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 novel insights for the brain’s functional architecture, dissolving the artificial boundary between mind and body, and unifying mental and physical illness.
The brain contains intrinsic systems for processing exteroceptive sensory inputs from the world, such as vision, audition, and proprioception/touch (e.g., 1). Accumulating evidence indicates that these systems work via the principles of predictive coding (e.g., 2–7), where sensations are anticipated and then corrected by sensory inputs from the world. The brain, as a generative system, models the world by predicting, rather than reacting to, sensory inputs. Predictions guide action and perception by continually constructing possible representations of the immediate future based on their prior probabilities relative to the present context8,9. We and others have recently began studying the hypothesis that ascending sensory inputs from the organs and systems within the body’s internal milieu are similarly anticipated and represented (i.e., autonomic visceral and vascular function, neuroendocrine fluctuations, and neuroimmune function)10−15. These sensations are referred to as interoception16–18. Engineering studies of neural design19, along with physiological evidence20, indicate that the brain continually anticipates the body’s energy needs in an efficient manner and prepares to meet those needs before they arise (e.g., movements to cool the body’s temperature before it gets too hot). This process is called allostasis19−21. Allostasis is not a condition or state of the body – it is the process by which the brain efficiently maintains energy regulation in the body. Allostasis is defined in terms of prediction, and recent theories propose that the prediction of interoceptive signals is necessary for successful allostasis (e.g., 10,15,22–24). Thus, in addition to the ascending pathways and brain regions important for interoception (e.g., 16,17,25,26), recent theoretical discussions (e.g.,11) have proposed the existence of a distributed intrinsic allostatic/interoceptive system in the brain (analogous to the exteroceptive systems). A full investigation of the predictive nature of an allostatic/interoceptive brain system requires multiple studies under various conditions. Here, we begin this line of research by identifying the anatomical and functional substrates for a unified allostatic/interoceptive system in the human brain and reporting an association between connectivity within this system and individual differences in interoceptive-related behavior during allostatically-relevant events.
In this paper, we first review tract-tracing studies of non-human animals that provide the anatomical substrate for our hypothesis that the brain contains a unified, intrinsic system for allostasis and interoception. Next, we present evidence of this hypothesized system in humans using functional connectivity analyses on three samples of task-independent (i.e., “resting state”) functional magnetic resonance imaging (fMRI) data (also called “intrinsic” connectivity). We then present brain-behavior evidence to validate the hypothesized allostatic/interoceptive system by using an implicit measure of interoception during an allostatically challenging task. Finally, we summarize empirical evidence to show that this allostatic/interoceptive system is a domain-general system that supports a wide range of psychological functions including interoception, emotion, memory, reward, cognitive control, etc.27,28. That is, whatever else this system might be doing – remembering, directing attention, etc., – they are also predictively regulating the body’s physiological systems in the service of allostasis to achieve those functions22.
The novelty of our work is the synthesis of anatomical and functional brain studies that together evidence a single brain system – comprised of the salience and default mode networks – that supports not just allostasis but a wide range of psychological functions (emotion, pain, memory, decision-making, etc.) that can all be explained by their reliance on allostasis. To our knowledge, this evidence and our simple yet powerful explanation has not been presented despite the fact that many functional imaging studies show that the salience and default mode networks support a wide range of psychological functions (i.e., they are domain general; e.g., 29; for review, see 27,28). Our paper provides the groundwork for a theoretical and empirical framework for making sense of these findings in an anatomically principled way. Our key hypotheses and results are summarized in Table 1.
