzed. However, SDNN and RMSSD were significantly higher when extracted from the PPG compared to the ECG. Although we found a significant correlation of anxiety and the decrease in HRV from LAB to MRI, a familiarization session did not change the HRV outcome. Our results suggest that psychological factors are less influential on the HRV outcome during MRI than the methodological choice of the cardiac signal to analyze.

The Influence of Heart Rate Variability Biofeedback on Cardiac Regulation and Functional Brain Connectivity.

BACKGROUND: Heart rate variability (HRV) biofeedback has a beneficial impact on perceived stress and emotion regulation. However, its impact on brain function is still unclear. In this study, we aimed to investigate the effect of an 8-week HRV-biofeedback intervention on functional brain connectivity in healthy subjects. METHODS: HRV biofeedback was carried out in five sessions per week, including four at home and one in our lab. A control group played jump'n'run games instead of the training. Functional magnetic resonance imaging was conducted before and after the intervention in both groups. To compute resting state functional connectivity (RSFC), we defined regions of interest in the ventral medial prefrontal cortex (VMPFC) and a total of 260 independent anatomical regions for network-based analysis. Changes of RSFC of the VMPFC to other brain regions were compared between groups. Temporal changes of HRV during the resting state recording were correlated to dynamic functional connectivity of the VMPFC. RESULTS: First, we corroborated the role of the VMPFC in cardiac autonomic regulation. We found that temporal changes of HRV were correlated to dynamic changes of prefrontal connectivity, especially to the middle cingulate cortex, the left insula, supplementary motor area, dorsal and ventral lateral prefrontal regions. The biofeedback group showed a drop in heart rate by 5.2 beats/min and an increased SDNN as a measure of HRV by 8.6 ms (18%) after the intervention. Functional connectivity of the VMPFC increased mainly to the insula, the amygdala, the middle cingulate cortex, and lateral prefrontal regions after biofeedback intervention when compared to changes in the control group. Network-based statistic showed that biofeedback had an influence on a broad functional network of brain regions. CONCLUSION: Our results show that increased heart rate variability induced by HRV-biofeedback is accompanied by changes in functional brain connectivity during resting state.

Attenuated neuronal and autonomic responses during error processing in anorexia nervosa.

INTRODUCTION: Anorexia nervosa (AN) is a severe psychiatric illness with alarming mortality rates. Nevertheless, despite former and recent research results, the etiology of AN is still poorly understood. Of particular interest is that, despite exaggerated response control and increased perfectionism scores, patients with AN seem not to perform better that those unaffected in tasks that require inhibitory control. One reason might be aberrant processing of errors. The objective of our study was thus to obtain further insight into the pathopsychology of AN. We were particularly interested in neuronal and autonomic responses during error processing and their association with behavior. METHODS: We analyzed 16 acute patients suffering from restrictive type AN and 21 healthy controls using functional magnetic resonance imaging (fMRI) with simultaneous physiological recordings during a Go/Nogo response inhibition task. Data were corrected for noise due to cardiac and respiratory influence. RESULTS: Patients and controls had similarly successful response inhibition in Nogo trials. However, in failed Nogo trials, controls had significantly greater skin conductance responses (SCR) than in correct Nogo trials. Patients did not exhibit elevated SCR to errors. Furthermore, we found significantly increased neuronal responses, especially in the amygdala and hippocampus, in controls compared to patients during error trials. We also found significant positive correlations in controls but not in patients between Nogo performance and activation in the salience network core regions after errors. CONCLUSION: Acute restrictive type AN patients seem to lack neuronal and autonomic responses to errors that might impede a flexible behavior adaption.

Working memory in schizophrenia: The role of the locus coeruleus and its relation to functional brain networks.

Evidence suggests functional brain networks, especially the executive control network (ECN) and default mode network (DMN), to be abnormal in schizophrenia. Dysfunctions within the locus coeruleus (LC)-noradrenaline (NE) system, which is supposed to be pivotal to modulate neuronal network activation during executive control (e.g., working memory function), are also considered to play a vital role in the occurrence of positive (e.g., hallucinatory) or negative (e.g., inattentive) symptoms in these patients. In the present study, we sought to shed further light on the role of the LC-NE system in patients with schizophrenia. More specifically, we wanted to improve our understanding of the relationship and possible disturbances of the ECN and DMN during a working memory task in patients. A total of 58 healthy control subjects and 40 medicated patients with schizophrenia were investigated using a working memory 3-back task during functional magnetic resonance imaging. Main findings of our present study were differential dynamics of ECN and DMN blood oxygenation level-dependent (BOLD) activations with increasing task demands in both patients and controls. Moreover, we found increased BOLD activation in the LC in patients compared to controls in the interaction contrast between groups and conditions. LC BOLD activation significantly correlated with both, the main hub of the ECN, that is, the dorsolateral prefrontal cortex, and of the DMN, that is, the posterior cingulate cortex. Thus, the LC-NE system seems to be crucial in modulating neuronal network activity in a 3-back working memory task and might significantly contribute to cognitive impairments in schizophrenia.

