Publications by authors named "Andy Schumann"

28 Publications

  • Page 1 of 1

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

Transl Psychiatry 2021 Feb 4;11(1):95. Epub 2021 Feb 4.

Lab for Autonomic Neuroscience, Imaging and Cognition (LANIC), Department of Psychosomatic Medicine and Psychotherapy, Jena University Hospital, Jena, Germany.

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.
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http://dx.doi.org/10.1038/s41398-021-01237-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862305PMC
February 2021

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

Schizophr Res 2020 Nov 18. Epub 2020 Nov 18.

Lab for Autonomic Neuroscience, Imaging and Cognition (LANIC), Department of Psychosomatic Medicine and Psychotherapy, Jena University Hospital, Jena, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.schres.2020.11.017DOI Listing
November 2020

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

Hum Brain Mapp 2021 Feb 31;42(3):811-823. Epub 2020 Oct 31.

Lab for Autonomic Neuroscience, Imaging and Cognition (LANIC), Department of Psychosomatic Medicine and Psychotherapy, Jena University Hospital, Germany.

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.
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http://dx.doi.org/10.1002/hbm.25264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814772PMC
February 2021

Cortical thickness and resting-state cardiac function across the lifespan: A cross-sectional pooled mega-analysis.

Psychophysiology 2020 Oct 10. Epub 2020 Oct 10.

Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

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.
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http://dx.doi.org/10.1111/psyp.13688DOI Listing
October 2020

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

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:549-552

Quantification of directed (nonlinear) brain-heart interactions has turned to be an emerging topic of research and is important for the better understanding of central autonomic processing during specific diseases such as schizophrenia. Convergent Cross Mapping (CCM) was able to provide directed, frequency-selective and topographic views on existent interaction pattern of those patients. Investigations of the influence of individual heart rate (HR) on CCM estimations may further contribute to this topic. Relationship of mean HR and CCM was analyzed in a group of schizophrenic patients (N=17) and healthy controls (N=21). Influence of individual HR values was most pronounced for patients, for interactions from brain to heart and for the subgroup of patients with highest mean HR values.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175826DOI Listing
July 2020

Sympathetic and Parasympathetic Modulation of Pupillary Unrest.

Front Neurosci 2020 11;14:178. Epub 2020 Mar 11.

Lab for Autonomic Neuroscience, Imaging and Cognition (LANIC), Department of Psychosomatic Medicine and Psychotherapy, Jena University Hospital, Jena, Germany.

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 ( < 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.
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http://dx.doi.org/10.3389/fnins.2020.00178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078331PMC
March 2020

Cardio-Respiratory Fitness and Autonomic Function in Patients with Major Depressive Disorder.

Front Psychiatry 2019 5;10:980. Epub 2020 Feb 5.

Psychiatric Brain and Body Research Group, Department of Psychosomatic Medicine, University Hospital, Jena, Germany.

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.
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http://dx.doi.org/10.3389/fpsyt.2019.00980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011194PMC
February 2020

The relation of skin conductance and pupillary fluctuations assessed by phase-rectified signal averaging.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:725-728

The reaction of pupil diameter and skin conductance are widely studied marker of the autonomic response to arousing stimuli. However, little is known about their relation at rest. In this study, we used bivariate phase-rectified signal averaging to investigate the relationship of skin conductance fluctuations (SCF) and pupillary fluctuations in 83 healthy volunteers. The onset of each SCF was detected by a pattern matching algorithm. Those time points were corrected for a different neurotransmission delay. Cross-correlation of temporal derivatives of pupil diameter and skin conductance revealed an average time lag of 2.5s. Thus, anchor points 2.5s before an SCF were defined. The pupillary signal following these anchors (7s) were extracted and normalized to baseline 1s prior to the anchor point. Aligned segments were averaged to determine the amplitude and area under the curve (AUC) of characteristic pupil diameter fluctuations (PDF) concurrent to SCF. The same procedure was applied to random time points (non-SCF) with at least 1s distance to actually detected SCF which served as control condition. SCF were accompanied by increases of pupil diameter with a maximum dilation of 9% on average. The one sample t-test indicated an AUC of PDF (70 ± 110 n.u., p<; 0.001). The maximum change and AUC of pupillary reactions were significantly higher when PDF extraction was triggered by actual SCF (both p<; 0.001). Both measures of pupillary dilations contributed significantly to pupillary unrest. Our results suggest that sympathetic arousal as detected by skin conductance fluctuations is accompanied by pupil dilation.
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http://dx.doi.org/10.1109/EMBC.2019.8857713DOI Listing
July 2019