Anatomical evidence supporting the proposed allostatic/interoceptive system
Over three decades of tract-tracing studies of the macaque monkey brain clearly demonstrate an anatomical substrate for the proposed flow of the brain’s prediction and prediction error signals. Specifically, anatomical studies indicate a flow of information within the laminar gradients of these cortical regions according to the structural model of corticocortical connections developed by Barbas colleagues (30; for a review, see 31). In addition, the structural model of corticocortical connections have been seamlessly integrated with a predictive coding framewor11,12. Unlike other models of information flow that work in specific regions of cortex, the structural model successfully predicts information flow in frontal, temporal, parietal, and occipital cortices32–36. Accordingly, prediction signals flow from regions with less laminar development (e.g., agranular regions) to regions with greater laminar development (e.g., granular regions), whereas prediction error signals flow in the other direction. In our recently developed theory of interoception, called the Embodied Predictive Interoception Coding (EPIC) model11, we integrated Friston’s active inference approach to predictive coding37–39 with Barbas’s structural model to hypothesize that less-differentiated agranular and dysgranular visceromotor cortices in the cingulate cortex and anterior insula initiate visceromotor predictions through their cascading connections to the hypothalamus, the periaqueductal gray (PAG), and other brainstem nuclei known to control the body’s internal milieu40–43 (also see 31; red pathways in Fig 1); simultaneously, the cingulate cortex and anterior insula send the anticipated sensory consequences of those visceromotor actions (i.e., interoceptive predictions) to the more granular primary interoceptive cortex in the dorsal mid to posterior insula (dmIns/dpIns17,44,45; blue solid pathways; Fig 1). Using this logic, we identified a key set of cortical regions with visceromotor connections that should form the basis of our unified system for interoception and allostasis (we also included one subcortical region, the dorsal amygdala (dAmy), in this analysis due to the role of the central nucleus in visceromotor regulation; for details, see endnote 1). This evidence is summarized in Table 2. As predicted by our EPIC model, most of the key visceromotor regions in the proposed interoceptive system do, in fact, have monosynaptic, bidirectional connections to primary interoceptive cortex, reinforcing the hypothesis that they directly exchange interoceptive prediction and prediction error signals. We also confirmed that these visceromotor cortical regions indeed monosynaptically project to the subcortical and brainstem regions that control the internal milieu (i.e., the autonomic nervous system, immune system, and neuroendocrine system), such as the hypothalamus, PAG, parabrachial nucleus (PBN), ventral striatum, and nucleus of the solitary tract (NTS) (Table 2, right column).
Next, we tested for evidence of these connections in functional data from human brains. Axonal connections between neurons, both direct (monosynaptic) and indirect (e.g., disynaptic) connections, are closely reflected in intrinsic brain systems (for a review, see 46,47). As such, we tested for evidence of these connections in functional connectivity analyses on two samples of low-frequency Blood Oxygenation Level Dependent (BOLD) signals during task-independent (i.e., “resting state”) fMRI scans collected on human participants (discovery sample, N = 280, 174 female, mean age = 19.3 years, SD = 1.4 years; replication sample, N = 270,142 female, mean age = 22.3 years, SD = 2.1 years). We then examined the validity of these connections in a third independent sample of participants (N = 41, 19 female, mean age = 33.5 years, SD = 14.1 years), following which we situated these findings in the larger literature on network function.
Results
Cortical and amygdalar intrinsic connectivity supporting a unified allostatic/interoceptive system in humans
Our seed-based approach estimated the functional connectivity between a set of voxels of interest (i.e., the seed) and the voxels in the rest of the brain as the correlation between the low-frequency portion of their BOLD signals over time, producing a discovery map for each seed region. Starting with the anatomical regions of interest specified by the EPIC model, and verified in the anatomical literature, we selected seed regions guided by previously published functional studies. We selected two groupings of voxels in primary interoceptive cortex (dpIns and dmIns) that consistently showed increased activity during task-dependent fMRI studies of interoception (Table 3, first and second rows). We selected seed regions for cortical visceromotor regions and the dAmy using related studies (Table 3, remaining rows). As predicted, the voxels in primary interoceptive cortex and visceromotor cortices showed statistically significant intrinsic connectivity (Fig. 2; replication sample Fig. S1). The dpIns was intrinsically connected to all visceromotor areas of interest (seven two-tailed, one-sample t-tests were each significant at p < 10-7; Table S1), and dmIns was intrinsically connected to most of them (Table S1). The discovery and replication samples demonstrated high reliability for connectivity profiles of all seeds (η2 mean = 0.99, SD = 0.004).
Next, we computed η2 for all pairs of maps to determine their spatial similarity48 (mean = 0.56, SD = 0.17), and then performed K-means clustering of the η2 similarity matrix to determine the configuration of the system. Results indicated that the allostatic/interoceptive system is composed of two intrinsic networks connected in a set of overlapping regions (Fig. 3; replication sample, Fig. S2). The spatial topography of one network resembled an intrinsic network commonly known as the default mode network (Fig. S3 and Fig. S4; for a review, see 49). The second network resembled an intrinsic network commonly known as the salience network (Fig.S3 and Fig. S4; e.g., 50,51), the cingulo-opercular network52, or the ventral attention network53. Resemblance was confirmed quantitatively by comparing the percent overlap in our observed networks to reconstructions of the default mode and salience networks reported in Yeo, et al.54 (Table S2). Other cortical regions within the interoceptive system shown in Fig. 3 (e.g., dorsomedial prefrontal cortex, middle frontal gyrus), not listed in Table 2, support visceromotor control via direct anatomical projections to the hypothalamus and PAG (Table S3), supporting our hypothesis that this system plays a fundamental role in visceromotor control and allostasis.
