The Brain Circuitry Underlying the Temporal Evolution of Nausea in Humans

Abstract

Nausea is a universal human experience. It evolves slowly over time, and brain mechanisms underlying this evolution are not well understood. Our functional magnetic resonance imaging (fMRI) approach evaluated brain activity contributing to and arising from increasing motion sickness. Subjects rated transitions to increasing nausea, produced by visually induced vection within the fMRI environment. We evaluated parametrically increasing brain activity 1) precipitating increasing nausea and 2) following transition to stronger nausea. All subjects demonstrated visual stimulus-associated activation (P < 0.01) in primary and extrastriate visual cortices. In subjects experiencing motion sickness, increasing phasic activity preceding nausea was found in amygdala, putamen, and dorsal pons/locus ceruleus. Increasing sustained response following increased nausea was found in a broader network including insular, anterior cingulate, orbitofrontal, somatosensory and prefrontal cortices. Moreover, sustained anterior insula activation to strong nausea was correlated with midcingulate activation (r = 0.87), suggesting a closer linkage between these specific regions within the brain circuitry subserving nausea perception. Thus, while phasic activation in fear conditioning and noradrenergic brainstem regions precipitates transition to strong nausea, sustained activation following this transition occurs in a broader interoceptive, limbic, somatosensory, and cognitive network, reflecting the multiple dimensions of this aversive commonly occurring symptom.

Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

“…Nevertheless, the neuronal control of nausea is poorly understood but is clearly distinctive from the emesis control. A recent human functional magnetic resonance imaging (fMRI) study suggested that sustained nausea activates an extensive network of limbic, interoceptive and cognitive brain areas including the insular cortex and the anterior cingulate (Napadow et al 2013). Correlation between the activity of the insular cortex and midcingulate predicted the development of strong nausea (Napadow et al 2013).…”

“…A recent human functional magnetic resonance imaging (fMRI) study suggested that sustained nausea activates an extensive network of limbic, interoceptive and cognitive brain areas including the insular cortex and the anterior cingulate (Napadow et al 2013). Correlation between the activity of the insular cortex and midcingulate predicted the development of strong nausea (Napadow et al 2013). In addition, a recent PET study demonstrated that nausea as a premonitory symptom during nitroglycerin‐induced migraine is centrally driven by activation of the PAG and rostral dorsal medulla or regions that control their activity (Maniyar et al 2014).…”

What the Gut Can Teach Us About Migraine

“…Nausea was also the only individual symptom statistically associated with delayed gastric emptying in 50 children studied [50]. Recent functional MRI findings suggest increasing phasic activity in the amygdala, putamen, and dorsal pons/locus coeruleus preceding nausea with increasing sustained response with increased nausea with activation of the insular, anterior cingulate, orbitofrontal, somatosensory, and prefrontal cortices [51].…”

Suppression of acute and anticipatory nausea by peripherally restricted fatty acid amide hydrolase inhibitor in animal models: role of PPARα and CB1 receptors

“…Sticht et al (2016) demonstrated that endocannabinoid regulation of nausea in the IIC, a cortical site responsible for the experience of nausea (Penfield and Faulk, 1955;Napadow et al, 2013), is mediated by the action of 2-AG, not AEA, on CB 1 receptors. Intra-IIC administration of the MAGL inhibitor MJN110 (which elevated 2-AG) suppressed acute LiClinduced nausea as expressed by conditioned gaping reactions, but the FAAH inhibitors, PF8345 and URB597, did not.…”

“…The action of AEA, OEA and PEA can be prolonged by up to 24 h by pharmacological inhibition of their degradation by FAAH, and the action of 2-AG can be prolonged by up to 24 h by MAGL inhibition (Cravatt et al, 1996), providing effective strategies for reducing acute and anticipatory nausea as assessed by the rat gaping models (Rock et al, 2014;Sticht et al, 2015). Sticht et al (2016) demonstrated that elevation of 2-AG by MAGL inhibition in the interoceptive insular cortex (IIC), a cortical site responsible for the experience of nausea (Penfield and Faulk, 1955;Napadow et al, 2013), reduces nauseainduced conditioned gaping in rats. However, the site of action of the anti-nausea effects of FAAH inhibition remains unknown because FAAH inhibition in the IIC neither reduced nausea-induced conditioned gaping nor elevated AEA (Sticht et al, 2016), but systemic administration of the FAAH inhibitor, PF3845 (Ahn et al, 2009), suppressed acute nausea , and both PF3845 and URB597 reduced anticipatory nausea (Rock et al, 2008.…”