Andy Schumann

Advances in functional magnetic resonance imaging of the human brainstem.

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.

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

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.

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.

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.

Spectral decomposition of pupillary unrest using wavelet entropy.

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 pupils fluctuations evaluating the status of the autonomic nervous system.

Differences of sympathetic and parasympathetic modulation in major depression

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

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

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

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.

Baroreflex Coupling Assessed by Cross-Compression Entropy

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 CCEBRS was compared between 21 patients suffering from acute schizophrenia and 21 matched controls. The CCEBRS 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. CCEBRS decreased from 0.553 ± 0.030 at rest to 0.514 ± 0.035 during exercise (p < 0.001). In acute schizophrenia, heart rate, and blood pressure were elevated. Heart rate variability indicated a change of sympathovagal balance. The CCEBRS of patients with schizophrenia was reduced compared to healthy controls (0.546 ± 0.042 vs. 0.507 ± 0.046, p < 0.01) and revealed a decrease of blood pressure influence on heart rate in patients with schizophrenia. Our results indicate that CCE is suitable for the investigation of linear and non-linear coupling in cardiovascular time series. CCE can quantify causal interactions in short, noisy and non-stationary physiological time series.