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Miriam Kunz,1 Stefanie F Bunk,2 Anna J Karmann,3 Karl-Jürgen Bär,4 Stefan Lautenbacher3 1Department of Medical Psychology and Sociology, University of Augsburg, Augsburg, Germany; 2Department of General Practice and Elderly Care Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 3Physiological Psychology, Otto-Friedrich University Bamberg, Bamberg, Germany; 4Department of Psychosomatic Medicine and Psychotherapy, University Hospital, Jena, GermanyCorrespondence: Miriam KunzDepartment of Medical Psychology and Sociology, University of Augsburg, Augsburg, GermanyTel +49 821 598-3720Fax +49 821 598-5116Email Miriam.kunz@med.uni-augsburg.dePurpose: Conditioned pain modulation (CPM) is most often assessed using self-report of pain. However, self-report of pain is not always available (eg in individuals with cognitive impairment) and is susceptible to report bias. In comparison, the facial expression of pain is more reflex-like and represents one of the most sensitive and specific non-verbal signals of pain. The aim of the present study was to investigate whether the facial expression of pain is sensitive enough to capture endogenous pain inhibition as elicited during CPM paradigms.Patients and Methods: In total, 26 female participants took part in this study. Facial and verbal responses to phasic heat pain were assessed once while participants immersed their hand in a hot water bath and once without additional stimulation. Facial responses were analyzed using the Facial Action Coding System (FACS). Verbal responses were assessed using a Numerical Rating Scale (NRS).Results: Pain-relevant facial responses as well as pain ratings to phasic heat pain were significantly reduced when participants simultaneously immersed their hand in a hot water bath compared to baseline. Thus, CPM effects could be demonstrated both on subjective as well as on facial responses. Moreover, CPM-induced changes in pain-relevant facial responses and in NRS ratings were significantly correlated.Conclusion: The present study shows that facial expressions of pain are sensitive enough to capture CPM effects. Given the proven clinical usefulness of assessing CPM, the parallel assessment of verbal and facial CPM effects might be a promising approach with wider scope of applications. Further research in other demographic healthy participant and clinical cohorts is warranted.Keywords: pain, CPM, conditioned pain modulation, facial expression, FACS

Underlying biological mechanisms leading to the dramatically increased cardiac mortality in patients with schizophrenia (SCZ) are largely unknown. Cardiac autonomic dysfunction (CADF), which has been extensively described in patients with SCZ, represents an important physiological link to cardiovascular disease (CVD). This study investigated the prevalence of CADF in patients with SCZ using HRV across multiple domains (time and frequency, nonlinear dynamics, complexity measures, symbolic dynamics, and segmented Poincaré plot analysis). HRV-based clustering classified 119 SCZ patients as having or not having CADF based on deviations from 119 age- and sex-matched healthy controls. Our findings showed that approximately half of the patients had normal cardiac autonomic function, while the other half had significant abnormalities. The severity of CADF correlated with age, body mass indes (BMI), disease duration, and symptom severity. About half of SCZ patients have significant CADF, which increases their risk for cardiac events. These findings highlight the potential of HRV-based biomarkers in improving CVD risk prediction and stratification in SCZ. Future research should explore integrating HRV analysis with other biomarkers to enhance early detection and intervention strategies., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The detection and quantification of coupling strength and direction are important aspects for achieving a deeper understanding of physiological regulatory processes in the field of network physiology. Due to the limitations of established approaches, we developed directionality indices based on simple mathematical symbolization principles and simple computational procedures that allow a quick and comprehensive understanding of the underlying couplings. We introduced a new directionality index ( D HRJSD ) derived from the pattern family density matrix of the High-Resolution Joint Symbolic Dynamics (HRJSD) approach and its multivariate version (mHRJSD) to determine coupling direction and driver-response relationships. The mHRJSD approach contains the multivariate directionality index D mHRJSD ( D mHRJSD ( x , y | z ), D mHRJSD ( x , z | y ), and D mHRJSD ( y , z | x )), allowing us to determine the primary driver **D mHRJSD , the secondary driver *D mHRJSD, and the dominant responder - D mHRJSD in multivariate systems that are at least weakly coupled. Different linear and non-linear bi- and multivariate coupled systems (Gaussian autoregressive models) with different mutual influences were generated to validate these indices. The simulation results showed that D HRJSD was able to correctly detect the dominant coupling direction in linear bivariate coupled systems but was partly able to detect the dominant coupling direction in non-linear bivariate coupled systems. The proposed directionality index D mHRJSD derived from the mHRJSD approach is able to correctly detect the driver-responder relationships in linear coupled systems. The main advantages of the newly introduced directionality indices include their insensitivity to non-stationary time series, their ability to capture couplings through a simple, fast, and easy-to-implement symbolization procedure, and their scale invariance. Additionally, they are independent of time series length, model order selection, and the procedure for determining their significance level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Schulz, Schumann, Bär, Haueisen, Seifert and Voss.)

