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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.)

Brainstem and midbrain nuclei are closely linked to cognitive performance and autonomic function. To advance the localization in this area, precise functional imaging is fundamental. In this study, we used a sophisticated fMRI technique as well as physiological recordings to investigate the involvement of brainstem/midbrain nuclei in cognitive control during a Stroop task. The temporal signal-to-noise ratio (tSNR) increased due to physiological noise correction (PNC) especially in regions adjacent to arteries and cerebrospinal fluid. Within the brainstem/cerebellum template an average tSNR of 68 ± 16 was achieved after the simultaneous application of a high-resolution fMRI, specialized co-registration, and PNC. The analysis of PNC data revealed an activation of the substantia nigra in the Stroop interference contrast whereas no significant results were obtained in the midbrain or brainstem when analyzing uncorrected data. Additionally, we found that pupil size indicated the level of cognitive effort. The Stroop interference effect on pupillary responses was correlated to the effect on reaction times ( R 2 = 0.464, p < 0.05). When Stroop stimuli were modulated by pupillary responses, we observed a significant activation of the LC in the Stroop interference contrast. Thus, we demonstrated the beneficial effect of PNC on data quality and statistical results when analyzing neuronal responses to a cognitive task. Parametric modulation of task events with pupillary responses improved the model of LC BOLD activations in the Stroop interference contrast.

Brainstem and midbrain nuclei are closely linked to effective cognitive performance and autonomic function. In the present study, we aimed to investigate indices of successful and unsuccessful response inhibition paying particular attention to the interplay between locus coeruleus (LC), ventral tegmental area (VTA)/substantia nigra (SN) and, most importantly, peripheral markers. We aimed to get insight in the predictive value of neural and physiological signals in response inhibition. A total of 35 healthy controls were recruited from the local community and a typical task of behavioral response inhibition (Go/No-Go paradigm) was applied. We used high-resolution fMRI, advanced brainstem analyses and specifically corrected for respiratory signal and cardiac noise. Our main results characterize specific neural activation patterns during successful and unsuccessful response inhibition especially comprising the anterior cingulate as well as the medial and lateral prefrontal cortex. A significant activation of the dopaminergic nuclei (VTA/SN) was found during error processing, but not during response inhibition. Most remarkably, specific neural activation patterns (i.e., dorsal anterior cingulate cortex) as well as accompanying autonomic indices (i.e., skin conductance response (SCR)) were identified to hold predictive information on an individual's performance. In summary, the importance of the VTA/SN during error processing was shown. Furthermore, autonomic indices and specific neural activation patterns may contain valuable information to predict task performance., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: The new interdisciplinary field of network physiology is increasingly becoming a focus of interest in medicine. Autonomic nervous system (ANS) dysfunction is well described in schizophrenia (SZO). However, the linear and nonlinear coupling between the ANS and central nervous system (CNS) has only been partly addressed until now. This coupling can be assumed to be a feedback-feedforward network, reacting with flexible and adaptive responses to internal and external factors., Approach: For the first time, in this study we investigated linear and nonlinear short-term central-cardiorespiratory coupling of 17 patients suffering from paranoid SZO in comparison to 17 age-gender matched healthy subjects analyzing heart rate (HR), respiration (RESP), and the power of frontal electroencephalogram (EEG) activity (P EEG ). The objective is to determine how the different regulatory aspects of the CNS-ANS affect the central-cardiorespiratory network (CCRN). To quantify these couplings within the CCRN normalized short time partial directed coherence and the new multivariate high-resolution joint symbolic dynamics were applied., Main Results: We found that the CCRN in SZO can be characterized as a bidirectional one, with stronger central driving mechanisms (P EEG   →  HR) towards HR regulation than vice versa, and with stronger respiratory influence (RESP  →  P EEG ) on central activity than vice versa. This suggests that the central-cardiorespiratory process (closed-loop) is mainly focused on adapting the HR via the sinoatrial node than focusing on respiratory regulation. On the other hand, the feedback-loop from ANS to CNS is strongly dominated via respiratory activity., Significance: We demonstrated a considerably significantly different CCRN structure in SZO with a strong central influence on the cardiac system and a strong respiratory influence on the CNS. Moreover, this study provides a more in-depth understanding of the interplay of the central and autonomic regulatory network in healthy subjects and SZO patients.

The elevated cardiovascular risk of patients with schizophrenia contributes to a reduced life expectancy of 15-20years. This study investigated whether cardiac autonomic dysfunction (CADF) in schizophrenia is related to chronotropic incompetence, an established cardiovascular risk marker. We investigated thirty-two patients suffering from paranoid schizophrenia and thirty-two control subjects matched for age, sex, body mass index and fat free mass. A cardiopulmonary exercise test (CPET) was performed to study heart rate responses to exercise as well as submaximal (ventilatory threshold 1, VT 1 ) and maximal endurance capacities (peak oxygen consumption, VO 2peak ; peak power output, P peak ). In addition, epinephrine and norepinephrine levels were assessed in a subset of patients. Fitness parameters were significantly reduced in all patients. Most investigated physiological parameters were significantly different at rest as well as during peak exercise being in line with previously described CADF in schizophrenia. In particular, 14 out of 32 patients were classified as chronotropically incompetent whereas no control subject was below the cut-off value. In addition, a positive correlation of a slope reflecting chronotropic incompetence with peak oxygen uptake (p<0.001) was observed in patients only indicating a close correlation to the lack of physical fitness. The catecholamine increase was reduced in patients after exercise. This study identified a novel cardiac risk factor in patients with schizophrenia. Moreover, it seems to be associated with reduced physical fitness and indicates targets for exercise intervention studies. Future studies are warranted to elucidate pathophysiological mechanisms of this cardiac condition., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The identification of brain markers of suicidal risk is highly expected. However, neuroimaging studies have yielded mixed results, possibly due to phenotypic heterogeneity. In the present study, we addressed this issue using structural brain imaging. First, two independent samples of suicide attempters (n = 17 in Montreal, 32 in Jena), patient controls (n = 26/34), and healthy controls (n = 66/34) were scanned with magnetic resonance imaging. Groups were compared with FSL. We then reviewed the literature and run a GingerALE meta-analysis of 12 structural imaging studies comparing suicide attempters and patient controls with whole-brain analyses (n = 693). Finally, we explored the potential contribution of two variables previously associated with biological/cognitive deficits: a family history of suicide (FHoS), and the use of a violent suicidal means (VSM). Here, we added two groups of healthy first-degree biological relatives of suicide victims and depressed patients (n = 32). When comparing all suicide attempters and controls, very limited between-group differences were found in the two samples, and none in the meta-analysis. In contrast, a FHoS was associated with reduced volumes in bilateral temporal regions, right dorsolateral prefrontal cortex, and left putamen, several of these differences being observed across groups. VSM was associated with increased bilateral caudate (and left putamen) volumes. Some morphometric variations in cortico-subcortical networks may therefore be endophenotypes increasing the suicidal vulnerability, while others (notably in striatum) may modulate action selection. These results therefore confirm at the neural level two phenotypes at high lethal risk with a strong biological background, and uncover motives of heterogeneous findings in neuroimaging studies of suicidal behavior.

