The central autonomic network at rest: Uncovering functional MRI correlates of time-varying autonomic outflow.

Peripheral measures of autonomic nervous system (ANS) activity at rest have been extensively employed as putative biomarkers of autonomic cardiac control. However, a comprehensive characterization of the brain-based central autonomic network (CAN) sustaining cardiovascular oscillations at rest is missing, limiting the interpretability of these ANS measures as biomarkers of cardiac control. We evaluated combined cardiac and fMRI data from 34 healthy subjects from the Human Connectome Project to detect brain areas functionally linked to cardiovagal modulation at rest. Specifically, we combined voxel-wise fMRI analysis with instantaneous heartbeat and spectral estimates obtained from inhomogeneous linear point-process models. We found exclusively negative associations between cardiac parasympathetic activity at rest and a widespread network including bilateral anterior insulae, right dorsal middle and left posterior insula, right parietal operculum, bilateral medial dorsal and ventrolateral posterior thalamic nuclei, anterior and posterior mid-cingulate cortex, medial frontal gyrus/pre-supplementary motor area. Conversely, we found only positive associations between instantaneous heart rate and brain activity in areas including frontopolar cortex, dorsomedial prefrontal cortex, anterior, middle and posterior cingulate cortices, superior frontal gyrus, and precuneus. Taken together, our data suggests a much wider involvement of diverse brain areas in the CAN at rest than previously thought, which could reflect a differential (both spatially and directionally) CAN activation according to the underlying task. Our insight into CAN activity at rest also allows the investigation of its impairment in clinical populations in which task-based fMRI is difficult to obtain (e.g., comatose patients or infants).This work was supported by the US National Institutes for Health (NIH), Office of the Director (OT2-OD023867 to VN); National Center for Complementary and Integrative Health (NCCIH), NIH (P01-AT009965, R61-AT009306, R33-AT009306, R01-AT007550 to VN); the National Institute for Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH (R01-AR064367 to VN); the Medical Research Council (MRC), UK (MR/P01271X/1 to LP); the American Heart Association (16GRNT26420084 to RB)

Dominant hemisphere lateralization of cortical parasympathetic control as revealed by frontotemporal dementia.

The brain continuously influences and perceives the physiological condition of the body. Related cortical representations have been proposed to shape emotional experience and guide behavior. Although previous studies have identified brain regions recruited during autonomic processing, neurological lesion studies have yet to delineate the regions critical for maintaining autonomic outflow. Even greater controversy surrounds hemispheric lateralization along the parasympathetic-sympathetic axis. The behavioral variant of frontotemporal dementia (bvFTD), featuring progressive and often asymmetric degeneration that includes the frontoinsular and cingulate cortices, provides a unique lesion model for elucidating brain structures that control autonomic tone. Here, we show that bvFTD is associated with reduced baseline cardiac vagal tone and that this reduction correlates with left-lateralized functional and structural frontoinsular and cingulate cortex deficits and with reduced agreeableness. Our results suggest that networked brain regions in the dominant hemisphere are critical for maintaining an adaptive level of baseline parasympathetic outflow

Causal influence of brainstem response to transcutaneous vagus nerve stimulation on cardiovagal outflow

background: the autonomic response to transcutaneous auricular vagus nerve stimulation (taVNS) has been linked to the engagement of brainstem circuitry modulating autonomic outflow. However, the physiological mechanisms supporting such efferent vagal responses are not well understood, particularly in humans. hypothesis: we present a paradigm for estimating directional brain-heart interactions in response to taVNS. We propose that our approach is able to identify causal links between the activity of brainstem nuclei involved in autonomic control and cardiovagal outflow. methods: we adopt an approach based on a recent reformulation of granger causality that includes permutation-based, nonparametric statistics. The method is applied to ultrahigh field (7T) functional magnetic resonance imaging (fMRI) data collected on healthy subjects during taVNS. results: our framework identified taVNS-evoked functional brainstem responses with superior sensitivity compared to prior conventional approaches, confirming causal links between taVNS stimulation and fMRI response in the nucleus tractus solitarii (NTS). furthermore, our causal approach elucidated potential mechanisms by which information is relayed between brainstem nuclei and cardiovagal, i.e., high-frequency heart rate variability, in response to taVNS. Our findings revealed that key brainstem nuclei, known from animal models to be involved in cardiovascular control, exert a causal influence on taVNS-induced cardiovagal outflow in humans. conclusion: our causal approach allowed us to noninvasively evaluate directional interactions between fMRI BOLD signals from brainstem nuclei and cardiovagal outflow

