Evidence for a Large-Scale Brain System Supporting Allostasis and Interoception in Humans

Abstract

Large-scale intrinsic brain systems have been identified for exteroceptive senses (e.g., sight, hearing, touch). We introduce an analogous system for representing sensations from within the body, called interoception, and demonstrate its relation to regulating peripheral systems in the body, called allostasis. Employing the recently introduced Embodied Predictive Interoception Coding (EPIC) model, we used tract-tracing studies of macaque monkeys, followed by two intrinsic functional magnetic resonance imaging samples (N = 280 and N = 270) to evaluate the existence of an intrinsic allostatic/interoceptive system in the human brain. Another sample (N = 41) allowed us to evaluate the convergent validity of the hypothesized allostatic/interoceptive system by showing that individuals with stronger connectivity between system hubs performed better on an implicit index of interoceptive ability related to autonomic fluctuations. Implications include insights for the brain's functional architecture, dissolving the artificial boundary between mind and body, and unifying mental and physical illness.

Fig 1

We identified key visceromotor cortical regions (in red) that provide cortical control the body’s internal milieu, including the anterior mid cingulate cortex (aMCC; also called dorsal anterior cingulate cortex (dACC), e.g., ^,), pregenual anterior cingulate cortex (pACC), subgenual anterior cingulate cortex (sgACC; for a review of the cingulate, see ), and the ventral anterior insula (vaIns; also called agranular insula^, or posterior orbitofrontal cortex); these regions have a less-developed laminar structure (i.e., they are agranular or dysgranular^,). We also included the dorsal amygdala because it contains the central nucleus which is also involved in visceromotor control (for a review, see ). Primary interoceptive cortex spans the dorsal mid insula (dmIns) to the dorsal posterior insula (dpIns) along a dysgranular to granular gradient (green regions). Barrett & Simmons (2015) summarized preliminary tract-tracing evidence, supporting the EPIC model, that allostasis and interoception are maintained within an integrated system involving limbic cortices (in red) that initiate visceromotor directions to the hypothalamus and brainstem nuclei (e.g., periaqueductal gray, parabrachial nucleus, nucleus of the solitary tract; citations in Table 2) to regulate the autonomic, neuroendocrine, and immune systems (red paths). These visceromotor control regions (less developed laminar organization) also send anticipated sensory consequences of visceromotor changes (as interoceptive prediction signals) to primary interoceptive cortex (more-developed laminar organization; solid blue paths). The incoming sensory inputs from the internal milieu of the body are carried along the vagus nerve and small diameter C and Aδ fibers (dashed green paths) to primary interoceptive cortex in the dorsal sector of the mid to posterior insula (for a review, see ); comparisons between prediction signals and ascending sensory input results in interoceptive prediction error. Current interoceptive predictions can be updated by passing prediction error signals to visceromotor regions (dashed blue paths); prediction errors are learning signals and also adjust subsequent predictions. (For simplicity, ascending feedback to visceromotor regions is not shown). aMCC = anterior midcingulate cortex; dAmy = dorsal amygdala; dmIns = dorsal mid insula; dpIns = dorsal posterior insula; pACC = pregenual anterior cingulate cortex; sgACC = subgenual anterior cingulate cortex; vaIns = ventral anterior insula.