Subcortical, hippocampal, brainstem, and cerebellar connectivity supporting a unified allostatic/interoceptive system in humans
Using a similar analysis strategy, we assessed the intrinsic connectivity between the cortical and dorsal amygdalar seeds of interest and the thalamus, hypothalamus, cerebellum, the entire amygdala, hippocampus, ventral striatum, PAG, PBN, and NTS. The observed functional connections with these cortical and amygdalar seeds, which regulate energy balance, strongly suggest that the proposed allostatic/interoceptive system itself also regulates energy balance (see Supplementary Results for details). All results replicated in our independent sample (N = 270; Fig. S5, η2 mean = 0.98, SD = 0.008). Fig. 4 illustrates the connectivity between default mode and salience networks and the non-cortical targets in the discovery sample. Fig. S6 shows connectivity between the individual cortical and amygdalar seed regions listed in Table 2. We also observed specificity in the proposed allostasis/interoception system: non-visceromotor brain regions that are unimportant to interoception and allostasis, such as the superior parietal lobule (Fig. S7), did not show functional connectivity to the subcortical regions of interest.
The cortical hubs of the allostatic/interoceptive system also overlapped in their connectivity to non-cortical regions involved in allostasis (purple in Fig. 4), including the dAmy,the hypothalamus, the PBN, and two thalamic nuclei – the VMpo and both the medial and lateral sectors of the mediodorsal nucleus (MD, which shares strong reciprocal connections with medial and orbital sectors of the frontal cortex, the lateral sector of the amygdala, and other parts of the basal forebrain; for a review, see 55). Additionally, the connector hubs also shared projections in the cerebellum and hippocampus (see Fig. 4).
Taken together, our intrinsic connectivity analyses failed to confirm only five monosynaptic connections (8%) that were predicted from non-human tract-tracing studies: hypothalamus-dAmy, hypothalamus-dpIns, PAG-dAmy, PAG-medial ventral anterior insula (mvaIns), and NTS-subgenual anterior cingulate cortex (sgACC). This is approximately what we would expect by chance; however, there are several factors that might account for why these predicted connections did not materialize in our discovery and replication samples. First, all discrepancies involved the sgACC, PAG, or hypothalamus, whose BOLD data exhibit poor signal to noise ratio due to their small size and their proximity to white matter or pulsating ventricles and arteries56. Second, individual differences in anatomical structure can make inter-subject alignment challenging, particularly in 3-T imaging of the brainstem where clear landmarks are not always available. Of the connections that did not replicate, one involved the anterior insula; there is some disagreement in the macaque anatomical literature as to the exact location of the anterior insula (e.g., 44,57–59), which might help explain any lack of correspondence between intrinsic and tract-tracing findings that we observed.
Validating the functions of the allostatic/interoceptive system in humans
The allostatic/interoceptive system reported in Fig. 3 replicated in the validation sample (η2 mean = 0.84, SD = 0.05 compared with discovery sample cortical maps; η2 mean = 0.76, SD = 0.07 compared with discovery sample subcortical maps). These η2 values are respectable and demonstrate adequate reliability of the system according to conventional psychometric theory, although the lower η2 values are likely due to the smaller sample size which magnifies the effects of poor signal-to-noise ratio in subcortical regions. Convergent validity for the proposed allostatic/interoceptive system was demonstrated in that individuals with stronger functional connectivity within the system also reported greater arousal while viewing images that evoked greater sympathetic nervous system activity. Participants viewed ninety evocative photos known to induce a range of autonomic nervous system changes and corresponding feelings of arousal60, as well as changes in BOLD activity within these regions61,62. We predicted, and found, that individuals showing stronger intrinsic connectivity within the allostatic/interoceptive system (specifically, connectivity between dpIns and anterior midcingulate cortex (aMCC)) also demonstrated a stronger concordance between objective and subjective measures of bodily arousal while viewing allostatically relevant images (p = 0.003; see Fig. S8; see Supplementary Results for details).
There were three reasons for demonstrating the convergent validity of the proposed allostatic/interoceptive system using this task. First, there is a decades-old body of research indicating that interoception enables the subjective experience of arousal (63; e.g., 64,65). Thus, the amount of joint information shared by an objective, psychophysiological measure of visceromotor change (skin conductance) and the subjective experience of arousal (self-report ratings) is an implicit, behavioral measure of interoceptive ability. Indeed, individuals with more accurate interoceptive ability exhibit a stronger correspondence between subjective arousal and physiological arousal in response to similar evocative photos66. Second, explicit reports of interoceptive performance on heartbeat detection tasks (e.g., 67–69) require synthesizing and comparing information from other systems, including the somatosensory system70, frontoparietal control systems, and, for heartbeat detection, the auditory system – adding an additional level of difficulty and complexity – in tasks that are sometimes too hard (yielding floor effects) or have questionable validity69.