EEG cortical activity and connectivity correlates of early sympathetic response during cold pressor test

Previous studies have identified several brain regions involved in the sympathetic response and its integration with pain, cognition, emotions and memory processes. However, little is known about how such regions dynamically interact during a sympathetic activation task. In this study, we analyzed EEG activity and effective connectivity during a cold pressor test (CPT). A source localization analysis identified a network of common active sources including the right precuneus (r-PCu), right and left precentral gyri (r-PCG, l-PCG), left premotor cortex (l-PMC) and left anterior cingulate cortex (l-ACC). We comprehensively analyzed the network dynamics by estimating power variation and causal interactions among the network regions through the direct directed transfer function (dDTF). A connectivity pattern dominated by interactions in α (8–12) Hz band was observed in the resting state, with r-PCu acting as the main hub of information flow. After the CPT onset, we observed an abrupt suppression of such α -band interactions, followed by a partial recovery towards the end of the task. On the other hand, an increase of δ -band (1–4) Hz interactions characterized the first part of CPT task. These results provide novel information on the brain dynamics induced by sympathetic stimuli. Our findings suggest that the observed suppression of α and rise of δ dynamical interactions could reflect non-pain-specific arousal and attention-related response linked to stimulus’ salience

Representation of Somatosensory Afferents in the Cortical Autonomic Network

The relationship between somatosensory stimulation and the autonomic nervous system has been established with effects on heart rate (HR) and sympathetic tone. However, the involvement of the cortical autonomic network (CAN) during muscle sensory afferent stimulation has not been identified. The main objective of the research in this dissertation was to determine the representation of somatosensory afferents in the CAN and their physiologic impact on cardiovascular control. Somatosensory afferent activation was elicited by electrical stimulation of type I and II afferents (sub-motor threshold) and type III and IV afferents (motor threshold), and CAN patterns were assessed using blood-oxygenation level-dependent functional magnetic resonance imaging. Study 1 (Chapter 2) established CAN regions associated with sub-motor stimulation including the ventral medial prefrontal cortex (vMPFC), subgenual anterior cingulate cortex (sACC), and posterior insula, along with a trend towards increased heart rate variability (HRV). Motor threshold stimulation was associated with activation in the posterior insula. Having established the CAN regions affected by sensory afferent input, diffusion tensor imaging was used (Chapter 3) to establish structural connections between the cortical regions associated with functional cardiovascular control. We identified two discrete patterns of white matter connectivity between the anterior insula-sACC and posterior insula-posterior cingulate cortex, suggesting that a structural network may underlie functional roles in autonomic regulation and sensory processing. As somatosensory stimulation had modest impact on cardiovascular control under baseline conditions, Study 3 (Chapter 4) aimed to establish the effects of somatosensory stimulation during baroreceptor unloading (lower-body negative pressure, LBNP) on muscle sympathetic nerve activity (MSNA) and cortical activity. Sensory stimulation during LBNP led to an attenuated increase in MSNA burst frequency, as well as absent activity in the right insula and dorsal ACC, supporting the sympatho-excitatory role of these regions. No effect of somatosensory stimulation during chemoreflex-mediated sympatho-excitation was observed on MSNA, while right insular and dorsal ACC activities were maintained. Overall, the results of these studies provide evidence of somatosensory representation within the CAN regions that are anatomically linked, and highlight a role for type I and II sensory afferents in modulating autonomic outflow in a manner that depends upon baroreceptor loading

Somatosensory stimulation modulates heart rate variability changes induced by isometric handgrip exercise

