Brain Circuitry Supporting Multi-Organ Autonomic Outflow in Response to Nausea

Abstract

While autonomic outflow is an important co-factor of nausea physiology, central control of this outflow is poorly understood. We evaluated sympathetic (skin conductance level) and cardiovagal (high-frequency heart rate variability) modulation, collected synchronously with functional MRI (fMRI) data during nauseogenic visual stimulation aimed to induce vection in susceptible individuals. Autonomic data guided analysis of neuroimaging data, using a stimulus-based (analysis windows set by visual stimulation protocol) and percept-based (windows set by subjects' ratings) approach. Increased sympathetic and decreased parasympathetic modulation was associated with robust and anti-correlated brain activity in response to nausea. Specifically, greater autonomic response was associated with reduced fMRI signal in brain regions such as the insula, suggesting an inhibitory relationship with premotor brainstem nuclei. Interestingly, some sympathetic/parasympathetic specificity was noted. Activity in default mode network and visual motion areas was anti-correlated with parasympathetic outflow at peak nausea. In contrast, lateral prefrontal cortical activity was anti-correlated with sympathetic outflow during recovery, soon after cessation of nauseogenic stimulation. These results suggest divergent central autonomic control for sympathetic and parasympathetic response to nausea. Autonomic outflow and the central autonomic network underlying ANS response to nausea may be an important determinant of overall nausea intensity and, ultimately, a potential therapeutic target.

Globally conditioned Granger causality in brain–brain and brain–heart interactions: a combined heart rate variability/ultra-high-field (7 T) functional magnetic resonance imaging study

“…In general, our analysis does not show a large number of brain regions directly involved with sympathetic outflow. This is compatible with the idea that, as also stated in [18], the brain regions correlated with sympathetic versus parasympathetic response differ substantially, providing grounds to posit the existence of two distinct CANs with complementary roles. Also, while finding regional concordance in around four subjects (with a maximum of six in one brain region) out of nine may point towards low statistical power, it should be noted that this does not affect the validity of the results, which were detected as significant.…”

The Role of the Endocannabinoid System in the Brain–Gut Axis

“…Unlike vomiting, the brain circuitry responsible for evoking nausea is incompletely understood, but is being elucidated through the use of functional magnetic resonance imaging in humans and through the use of animal models 4, 69, 70 . These studies have associated nausea with activation of many complex neural circuits, involving brainstem, limbic, interoceptive, somatosensory, and cognitive neural networks 69, 70 .…”

“…These studies have associated nausea with activation of many complex neural circuits, involving brainstem, limbic, interoceptive, somatosensory, and cognitive neural networks 69, 70 . In a rat model of nausea, when levels of endocannabinoid were increased systemically by administration of a FAAH inhibitor, nausea was reduced.…”

“…In contrast, inhibition of MAGL, which increases levels of 2-AG, is mediated by CB1. Studies of humans and animals have found the insular cortex to be involved in the perception of nausea (human studies) and physiologic responses to nausea (animal studies) 69, 70, 73 . Activation of the ECS in the insular cortex can regulate the expression of nausea in animals; interestingly, it appears that 2-AG, rather than anandamide, mediates this regulatory control system 71, 74 (Figure 5).…”

What is nausea? A historical analysis of changing views

“…Often the stimulus used in these experiments was a moving visual field (Farmer et al, 2015; Koch, 1999; Sclocco et al, 2015; Sclocco et al, 2016), which is regularly (but erroneously) referred to as “vection.” Vection is an illusion of self-motion, and studies that utilize moving visual fields to induce motion sickness rarely attempt to validate if the stimulus evokes a perception of self-movement (Lawson et al, 2015). Although some experimental studies in humans used agents such as apomorphine or ipecacuanha to induce nausea (Axelsson et al, 2006; Nussey et al, 1988; Proctor et al, 1978; Rowe et al, 1979), employing moving visual fields has two principal advantages: it is not necessary to administer agents that could produce extraneous side effects and the stimulus can be rapidly terminated at the subject’s request.…”