At this juncture, it is tempting to ask if the unified allostatic/interoceptive system is specific to allostasis and interoception. From our perspective, this is the wrong question to be asking. The last two decades of neuroscience research have brought us to the brink of a paradigm shift in understanding the workings of the brain, setting the stage to revolutionize brain: mind mapping. Neuroscience research is increasingly acknowledging that brain networks have a one (network) to many (function) mappings 27–29,71–73. Our findings contribute to this discussion: a brain system that is fundamental to allostasis and interoception is not unique to those functions, but instead is also important for a wide range of psychological phenomena that span cognitive, emotional, and perceptual domains (Fig. 5.). This finding is not a failure of reverse inference. It suggests a functional feature of how the brain works.
Discussion
The integrated allostatic/interoceptive brain system is a complex cortical and subcortical system consisting of connected intrinsic networks. The novelty of our work is our demonstration of a single brain system that supports not just allostasis but also a wide range of psychological phenomena (emotions, memory, decision-making, pain) that can all be explained by their reliance on allostasis. Other studies have already shown that regions controlling physiology are also regions that control emotion. In fact, this was Papez’s original logic for assuming that the “limbic system” was functionally for emotion. This paper goes beyond this observation. Regions controlling and mapping of inner body physiology lie in networks that also social affiliation, pain, judgments, empathy, reward, addiction, memory, stress, craving, decision making, etc. (Fig. 5). More and more, functional imaging studies are finding that the salience and default mode networks are domain-general (e.g., 29; for review, see 27,28). Our paper provides the groundwork for a theoretical and empirical framework for making sense of these findings in an anatomically principled way.
Our investigation was strengthened by our theoretical framework (the EPIC model11), the converging evidence from structural studies of the brain (i.e., tract-tracing studies in monkeys plus the well-validated structural model of information flow), our use of multiple methods (intrinsic connectivity in humans, as well as brain-behavior relationships), and our ability to replicate the system in three separate samples totaling over 600 human participants. Our results are consistent with prior anatomical and functional studies that have investigated portions of this system at cortical and subcortical levels (e.g.,16 ,17,25,26,74,-77), including evidence that limbic cortical regions control the brainstem circuitry involved with allostatic functions such as cardiovascular control, respiratory control, and thermoregulatory control78, as well as prior investigations that focused on the intrinsic connectivity of individual regions such as the insula (e.g., 79), the cingulate cortex (e.g., 80), the amygdala (e.g.,81), and the ventromedial prefrontal cortex (e.g., 82); importantly, our results go beyond these prior studies in several ways. First, we observed an often-overlooked finding when interpreting the functional significance of certain brain regions: the dorsomedial prefrontal cortex, the ventrolateral prefrontal cortex, the hippocampus, and several other regions have both a structural and functional pattern of connectivity that indicates their role in visceromotor control. A second often-overlooked finding is that relatively weaker connectivity patterns (e.g., between the visceromotor sgACC and primary interoceptive cortex) are reliable, and future studies may find that they are of functional significance. Third, we demonstrated behavioral relevance of connectivity within this network, something that prior studies of large-scale autonomic control networks have yet to test (e.g., 74–76). Taken together, our results strongly support the EPIC model’s hypothesis that visceromotor control and interoceptive inputs are integrated within one unified system11, as opposed to the traditional view that the cerebral cortical regions sending visceromotor signals and those that receive interoceptive signals are organized as two segregated systems, similar to the corticospinal skeletomotor efferent system and the primary somatosensory afferent system.
Perhaps most importantly, the allostatic/interoceptive system has been shown to play a role in a wide range of psychological phenomena, suggesting that allostasis and interoception are fundamental features of the nervous system. Anatomical, physiological, and signal processing evidence suggests that a brain did not evolve for rationality, happiness, or accurate perception; rather, all brains accomplish the same core task19: to efficiently ensure resources for physiological systems within an animal’s body (i.e., its internal milieu) so that an animal can grow, survive, thrive, and reproduce. That is, the brain evolved to regulate allostasis20. All psychological functions performed in the service of growing, surviving, thriving, and reproducing (such as remembering, emoting, paying attention, deciding, etc.) require the efficient regulation of metabolic and other biological resources.