Background: The central control of the autonomic nervous system (ANS) and the complex interplay of its components can be described by a functional integrated mode - the central autonomic network (CAN). CAN represents the integrated functioning and interaction between the central nervous system (CNS) and ANS (parasympathetic and sympathetic activity)., Objective: This study investigates the central cardiovascular network (CCVN) as a part of the CAN, during which heart rate (HR), systolic blood pressure (SYS) and frontal EEG activity in 21 healthy subjects (CON) will be analysed. The objective of this study is to determine how these couplings (central-cardiovascular) are composed by the different regulatory aspects of the CNS-ANS interaction., Methods: To quantify the short-term instantaneous causal couplings within the CCVN, the normalized short time partial directed coherence (NSTPDC) approach was applied. It is based on an m-dimensional MAR process to determine Granger causality in the frequency domain., Results: We found that CCVN were of bidirectional character, and that the causal influences of central activity towards HR were stronger than those towards systolic blood pressure. This suggests that the central-cardiac closed-loop regulation process in CON focuses mainly on adapting the heart rate via the sinoatrial node rather than focusing on SYS. The CNS-ANS coupling directions with respect to central spectral power bands were characterized as mostly bidirectional, where HR and SYS acted as drivers in nearly every frequency band (unidirectional for α, α 1 and α 2 )., Conclusion: This study provides a more indepth understanding of the interplay of neuronal and autonomic cardiovascular regulatory processes in healthy subjects, as well as a greater insight into the complex CAN., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Schattauer GmbH.)

Impulsive behavior, difficulties in controlling anger and suicidal behavior are typical patterns of affective/behavioral dysregulation in patients with borderline personality disorder (BPD). Previous functional MRI studies in the resting state condition demonstrated altered functional connectivity (FC) between the anterior cingulate cortex (ACC) and the frontoparietal executive control network (ECN), which was significantly associated with impulsivity in BPD. Impulsivity is often defined as a function of inhibitory control, strongly relying on the proper functioning of the fronto-cingulo-striatal network. Noradrenergic, dopaminergic and serotonergic neurotransmitter systems are assumed to be involved in different forms of impulsive behavior and inhibitory control. In our previous study, we investigated the FC of the main monoamine-producing nuclei within the midbrain and brainstem, which were functionally integrated in specific resting-state networks. In the present study we investigated the resting-state FC of midbrain/brainstem nuclei in 33 unmedicated female patients with BPD and 33 matched healthy controls. We further related altered functional connectivity of these nuclei to the patient's degree of impulsivity. The main finding was that BPD patients showed stronger FC from the noradrenergic locus coeruleus (LC) to the ACC. Functional connectivity between the LC and ACC was positively associated with the degree of motor impulsivity in the total group. Controlling for aggression, a stronger FC was also found between serotonergic nucleus centralis superior (NCS) and the frontopolar cortex (FPC) in patients compared to controls. Furthermore, patients showed a weaker "anti-correlation" from the substantia nigra (SNc) to the left dorsolateral prefrontal cortex (DLPFC). The observed enhanced LC-ACC FC in BPD and its association with the motor impulsivity might be indicative of a noradrenergic dysfunction in the neural inhibitory control network, whereas the significant relationship between NCS-FPC FC and aggression points toward serotonergic contribution to prefrontal control of aggressive reactions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Elite young athletes have to cope with multiple psychological demands such as training volume, mental and physical fatigue, spatial separation of family and friends or time management problems may lead to reduced mental and physical recovery. While normative data regarding symptoms of anxiety and depression for the general population is available (Hinz and Brähler, 2011), hardly any information exists for adolescents in general and young athletes in particular. Therefore, the aim of this study was to assess overall symptoms of anxiety and depression in young athletes as well as possible sex differences. The survey was carried out within the scope of the study "Resistance Training in Young Athletes" (KINGS-Study). Between August 2015 and September 2016, 326 young athletes aged (mean ± SD) 14.3 ± 1.6 years completed the Hospital Anxiety and Depression Scale (HAD Scale). Regarding the analysis of age on the anxiety and depression subscales, age groups were classified as follows: late childhood (12-14 years) and late adolescence (15-18 years). The participating young athletes were recruited from Olympic weight lifting, handball, judo, track and field athletics, boxing, soccer, gymnastics, ice speed skating, volleyball, and rowing. Anxiety and depression scores were (mean ± SD) 4.3 ± 3.0 and 2.8 ± 2.9, respectively. In the subscale anxiety, 22 cases (6.7%) showed subclinical scores and 11 cases (3.4%) showed clinical relevant score values. When analyzing the depression subscale, 31 cases (9.5%) showed subclinical score values and 12 cases (3.7%) showed clinically important values. No significant differences were found between male and female athletes ( p ≥ 0.05). No statistically significant differences in the HADS scores were found between male athletes of late childhood and late adolescents ( p ≥ 0.05). To the best of our knowledge, this is the first report describing questionnaire based indicators of symptoms of anxiety and depression in young athletes. Our data implies the need for sports medical as well as sports psychiatric support for young athletes. In addition, our results demonstrated that the chronological classification concerning age did not influence HAD Scale outcomes. Future research should focus on sports medical and sports psychiatric interventional approaches with the goal to prevent anxiety and depression as well as teaching coping strategies to young athletes.