Body image is a core identity facet in anorexia nervosa (AN). Current literature outlines body image as a multidimensional construct, characterized by perceptual, cognitive, and emotional components, which explain how individuals perceive, think, and behave in relation to their body. The purpose of this scoping review is to uncover neuropsychological disturbances in AN related to body image by focusing on its different behavioral and neuronal assessments, aiming to provide a broad overview of common findings and limitations. Additionally, we explore the role of somato-sensory/somato-motor components and physiological markers underlying body image disturbances, which have not been extensively examined in previous studies. Literature screening was performed across three databases (PubMed, PsycINFO, Scopus). We classified behavioral, physiological, and neuroimaging studies according to their degree of involvement with body image dimensions and discussed the primary findings for each component. A total of 4015 studies were identified, of which 107 were eligible (84 behavioral and 23 neuroimaging studies) based on eligibility criteria, covering research from 1973 to 2024. Notably, of those which specified the following factors: 16 studies focused on the restrictive subtype (AN-r), two on the binge-eating/purging subtype (AN-b/p), and 19 examined both AN-r and AN-b/p; finally four on the atypical subtype; 11 on the weight-recovered state (WR) and three included also male participants. The mean age across all studies was 20.1 years (SD = 3.79). Our findings reveal that body image disturbances in AN are not limited to the overestimation of body size but also encompass cognitive, emotional, and somato-sensory aspects. A strong drive for thinness emerged as a prominent cognitive factor in maintaining the disturbance, along with altered autobiographical recall, executive function, and attentional biases toward body-related stimuli. Emotional regulation difficulties, altered interoceptive awareness, and distorted somato-sensory aspects-reflected in tactile and motor processes-were highlighted. In addition, increased autonomic reactivity to body image stimuli, indicating a sympathetic/parasympathetic imbalance, is supported by specific cortical-subcortical functional alterations. Our review emphasizes that body image distortion in AN should not be viewed merely as a perceptual deficit but rather as a complex cognitive-emotional and somato-sensory process., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Competing interests: No support was received for the work. The authors declared that they do not have conflicts of interest., (© 2025. The Author(s).)

Objective . Heart rate variability (HRV) is an important indicator of cardiac autonomic function. Given its clinical significance, reliable HRV assessment is crucial. Here, we assessed test-retest stability, as a key aspect of reliability, quantifying the consistency of a measure when repeated under the same conditions. Approach . This observational study includes healthy individuals. A 20 min electrocardiogram was recorded at rest in a supine position and during deep breathing in two lab sessions within one week, at the same time of day. HRV indices from time domain, frequency domain, nonlinear dynamics, and information-theoretic complexity were assessed using a validated toolbox. Additionally, heart rate variations per respiratory cycle were evaluated during deep breathing. Lifestyle factors such as perceived stress, mood, physical activity, sleep quality were assessed prior to both sessions. Intra-class correlation (ICC) and coefficients of variation (CVs) were used to assess the concordance between the two measurements and the relative deviation, respectively. Main results . From 62 screened individuals, 51 participants were recruited from the local community. One participant opted out for personal reasons, and another with frequent premature beats was excluded, leaving a final sample of 49 individuals. Most self-rated psychological and lifestyle indicators showed substantial agreement, though participants reported less stress and better mood in the second session. At rest, ICC of HRV ranged from 0.50 to 0.83, with CV from 5% to 41%. Spectral HRV measures were less reliable than time domain parameters. Nonlinear and time domain features had substantial to nearly perfect agreement. Complexity measures had low CVs but limited test-retest correlation. The stability indices of HRV during deep breathing were not significantly different from those during rest. Test-retest differences in root mean square of the successive beat-to-beat interval difference were not sufficiently explained by lifestyle factors. Significance. Test-retest stability of HRV depends considerably on chosen measures. Our data suggest that HRV can be assessed reliably using time-domain indices at rest., (Creative Commons Attribution license.)

Heart rate variability (HRV) is a key indicator of cardiac autonomic function, making reliable assessment crucial. To examine the test-retest stability of resting HRV in healthy individuals, fifty participants attended two lab sessions within a week, at the same time of day. After a 5-minute acclimatization period, electrocardiogram and respiration were recorded at rest. For validation, average heart rate and RMSSD were assessed over 15 minutes using a validated open-source toolbox. Test-retest agreement was evaluated using intra-class correlation (ICC), and coefficients of variation (CV). Mean heart rate showed high stability (ICC = 0.81, CV = 6%), while RMSSD had lower concordance (ICC = 0.75) and greater variation (CV = 30%). These findings indicate good test-retest agreement for standard HRV features. However, a wide range of methodologies exists for assessing various properties of heart rate dynamics. This database is intended to support other researchers in testing additional HRV metrics to evaluate their reliability in healthy individuals., Competing Interests: Competing interests: All contributors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2025. The Author(s).)