Our findings add an important new dimension to the existing observations that the default mode and salience networks serve as a high-capacity backbone for integrating information across the entire brain83. Diffusion tensor imaging studies indicate, for example, that these two networks contain the highest proportion of hubs belonging to the brain’s “rich club,” defined as the most densely interconnected regions in the cortex72,84 (several of which are connector hubs within the allostatic/interoceptive system; see Fig. 3, Table S4). All other sensory and motor networks communicate with the default mode and salience networks, and potentially with one another, through these hub1,84. The agranular hubs within the two networks, which are also visceromotor control regions, are the most powerful predictors in the brai11,31. Indeed, hub regions in these networks display a pattern of connectivity that positions them to easily send prediction signals to every other sensory system in the brain12,31.
The fact that default mode and salience networks are concurrently regulating and representing the internal milieu, while they are routinely engaged during a wide range of tasks spanning cognitive, perceptual, and emotion domains, all of which involve value-based decision-making and action85 (e.g., 86–88; 29; for a review, see 87), suggest a provocative hypothesis for future research: whatever other psychological functions the default mode and salience networks are performing during any given brain state, they are simultaneously maintaining or attempting to restore allostasis and are integrating sensory representations of the internal milieu with the rest of the brain. Therefore, our results, when situated in the published literature, suggest that the default mode and salience networks create a highly connected functional ensemble for integrating information across the brain, with interoceptive and allostatic information at its core, even though it may not be apparent much of the time.
When understood in this framework, our current findings do more than just pile on more functions to the ever-growing list attributed to the default mode and salience networks (which currently spans cognition, attention, emotion, perception, stress, and action; see 27,29). Our results offer an anatomically plausible computational hypothesis for a set of brain networks that have long been observed but whose functions have not been fully understood. The observation that allostasis (regulating the internal milieu) and interoception (representing the internal milieu) are at the anatomical and functional core of the nervous system17,19 further offer a generative avenue for further behavioral hypotheses. For example, it has recently been observed that many of the visceromotor regions within the unified allostatic/interoceptive system contribute to the ability of SuperAgers to perform memory and executive function tasks like young89.
Furthermore, our findings also help to shed light on two psychological concepts that are constantly confused in the psychological and neuroscience literatures: affect and emotion. If, whatever else your brain is doing—thinking, feeling, perceiving, moving—it is also regulating your autonomic nervous system, your immune system, and your endocrine system, then it is also continually representing the interoceptive consequences of those physical changes. Interoceptive sensations are usually experienced as lower-dimensional feelings of affect90,91. As such, the properties of affect—valence and arousal92,93—can be thought of as basic features of consciousness94–100 that, importantly, are not unique to instances of emotion.
Perhaps the most valuable aspect of our findings is their value for moving beyond traditional domain-specific or “modular” views of brain structure/function relationships101, which assume a significant degree of specificity in the functions of various brain systems. A growing body of evidence requires that these traditional modular views be abandoned27,102,103in favor of models that acknowledge that neural populations are domain-general or multi-use. The idea of domain-generality even applies to primary sensory networks, as evidenced by the fact that multisensory processing occurs in brain regions that are traditionally considered unimodal (e.g., auditory cortex responding to visual stimulatio104,105). The absence of specificity in brain structure/function relationships is not a measurement error or some biological dysfunction, but rather it is a useful feature that reflects core principles of biological degeneracy that are also evident in the genome, the immune system, and every other biological system shaped by natural selection106.
No study is without limitations. First, there are potential issues identifying homologous regions between monkey and human brains46; nonetheless, we still found evidence for the majority of the monosynaptic connections predicted by the EPIC model. Second, we used an indirect measure of brain connectivity in humans (functional connectivity analyses of low-frequency BOLD data acquired at rest) that reflects both direct and indirect connections and can, in principle, inflate the extent of an intrinsic network46. Moreover, low frequency BOLD correlations may reflect vascular rather than neural effects in brain107. Nonetheless, our results exhibit specificity: the integrated allostatic/interoceptive system conforms to well-established salience and default mode networks and is remarkably consistent with both cortical and subcortical connections repeatedly observed in tract-tracing studies of non-human animals. Third, although our fMRI procedures were not optimized to identify subcortical and brainstem structures and study their connectivity (e.g., 56,74,75,108), we nonetheless observed 92% of the predicted connectivity results. Finally, many studies find that activity in the default mode and salience networks have an inverse or negative relationship (sometimes referred to as “anticorrelated”), meaning that as one network increases its neural activity relative to baseline, the other decreases. Such findings and interpretations have recently been challenged on both statistical and theoretical grounds (e.g., 109; see Supplementary Results). In fact, when global signal is not removed in pre-processing, the two networks can show a pattern of positive connectivity (e.g., 110). Fourth, our demonstration of a brain/behavior relationship (using the evocative pictures) was merely a first look at how individual differences in the function of this system are related to individual differences in behavior. Additionally, our use of electrodermal activity as a measure of sympathetic nervous system activity is arguably too specific because different components of the sympathetic nervous system react differently111, and peripheral sensations associated with SCRs themselves might not be processed by the interoceptive brain circuitry that we are studying here, thus complicating the interpretation of our results. However, we did not intend to assess a particular path carrying information about SCRs specifically, and we believe that – despite their limitations – our results are still useful and hypothesis-generating. Future work will be needed to understand this and other brain/behavior relationships of this system more thoroughly.
