Feliberto de la Cruz

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

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.

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

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.

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

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.

Evidence for alterations of cortical folding in anorexia nervosa

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.

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

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.

Resting-state functional connectivity of neurotransmitter producing sites in female patients with borderline personality disorder

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

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

ABSTRACT 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 individuals 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. HighlightsHigh‐resolution fMRI and advanced brainstem analyses.Respiratory signal and cardiac noise correction.Involvement of the dopaminergic neurotransmitter system in error processing.Autonomic parameters contain predictive information on performance.Autonomic indices correlate with brain regions involved in behavioral monitoring.

The Use of Physiological Signals in Brainstem/Midbrain fMRI

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 (R2 = 0.464, p < 0.05). When Stroop stimuli were modulated by pupillary responses, we observed a significant activation of the LC in the Stroop interference contrast. Thus, we demonstrated the beneficial effect of PNC on data quality and statistical results when analyzing neuronal responses to a cognitive task. Parametric modulation of task events with pupillary responses improved the model of LC BOLD activations in the Stroop interference contrast.

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

&NA; 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 subjects 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. HighlightsThe shape of the cardiac response function strongly depends on the mean HR.For heart rates below and above 68 bpm two distinct CRF shapes were detected.We recommend using a CRF based on the mean HR of subjects.

Detecting spatially highly resolved network modules: A multi subject approach

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.