The process of healthy aging involves complex alterations in neural structures, with white matter (WM) changes significantly impacting cognitive and motor functions. Conventional methods such as diffusion tensor imaging provide valuable insights, but their limitations in capturing complex WM geometry advocate for more advanced approaches. In this study involving 120 healthy volunteers, we investigated whole-brain WM differences between young and old individuals using a novel technique called fixel-based analysis (FBA). This approach revealed that older adults exhibited reduced FBA-derived metrics in several WM tracts, with frontal areas particularly affected. Surprisingly, age-related differences in FBA-derived measures showed no significant correlation with risk factors such as alcohol consumption, exercise frequency, or pulse pressure but predicted cognitive performance. These findings emphasize FBA's potential in characterizing complex WM changes and the link between cognitive abilities and WM alterations in healthy aging. Overall, this study advances our understanding of age-related neurodegeneration, highlighting the importance of comprehensive assessments that integrate advanced neuroimaging techniques, cognitive evaluation, and demographic factors to gain insights into healthy aging., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Cardiac autonomic dysfunction (CADF), mainly characterized by increased heart rate, decreased heart rate variability, and loss of vagal modulation, has been extensively described in patients with schizophrenia (SCZ) and their healthy first-degree relatives. As such, it represents an apparent physiological link that contributes to the increased cardiovascular mortality in these patients. Common genetic variation is a putative underlying mechanism, along with lifestyle factors and antipsychotic medications. However, the extent to which CADF is associated with genetic factors for SCZ is unknown. A sample of 83 drug-naive SCZ patients and 96 healthy controls, all of European origin, underwent a 30-minute autonomic assessment under resting conditions. We incorporated parameters from several domains into our model, including time and frequency domains (mean heart rate, low/high frequency ratio) and compression entropy, each of which provides different insights into the dynamics of cardiac autonomic function. These parameters were used as outcome variables in linear regression models with polygenic risk scores (PRS) for SCZ as predictors and age, sex, BMI, smoking status, principal components of ancestry and diagnosis as covariates. Of the three CADF parameters, SCZ PRS was significantly associated with mean heart rate in the combined case/control sample. However, this association was was no longer significant after including diagnosis as a covariate (p = 0.29). In contrast, diagnostic status is statistically significant for all three CADF parameters, accounting for a significantly greater proportion of the variance in mean heart rate compared to SCZ PRS (approximately 16% vs. 4%). Despite evidence for a common genetic basis of CADF and SCZ, we were unable to provide further support for an association between the polygenic burden of SCZ and cardiac autonomic function beyond the diagnostic state. This suggests that there are other important characteristics associated with SCZ that lead to CADF that are not captured by SCZ PRS., (© 2024. The Author(s).)

Objective: The influence of unconscious emotional processes on pain remains poorly understood. The present study tested whether cues to forgotten unpleasant images might amplify pain (i.e., in the absence of conscious recall)., Methods: Seventy-two healthy female adults (19 to 34 years) performed an adapted Think/No-think paradigm (T/NT) using 72 combinations of neutral face images (cues) paired with 36 neutral and 36 unpleasant images. After completion of the T/NT task, cues associated with forgotten neutral or unpleasant images were identified. Cues to either neutral or unpleasant images from the NT condition were then presented in randomized order while participants received intermediate-level thermal pain stimulation on the left hand. Ratings of both pain intensity and unpleasantness were acquired after each trial., Results: Mean pain unpleasantness ratings were greater during presentation of cues to forgotten negative versus neutral images (5.52 [SD = 2.06] versus 5.23 [SD = 2.10]; p = .02). This pattern was also present when comparing cues to remembered negative versus neutral images (5.62 [SD = 1.94] versus 5.04 [SD = 1.90]; p < .001). Mean pain intensity ratings were higher for cues to negative versus neutral images when remembered (5.48 [SD = 1.79] versus 5.00 [SD = 1.69]; p < .001), but not when forgotten (5.27 [SD = 1.96] versus 5.16 [SD = 1.93]; p = .30)., Conclusions: Using an adapted T/NT-Pain paradigm, this study demonstrated that cues to nonrecallable (but potentially unconsciously activated) negative emotional memories amplify pain unpleasantness, similar to known effects of conscious negative emotions., (Copyright © 2024 by the American Psychosomatic Society.)

Regular participation in sports results in a series of physiological adaptations. However, little is known about the brain adaptations to physical activity. Here we aimed to investigate whether young endurance athletes and non-athletes differ in the gray and white matter of the brain and whether cardiorespiratory fitness (CRF) is associated with these differences. We assessed the CRF, volumes of the gray and white matter of the brain using structural magnetic resonance imaging (sMRI), and brain white matter connections using diffusion magnetic resonance imaging (dMRI) in 20 young male endurance athletes and 21 healthy non-athletes. While total brain volume was similar in both groups, the white matter volume was larger and the gray matter volume was smaller in the athletes compared to non-athletes. The reduction of gray matter was located in the association areas of the brain that are specialized in processing of sensory stimuli. In the microstructure analysis, significant group differences were found only in the association tracts, for example, the inferior occipito-frontal fascicle (IOFF) showing higher fractional anisotropy and lower radial diffusivity, indicating stronger myelination in this tract. Additionally, gray and white matter brain volumes, as well as association tracts correlated with CRF. No changes were observed in other brain areas or tracts. In summary, the brain signature of the endurance athlete is characterized by changes in the integration of sensory and motor information in the association areas., (© 2023 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

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.