Functional imaging reveals overlapping forebrain and basal ganglia regions associated with heart rate (HR) and heart rate variability (HRV) regulation. Somatosensory stimulation (STIM) and isometric handgrip (HG) were used to test the hypotheses that a) STIM would modulate HG-induced changes to HR and HRV, and b) HG+STIM would produce different cortical activation relative to HG alone (n=12). During STIM, high-frequency (HF)-HRV increased (p\u3c0.05), whereas HR did not change. During HG, HF-HRV decreased (p\u3c0.01) while HR increased (p\u3c0.001). HG+STIM reversed the HG-induced change in HF-HRV (p\u3c0.01). However, the HR response to HG remained unaffected. HG increased insular activation, while ventral medial prefrontal cortex (vMPFC) activity decreased. HG+STIM produced similar vMPFC deactivation. However, insular activation was no longer evident. These data indicate that somatosensory inputs through STIM can modulate HG-induced changes to HF-HRV. Different insular activations during HG versus HG+STIM suggest afferent signals to the insula may inhibit descending motor signals affecting HF-HRV

Functional assessment of bidirectional cortical and peripheral neural control on heartbeat dynamics: A brain-heart study on thermal stress

The study of functional Brain-Heart Interplay (BHI) from non-invasive recordings has gained much interest in recent years. Previous endeavors aimed at understanding how the two dynamical systems exchange information, providing novel holistic biomarkers and important insights on essential cognitive aspects and neural system functioning. However, the interplay between cardiac sympathovagal and cortical oscillations still has much room for further investigation. In this study, we introduce a new computational framework for a functional BHI assessment, namely the Sympatho-Vagal Synthetic Data Generation Model, combining cortical (electroencephalography, EEG) and peripheral (cardiac sympathovagal) neural dynamics. The causal, bidirectional neural control on heartbeat dynamics was quantified on data gathered from 26 human volunteers undergoing a cold-pressor test. Results show that thermal stress induces heart-to-brain functional interplay sustained by EEG oscillations in the delta and gamma bands, primarily originating from sympathetic activity, whereas brain-to-heart interplay originates over central brain regions through sympathovagal control. The proposed methodology provides a viable computational tool for the functional assessment of the causal interplay between cortical and cardiac neural control

Cortical Autonomic Alterations with Hypertension

Objective: This study tested whether the medial prefrontal cortex (MPFC) is differentially involved in human cardiovagal control in normotensive (NT) versus hypertensive (HT) subjects. Design: Functional magnetic resonance imaging was combined with measures of heart rate (HR) and baroreflex sensitivity (BRS) during a 30-sec static handgrip (HG; 30% maximal strength) task. Results: Baseline HR was higher in HT (68±3 bpm) versus NT (59±2 bpm). Cardiovagal baroreflex sensitivity was lower in HT (6.8±1.7 msec/mniHg) versus NT (16.4±2.2 msec/mmHg). During HG, HR increased similarly in HT (2±1 bpm) and NT (4±1 bpm). In NT, the HR response was associated with deactivation in the MPFC. MPFC activity did not change in HT. In 11 of the total 23 subjects, HR increased \u3e 3 bpm and MPFC deactivation was correlated with the HR time course. Conclusions: Overall, hypertension appears to be equivalent to normotension in terms of the HR response to HG and the MPFC-HR associatio

Functional assessment of bidirectional cortical and peripheral neural control on heartbeat dynamics: A brain-heart study on thermal stress

The study of functional Brain-Heart Interplay (BHI) from non-invasive recordings has gained much interest in recent years. Previous endeavors aimed at understanding how the two dynamical systems exchange information, providing novel holistic biomarkers and important insights on essential cognitive aspects and neural system functioning. However, the interplay between cardiac sympathovagal and cortical oscillations still has much room for further investigation. In this study, we introduce a new computational framework for a functional BHI assessment, namely the Sympatho-Vagal Synthetic Data Generation Model, combining cortical (electroencephalography, EEG) and peripheral (cardiac sympathovagal) neural dynamics. The causal, bidirectional neural control on heartbeat dynamics was quantified on data gathered from 26 human volunteers undergoing a cold-pressor test. Results show that thermal stress induces heart-to-brain functional interplay sustained by EEG oscillations in the delta and gamma bands, primarily originating from sympathetic activity, whereas brain-to-heart interplay originates over central brain regions through sympathovagal control. The proposed methodology provides a viable computational tool for the functional assessment of the causal interplay between cortical and cardiac neural control