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

Neuroimage 2020 02 16;207:116362. Epub 2019 Nov 16.

Psychiatric Brain and Body Research Group, Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuroimage.2019.116362DOI Listing
February 2020

Brain-heart interactions considering complex physiological data: processing schemes for time-variant, frequency-dependent, topographical and statistical examination of directed interactions by convergent cross mapping.

Physiol Meas 2019 12 2;40(11):114001. Epub 2019 Dec 2.

Institute of Medical Statistics, Computer and Data Sciences, Jena University Hospital, Jena, Germany.

Background: A multitude of complex methods is available to quantify interactions in highly complex physiological systems. Brain-heart interactions play an important role in identifying couplings between the central nervous system and the autonomic nervous system during defined physiological states or specific diseases. The crucial point of those interaction analyses is adequate pre-processing taking into account nonlinearity of data, intuitive graphical representation and suitable statistical evaluation of the achieved results.

Objective: The aim of this study is to provide generalized processing schemes for such investigations taking into account pre-processing, graphical representation and statistical analysis.

Approach: Two defined data sets were used to develop these processing schemes. Brain-heart interactions in children with temporal lobe epilepsy during the pre-ictal, ictal and post-ictal periods as well as in patients with paranoid schizophrenia and healthy control subjects during the resting state period were investigated by nonlinear convergent cross mapping (CCM). Surrogate data, bootstrapping and linear mixed-effects model approaches were utilized for statistical analyses.

Main Results: CCM was able to reveal specific and statistically significant time- and frequency-dependent patterns of brain-heart interactions for children with temporal lobe epilepsy and provide a statistically significant pattern of topographic- and frequency-dependent brain-heart interactions for schizophrenic patients, as well as to show the differences from healthy control subjects. Suitable statistical models were found to quantify group differences.

Significance: Generalized processing schemes and crucial points of pre-processing, adapted interaction analysis and performed statistical analysis are provided. The general concept of analyses is transferable also to other methods of interactions analysis and data representing even more complex physiological systems.
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http://dx.doi.org/10.1088/1361-6579/ab5050DOI Listing
December 2019

Effect of an eight-week smartphone-guided HRV-biofeedback intervention on autonomic function and impulsivity in healthy controls.

Physiol Meas 2019 07 1;40(6):064001. Epub 2019 Jul 1.

Psychiatric Brain and Body Research Group Jena, Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.

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.
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http://dx.doi.org/10.1088/1361-6579/ab2065DOI Listing
July 2019

The relationship between heart rate and functional connectivity of brain regions involved in autonomic control.

Neuroimage 2019 08 11;196:318-328. Epub 2019 Apr 11.

Psychiatric Brain and Body Research Group, Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuroimage.2019.04.014DOI Listing
August 2019

Nonlinear Interaction Analysis of Cardiovascular-Respiratory Data by Means of Convergent Cross Mapping.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:267-270

Appropriate analyses of directed complex interactions within the cardiovascular-respiratory system are of growing interest for a better understanding of physiological regulatory mechanisms in healthy subjects and diseased persons. There are various concepts to analyze such interactions. Convergent Cross Mapping (CCM) provides the possibility to define directed interactions in terms of nonlinear stability. A proof-of-principle approach is introduced to apply CCM to cardiovascular-respiratory data of healthy subjects during resting state period. Showing group results of time-invariant as well as single subject results of interval-based CCM, the introduced approach was able to quantify correct directionality and strength of interactions within the cardiovascular-respiratory system and to provide statistical thresholds for significant interactions. These results may serve as a methodological base to compare healthy subjects and diseased persons.
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http://dx.doi.org/10.1109/EMBC.2018.8512213DOI Listing
July 2018

The Use of Physiological Signals in Brainstem/Midbrain fMRI.