Rationale: Although interest in the neurobiology of facial communication of pain has increased over the last decades, little is known about which neurotransmitter systems might be involved in regulating facial expressions of pain., Objectives: We aim to investigate whether the serotonergic system (5-HT), which has been implicated in various aspects of pain processing as well as in behavioral response inhibition, might play a role in facial expressions of pain. Using acute tryptophan depletion (ATD) to manipulate 5-HT function, we examined its effects on facial and subjective pain responses., Methods: In a double-blind, placebo-controlled within-subject design, 27 participants received either an ATD or a control drink in two separate sessions. Approximately 5-h post-oral consumption, we assessed pain thresholds (heat, pressure) as well as facial and subjective responses to phasic heat pain. Moreover, situational pain catastrophizing and mood were assessed as affective state indicators., Results: ATD neither influenced pain thresholds nor self-report ratings, nor catastrophizing or mood. Only facial responses were significantly affected by ATD. ATD led to a decrease in pain-indicative as well as in pain-non-indicative facial responses to painful heat, compared to the control condition., Conclusions: Decrease in brain 5-HT synthesis via ATD significantly reduced facial responses to phasic heat pain; possibly due to (i) diminished disposition to display social behavior or due to (ii) decreased facilitation of excitatory inputs to the facial motor neuron., (© 2023. The Author(s).)

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., (© 2023 Wiley Periodicals LLC.)

A large body of literature exists on white matter (WM) abnormalities in individuals with anorexia nervosa (AN). However, these studies have primarily relied on the diffusion tensor imaging (DTI), a technique known for its limited ability to resolve complex WM fibre arrangements. To overcome limitations of DTI, this study employed fixel-based analysis (FBA) to investigate fibre-specific WM abnormalities in AN. FBA, which incorporates information on connectivity and crossing-fibres, offers greater anatomical specificity and interpretability than DTI. Twenty-six acute AN patients and thirty-one healthy controls underwent diffusion-weighted imaging scanning, and FBA and DTI metrics were compared between groups. Results revealed significant reductions in fibre-bundle cross-section within the anterior corona radiata and genu of corpus callosum, indicating morphological atrophy in AN patients. These specific tracts, identified by FBA, connect brain regions involved in the symptomatology of AN. DTI showed increased axial diffusivity in the cerebellar peduncles of AN patients but did not show significant differences in other metrics. Notably, there was no overlap between findings of FBA and DTI analyses. Overall, this study highlights the potential of FBA to detect WM abnormalities not accounted for by DTI and suggests that myelin loss contributes to the observed clinical picture in AN patients., Competing Interests: Declaration of Competing Interest The authors report no biomedical financial interests or potential conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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 β-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., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

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/m ² ) 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schumann, Gaser, Sabeghi, Schulze, Festag, Spreckelsen and Bär.)

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.

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.

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., (© 2022. The Author(s).)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schumann, Helbing, Rieger, Suttkus and Bär.)

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., (© 2022. The Author(s).)

Pain perception and the ability to modulate arising pain vary tremendously between individuals. It has been shown that endurance athletes possess higher pain tolerance thresholds and a greater effect of conditioned pain modulation than nonathletes, both indicating a more efficient system of endogenous pain inhibition. The aim of the present study was to focus on the neural mechanisms of pain processing in endurance athletes that have not been investigated yet. Therefore, we analyzed the pain processing of 18 male athletes and 19 healthy male nonathletes using functional magnetic resonance imaging. We found lower pain ratings in endurance athletes compared to nonathletes to physically identical painful stimulation. Furthermore, brain activations of athletes versus nonathletes during painful heat stimulation revealed reduced activation in several brain regions that are typically activated by nociceptive stimulation. This included the thalamus, primary and secondary somatosensory cortex, insula, anterior cingulate cortex, midcingulate cortex, dorsolateral prefrontal cortex, and brain stem (BS). Functional connectivity analyses revealed stronger network during painful heat stimulation in athletes between the analyzed brain regions except for connections with the BS that showed reduced functional connectivity in athletes. Post hoc correlation analyses revealed associations of the subject's fitness level and the brain activation strengths, subject's fitness level and functional connectivity, and brain activation strengths and functional connectivity. Together, our results demonstrate for the first time that endurance athletes do not only differ in behavioral variables compared to nonathletes, but also in the neural processing of pain elicited by noxious heat., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

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.

More than 800,000 individuals die from suicide each year in the world, which has a devastating impact on families and society. Ten to twenty times more attempt suicide. Previous studies showed that suicide attempters represent a heterogeneous group regarding demographic characteristics, individual characteristics of a suicidal attempt, and the assumed clinical factors, e.g., hopelessness or impulsivity, thus differently contributing to the likelihood of suicidal behavior. Therefore, in the present study, we aim to give a comprehensive clinical description of patients with repeated suicide attempts compared to single attempters. We explored putative differences between groups in clinical variables and personality traits, sociodemographic information, and specific suicide attempt-related information. A sample of patients with a recent suicide attempt ( n = 252), defined according to DSM-5 criteria for a suicidal behavior disorder (SBD), was recruited in four psychiatric hospitals in Thuringia, Germany. We used a structured clinical interview to assess the psychiatric diagnosis, sociodemographic data, and to collect information regarding the characteristics of the suicide attempt. Several clinical questionnaires were used to measure the suicide intent and suicidal ideations, depression severity, hopelessness, impulsivity, aggression, anger expression, and the presence of childhood trauma. Univariate and multivariate statistical methods were applied to evaluate the postulated risk factors and, to distinguish groups based on these measures. The performed statistical analyses indicated that suicide attempters represent a relatively heterogeneous group, nevertheless associated with specific clinical profiles. We demonstrated that the re-attempters had more severe psychopathology with significantly higher levels of self-reported depression, suicidal ideation as well as hopelessness. Furthermore, re-attempters had more often first-degree relatives with suicidal behavior and emotional abuse during childhood. They also exhibited a higher degree of specific personality traits, i.e., more "urgency" as a reaction to negative emotions, higher excitability, higher self-aggressiveness, and trait anger. The multivariate discriminant analysis significantly discriminated the re-attempters from single attempters by higher levels of self-aggressiveness and suicidal ideation. The findings might contribute to a better understanding of the complex mechanisms leading to suicidal behavior, which might improve the early identification and specific treatment of subjects at risk for repeated suicidal behavior., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lübbert, Bahlmann, Josfeld, Bürger, Schulz, Bär, Polzer, Walter, Kastner, Sobanski and Wagner.)