This work is the first in a series of studies to precisely test the EPIC model, including its predictive coding features (not just the anatomical and functional correlates as shown here). Future research must focus on the ongoing dynamics by which the default mode and salience networks support allostasis and interoception, including the predictions they issue to other sensory and motor systems. It is possible, for example, that both networks use past experience in a generative way to issue prediction signals, but that the default mode network generates an internal model of the world via multisensory predictions (consistent with 112–114), whereas the salience network issues predictions, as precision signals, to tune this model with prediction error (consistent with the salience network’s role in attention regulation and executive control; e.g., 50,115,116). Unexpected sensory inputs that are anticipated to have allostatic implications (i.e., likely to impact survival, offering reward or threat) will be encoded as “signal” and learned to better support allostasis in the future, with all other prediction error is treated as “noise” and safely ignored (117; for discussion, see 118). These and other hypotheses regarding the flow of predictions and prediction errors in the brain (e.g., incorporating the cerebellum, ventral striatum, and thalamus23 can be tested using new methods such laminar MRI scanning at high (7 T) magnetic field strengths (e.g., 119).
Future research that provides a more mechanistic understanding of how the default mode and salience networks support interoception and allostasis will also reveal new insights into the mind-body connections at the root of mental and physical illness and their comorbidities. For example, in illness, the neural representations of the world that underlie action and experience may be directed more by predicted allostatic relevance of information than by the need for accuracy and completeness in representing the environment. Indeed, atrophy or dysfunction within parts of the interoceptive system are considered common neurobiological substrates for mental and physical illness120–112, including depression123, anxiety124, addiction125, chronic Pain126, obesity 127, and chronic stress128,129. By contrast, increased cortical thickness in MCC is linked to the preserved memory of SuperAgers relative to their more typically performing elderly peers130,131, suggesting a potential mechanism for how exercise (via the sustained visceromotor regulation it requires) benefits cognitive function in aging132 and why certain activities, such as mindfulness or contemplative practice, can be beneficial (e.g., 133,134). Ultimately, a better understanding of how the mind is linked to the physical state of the body through allostasis and interoception may help to resolve some of the most critical health problems of our time, such as the comorbidities among mental and physical disorders related to metabolic syndrome (e.g., depression and heart disease135), or how chronic stress speeds cancer progression136, as well as offer key insights into how an opioid crisis137 and recorded numbers of suicides138 emerge.
Author contributions
The study was designed by all the authors, analyzed by all the authors, and the manuscript was written by I.R.K. and L.F.B with comments and edits from other authors. The authors acknowledge Miguel Angel Garcia-Cabezas for comments and advice on neuroanatomy and Henry Evrard for helpful discussions on anatomical connectivity. This research was supported by the National Institutes on Aging (R01 AG030311) to L.F.B. and B.C.D., the US Army Research Institute for the Behavioral and Social Sciences Contracts (W5J9CQ-11-C-0046 and W5J9CQ-12-C-0049) to L.F.B., the National Institute of Mental Health Ruth L. Kirschstein National Research Service Award (F32MH096533) to I.R.K., as well as the National Institutes of Mental Health (K01MH096175-01) and Oklahoma Tobacco Research Center grants to W.K.S, and the Fonds de recherche sante Quebec fellowship award to C.X. The views, opinions, and/or findings contained in this paper are those of the authors and shall not be construed as an official Department of the Army position, policy, or decision, unless so designated by other documents.
Supplementary Results
Detailed description of subcortical, hippocampal, brainstem, and cerebellar connectivity within the interoceptive system
Here, we briefly justify the inclusion of each non-cortical region in our connectivity analyses, report its observed intrinsic connectivity patterns with the allostatic/interoceptive system seeds (Fig. 4 and Fig. S6), and compare our results with published tract-tracing studies showing monosynaptic anatomical connectivity among these regions (Table 2). Discrepancies between our results and tract-tracing are only indicated if our fMRI results failed to show connectivity between regions that are monosynaptically connected. fMRI intrinsic connectivity reflects both direct and indirect (multisynaptic) connections46,47 and thus our results sometimes show connectivity for regions that are disynaptically connected.