Front Neurosci 2018 16;12:718. Epub 2018 Oct 16.

Psychiatric Brain and Body Research Group Jena, Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.

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 ( = 0.464, < 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.
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http://dx.doi.org/10.3389/fnins.2018.00718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198067PMC
October 2018

Towards response success prediction: An integrative approach using high-resolution fMRI and autonomic indices.

Neuropsychologia 2018 10 6;119:182-190. Epub 2018 Aug 6.

Psychiatric Brain and Body Research Group, Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuropsychologia.2018.08.003DOI Listing
October 2018

Chronotropic incompetence of the heart is associated with exercise intolerance in patients with schizophrenia.

Schizophr Res 2018 07 9;197:162-169. Epub 2018 Mar 9.

Psychiatric Brain and Body Research Group, Department of Psychiatry and Psychotherapy, University Hospital Jena, Germany. Electronic address:

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) and maximal endurance capacities (peak oxygen consumption, VO; peak power output, P). 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.
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http://dx.doi.org/10.1016/j.schres.2018.02.020DOI Listing
July 2018

Chronotropic incompetence of the heart is associated with exercise intolerance in patients with schizophrenia.

Schizophr Res 2018 07 9;197:162-169. Epub 2018 Mar 9.

Psychiatric Brain and Body Research Group, Department of Psychiatry and Psychotherapy, University Hospital Jena, Germany. Electronic address:

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) and maximal endurance capacities (peak oxygen consumption, VO; peak power output, P). 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.
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http://dx.doi.org/10.1016/j.schres.2018.02.020DOI Listing
July 2018

Impact of the heart rate on the shape of the cardiac response function.

Neuroimage 2017 11 5;162:214-225. Epub 2017 Sep 5.

Psychiatric Brain and Body Research Group, Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuroimage.2017.08.076DOI Listing
November 2017

Differences of sympathetic and parasympathetic modulation in major depression.

Prog Neuropsychopharmacol Biol Psychiatry 2017 10 12;79(Pt B):324-331. Epub 2017 Jul 12.

Psychiatric Brain and Body Research Group, Department of Psychiatry and Psychotherapy, University Hospital Jena, Jena, Germany. Electronic address:

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, 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.
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http://dx.doi.org/10.1016/j.pnpbp.2017.07.009DOI Listing
October 2017

Baroreflex Coupling Assessed by Cross-Compression Entropy.

Front Physiol 2017 10;8:282. Epub 2017 May 10.

Psychiatric Brain and Body Research Group, Department of Psychiatry and Psychotherapy, University Hospital JenaJena, Germany.

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 was compared between 21 patients suffering from acute schizophrenia and 21 matched controls. The CCE 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 decreased from 0.553 ± 0.030 at rest to 0.514 ± 0.035 during exercise ( < 0.001). In acute schizophrenia, heart rate, and blood pressure were elevated. Heart rate variability indicated a change of sympathovagal balance. The CCE of patients with schizophrenia was reduced compared to healthy controls (0.546 ± 0.042 vs. 0.507 ± 0.046, < 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.
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http://dx.doi.org/10.3389/fphys.2017.00282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423936PMC
May 2017

ECG derived respiration: comparison of time-domain approaches and application to altered breathing patterns of patients with schizophrenia.

Physiol Meas 2017 04 10;38(4):601-615. Epub 2017 Feb 10.

Department of Medical Engineering, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany.