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., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Major Depressive Disorder is a major public health problem and has a high rate of treatment resistance. Fear conditioning has been proposed as a potential mechanism sustaining negative affect in mood disorders. With the aim of exploring cognitive effects of rapid-acting antidepressant treatments as a potential mechanism of action that can be targeted by neuromodulation, we performed a narrative review of the extant literature on effects of electroconvulsive therapy, ketamine or esketamine, and sleep deprivation on emotional/fear memory retrieval-reconsolidation. We explore interference with reconsolidation as a potential common pathway that explains in part the efficacy of rapid-acting antidepressant treatments with disparate mechanisms of action. We propose the testable hypothesis that fear learning circuits can be specifically targeted by neuromodulation to attempt rapid amelioration of depressive symptoms (especially repetitive negative thinking) while limiting unspecific, untoward cognitive side effects., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research., (© 2020 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schumann, de la Cruz, Köhler, Brotte and Bär.)

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., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

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., Competing Interests: Declaration of competing interest All authors are declare to not have any actual or potential conflict of interest including any financial, personal or other relationships, that could inappropriately influence, or be perceived to influence, the work., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The perception of pain to noxious stimuli, also known as pain sensitivity, varies among individuals. The comprised brain structures and their white matter pathways are complex and elusive. Here, we aimed to investigate whether variation of microstructure of the medial forebrain bundle (MFB), a tract connecting the basal forebrain with the brain stem, is associated with interindividual pain sensitivity. We assessed interindividual pain sensitivity as a rating of pain intensity to heat stimuli (45, 47, and 48.9°C) in 38 healthy men (age: 27.05 ± 5.7 years). We also reconstructed the MFB using multitensor tractography from diffusion magnetic resonance imaging (dMRI) and calculated free-water corrected dMRI measures of fractional anisotropy (FA t ), radial diffusivity (RD t ), and axial diffusivity (AD t ). Lower ratings of interindividual pain intensity correlated with higher FA t and lower RD t of the MFB. As changes in FA t and RD t may reflect abnormalities in myelination, the results might be interpreted as that a lower pain rating is associated with higher degree of myelination of the MFB and could represent an inhibitory pathway of pain. Our results suggest that alteration of microstructure in the MFB contributes to the interindividual variation of pain perception., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

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., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

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.

The transition from suicidal ideas to a suicide act is an important topic of research for the identification of those patients at risk of acting out. We investigated here whether specific brain activity and connectivity measures at rest may be differently associated with suicidal thoughts and behaviors. A large sample of acutely depressed patients with major depressive disorder was recruited in three different centers (Montreal/Canada, Stanford/USA, and Jena/Germany), covering four different phenotypes: patients with a past history of suicide attempt (n = 53), patients with current suicidal ideas but no past history of suicide attempt (n = 40), patients without current suicidal ideation nor past suicide attempts (n = 42), and healthy comparison subjects (n = 107). 3-T resting-state functional magnetic resonance imaging (fMRI) measures of the amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) were obtained and examined in a whole-brain data-driven analysis. Past suicide attempt was associated with a double cortico-subcortical dissociation in ALFF values. Decreased ALFF and DC values mainly in a frontoparietal network and increased ALFF values in some subcortical regions (hippocampus and thalamus) distinguished suicide attempters from suicide ideators, patient controls, and healthy controls. No clear neural differences were identified in relation to suicidal ideas. Suicide attempters appear to be a distinct subgroup of patients with widespread brain alterations in functional activity and connectivity that could represent factors of vulnerability. Our results also indirectly support at the neurobiological level the relevance of the transition model described at the psychological and clinical levels. The brain bases of suicidal ideas occurrence in depressed individuals needs further investigations.

Animals and humans are able to inhibit pain by activating their endogenous pain-inhibition system. Endurance athletes possess a higher pain-tolerance threshold and a greater conditioned pain modulation (CPM) effect than nonathletes, suggesting better endogenous pain inhibition. In addition to CPM, placebo is another prominent paradigm used to test endogenous pain inhibition. However, whether the placebo effect and the CPM effect share the same mechanisms of pain inhibition has not been investigated. If there is a shared mechanism, then endurance athletes should show not only a better CPM effect than nonathletes but also a greater placebo effect. Here, we investigated 16 male endurance athletes and 17 male nonathletes in well-established placebo and CPM paradigms to assess whether endurance athletes have a better endogenous pain-inhibition system than nonathletes. As expected, we find a significantly greater CPM effect in athletes than in nonathletes. In contrast, we could only find a significant placebo effect in nonathletes. Explorative analyses reveal negative associations between the placebo effect and heart rate variability as well as between the placebo effect and interoceptive awareness. Together, the results demonstrate a dissociation of endogenous pain inhibition of CPM and placebo effect between endurance athletes and nonathletes. This suggests that both effects are based, at least in part, on different biological mechanisms., (Copyright © 2020 Geisler, Herbsleb, Bär and Weiss.)