To explore brain activity and the related neurochemical processes, current research focuses increasingly on the combined acquisition of 1 H MR spectra and fMRI data to investigate potential associations between local metabolite resting state levels and stimulus-induced BOLD signal changes. In this study, whole-brain fMRI measurements and localized functional 1 H MEGA-PRESS MRS scans were conducted at 3T in healthy subjects prior to and during acute pain stimulation to quantify resting state GABA+/tCr and Glx/tCr levels in the insular cortex together with their stimulus-induced changes and to explore associations between these neurochemical parameters with intra-regional but also inter-regional BOLD responses. Inter-regionally, a significant negative correlation between the BOLD signal of a cluster in the supplementary motor area with overlap to the mid-cingulate cortex (R = -0.56, p = 0.004) and the insular resting state GABA+/tCr was obtained. Furthermore, pain induced insular ΔGlx was significantly positively associated with the BOLD signal in the left superior frontal gyrus, left and right inferior frontal gyrus, left inferior parietal lobe, left superior temporal gyrus, left anterior insula and right posterior insula, with R values ranging from 0.59 to 0.73 (p < 0.005). No intra-regional association was observed between BOLD and metabolite measures. These findings point toward interactions between metabolite levels and stimulus-induced BOLD responses in brain regions belonging to the pain processing network. The combination of fMRS and fMRI provides a powerful tool to improve our understanding about the complex system of neurochemical processes and brain activity within brain networks., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

There is limited understanding about how heart rate (HR) influences the blood-oxygen level dependent (BOLD) signal. While the mechanism by which respiration induces fluctuation in the BOLD signal is relatively well understood, the mechanisms regarding the HR remains unclear. The application of canonical cardiac response function (CRF), or subject-specific CRF, is an effective method for creating nuisance regressors, which can be used to remove cardiac-induced fluctuations in the BOLD signal. However, the relationship between physiological parameters and the characteristics of the CRF has not been systematically investigated. In the present investigation, we studied the relationship between the variations in mean HR and the shape of the cardiac response function in 84 healthy subjects with a wide range of HR lying between 47 and 97 beats per minute (bpm). Three groups (n = 28) were created based on the subject's mean HR. We demonstrated that the HR plays an important role in determining the shape of the CRFs. We also observed that the canonical CRF explains more variance in subjects with a slow HR, than in subjects exhibiting faster HR. We found that the amount of explained variance significantly increased in each group when a group-specific CRF was used. In a further analysis, we found two forms of a CRF, which explain a considerable amount of variance in subjects with a mean HR below and above 68 bpm. The shape of the CRF in subjects below 68 bpm is characterized by a shape similar to the canonical CRF, while in subjects with a HR above 68 bpm a well-defined second maximum was identified around 17 s. Thus, in the present study, we provide evidence for the necessity to use mean HR-based CRFs, rather than one canonical CRF, in order to optimally describe the interaction between BOLD and HR signal in subjects with varying heart rates., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Inconsistent results have been reported with respect to cardiac autonomic function in major depression. The aim of our study was to investigate autonomic function in various branches of the autonomic nervous system in order to better understand parasympathetic and sympathetic modulation in the disease. We investigated 29 unmedicated patients suffering from major depression (MD) in comparison to matched control subjects (gender, age, BMI). The autonomic assessment at rest included values of heart rate variability (HRV), blood pressure variability (BPV), baroreflex sensitivity (BRS), respiration, skin conductance (SC) as well as the calculation of pupillary diameter and the unrest index (PUI). Results were compared by means of a multivariate analysis of variance. In a classification analysis, we identified suitable parameters for patient - control separation. Finally, to analyze interrelations of pupillometric parameters and autonomic indices, we estimated Pearson correlation coefficients and fitted a linear regression model. Apart from a significantly increased heart rate (75±12 vs. 65±6min -1 , p<0.001) and decreased BRS (14±13 vs. 20±15ms/mmHg, p<0.05), we observed a lack of significant differences in HRV and BPV analysis between patients and controls. However, pupillary diameter (left: 4.3±0.9 vs. 3.8±0.6, p<0.01; right: 4.3±0.9 vs. 3.7±0.6mm, p<0.01) and PUI (left: 14.8±6.0 vs. 10.7±4.5mm/min, p<0.01; right: 14.1±5.5 vs. 10.7±4.8mm/min, p<0.01), as well as the level (left: 7.3±6.2 vs. 4.3±4.4 μS, p<0.05) and fluctuations of skin conductance (left: 4.2±4.1 vs. 2.5±3.6, p<0.05; right: 4.2±4.4 vs. 2.6±3.2, p<0.05) were significantly different. The classification accuracy was 88.5% with high specificity (e=92.9%) and sensitivity (s=83.3%) including heart rate, PUI and skin conductance. HRV indices correlated to PUI in controls but not in patients. Our data add evidence to the current debate on autonomic function in major depression. We suggest that diverse results are mainly caused by methodological shortcomings, in particular by the application of HRV assessment only, which misses changes of sympathetic modulation. The application of broader analyzing tools will clarify the pattern of autonomic function in depression and ultimately its role in cardiac morbidity and mortality., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Previous functional magnetic resonance imaging (fMRI) studies demonstrated an abnormally coordinated network functioning in Major Depression Disorder (MDD) during rest. The main monoamine-producing nuclei within midbrain/brainstem are functionally integrated within these specific networks. Therefore, we aimed to investigate the resting-state functional connectivity (RSFC) of these nuclei in 45 MDD patients and differences between patients receiving two different classes of antidepressant drugs. Patients showed reduced RSFC from the ventral tegmental area (VTA) to dorsal anterior cingulate cortex (dACC) and stronger RSFC to the left amygdala and dorsolateral prefrontal cortex (DLPFC). Patients treated with antidepressants influencing noradrenergic and serotonergic neurotransmission showed different RSFC from locus coeruleus to DLPFC compared to patients treated with antidepressants influencing serotonergic neurotransmission only. In the opposite contrast patients showed stronger RSFC from dorsal raphe to posterior brain regions. Enhanced VTA-RSFC to amygdala as a central region of the salience network may indicate an over-attribution of the affective salience to internally-oriented processes. Significant correlation between decreased VTA-dACC functional connectivity and the BDI-II somatic symptoms indicates an association with diminished volition and behavioral activation in MDD. The observed differences in the FC of the midbrain/brainstem nuclei between two classes of antidepressants suggest differential neural effects of SSRIs and SNRIs.

