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

Abstract

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.

Keywords: brainstem; central autonomic network; cognition; exercise; heart; hippocampus; physical fitness; vagal.

Figure 1

Flow chart of the study.

Figure 2

The calculation of the vagal threshold is depicted using data from one subject for illustration. The deflection point is the point in time at which no subsequent decline in heart rate variability occurs. DP was determined when the heart rate variability dropped below a threshold (mean value of the heart rate variability plus 3 times the standard deviation during the last 30% of the “exercise time”). In this time period, the decline in heart rate variability was completed and there were almost no variations in heart rate variability observed.

Figure 3

Exercise-induced changes of heart rate (A), RMSSD (root mean square of successive heart beat interval differences, B) and vagal threshold (C) are displayed. ^*p < 0.05; n.s., not significant.

Figure 4

Significant exercise-induced changes of the functional connectivity of the right aHC at the whole-brain level. On the right-hand side: significant Group (exercise vs. control group) × Time (before vs. after intervention) interaction (post-hoc t-test) for the functional connectivity (FC) of the right anterior hippocampus (p < 0.001 uncorr, p < 0.05 cluster-level FWE corr.) at the whole-brain level. The box chart depicts significant changes in the FC between the right aHC and VMPFC/perigenual ACC (pACC). On the left-hand side: the correlations between the time series derived from the right aHC and the VMPFC/pACC are depicted in one subject before and after physical exercise intervention. DST, dorsal striatum; VMPFC, ventromedial prefrontal cortex; pACC, perigenual anterior cingulate cortex.

Figure 5

Significant exercise-induced changes of the functional connectivity of the right aHC at the brainstem/cerebellum level. Significant Group (exercise vs. control group) × Time (before vs. after intervention) interaction (post-hoc t-test) for the functional connectivity of the right anterior hippocampus (p < 0.001 uncorr, p < 0.05 cluster-level FWE corr.) at the brainstem/cerebellum level as preprocessed with the SUIT toolbox. The box chart depicts significant changes in the FC between the right aHC and a significant cluster located in the dorsomedial medulla, where a number of autonomic centers are located and which is in the vicinity of the previously described dorsal vagal complex (DVC, Blessing, 1997).

Figure 6

Scatterplot of the significant negative correlation between exercise-induced changes in the functional connectivity from the right aHC to DVC and RMSSD. On the right-hand side, the scatterplot illustrates the significant negative correlation in the exercise group between post-pre differences of functional connectivity of the right aHC to DVC and post-pre differences in RMSSD, which was measured during the resting state fMRI. RMSSD is considered as a parameter of heart rate variability, reflecting the integrity of vagus nerve-mediated autonomic control of the heart. On the left-hand side, a figure of the anatomical position of the autonomic medullary centers from the Duvernoy's Atlas of the Human Brain Stem and Cerebellum is depicted, corresponding to the significant cluster (DVC) of decreased function connectivity from the aHC after exercise. NST, nucleus of the solitary tract (a: rostral portion, b: midportion, c: caudal portion); COMM.N, commissural nucleus; DMV, dorsal motor nucleus of the vagus; AP, area postrema; DLF, dorsal longitudinal fasciculus; VLM, ventrolateral medullary center (r: rostral portion, c: caudal portion); N.AM, nucleus ambiguous; SAL, salivatory nucleus; MPN, medial parabrachial nucleus; LPN, lateral parabrachial nucleus; KF, nucleus of Kölliker-Fuse; EW, Edinger-Westphal. “With kind permission from Springer Science+Business Media: Duvernoy's Atlas of the Human Brain Stem and Cerebellum, Section III: Major Functions of the Human Brain Stem, 2009, page 115, Naidich, T.P., Duvernoy, H.M, Delman, B.N., Sorensen, A.G., Kollias, S.S., Haacke, E.M., Figure 3.13.”