Exercise therapy has proven to be effective in the treatment of multiple mental illnesses. As mental disorders result in tremendous costs for the healthcare system as well as a huge burden for the affected individuals, improving treatment strategies according to latest scientific evidence should be of highest priority. In 2016 a first study provided indications that only a minority of patients are treated with exercise therapy during their stay in hospital. Hence, the aim of this study was to assess the actual extent of exercise therapy usage in psychiatric inpatients in Germany, thereby giving a scientific foundation to the call for a better standard of care. To achieve this, a retrospective analysis was performed on pre-existing data from 2693 patients who were treated in 1 of 4 participating university hospitals. Only 23% of these patients participated in exercise therapy with a mean training duration of 36 min per week. Patients with the diagnosis of schizophrenia or patients with multiple comorbidities were even less likely to participate in exercise therapy. With these findings it becomes evident that the healthcare situation concerning exercise therapy is insufficient. Solid evidence for the effectiveness of exercise therapy, the current treatment guidelines as well as the positive side effects, especially when compared to side effects of pharmacotherapy (i.e. weight gain) should motivate healthcare officials to make an effort to improve this situation.

Impaired heart rate- and respiratory regulatory processes as a sign of an autonomic dysfunction seems to be obviously present in patients suffering from schizophrenia. Since the linear and non-linear couplings within the cardiorespiratory system with respiration as an important homeostatic control mechanism are only partially investigated so far for those subjects, we aimed to characterize instantaneous cardiorespiratory couplings by quantifying the casual interaction between heart rate (HR) and respiration (RESP). Therefore, we investigated causal linear and non-linear cardiorespiratory couplings of 23 patients suffering from schizophrenia (SZO), 20 healthy first-degree relatives (REL) and 23 healthy subjects, who were age-gender matched (CON). From all participants' heart rate (HR) and respirations (respiratory frequency, RESP) were investigated for 30 min under resting conditions. The results revealed highly significant increased HR, reduced HR variability, increased respiration rates and impaired cardiorespiratory couplings in SZO in comparison to CON. SZO were revealed bidirectional couplings, with respiration as the driver (RESP → HR), and with weaker linear and non-linear coupling strengths when RESP influencing HR (RESP → HR) and with stronger linear and non-linear coupling strengths when HR influencing RESP (HR → RESP). For REL we found only significant increased HR and only slightly reduced cardiorespiratory couplings compared to CON. These findings clearly pointing to an underlying disease-inherent genetic component of the cardiac system for SZO and REL, and those respiratory alterations are only clearly present in SZO seem to be connected to their mental emotional states., (Copyright © 2020 Schulz, Haueisen, Bär and Voss.)

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., (Copyright © 2020 Schumann, Kietzer, Ebel and Bär.)

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 ​= ​24.5 ​± ​4.4 ​yrs) were included in the final analysis. ATD resulted in a 90% decrease of TRP in the serum relative to baseline. Compared to TRYP ​+ ​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., (Copyright © 2019. Published by Elsevier Inc.)

Patients with major depressive disorder (MDD) have an augmented risk of cardiovascular morbidity and mortality. Although a link between depression and autonomic dysfunction as well as reduced cardio-respiratory fitness (CRF) is well documented, the underlying cause is a matter of debate. Therefore, we studied the interplay between autonomic function, body composition and severity of the disease to disentangle possible physiological factors influencing the assumed lack of CRF in MDD patients. We investigated seventeen patients suffering from MDD and seventeen control subjects matched with respect to age, sex, body-mass-index, and smoking habits. A resting baseline assessment and a cardiopulmonary exercise test including a prolonged recovery period were performed to study autonomic function (i.e., heart rate responses and heart rate variability) during rest, exercise and recovery as well as CRF. Most investigated autonomic indices were significantly different at rest, during exercise as well as during recovery indicating altered autonomic modulation. Nevertheless, none of our participants was classified as chronotropically incompetent. As expected, a reduced CRF (i.e., peak oxygen uptake and peak power output, p < 0.01) was observed in patients compared to controls. In addition, a correlation of baseline heart rate and of heart rate during recovery with the ventilatory threshold 1 (p < 0.05) was found in patients only, indicating a relation to the lack of CRF. Furthermore, we observed a positive correlation of the severity of the disease with the weekly sitting time (p < 0.01) as well as a negative correlation with the activity time in the intensity domain walking (p < 0.001) and with the total score of the International Physical Activity Questionnaire (p < 0.01) for patients. This study shows that patients with MDD have altered autonomic function not only during resting conditions but also during exercise as well as recovery from exercise. Intervention studies are needed to evaluate how the described autonomic alterations can be influenced by increasing CRF due to appropriate exercise training programs., (Copyright © 2020 Herbsleb, Schumann, Lehmann, Gabriel and Bär.)