Background: The regular update of the guidelines on fibromyalgia syndrome, AWMF number 145/004, was scheduled for April 2017., Methods: The guidelines were developed by 13 scientific societies and 2 patient self-help organizations coordinated by the German Pain Society. Working groups (n =8) with a total of 42 members were formed balanced with respect to gender, medical expertise, position in the medical or scientific hierarchy and potential conflicts of interest. A literature search for systematic reviews of randomized controlled drug trials from December 2010 to May 2016 was performed in the Cochrane library, MEDLINE, PsycINFO and Scopus databases. Levels of evidence were assigned according to the classification system of the Oxford Centre for Evidence-Based Medicine version 2009. The strength of recommendations was achieved by multiple step formalized procedures to reach a consensus. Efficacy, risks, patient preferences and applicability of available therapies were weighed up against each other. The guidelines were reviewed and approved by the board of directors of the societies engaged in the development of the guidelines., Results and Conclusion: Amitriptyline and duloxetine are recommended in the case of comorbid depressive disorders or generalized anxiety disorder and pregabalin in the case of generalized anxiety disorder. Off-label use of duloxetine and pregabalin can be considered if there are no comorbid mental disorders or no generalized anxiety disorder. Strong opioids are not recommended.

Background: The regular update of the guidelines on fibromyalgia syndrome, AWMF number 145/004, was scheduled for April 2017., Methods: The guidelines were developed by 13 scientific societies and 2 patient self-help organizations coordinated by the German Pain Society. Working groups (n =8) with a total of 42 members were formed balanced with respect to gender, medical expertise, position in the medical or scientific hierarchy and potential conflicts of interest. A systematic search of the literature from December 2010 to May 2016 was performed in the Cochrane library, MEDLINE, PsycINFO and Scopus databases. Levels of evidence were assigned according to the classification system of the Oxford Centre for Evidence-Based Medicine version 2009. The strength of recommendations was achieved by multiple step formalized procedures to reach a consensus. The guidelines were reviewed and approved by the board of directors of the societies engaged in the development of the guidelines., Results and Conclusion: The clinical diagnosis of fibromyalgia syndrome can be established by the American College of Rheumatology (ACR) 1990 classification criteria (with examination of tender points) or without the examination of tender points by the modified preliminary diagnostic ACR 2010 or 2011 criteria.

Estimating interactions between physiological systems is an important challenge in modern biomedical research. Here, we explore a new concept for quantifying information common in two time series by cross-compressibility. Cross-compression entropy (CCE) exploits the ZIP data compression algorithm extended to bivariate data analysis. First, time series are transformed into symbol vectors. Symbols of the target time series are coded by the symbols of the source series. Uncoupled and linearly coupled surrogates were derived from cardiovascular recordings of 36 healthy controls obtained during rest to demonstrate suitability of this method for assessing physiological coupling. CCE at rest was compared to that of isometric handgrip exercise. Finally, spontaneous baroreflex interaction assessed by CCE BRS was compared between 21 patients suffering from acute schizophrenia and 21 matched controls. The CCE BRS of original time series was significantly higher than in uncoupled surrogates in 89% of the subjects and higher than in linearly coupled surrogates in 47% of the subjects. Handgrip exercise led to sympathetic activation and vagal inhibition accompanied by reduced baroreflex sensitivity. CCE BRS decreased from 0.553 ± 0.030 at rest to 0.514 ± 0.035 during exercise ( p < 0.001). In acute schizophrenia, heart rate, and blood pressure were elevated. Heart rate variability indicated a change of sympathovagal balance. The CCE BRS of patients with schizophrenia was reduced compared to healthy controls (0.546 ± 0.042 vs. 0.507 ± 0.046, p < 0.01) and revealed a decrease of blood pressure influence on heart rate in patients with schizophrenia. Our results indicate that CCE is suitable for the investigation of linear and non-linear coupling in cardiovascular time series. CCE can quantify causal interactions in short, noisy and non-stationary physiological time series.

Early neuropathological changes characteristic of late-onset Alzheimer's disease (LOAD) involve brain stem and limbic structures that regulate neurovegetative functions, including sleep-wake rhythm. Indeed, sleep pattern is an emerging biomarker and a potential pathophysiological mechanism in LOAD. We hypothesized that cognitively asymptomatic, middle-aged offspring of patients with LOAD (O-LOAD) would display a series of circadian rhythm abnormalities prior to the onset of objective cognitive alterations. We tested 31 children of patients with LOAD (O-LOAD) and 19 healthy individuals without family history of Alzheimer's disease (control subjects, CS) with basic tests of cognitive function, as well as actigraphy measures of sleep-wake rhythm, cardiac autonomic function, and bodily temperature. Unexpectedly, O-LOAD displayed subtle but significant deficits in verbal episodic memory (Rey Auditory Verbal Learning Test delayed recall 10.6 ± 0.4 vs. 8.6 ± 0.6, t = 4.97, df = 49, p < 0.01) and language (Weschler's vocabulary 51.4 ± 1.3 vs. 44.3 ± 1.5, t = 2.49, df = 49, p < 0.001) compared to CS, even though all participants had results within the clinically normal range. O-LOAD showed a phase-delayed rhythm of body temperature (2.56 ± 0.47 h vs. 3.8 ± 0.26 h, t = 2.48, df = 40, p = 0.031). Cognitive performance in O-LOAD was associated with a series of cardiac autonomic sleep-wake variables; specifically indicators of greater sympathetic activity at night were related to poorer cognition. The present results suggest sleep pattern deserves further study as a potential neurobiological signature in LOAD, even in middle-aged, at risk individuals.