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   =  0.97, r   =  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.
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http://dx.doi.org/10.1088/1361-6579/aa5febDOI Listing
April 2017

Changes in fMRI activation in anterior hippocampus and motor cortex during memory retrieval after an intense exercise intervention.

Biol Psychol 2017 03 21;124:65-78. Epub 2017 Jan 21.

Psychiatric Brain & Body Research Group Jena, Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.biopsycho.2017.01.003DOI Listing
March 2017

Hippocampal-Brainstem Connectivity Associated with Vagal Modulation after an Intense Exercise Intervention in Healthy Men.

Front Neurosci 2016 7;10:145. Epub 2016 Apr 7.

Psychiatric Brain and Body Research Group, Department of Psychiatry and Psychotherapy, University Hospital Jena Jena, Germany.

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.
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http://dx.doi.org/10.3389/fnins.2016.00145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823309PMC
April 2016

Functional connectivity and network analysis of midbrain and brainstem nuclei.

Neuroimage 2016 07 1;134:53-63. Epub 2016 Apr 1.

Psychiatric Brain & Body Research Group Jena, Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.

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.
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http://dx.doi.org/10.1016/j.neuroimage.2016.03.071DOI Listing
July 2016

Spectral decomposition of pupillary unrest using wavelet entropy.

Annu Int Conf IEEE Eng Med Biol Soc 2015 ;2015:6154-7

Respiratory and cardiovascular rhythms were discovered in the temporal fluctuations of pupil sizes. The mechanism is physiologically explainable but the potential clinical importance of pupillary unrest has not been studied extensively in the past. Here we analyzed the pupillograms of 29 healthy controls on different time scales and correlated the results to established indices of cardiovascular and cardiorespiratory autonomic function. We discovered a clear lateralization of pupil unrest dependencies. Correlation to vagal heart rate regulation and baroreflex sensitivity indicates the significance of the left pupil's fluctuations evaluating the status of the autonomic nervous system.
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http://dx.doi.org/10.1109/EMBC.2015.7319797DOI Listing
September 2016

A data-driven approach to mapping cortical and subcortical intrinsic functional connectivity along the longitudinal hippocampal axis.

Hum Brain Mapp 2016 Feb 5;37(2):462-76. Epub 2015 Nov 5.

Department of Psychiatry and Psychotherapy, Jena University Hospital, Pain and Autonomics Integrative Research, Jena, Germany.

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.
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http://dx.doi.org/10.1002/hbm.23042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867561PMC
February 2016

Hippocampal structure, metabolism, and inflammatory response after a 6-week intense aerobic exercise in healthy young adults: a controlled trial.

J Cereb Blood Flow Metab 2015 Oct 17;35(10):1570-8. Epub 2015 Jun 17.

Psychiatric Brain and Body Research Group Jena, Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.

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.
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http://dx.doi.org/10.1038/jcbfm.2015.125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640322PMC
October 2015

Advances in functional magnetic resonance imaging of the human brainstem.

Neuroimage 2014 Feb 9;86:91-8. Epub 2013 Aug 9.

Pain & Autonomics - Integrative Research (PAIR), Department of Psychiatry and Psychotherapy, University Hospital Jena, Germany.

The brainstem is of tremendous importance for our daily survival, and yet the functional relationships between various nuclei, their projection targets, and afferent regulatory areas remain poorly characterized. The main reason for this lies in the sub-optimal performance of standard neuroimaging methods in this area. In particular, fMRI signals are much harder to detect in the brainstem region compared to cortical areas. Here we describe and validate a new approach to measure activation of brainstem nuclei in humans using standard fMRI sequences and widely available tools for statistical image processing. By spatially restricting an independent component analysis to an anatomically defined brainstem mask, we excluded those areas from the analysis that were strongly affected by physiological noise. This allowed us to identify for the first time intrinsic connectivity networks in the human brainstem and to map brainstem-cortical connectivity purely based on functionally defined regions of interest.
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http://dx.doi.org/10.1016/j.neuroimage.2013.07.081DOI Listing
February 2014