Understanding the neural mechanisms of suicidal behavior is crucial. While regional brain alterations have previously been reported, knowledge about brain functional connectomics is currently limited. Here, we investigated differences in global topologic network properties and local network-based functional organization in both suicide attempters and suicide relatives. Two independent samples of depressed suicide attempters (N = 42), depressed patient controls (N = 43), healthy controls (N = 66) as well as one sample of healthy relatives of suicide victims (N = 16) and relatives of depressed patients (N = 16) were investigated with functional magnetic resonance imaging in the resting-state condition. Graph theory analyses were performed. Assortativity, clustering coefficients, global efficiency, and rich-club coefficients were calculated. A network-based statistic approach was finally used to examine functional connectivity matrices. In comparison to healthy controls, both patient groups showed significant reduction in assortativity, and decreased functional connectivity in largely central and posterior brain networks. Suicide attempters only differed from patient controls in terms of higher rich-club coefficients for the highest degree nodes. Compared to patient relatives and healthy controls, suicide relatives showed reduced assortativity, reduced clustering coefficients, increased global efficiency, and increased rich-club coefficients for the highest degree nodes. Suicide relatives also showed reduced functional connectivity in one anterior and one posterior sub-network in comparison to healthy controls, and in a largely anterior brain network in comparison to patient relatives. In conclusion, these results suggest that the vulnerability to suicidal behavior may be associated with heritable deficits in global brain functioning - characterized by weak resilience and poor segregation - and in functional organization with reduced connectivities affecting the ventral and dorsal prefrontal cortex, the anterior cingulate, thalamus, striatum, and possibly the insula, fusiform gyrus and the cerebellum.

There is growing evidence for structural brain alterations in obsessive-compulsive disorder (OCD). The overall picture is however rather heterogeneous. To detect meaningful associations between clinical symptom profiles and structural alterations, we applied a classification approach, the k-means cluster analysis on clinical data, i.e., the Obsessive Compulsive Inventory-Revised (OCI-R) questionnaire. 73 OCD patients were assigned to three distinct symptom profiles. Using structural MRI and surface-based morphometric analysis (SBM), we compared cortical thickness between all OCD patients and 69 matched healthy subjects as well as among patients according to three symptom profiles. The total sample of OCD patients exhibited a thicker cortex in the pre-supplementary motor cortex (pre-SMA), dorsomedial prefrontal (DMPFC), anterior cingulate cortex and in the right anterior insula. Comparing patients of the three symptom clusters, a subgroup of OCD patients with a specific symptom profile was identified, which showed a thicker cortex in pre-SMA/DMPFC and in the contralateral primary motor cortex. In contrast to both other subgroups, patients in this group were mainly characterized by the predominance of a combination of checking and washing rituals. The other two OCD symptom subgroups showed comparable cortical thickness to healthy controls. Higher cortical thickness in regions of the motor circuitry seems to be related to motor activity-induced neuroplasticity in a specific group of OCD patients. Thicker anterior insular cortex in the total sample of patients points toward a more general pathophysiological process in OCD and potentially indicates abnormal interoceptive processing in OCD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The peripheral autonomic nervous system (ANS) adjusts the heart rate (HR) to intrinsic and extrinsic demands. It is controlled by a group of functionally connected brain regions assembling the so-called central autonomic network (CAN). More specifically, forebrain cortical regions, limbic and brainstem structures within the CAN have been identified as important components of circuits involved in HR regulation. The present study aimed to investigate whether functional connectivity (FC) between these regions varies in subjects with different heart rates. Thus, 84 healthy subjects were separated according to their HR in slow, medium and fast. We observed a direct association between HR and FC in CAN regions, where stronger FC was related to slower HR. This relationship, however, is non-linear, follows an exponential course and is not restricted to CAN areas only. The network-based analysis (NBS) using time series from 262 independent anatomical ROIs revealed significantly increased functional connectivity in subjects with slow HR compared to subjects with fast HR mainly in regions being part of the salience network, but also of the default-mode network. We additionally simulated the effect of aliasing on the functional connectivity using several TRs and heart rates to exclude the possibility that FC differences might be due to different aliasing effects in the data. The result of the simulation indicated that aliasing cannot explain our findings. Thus, present results imply a functionally meaningful coupling between FC and HR that need to be accounted for in future studies. Moreover, given the established link between HR and emotional, cognitive and social processes, present findings may also be considered to explain individual differences in brain activation or connectivity when using corresponding paradigms in the MR scanner to investigate such processes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The multivariate analysis of coupling pathways within physiological (sub)systems focusing on identifying healthy and diseased conditions. In this study, we investigated a part of the central-autonomic-network (CAN) in 17 patients suffering from schizophrenia (SZO) compared to 17 age-gender matched healthy controls (CON) applying linear and nonlinear causal coupling approaches (normalized short time partial directed coherence, multivariate transfer entropy). Therefore, from all subjects continuous heart rate (successive beat-to-beat intervals, BBI), synchronized maximum successive systolic blood pressure amplitudes (SYS), synchronized calibrated respiratory inductive plethysmography signal (respiratory frequency, RESP), and the power P EEG of frontal EEG activity were investigated for 15 min under resting conditions. The CAN revealed a bidirectional coupling structure, with central driving towards blood pressure (SYS), and respiratory driving towards P EEG . The central-cardiac, central-vascular, and central-respiratory couplings are more dominated by linear regulatory mechanisms than nonlinear ones. The CAN showed significantly weaker nonlinear central-cardiovascular and central-cardiorespiratory coupling pathways, and significantly stronger linear central influence on the vascular system, and on the other hand significantly stronger linear respiratory and cardiac influences on central activity in SZO compared to CON, and thus, providing better understanding of the interrelationship of central and autonomic regulatory mechanisms in schizophrenia might be useful as a biomarker of this disease.