Thalamus
We examined connectivity to two thalamic nuclei: the posterior part of the ventromedial nucleus (VMpo; for a review, see 16) for interoceptive input specifically and the larger ventral posterior (VP) complex for somatic input more broadly55. Our fMRI results revealed that all cortical and amygdalar seeds exhibited connectivity with the VMpo and VP. This is entirely consistent with tract-tracing studies showing direct projections of VMpo or VP to dpIns, dmIns, and dorsal ACC/aMCC (for a review, see 16). Our other cortical and amygdalar seeds have multisynaptic connectivity to VMpo and VP by way of aMCC.
Hypothalamus
The hypothalamus is a critical region for allostatic regulation of the body; the paraventricular nucleus in the medial zone is particularly responsible for visceromotor control of autonomic, endocrine, and immune function225. Our review of tract tracing studies clearly indicated connectivity from each cortical and amygdalar seed except with dpIns, despite evidence from tract-tracing, and with lvaIns to the hypothalamus (which was not predicted) 42,58,140,145,156,157,169. The lack of functional connectivity between lvaIns and the hypothalamus is not surprising because the lateral portion of the ventral anterior insula is part of a sensory integration network in orbitofrontal cortex in monkeys and humans42,58 that has little connection to the hypothalamus, except for light connections to the posterior lateral hypothalamus at the level of the mammillary bodies42. We were unable to identify the expected connectivity between the dAmy and any part of the hypothalamus.
Cerebellum
The cerebellum is a key structure in sensorimotor regulation because it sends efferent copies (i.e., predictions) to the cortex to help the brain distinguish between the anticipated sensory consequences of self-initiated by the body vs. those that are unexpected226,227. All cortical seeds and the dAmy seed exhibited connectivity with the cerebellum. More specifically, all seeds exhibited connectivity to lobules IV, V, VI and VIIIB, consistent with the cerebellar “somatosensory” network. The default mode portion of the interoceptive system is additionally connected to lobule IX and Crus I, whereas the salience portion of system is additionally connected to lobule VIIIA (for a specific parcellation of cerebellar intrinsic connectivity, see 214).
Amygdala
The amygdala is a key subcortical region for both interoceptive input (via its lateral nucleus) and visceromotor control (via its central nucleus)228, and is part of both the salience and the default mode networks49,51. All of our cortical seeds exhibited connectivity to the amygdala seed except for the pACC seed, which had limited connectivity to the left amygdala (only the dorsal section, which contains the central nucleus). This is consistent with results from tract-tracing studies, which show that each of our cortical seeds projects monosynaptically to the dorsal amygdala59,140,142,144,151,152.
Hippocampus
The hippocampus is a key subcortical hub in the default mode network49 that is strongly connected to the amygdala (for a review, see 229). Our fMRI results showed that all cortical seeds and the dAmy seed exhibited connectivity to the entire hippocampus except for the aMCC seed, which exhibited connectivity to only the posterior hippocampus, and the dmIns seed, which exhibited connectivity only to the anterior and posterior hippocampus. Our results are consistent with tract-tracing studies indicating direct projections from the amygdala to the hippocampus and indirect projections from many regions of the cortex to the hippocampus; specifically, vaIns, sgACC, pACC, and aMCC all project to the entorhinal cortex, which projects to the hippocampus (for a review, see 229). Other cortical regions such as the aMCC and dmIns can connect to the hippocampus in three steps: first to a cortical hub (e.g., vaIns), then to and the entorhinal cortex, then to the hippocampus.
Ventral striatum
The striatum is a subcortical region in the basal ganglia comprising the caudate, putamen, and nucleus accumbens, and its ventral portion is important for controlling inhibitory signals to brainstem visceromotor targets230,231Specifically, cortical regions send excitatory (glutamatergic) signals to the striatum, which enhance inhibition of brainstem visceromotor targets; these connections also have the capacity to release visceromotor targets from tonic inhibition via striatal connections to the pallidum231. All of our cortical and amygdalar seeds exhibited connectivity to the ventral striatum, except for dmIns, which exhibited connectivity to a portion of the ventral striatum. This is consistent with tract-tracing studies showing monosynaptic connections from each of our seeds to the ventral striatum149,153,157,160,163,164.
Periaqueductal gray (PAG)
The PAG is a midbrain nucleus important visceromotor control232. It is difficult to precisely localize using 3-T scanning procedures because it encircles the cerebral aqueduct (e.g., 108). Nonetheless, the results of our intrinsic connectivity analysis largely mirror those for the hypothalamus. The tract-tracing literature has identified monosynaptic connectivity to the PAG from all seeds60,121 except the dmIns and dpIns146, and the lvaIns146. All cortical visceromotor seeds demonstrated the expected connections with the PAG: aMCC, pACC, and sgACC. We did not observe the expected connectivity with the mvaIns nor with the dAmy. As expected, connectivity with the lvaIns and dpIns was not observed.