Although depression is associated with more clinical pain complaints, psychophysical data sometimes point to hypoalgesic alterations. Studying the more reflex-like facial expression of pain in patients with depression may offer a new perspective. Facial and psychophysical responses to nonpainful and painful heat stimuli were studied in 23 patients with major depressive disorder (MDD) and 23 matched control participants. As psychophysical data, pain thresholds, tolerance thresholds, and self-report were assessed. Facial responses were videotaped and subjected offline to Facial Action Coding System analysis. One of the key facial responses of pain, which is a known facial signal of negative affect (contraction of the eyebrows), was significantly increased in MDD patients. Moreover, facial expressions and pain ratings were strongly correlated in MDD patients, whereas these 2 response systems were-in line with established findings-only weakly related in healthy participants. Pain psychophysics was unaltered in MDD patients compared with healthy control participants. In conclusion, the facial expression of pain in MDD patients indicates rather hyper- than hypoalgesia, with enhanced affective pain processing. Moreover, the linkage between subjective and facial responses was much stronger in MDD patients, which may be due to a reduced influence of social display rules, which normally complicate this relationship., Perspective: The facial expression of pain in patients with depression indicates stronger affective pain processing and stronger association with self-report than in healthy individuals., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

In life-threatening diseases and in several clinical interventions, monitoring of vital parameters is essential to guarantee the safety of patients. Besides monitoring the electrocardiogram (ECG), it is helpful to assess respiratory activity. If the respiration signal itself is not recorded, it can be extracted from the ECG (i.e. ECG derived respiration, EDR). In the present paper, we compared six EDR approaches, namely RS-decline quantified by central moments, respiratory sinus arrhythmia (RSA), R-wave amplitude, QRS area, RS-distance and maximum RS-slope. In order to evaluate the performance of each approach, we applied each method to a database of ECGs and reference respiration signals of 41 healthy subjects. All considered methods revealed relatively small absolute mean errors of the breathing rate (BR) at rest (0.75-1.3 Bpm). The method based on higher order central moments revealed a minimum mean absolute error of 0.75 Bpm (4.40%) and a maximum correlation and concordance with the reference BR (r p   =  0.97, r c   =  0.97). Using this technique, we analyzed changes of respiration in patients suffering from acute schizophrenia. An increased respiration rate of about 4 Bpm was found. Additionally, alteration of respiratory ratio and reduced respiratory sinus arrhythmia was demonstrated. We conclude that a precise dynamic monitoring of breathing and the investigation of changes in breathing patterns is possible without recording respiration per se.

Strong evidence indicates that regular aerobic training induces beneficial effects on cognitive functions. The present controlled fMRI study was designed to investigate the impact of a short-term intense aerobic exercise on the pattern of functional activation during the retrieval of learned pair-associates in 17 young and healthy male adults compared to 17 matched control subjects. We further aimed to relate putative changes in hippocampal activation to postulated changes in the exercised-induced brain derived neurotrophic factor (BDNF). The supervised exercise program was performed on a bicycle ergometer and lasted six weeks, with three aerobic sessions per week. We found profound improvement of physical fitness in most subjects indicated by the target parameter 'individual anaerobic threshold'. Significant improvements in the cognitive performance were detected in the exercise group, but also in the control group. We observed significant differences in the activation pattern of the left anterior hippocampus during the pair-associates task after the intervention. We could also show a significant positive correlation between changes in exercise-induced BDNF and left anterior hippocampal activation. Moreover, we observed the brain's motor network to be significantly stronger activated after the exercise intervention. Thus, our results suggest BDNF dependent activation changes of the hippocampus in addition to previously described structural changes after exercise., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Anorexia nervosa (AN) is highly heritable, and the perspective on the etiology of AN has changed from a behavioral to a neurobiological and neurodevelopmental view. However, cortical folding as an important marker for deviations in brain development has yet rarely been explored in AN. Hence, in order to determine potential cortical folding alterations, we investigated fine-grained cortical folding in a cohort of 26 patients with AN, of whom 6 patients were recovered regarding their weight at the time point of MRI measurement. MRI-derived cortical folding was computed and compared between patients and healthy controls at about 150,000 points per hemisphere using a surface-based technique (FreeSurfer). Patients with AN exhibited highly significant increased cortical folding in a right dorsolateral prefrontal cortex region (DLPFC). Furthermore, a statistical trend in the same direction was found in the right visual cortex. We did not find a correlation of local cortical folding and current symptoms of the disease. In conclusion, our analyses provide first evidence that altered DLPFC cortical folding plays a role in the etiology of AN. The absence of correlations with clinical parameters implicates a relatively independence of cortical folding alterations from the current symptomatology and might thus be regarded as a trait characteristic of the disease potentially related to other neurobiological features of AN.