A large body of scientific studies suggest a close relationship between increased vagal function and better cognitive performance., Objective: In the current study, we investigated the association between autonomic function and behavioral impulsivity. We hypothesized that heart rate variability (HRV) biofeedback training increases HRV and enhances inhibitory control., Approach: A total of 28 healthy participants were recruited. After drop-out, 14 participants completed an eight-week HRV biofeedback training with five training sessions per week including one session at the clinic's laboratory and four sessions at home using a mobile application running on their smartphone. Ten control subjects matched with respect to age and gender played a mobile game according to the same schedule as the biofeedback group. The assessment of autonomic status and the stop-signal task were conducted before the beginning of the training (T1) and after finishing the schedule (T2)., Main Results: We found a relationship of reaction times in the stop-signal task and standard HRV as well as cardiorespiratory indices. After biofeedback training, short-term HRV and baroreflex function significantly increased by 33% (CI [2%, 64%], p   <  0.05) and 21% (CI [5%, 36%], p   <  0.05), respectively. The performance in the stop-signal task was not affected by the biofeedback intervention. Compared to the changes of autonomic indices in the control group, only a decrease of skin conductance levels in the biofeedback group remained statistically significant., Significance: Our results indicate that a smartphone-based HRV biofeedback intervention can be applied to improve cardiovagal function in healthy subjects. Although higher HRV was associated with higher levels of inhibitory control, HRV biofeedback had no effect on measures of impulsivity.

People with schizophrenia die on average 15-20 years earlier than age and gender matched controls in the general population. An essential part of this excess mortality in people with schizophrenia is caused by physical illnesses. Among the physical illnesses, cardiovascular disease (CVD) has been identified as the most common natural cause of death in up to 40-45% of the cases. Chronotropic incompetence (CI) is defined as the inability of the heart to increase its beating frequency in proportion to increased physical activity or higher metabolic demand. It is an established independent cardiovascular risk factor for major cardiac events and overall mortality and might explain adaptation intolerance of the cardiovascular system to even minor exercise courses. CI needs objective exercise testing for definitive diagnosis and therefore represents a biological marker indicating the integrity of the cardiovascular system. It was recently described in patients with schizophrenia and might help explain the reduced physical fitness in these patients and the inability of a subgroup of patients to benefit from exercise interventions. In this study, we tried to replicate the occurrence of CI in an independent sample of patients with schizophrenia and evaluated whether CI can be influenced by a continuous endurance training of 12 weeks. Therefore, we re-analyzed the fitness testing data of 43 patients with schizophrenia and 22 aged and gender matched healthy controls. Parameters of aerobic fitness and chronotropic response to exercise were calculated. Patients with schizophrenia were less physically fit than the healthy controls and displayed a significantly higher heart rate at rest. 10 of 43 patients with schizophrenia and no healthy control subject were classified as chronotropically incompetent. Chronotropic response to exercise did not change significantly after 12 weeks of continuous aerobic exercise training. No differences were observed for baseline heart rate and peak heart rate in both subgroups of schizophrenia patients. Aerobic fitness did not improve significantly in the patients with schizophrenia classified as chronotropically incompetent. Our results confirm the occurrence of CI in patients with multi-episode schizophrenia. This should be taken into account when planning an exercise or lifestyle intervention studies in this population. Schizophrenia patients with CI do not seem to benefit as well as schizophrenia patients without CI from aerobic exercise training interventions. Larger, prospective randomized controlled clinical trials with different training interventions are urgently needed to address the topic of schizophrenia patients not responding to exercise and the relationship to the illness itself.

Evidence suggests that cognitive control functions as well as the underlying brain network, anchored by the prefrontal cortex (PFC) and the dorsal anterior cingulate cortex (dACC), are dysfunctional in schizophrenia. Catecholamine producing midbrain and brainstem nuclei are densely connected with the PFC and dACC and exert profound contributions to cognitive control processes. Dysfunctions within the underlying neurotransmitter systems are considered to play a central role in the occurrence of various symptoms of schizophrenia. We sought to investigate the putatively abnormal activation pattern of the dopaminergic midbrain nuclei, that is, ventral tegmental area (VTA) and substantia nigra as well as that of the noradrenergic locus coeruleus (LC) in patients with schizophrenia during cognitive control. A total of 28 medicated patients and 27 healthy controls were investigated with the manual version of the Stroop task using event-related fMRI. The main finding was a reduced BOLD activation in the VTA during both Stroop task conditions in patients in comparison to controls, which correlated significantly with the degree of negative symptoms. We further detected a comparable LC activation in in patients and healthy controls. However, in controls LC activation was significantly correlated with the Stroop interference time, which was not observed in patients. The finding of reduced VTA activation in schizophrenia patients lends further support to the assumed dysfunction of the DA system in schizophrenia. In addition, despite comparable LC activation, the nonsignificant correlation with the Stroop interference time might indicate altered LC functioning in schizophrenia and, thus, needs further investigations., (© 2018 Wiley Periodicals, Inc.)