Parabrachial nucleus (PBN)
The PBN is a nucleus in the pons that relays interoceptive input from the body to the brain16 and also serves visceromotor functions233. All cortical seeds and the dAmy seed exhibited connectivity with the PBN. This is in agreement with the tract-tracing literature showing monosynaptic connectivity to the PBN from each of our seeds147,148,157,160,164 except for the aMCC162, which must first project to another cortical hub (e.g., vaIns) before projecting to the PBN.
Nucleus of the solitary tract (NTS)
The NTS is a key relay nucleus in the medulla that is on a cranial interoceptive pathway from the viscera to the brain12,13,22,23 and also contributes to visceromotor control16,17,25,26,233 We observed NTS connectivity with the dAmy seed and with all cortical seeds except for the sgACC. This is largely consistent with the tract-tracing literature showing monosynaptic projections to the NTS from each of our seeds148,158,159,164. Failure to observe the sgACC connection is perhaps due to the small size of the sgACC and increased noise due to partial-volume effects of the nearby white matter in the corpus callosum.
Laboratory validation of the allostatic/interoceptive system in humans
The following text details our findings of the association between connectivity in the allostatic/interoceptive system in humans and an index of interoception: the concordance between objective and subjective measures of bodily arousal. We measured sympathetic nervous system arousal using SCRs234 while participants viewed each photo for six seconds. We selected SCRs as an index of sympathetic nervous system activity, and that although effects from SCRs specifically might not ascend to interoceptive brain systems, the simultaneous non-SCR effects of sympathetic nervous system activity likely are processed through interoceptive pathways. After each image, participants reported their subjective experience of arousal using a validated self-report scale217. Using multi-level regression procedure to account for the nested and repeated-measures design of this experiment (for a review, see 235), we found that the number of SCRs in response a picture (either 0, 1, 2, 3, or 4 SCRs to a given picture) predicted the intensity of arousal experiences in response to the same picture across all participants and pictures (B = 0.21, p < 0.001), consistent with prior research (e.g., 236). Furthermore, as predicted, individuals with stronger intrinsic connectivity between primary interoceptive cortex (dpIns) and the aMCC had a stronger correspondence between sympathetic arousal and subjective experience of arousal than did those with weaker connectivity (regression B = 0.56; p < 0.003; Fig. S8). We focused on the aMCC because it was an a priori visceromotor seed region (Table 1), a connector hub72, and consistently replicated tract-tracing connectivity to non-cortical allostatic nuclei. For completeness, our results focused on the number of SCRs in response to each image and we did not find analogous results using the amplitude of SCRs in response to each image.
Reconciling prior studies that reported a negative correlation between default mode and salience network activity
Many studies have found that the default mode and salience networks have task-related activity that is negatively correlated (i.e., when the BOLD signal in one network goes up, the BOLD signal in the other network goes down). Such findings are often interpreted as evidence that the brain has either an internal focus on an external focus. This inverse relationship is often the consequence of removing the mean signal change from all voxels in each volume before proceeding with data analysis (called “global-signal regression”; e.g., 109). A more reasonable interpretation, however, may be that when one network increases its neural activity compared to some baseline, the other might show a relative decrease in activity from that baseline (which does not mean that network is irrelevant to the task at hand). Alternatively, one network might show a smaller increase than the other (which, when mean signal change is removed, would appear as a negative relationship between the two networks).
Endnotes:
Acknowledgments:
Footnotes
↵ǂ Shared senior authorship
↵1 We included the dAmy in our system because its central nucleus is known to have key visceromotor functions (for a review, see 139); the dAmy, being a subcortical region, does not have a laminar structure, but there are connections between the amygdala and primary interoceptive cortex (dmIns/dpIns; e.g., 59,140,141) that are predicted by the EPIC model (using Barbas’s structural model of information flow within the cortex). Similarly, the anterior cingulate cortex (ACC), a key limbic visceromotor region, is connected with the amygdala in a pattern consistent with the EPIC model hypothesis that the ACC sends visceromotor prediction signals to the central nucleus (the ACC primarily sends output from its deep layers and receives input from the amygdala in its upper layers142). Currently, there are insufficient data to test the EPIC model hypothesis that amygdala projections terminate in the upper layers of dmIns/dpIns and receives inputs from its deep layers, as these data are not available in prior tract-tracing studies involving the insula and amygdala (e.g., 59,140,141).