Cortical thinning and associated connectivity changes in patients with anorexia nervosa.

Structural brain abnormalities are a consistent finding in anorexia nervosa (AN) and proposed as a state biomarker of the disorder. Yet little is known about how regional structural changes affect intrinsic resting-state functional brain connectivity (rsFC). Using a cross-sectional, multimodal imaging approach, we investigated the association between regional cortical thickness abnormalities and rsFC in AN. Twenty-two acute AN patients and twenty-six age- and gender-matched healthy controls underwent a resting-state functional magnetic resonance imaging scan and cognitive tests. We performed group comparisons of whole-brain cortical thickness, seed-based rsFC, and network-based statistical (NBS) analyses. AN patients showed cortical thinning in the precuneus and inferior parietal lobules, regions involved in visuospatial memory and imagery. Cortical thickness in the precuneus correlated with nutritional state and cognitive functions in AN, strengthening the evidence for a critical role of this region in the disorder. Cortical thinning was accompanied by functional connectivity reductions in major brain networks, namely default mode, sensorimotor and visual networks. Similar to the seed-based approach, the NBS analysis revealed a single network of reduced functional connectivity in patients, comprising mainly sensorimotor- occipital regions. Our findings provide evidence that structural and functional brain abnormalities in AN are confined to specific regions and networks involved in visuospatial and somatosensory processing. We show that structural changes of the precuneus are linked to nutritional and functional states in AN, and future longitudinal research should assess how precuneus changes might be related to the evolution of the disorder.

A common variation in HCN1 is associated with heart rate variability in schizophrenia.

BACKGROUND: There is growing evidence for a shared genetic basis between schizophrenia risk and cardiovascular disease. Reduced efferent vagal activity, indexed by reduced heart rate variability (HRV), has been consistently described in patients with schizophrenia and may potentially contribute to the increased cardiovascular risk in these patients. In this study, we tested the hypothesis whether the established schizophrenia risk variant HCN1 rs16902086 (A > G) is associated with reduced HRV. METHODS: We analyzed the risk status of HCN1 rs16902086 (AG/GG vs. AA genotype) in 83 unmedicated patients with schizophrenia and 96 healthy controls and investigated genotype-related impacts on various HRV parameters. RESULTS: We observed significantly increased resting heart rates and a marked decrease of vagal modulation in our patient cohort. Strikingly, HCN1 rs16902086 (A > G) was associated with reduced HRV parameters in patients only. A trend towards more pronounced HRV deviations was observed in homozygous (GG) compared to heterozygous patients (AG). CONCLUSION: We present first evidence for a genetic risk factor that is associated with decreased vagal modulation in unmedicated patients with schizophrenia. Moreover, our findings suggest that HCN1 might be involved in reduced vagal modulation and possibly in increased cardiac mortality in schizophrenia patients. Thus, our data indicate that reduced vagal modulation might be an endophenotype of schizophrenia.

Interrelations between dopamine and serotonin producing sites and regions of the default mode network.

Recent functional magnetic resonance imaging (fMRI) studies showed that blood oxygenation level-dependent (BOLD) signal fluctuations in the default mode network (DMN) are functionally tightly connected to those in monoaminergic nuclei, producing dopamine (DA), and serotonin (5-HT) transmitters, in the midbrain/brainstem. We combined accelerated fMRI acquisition with spectral Granger causality and coherence analysis to investigate causal relationships between these areas. Both methods independently lead to similar results and confirm the existence of a top-down information flow in the resting-state condition, where activity in core DMN areas influences activity in the neuromodulatory centers producing DA/5-HT. We found that latencies range from milliseconds to seconds with high inter-subject variability, likely attributable to the resting condition. Our novel findings provide new insights into the functional organization of the human brain.

Influence of Individual Heart Rate on Nonlinear Brain-Heart Interactions Estimated by Convergent Cross Mapping in Schizophrenic Patients and Healthy Controls.

