Publications by authors named "Feliberto de la Cruz"

23 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

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

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

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

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

Checking and washing rituals are reflected in altered cortical thickness in obsessive-compulsive disorder.

Cortex 2019 08 26;117:147-156. Epub 2019 Mar 26.

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

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.
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http://dx.doi.org/10.1016/j.cortex.2019.03.012DOI Listing
August 2019

Resilience and cortical thickness: a MRI study.

Eur Arch Psychiatry Clin Neurosci 2020 Aug 12;270(5):533-539. Epub 2018 Dec 12.

Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.

Resilience is defined as the psychological resistance which enables the processing of stress and adverse life events and thus constitutes a key factor for the genesis of psychiatric illness. However, little is known about the morphological correlates of resilience in the human brain. Hence, the aim of this study is to examine the neuroanatomical expression of resilience in healthy individuals. 151 healthy subjects were recruited and had to complete a resilience-specific questionnaire (RS-11). All of them underwent a high-resolution T1-weighted MRI in a 3T scanner. Fine-grained cortical thickness was analyzed using FreeSurfer. We found a significant positive correlation between the individual extent of resilience and cortical thickness in a right hemispherical cluster incorporating the lateral occipital cortex, the fusiform gyrus, the inferior parietal cortex as well as the middle and inferior temporal cortex, i.e., a reduced resilience is associated with a decreased cortical thickness in these areas. We lend novel evidence for a direct linkage between psychometric resilience and local cortical thickness. Our findings in a sample of healthy individuals show that a lower resilience is associated with a lower cortical thickness in anatomical areas are known to be involved in the processing of emotional visual input. These regions have been demonstrated to play a role in the pathogenesis of stress and trauma-associated disorders. It can thus be assumed that neuroanatomical variations in these cortical regions might modulate the susceptibility for the development of stress-related disorders.
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http://dx.doi.org/10.1007/s00406-018-0963-6DOI Listing
August 2020

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

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

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

Treatment Associated Changes of Functional Connectivity of Midbrain/Brainstem Nuclei in Major Depressive Disorder.

Sci Rep 2017 08 17;7(1):8675. Epub 2017 Aug 17.

Psychiatric Brain and Body Research Group Jena, Department of Psychiatry and Psychotherapy, University Hospital Jena, Philosophenweg 3, Jena, 07743, Germany.

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.
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http://dx.doi.org/10.1038/s41598-017-09077-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561091PMC
August 2017

Detecting spatially highly resolved network modules: a multi subject approach.

Annu Int Conf IEEE Eng Med Biol Soc 2016 Aug;2016:5481-5484

The connectivity analysis of spatially highly resolved data results in networks comprising an immense number of nodes and edges which makes it hard or even impossible to investigate the high-dimensional (HD) network as a whole. A solution to this problem is offered by a connectivity-based segmentation of the HD networks into subsets of functionally similar nodes (network modules) that exhibit pronounced interaction. However, an investigation of the results at group level is problematic as identified modules are not assigned to each other across different subjects. In this work, we propose a rearrangement of the subject-specific networks into an integrative tensor which is subsequently decomposed into additive factors. This reorganization provides subject-independent networks together with subject-specific loadings enabling a group-wide segmentation of the resulting networks at the large scale.
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http://dx.doi.org/10.1109/EMBC.2016.7591967DOI Listing
August 2016

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

Resting state functional connectivity of the hippocampus along the anterior-posterior axis and its association with glutamatergic metabolism.

Cortex 2016 08 22;81:104-17. Epub 2016 Apr 22.

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

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.
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http://dx.doi.org/10.1016/j.cortex.2016.03.022DOI Listing
August 2016

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

Evidence for alterations of cortical folding in anorexia nervosa.

Eur Arch Psychiatry Clin Neurosci 2017 Feb 17;267(1):41-49. Epub 2015 Dec 17.

Department of Psychiatry and Psychotherapy, Jena University Hospital, Philosophenweg 3, 07740, Jena, Germany.

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.
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http://dx.doi.org/10.1007/s00406-015-0666-1DOI Listing
February 2017

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

Structural and functional differences in the cingulate cortex relate to disease severity in anorexia nervosa.

J Psychiatry Neurosci 2015 Jul;40(4):269-79

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

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478060PMC
http://dx.doi.org/10.1503/jpn.140193DOI Listing
July 2015

Structural and functional dysconnectivity of the fronto-thalamic system in schizophrenia: a DCM-DTI study.

Cortex 2015 May 2;66:35-45. Epub 2015 Mar 2.

Department of Neuroradiology, Klinikum rechts der Isar, Technische Universität München TUM, Munich, Germany; TUM-Neuroimaging Center of Klinikum rechts der Isar, Technische Universität München TUM, Munich, Germany.

Evidence suggests that cognitive deficits are a core feature of schizophrenia. The concept of "cognitive dysmetria" has been introduced to characterize disintegration of fronto-thalamic-cerebellar circuitry which constitutes a key network for a variety of neuropsychological symptoms in schizophrenia. The present multimodal study aimed at investigating effective and structural connectivity of the fronto-thalamic circuitry in schizophrenia. fMRI effective connectivity analysis using dynamic causal modeling (DCM) and diffusion tensor imaging (DTI) were combined to examine cognitive control processes in 38 patients with schizophrenia and 40 matched healthy controls. Significantly lower fractional anisotropy (FA) was detected in patients in the right anterior limb of the internal capsule (ALIC), the right thalamus and the right corpus callosum. During Stroop task performance patients demonstrated significantly lower activation relative to healthy controls in a predominantly right lateralized fronto-thalamo-cerebellar network. An abnormal effective connectivity was observed in the right connections between thalamus, anterior cingulate and dorsolateral prefrontal cortex. FA in the ALIC was significantly correlated with the thalamic BOLD signal, cognitive performance and fronto-thalamic effective connectivity in patients. Present data provide evidence for the notion of a structural and functional defect in the fronto-thalamo-cerebellar circuitry, which may be the basis of specific cognitive impairments in schizophrenia.
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http://dx.doi.org/10.1016/j.cortex.2015.02.004DOI Listing
May 2015

Neurophysiological, metabolic and cellular compartments that drive neurovascular coupling and neuroimaging signals.

Front Neuroenergetics 2013 28;5. Epub 2013 Mar 28.

Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández San Juan de Alicante, Spain.

Complete understanding of the mechanisms that coordinate work and energy supply of the brain, the so called neurovascular coupling, is fundamental to interpreting brain energetics and their influence on neuronal coding strategies, but also to interpreting signals obtained from brain imaging techniques such as functional magnetic resonance imaging. Interactions between neuronal activity and cerebral blood flow regulation are largely compartmentalized. First, there exists a functional compartmentalization in which glutamatergic peri-synaptic activity and its electrophysiological events occur in close proximity to vascular responses. Second, the metabolic processes that fuel peri-synaptic activity are partially segregated between glycolytic and oxidative compartments. Finally, there is cellular segregation between astrocytic and neuronal compartments, which has potentially important implications on neurovascular coupling. Experimental data is progressively showing a tight interaction between the products of energy consumption and neurotransmission-driven signaling molecules that regulate blood flow. Here, we review some of these issues in light of recent findings with special attention to the neuron-glia interplay on the generation of neuroimaging signals.
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http://dx.doi.org/10.3389/fnene.2013.00003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610078PMC
April 2013