Simultaneous presentation of alternating innocuous warm and cold stimuli induces in most humans a painful sensation called thermal grill illusion (TGI). Here, pain is elicited although nociceptors are not activated. Upon back-translation of behavioural correlates from humans to animals, we found that neither cats nor rodents show adverse reactions when exposed to TGI stimulation. These results question that a TGI observed as a pain-related change in behaviour can be elicited in animals. While distinct neuronal patterns as previously reported may be measurable in animals upon TGI stimulation, their translational meaning towards the sensation elicited in humans is unclear., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Animal and human studies suggest differing anatomical and functional connectivity patterns of the anterior and posterior hippocampus. The biochemical underpinnings of the hippocampal resting state connectivity along this anterior-posterior axis remain unclear. We investigated twenty-five healthy male subjects in a multimodal study. We aimed to examine the relationship between resting state functional connectivity (RSFC) of the left and right hippocampus separated along the anterior-posterior axis and the corresponding glutamatergic function assessed by proton magnetic resonance spectroscopy ((1)H-MRS) of the glutamate-glutamine (Glx) complex. We observed a clear functional differentiation of the hippocampal RSFC along this axis. Moreover, a highly significant correlation was observed between the concentration of Glx in the right anterior hippocampus and its corresponding functional connectivity, but not with the amplitude of local low frequency fluctuations. Lower Glx levels were associated with a higher functional connectivity to the medial prefrontal cortex, perigenual anterior cingulate cortex (pACC) and the left ventrolateral prefrontal cortex (VLPFC). In addition, the Glx concentration in the posterior hippocampus predicted the verbal memory performance, i.e., the degree of retroactive interference. The present findings demonstrate for the first time a modulation of the anterior hippocampal RSFC by Glx concentration., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

There is limited understanding of how monoamine-producing nuclei within midbrain and brainstem contribute to the formation and functional dynamics of brain networks across the human neocortex. We used resting state fMRI in 154 healthy participants to elucidate patterns of functional connectivity and network organization between cortical/subcortical regions and midbrain/brainstem nuclei. By means of univariate functional connectivity and graph-based analysis, we show that dopaminergic midbrain centers and the serotonergic dorsal raphe nucleus (DRN) are functionally integrated with the default mode network (DMN), whereas the remaining serotonergic raphe nuclei and the noradrenergic locus coeruleus are functionally integrated with the executive-control network (ECN). The majority of midbrain/brainstem nuclei show a high level of connectedness to other network modules classifying these nuclei as "connector" hubs. The additionally applied probabilistic independent component analysis (PICA) broadly corresponded with the results of the GT analysis, describing similar functionally-relevant cortical networks. Since monoaminergic neurotransmission is essential to neocortical function, and represents an important target for pharmacotherapy, our novel findings contribute to a comprehensive understanding of the functional organization of the human brain., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Several lines of evidence suggest that the lateral prefrontal cortex (PFC), the dorsal anterior cingulate cortex (dACC), the parietal cortex, and the thalamus are central cortical nodes in a network underlying cognitive control. However, the role of catecholamine producing midbrain and brainstem structures has rarely been addressed by functional magnetic resonance imaging (fMRI). We hypothesized differential activation patterns in the ventral tegmental area (VTA)/substantia nigra (SN) and locus coeruleus (LC) with respect to the degree of cognitive control during a Stroop task in healthy subjects. Forty-five healthy subjects were investigated by the manual version of the Stroop task in an event-related fMRI design. We observed significant BOLD activation of both the SN/VTA and LC during the Stroop interference condition (incongruent vs. congruent condition). LC, but not SN/VTA activation significantly correlated with the Stroop interference. Interestingly, a significant linear decrease in BOLD activation during the incongruent condition during the experiment was mainly observed in the fronto-cingulo-striatal network, but not in SN/VTA and LC. Using psychophysiological (PPI) analyses, a significant functional connectivity during cognitive control was observed between SN/VTA and the nigrostriatal/mesolimbic dopaminergic system. For the LC, distinct functional connectivity pattern was observed mainly to the dorsolateral and ventrolateral PFC. Both regions revealed significant functional connectivity to the dACC, parietal and occipital regions. Thus, we demonstrate for the first time that functional activation patterns in the SN/VTA and the LC are modulated by different demands of cognitive control. In addition, these nuclei exhibit distinguishable functional connectivity patterns to cortical brain networks. Hum Brain Mapp 37:2305-2318, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The autonomic nervous system (ANS) dysfunction has been well described in schizophrenia (SZ), a severe mental disorder. Nevertheless, the coupling between the ANS and central brain activity has been not addressed until now in SZ. The interactions between the central nervous system (CNS) and ANS need to be considered as a feedback-feed-forward system that supports flexible and adaptive responses to specific demands. For the first time, to the best of our knowledge, this study investigates central-autonomic couplings (CAC) studying heart rate, blood pressure and electroencephalogram in paranoid schizophrenic patients, comparing them with age-gender-matched healthy subjects (CO). The emphasis is to determine how these couplings are composed by the different regulatory aspects of the CNS-ANS. We found that CAC were bidirectional, and that the causal influence of central activity towards systolic blood pressure was more strongly pronounced than such causal influence towards heart rate in paranoid schizophrenic patients when compared with CO. In paranoid schizophrenic patients, the central activity was a much stronger variable, being more random and having fewer rhythmic oscillatory components. This study provides a more in-depth understanding of the interplay of neuronal and autonomic regulatory processes in SZ and most likely greater insights into the complex relationship between psychotic stages and autonomic activity., (© 2016 The Author(s).)

Regular physical exercise leads to increased vagal modulation of the cardiovascular system. A combination of peripheral and central processes has been proposed to underlie this adaptation. However, specific changes in the central autonomic network have not been described in human in more detail. We hypothesized that the anterior hippocampus known to be influenced by regular physical activity might be involved in the development of increased vagal modulation after a 6 weeks high intensity intervention in young healthy men (exercise group: n = 17, control group: n = 17). In addition to the determination of physical capacity before and after the intervention, we used resting state functional magnetic resonance imaging and simultaneous heart rate variability assessment. We detected a significant increase of the power output at the anaerobic threshold of 11.4% (p < 0.001), the maximum power output Pmax of 11.2% (p < 0.001), and VO2max adjusted for body weight of 4.7% (p < 0.001) in the exercise group (EG). Comparing baseline (T0) and post-exercise (T1) values of parasympathetic modulation of the exercise group, we observed a trend for a decrease in heart rate (p < 0.06) and a significant increase of vagal modulation as indicated by RMSSD (p < 0.026) during resting state. In the whole brain analysis, we found that the connectivity pattern of the right anterior hippocampus (aHC) was specifically altered to the ventromedial anterior cortex, the dorsal striatum and to the dorsal vagal complex (DVC) in the brainstem. Moreover, we observed a highly significant negative correlation between increased RMSSD after exercise and decreased functional connectivity from the right aHC to DVC (r = -0.69, p = 0.003). This indicates that increased vagal modulation was associated with functional connectivity between aHC and the DVC. In conclusion, our findings suggest that exercise associated changes in anterior hippocampal function might be involved in increased vagal modulation.