Quantification of directed (nonlinear) brain-heart interactions has turned to be an emerging topic of research and is important for the better understanding of central autonomic processing during specific diseases such as schizophrenia. Convergent Cross Mapping (CCM) was able to provide directed, frequency-selective and topographic views on existent interaction pattern of those patients. Investigations of the influence of individual heart rate (HR) on CCM estimations may further contribute to this topic. Relationship of mean HR and CCM was analyzed in a group of schizophrenic patients (N=17) and healthy controls (N=21). Influence of individual HR values was most pronounced for patients, for interactions from brain to heart and for the subgroup of patients with highest mean HR values.

Sympathetic and Parasympathetic Modulation of Pupillary Unrest.

Pupillary unrest is an established indicator of drowsiness or sleepiness. How sympathetic and parasympathetic activity contribute to pupillary unrest is not entirely unclear. In this study, we investigated 83 young healthy volunteers to assess the relationship of pupillary unrest to other markers of the autonomic nervous system. Sample entropy (SE) and the established pupillary unrest index (PUI) were calculated to characterize pupil size variability. Autonomic indices were derived from heart rate, blood pressure, respiration, and skin conductance. Additionally, we assessed individual levels of calmness, vigilance, and mood. In an independent sample of 26 healthy participants, we stimulated the cardiovagal system by a deep breathing test. PUI was related to parasympathetic cardiac indices and sleepiness. A linear combination of vagal heart rate variability [root mean square of heart beat interval differences (RMSSD)] and skin conductance fluctuations (SCFs) was suited best to explain interindividual variance of PUI. Complexity of pupil diameter (PD) variations correlated to indices of sympathetic skin conductance. Furthermore, we found that spontaneous fluctuations of skin conductance are accompanied by increases of pupil size. In an independent sample, we were able to corroborate the relation of PUI with RMSSD and skin conductance. A slow breathing test enhanced RMSSD and PUI proportionally to each other, while complexity of PD dynamics decreased. Our data suggest that the slow PD oscillations (f < 0.15 Hz) quantified by PUI are related to the parasympathetic modulation. Sympathetic arousal as detected by SCFs is associated to transient pupil size increases that increase non-linear pupillary dynamics.

Functional consequences of acute tryptophan depletion on raphe nuclei connectivity and network organization in healthy women.

Previous research on central nervous serotonin (5-HT) function provided evidence for a substantial involvement of 5-HT in the regulation of brain circuitries associated with cognitive and affective processing. The underlying neural networks comprise core subcortical/cortical regions such as amygdala and medial prefrontal cortex, which are assumed to be modulated amongst others by 5-HT. Beside the use of antidepressants, acute tryptophan depletion (ATD) is a widely accepted technique to manipulate of 5-HT synthesis and its respective metabolites in humans by means of a dietary and non-pharmacological tool. We used a double-blind, randomized, cross-over design with two experimental challenge conditions, i.e. ATD and tryptophan (TRP) supplementation (TRYP+) serving as a control. The aim was to perturb 5-HT synthesis and to detect its impact on brain functional connectivity (FC) of the upper serotonergic raphe nuclei, the amygdala and the ventromedial prefrontal cortex as well as on network organization using resting state fMRI. 30 healthy adult female participants (age: M â€‹= â€‹24.5 â€‹± â€‹4.4 â€‹yrs) were included in the final analysis. ATD resulted in a 90% decrease of TRP in the serum relative to baseline. Compared to TRYP â€‹+ â€‹for the ATD condition a significantly lower FC of the raphe nucleus to the frontopolar cortex was detected, as well as greater functional coupling between the right amygdala and the ventromedial prefrontal cortex. FC of the raphe nucleus correlated significantly with the magnitude of TRP changes for both challenge conditions (ATD & TRYP+). Network-based statistical analysis using time series from 260 independent anatomical ROIs revealed significantly greater FC after ATD compared to TRYP+ in several brain regions being part of the default-mode (DMN) and the executive-control networks (ECN), but also of salience or visual networks. Finally, we observed an impact of ATD on the rich-club organization in terms of decreased rich-club coefficients compared to TRYP+. In summary we could confirm previous findings that the putative decrease in brain 5-HT synthesis via ATD significantly alters FC of the raphe nuclei as well as of specific subcortical/cortical regions involved in affective, but also in cognitive processes. Moreover, an ATD-effect on the so-called rich-club organization of some nodes with the high degree was demonstrated. This may indicate effects of brain 5-HT on the integration of information flow from several brain networks.