Fig. 2

Eight regions (“seeds”) used to estimate the unified allostasis/interoceptive system connecting the cortical and amygdalar visceromotor regions and primary interoceptive regions. The left column shows the “seed” region for each discovery map on a human brain template. The middle column summarizes the anatomical connectivity derived from anterograde and/or retrograde tracers injected in macaque brains at a location homologous to the human seed (asterisks with blue arrows). The right column shows the human intrinsic connectivity discovery maps depicting all voxels whose time course is correlated with the seed’s (ranging from p < 10⁻⁵ in red to p < 10⁻⁴⁰ in yellow, uncorrected, N = 280). To avoid Type I and Type II errors, which are enhanced with the use of stringent statistical thresholds, we opted to separate signal from random noise using replication, according to the mathematics of classical measurement theory. These results replicated in a second sample, N = 270 participants, indicating that they are reliable and cannot be attributed to random error (Supplementary Figure 1). Functional connectivity to the entire amygdala and other subcortical regions are shown in Fig. 4. Tract tracing figures were adapted with permission as follows: subgenual anterior cingulate cortex (sgACC) via retrograde tracers in Fig 1 of Vogt & Pandya (1987), pregenual ACC (pACC) via retrograde tracers in Fig 5 of Morecraft, et al. (2012), anterior midcingulate cortex (aMCC) via retrograde tracers in Fig 7 of Morecraft, et al. (2012), dorsal amygdala (dAmy) via retrograde tracers in Fig 3 of Aggleton, et al. (1980), medial ventral anterior insula (mvaIns) and lateral ventral anterior insula (lvaIns) via anterograde tracers in Fig 1 of Mesulam & Mufson (1982), dorsal mid insula (dmIns) and dorsal posterior insula (dpIns) via anterograde tracers in Fig 3 of Mesulam & Mufson (1982). The monkey anatomical connectivity figures were colored red to visualize results and some were mirrored to match the orientation of the human brain maps. The figures from Morecraft, et al. (2012) were adapted to show the insula in its lateral view.

Fig. 3

The unified allostatic/interoceptive system is composed of two large-scale intrinsic networks (shown in red and blue) that share several hubs (shown in purple; for coordinates, see Supplementary Table 4). Hubs belonging to the “rich club” are shown in yellow. Rich club hubs figure adapted with permission from van den Heuval & Sporns (2013). All maps result from the sample of 280 participants binarized at p < 10⁻⁵ uncorrected from a one-sample two-tailed t-test. These results replicated in a second sample, N = 270 participants, indicating that they are reliable and cannot be attributed to random error (Supplementary Figure 2). aMCC = anterior midcingulate cortex; dAmy = dorsal amygdala; dpIns = dorsal posterior insula; dmIns = dorsal mid insula; IFG = inferior frontal gyrus; ITG = inferior temporal gyrus; lvaIns = lateral ventral anterior insula; MCC = midcingulate cortex; mvaIns = medial ventral anterior insula; pACC = pregenual anterior cingulate cortex; PHG = parahippocampal gyrus; pMCC = posterior midcingulate cortex; PostCG = postcentral gyrus; sgACC = subgenual anterior cingulate cortex; STS = superior temporal sulcus.

Fig. 4

Subcortical connectivity of the two integrated intrinsic networks within the allostatic/interoceptive system (N = 280; p < 0.05 uncorrected). These results replicated in a second sample of N = 270 (Supplementary Figure 5). PAG = periaqueductal gray; PBN = parabrachial nucleus; V. Striatum = ventral striatum; NTS = nucleus of the solitary tract.

Fig. 5

The default mode and salience networks each support a wide array of psychological functions, as evidenced by a literature review of psychological or other states that are sensitive to functional or structural features of these networks. These results are consistent with the idea that the default mode and salience networks are domain-general networks that support interoception and allostasis, which we propose are key processes that contribute to all psychological functions. Each sub-figure shows a set of results from an independent study, with citations as follows. Default mode network: Social fear, Physical fear, Atypical emotions, Emotion, Emotion concepts, Subjective value, Social affiliation, Chronic pain, Trait judgments, Empathy, Moral judgments, Theory of mind, Reward, Smoking addiction, Memory, Prospection, Association, and Concepts. Salience network: Atypical emotion, Affect, Effortful recall, Executive attention, Atrophy and stress (chronic yellow, current red), Atrophy and mental illness, Interoception, Recognition memory, Bilingualism, Multimodal integration, Thermal pain, Alcohol craving, Empathy, Decision making, Errors, Word form (yellow), Propranolol during aversion, and Hot spots.