The hippocampus (HPC) is functionally heterogeneous along the longitudinal anterior-posterior axis. In rodent models, gene expression maps define at least three discrete longitudinal subregions, which also differ in function, and in anatomical connectivity with the rest of the brain. In humans, equivalent HPC subregions are less well defined, resulting in a lack of consensus in neuroimaging approaches that limits translational study. This study determined whether a data-driven analysis, namely independent component analysis (ICA), could reproducibly define human HPC subregions, and map their respective intrinsic functional connectivity (iFC) with the rest of the brain. Specifically, we performed ICA of resting-state fMRI activity spatially restricted within the HPC, to determine the configuration and reproducibility of functional HPC components. Using dual regression, we then performed multivariate analysis of iFC between resulting HPC components and the whole brain, including detailed connectivity with the hypothalamus, a functionally important connection not yet characterized in human. We found hippocampal ICA resulted in highly reproducible longitudinally discrete components, with greater functional heterogeneity in the anterior HPC, consistent with animal models. Anterior hippocampal components shared iFC with the amygdala, nucleus accumbens, medial prefrontal cortex, posterior cingulate cortex, midline thalamus, and periventricular hypothalamus, whereas posterior hippocampal components shared iFC with the anterior cingulate cortex, retrosplenial cortex, and mammillary bodies. We show that spatially masked hippocampal ICA with dual regression reproducibly identifies functional subregions in the human HPC, and maps their respective brain intrinsic connectivity. Hum Brain Mapp 37:462-476, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Background: Previous research indicated the complexity of autonomic dysfunction during acute alcohol withdrawal. This study aimed to investigate the pupillary light reflex as an indicator of midbrain and brainstem regulatory systems in relation to cardiovascular autonomic function., Methods: Thirty male patients were included in the study. They were investigated during acute alcohol withdrawal syndrome and 24h later during clomethiazole treatment and compared to healthy controls. Parameters of pupillary light reflex of both eyes as well as heart rate variability, blood pressure variability and baroreflex sensitivity (BRS) were studied., Results: We observed significantly reduced sympathetic (small diameter, e.g., left eye: 5.00 in patients vs. 5.91 mm in controls) and vagal modulation (e.g., prolonged latencies, left eye: 0.28 vs. 0.26 ms) regarding both pupils during acute alcohol withdrawal syndrome. Cardiovascular parameters showed reduced vagal modulation (e.g., b-slope of BRS: 7. 57 vs. 13.59 ms/mm Hg) and mixed results for sympathetic influence. After 24h, autonomic dysfunction improved significantly, both for the pupils (e.g., left diameter: 5.38 mm) and the heart (e.g., b-slope of BRS: 9.34 ms/mm Hg). While parameters obtained from the pupil correlated with cardiac autonomic function (e.g, BRS and left diameter: r=0.564) in healthy controls, no such pattern was observed in patients., Conclusion: Results obtained from the pupil during acute alcohol withdrawal do not simply mirror autonomic dysfunction regarding the heart. Pupillary and cardiovascular changes after 24h indicate state dependencies of the results. The findings are discussed with respect to autonomic mechanisms and potentially involved brain regions., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Environmental influences are critical for the expression of genes putatively related to the behavioral and cognitive phenotypes of schizophrenia. Among such factors, psychosocial stress has been proposed to play a major role in the expression of symptoms. However, it is unsettled how stress interacts with pathophysiological pathways to produce the disease. We studied 21 patients with schizophrenia and 21 healthy controls aged 18 to 50years with 3T-fMRI, in which a period of 6min of resting state acquisition was followed by a block design, with three blocks of 1-min control-task, 1-min stress-task and 1-min rest after-task. Self-report of stress and PANSS were measured. Limbic structures were activated in schizophrenia patients by simple tasks and remained active during, and shortly after stress. In controls, stress-related brain activation was more time-focused, and restricted to the stressful task itself. Negative symptom severity was inversely related to activation of anterior cingulum and orbitofrontal cortex. Results might represent the neurobiological aspect of hyper-reactivity to normal stressful situations previously described in schizophrenia, thus providing evidence on the involvement of limbic areas in the response to stress in schizophrenia. Patients present a pattern of persistent limbic activation probably contributing to hypervigilance and subsequent psychotic thought distortions., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Interventional studies suggest that changes in physical fitness affect brain function and structure. We studied the influence of high intensity physical exercise on hippocampal volume and metabolism in 17 young healthy male adults during a 6-week exercise program compared with matched controls. We further aimed to relate these changes to hypothesized changes in exercised-induced brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). We show profound improvement of physical fitness in most subjects and a positive correlation between the degree of fitness improvement and increased BDNF levels. We unexpectedly observed an average volume decrease of about 2%, which was restricted to right hippocampal subfields CA2/3, subiculum, and dentate gyrus and which correlated with fitness improvement and increased BDNF levels negatively. This result indicates that mainly those subjects who did not benefit from the exercise program show decreased hippocampal volume, reduced BDNF levels, and increased TNF-α concentrations. While spectroscopy results do not indicate any neuronal loss (unchanged N-acetylaspartate levels) decreased glutamate-glutamine levels were observed in the right anterior hippocampus in the exercise group only. Responder characteristics need to be studied in more detail. Our results point to an important role of the inflammatory response after exercise on changes in hippocampal structure.

