Network Architecture Underlying Basal Autonomic Outflow: Evidence from Frontotemporal Dementia

Abstract

The salience network is a distributed neural system that maintains homeostasis by regulating autonomic nervous system activity and social-emotional function. Here we examined how within-network connectivity relates to individual differences in human (including males and females) baseline parasympathetic and sympathetic nervous activity. We measured resting autonomic nervous system physiology in 24 healthy controls and 23 patients with behavioral variant frontotemporal dementia (bvFTD), a neurodegenerative disease characterized by baseline autonomic deficits. Participants also underwent structural and task-free fMRI. First, we used voxel-based morphometry to determine whether salience network atrophy was associated with lower baseline respiratory sinus arrhythmia (a parasympathetic measure) and skin conductance level (a sympathetic measure) in bvFTD. Next, we examined whether functional connectivity deficits in 21 autonomic-relevant, salience network node-pairs related to baseline autonomic dysfunction. Lower baseline respiratory sinus arrhythmia was associated with smaller volume in left ventral anterior insula (vAI), weaker connectivity between bilateral vAI and bilateral anterior cingulate cortex (ACC), and stronger connectivity between bilateral ACC and bilateral hypothalamus/amygdala. Lower baseline skin conductance level, in contrast, was associated with smaller volume in inferior temporal gyrus, dorsal mid-insula, and hypothalamus; weaker connectivity between bilateral ACC and right hypothalamus/amygdala; and stronger connectivity between bilateral dorsal anterior insula and periaqueductal gray. Our results suggest that baseline parasympathetic and sympathetic tone depends on the integrity of lateralized salience network hubs (left vAI for parasympathetic and right hypothalamus/amygdala for sympathetic) and highly calibrated ipsilateral and contralateral network connections. In bvFTD, deficits in this system may underlie resting parasympathetic and sympathetic disruption. The salience network maintains homeostasis and regulates autonomic nervous system activity. Whether within-network connectivity patterns underlie individual differences in resting parasympathetic and sympathetic nervous system activity, however, is not well understood. We measured baseline autonomic nervous system activity in healthy controls and patients with behavioral variant frontotemporal dementia, a neurodegenerative disease characterized by resting autonomic deficits, and probed how salience network dysfunction relates to diminished parasympathetic and sympathetic outflow. Our results indicate that baseline parasympathetic and sympathetic tone are the product of complex, opposing intranetwork nodal interactions and depend on the integrity of highly tuned, lateralized salience network hubs (i.e., left ventral anterior insula for parasympathetic activity and right hypothalamus/amygdala for sympathetic activity).

Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology

“…VENs and fork cells express the alpha 1a adrenergic receptor (ADRA1A), the GABA-A receptor theta subunit (GABRQ), and the vesicular monoamine transporter (VMAT2), suggesting a role for VENs and fork cells in autonomic control circuits [20]. Thus, autonomic dysfunction in bvFTD, which we have strongly linked to ACC and FI degeneration and dysfunction [30, 72], may be initiated by FI VEN and fork cell dysfunction and degeneration before spreading throughout the system to undermine some of our most specialized social-emotional capacities.…”

Ventromedial prefrontal cortex connectivity during and after psychological stress in women

“…In particular, stress appeared to increase connectivity between the vmPFC and ventral attention network, the latter comprising the anterior insula and dorsal anterior cingulate (Yeo et al, ). This network is also referred to as the salience network (Seeley et al, ) and is implicated in autonomic regulation (Jennings et al, ; Sturm et al, ; Young et al, ). Invasive studies in humans, moreover, complement functional neuroimaging studies to suggest roles for the insula and dorsal anterior cingulate in autonomic cardiovascular control (Kim et al, ; Oppenheimer & Cechetto, ).…”

The Salience Network: A Neural System for Perceiving and Responding to Homeostatic Demands

“…They went on to show that this region, near the locus ceruleus and adjacent medial parabrachial nucleus (both key nodes for autonomic integration), featured the ACC and frontoinsula as its major cortical functional connections. Many groups, including ours, have highlighted the role of the salience network in autonomic processing (Critchley et al, 2011;Beissner et al, 2013;Guo et al, 2016;Sturm et al, 2018), but it has proved challenging to disentangle representations related to homeostatic salience from those that drive autonomic responses to that salience. Indeed, in a remarkable study of awake, behaving patients with epilepsy who underwent presurgical monitoring and electrophysiological mapping, direct stimulation of the ACC elicited not only an internal sense of a looming challenge but also heart rate acceleration and, perhaps most strikingly, the will to act and persevere in response to the perceived challenge (Parvizi et al, 2013).…”