Persistent pondering over negative self-related thoughts is a central feature of depressive psychopathology. In this study, we sought to investigate the neural correlates of abnormal negative self-referential processing (SRP) in patients with Major Depressive Disorder and its impact on subsequent cognitive control-related neuronal activation. We hypothesized aberrant activation dynamics during the period of negative and neutral SRP in the rostral anterior cingulate cortex (rACC) and in the amygdala in patients with major depressive disorder. Additionally, we assumed abnormal activation in the fronto-cingulate network during Stroop task execution. 19 depressed patients and 20 healthy controls participated in the study. Using an event-related functional magnetic resonance imaging (fMRI) design, negative, positive and neutral self-referential statements were displayed for 6.5 s and followed by incongruent or congruent Stroop conditions. The data were analyzed with SPM8. In contrast to controls, patients exhibited no significant valence-dependent rACC activation differences during SRP. A novel finding was the significant activation of the amygdala and the reward-processing network during presentation of neutral self-referential stimuli relative to baseline and to affective stimuli in patients. The fMRI analysis of the Stroop task revealed a reduced BOLD activation in the right fronto-parietal network of patients in the incongruent condition after negative SRP only. Thus, the inflexible activation in the rACC may correspond to the inability of depressed patients to shift their attention away from negative self-related stimuli. The accompanying negative affect and task-irrelevant emotional processing may compete for neuronal resources with cognitive control processes and lead thereby to deficient cognitive performance associated with decreased fronto-parietal activation., (© 2015 Wiley Periodicals, Inc.)

Background: The dysfunction of specific brain areas might account for the distortion of body image in patients with anorexia nervosa. The present study was designed to reveal brain regions that are abnormal in structure and function in patients with this disorder. We hypothesized, based on brain areas of altered activity in patients with anorexia nervosa and regions involved in pain processing, an interrelation of structural aberrations in the frontoparietal-cingulate network and aberrant functional activation during thermal pain processing in patients with the disorder., Methods: We determined pain thresholds outside the MRI scanner in patients with anorexia nervosa and matched healthy controls. Thereafter, thermal pain stimuli were applied during fMRI imaging. Structural analyses with high-resolution structural T1-weighted volumes were performed using voxel-based morphometry and a surface-based approach., Results: Twenty-six patients and 26 controls participated in our study, and owing to technical difficulties, 15 participants in each group were included in our fMRI analysis. Structural analyses revealed significantly decreased grey matter volume and cortical thickness in the frontoparietal-cingulate network in patients with anorexia nervosa. We detected an increased blood oxygen level-dependent signal in patients during the painful 45 °C condition in the midcingulate and posterior cingulate cortex, which positively correlated with increased pain thresholds. Decreased grey matter and cortical thickness correlated negatively with pain thresholds, symptom severity and illness duration, but not with body mass index., Limitations: The lack of a specific quantification of body image distortion is a limitation of our study., Conclusion: This study provides further evidence for confined structural and functional brain abnormalities in patients with anorexia nervosa in brain regions that are involved in perception and integration of bodily stimuli. The association of structural and functional deviations with thermal thresholds as well as with clinical characteristics might indicate a common neuronal origin.

The majority of excess mortality among people with schizophrenia seems to be caused by cardiovascular complications, and in particular, coronary heart disease. In addition, the prevalence of heart failure and arrhythmias is increased in this population. Reduced efferent vagal activity, which has been consistently described in these patients and their healthy first-degree relatives, might be one important mechanism contributing to their increased cardiac mortality. A decrease in heart rate variability and complexity was often shown in unmedicated patients when compared to healthy controls. In addition, faster breathing rates, accompanied by shallow breathing, seem to influence autonomic cardiac functioning in acute unmedicated patients substantially. Moreover, low-physical fitness is a further and independent cardiac risk factor present in this patient population. Interestingly, new studies describe chronotropic incompetence during physical exercise as an important additional risk factor in patients with schizophrenia. Some studies report a correlation of the autonomic imbalance with the degree of positive symptoms (i.e., delusions) and some with the duration of disease. The main body of psychiatric research is focused on mental aspects of the disease, thereby neglecting obvious physical health needs of these patients. Here, a joint effort is needed to design interventional strategies in everyday clinical settings to improve physical health and quality of life.

Purpose: To determine alterations in the retina of patients with Alzheimer's disease (AD) by the newly developed technique of fluorescence lifetime imaging ophthalmoscopy (FLIO) in a pilot study., Methods: FLIO set-up uses a scanning laser ophthalmoscope (HRA2, Heidelberg Engineering, Germany), which was modified by the use of an excitation pulse laser BLD440 (Becker&Hickl, Berlin, Germany) and detection of fluorescence lifetime by time-correlated single photon counting (TCSPC; Becker&Hickl) in two spectral channels (channel 1: 490-560 nm, channel 2: 560-700 nm). Least square fit of three exponential functions was used for fluorescence decay analysis. That resulted in three fluorescent components with lifetimes τi , amplitudes αi and relative contributions Qi . 16 patients with AD (mean age 77.2 ± 7.0 years) were investigated. After regular ophthalmic investigation, FLIO examination and OCT examination were performed. Alzheimer-specific clinical data were collected (MMSE, cerebrospinal fluid (CSF) concentration of amyloid-β (1-42), total-tau and phosphorylated tau181 (p-tau181) protein)., Results: The FLIO parameters of the second fluorescent component α2 and Q2 (channel 2) correlated significantly with MMSE score (Q2 , R = -0.757, p = 0.007; α2 , R = -0.618, p = 0.043) as well as p-tau181-protein concentration in CSF (Q2 , R = 0.919, p = 0.009; α2 , R = 0.881, p = 0.020) in patients with AD. OCT measurements of retinal nerve fibre layer thickness, optic disc excavation and macular thickness neither correlated with Alzheimer-specific CSF data nor MMSE score., Conclusions: Unlike conventional techniques, such as OCT, the new technique of FLIO revealed changes in the retina of patients with AD in relation to Alzheimer-specific markers in this pilot study., (© 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)