The neurobiology of interoception in health and disease · The neurobiology of interoception in...

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESSpecial Issue: Health NeuroscienceREVIEW

The neurobiology of interoception in health and disease

Lisa Quadt, 1 Hugo D. Critchley,1,2 and Sarah N. Garfinkel1,2

1Department of Psychiatry and Neuroscience, Brighton and Sussex Medical School (BSMS), Trafford Centre University ofSussex, Brighton, United Kingdom. 2Sackler Centre for Consciousness Science, University of Sussex, Brighton, UnitedKingdom

Address for correspondence: Lisa Quadt, Department of Psychiatry and Neuroscience, Brighton and Sussex Medical School(BSMS), Trafford Centre, University of Sussex, Falmer, Brighton BN1 9RY, UK. [email protected]

Interoception is the sensing of internal bodily sensations. Interoception is an umbrella term that encompasses (1) theafferent (body-to-brain) signaling through distinct neural and humoral (including immune and endocrine) channels;(2) the neural encoding, representation, and integration of this information concerning internal bodily state; (3) theinfluence of such information on other perceptions, cognitions, and behaviors; (4) and the psychological expressionof these representations as consciously accessible physical sensations and feelings. Interoceptive mechanisms ensurephysiological health through the cerebral coordination of homeostatic reflexes and allostatic responses that includemotivational behaviors and associated affective and emotional feelings. Furthermore, the conscious, unitary senseof self in time and space may be grounded in the primacy and lifelong continuity of interoception. Body-to-braininteractions influence physical and mental well-being. Consequently, we show that systematic investigation of howindividual differences, and within-individual changes, in interoceptive processing can contribute to the mechanisticunderstanding of physical and psychological disorders. We present a neurobiological overview of interoception anddescribe how interoceptive impairments at different levels relate to specific physical and mental health conditions,including sickness behaviors and fatigue, depression, eating disorders, autism, and anxiety. We frame these findingsin an interoceptive predictive processing framework and highlight potential new avenues for treatments.

Keywords: interoception; health; mental health; predictive processing; autism; anxiety; depression; eating disorders

Introduction

A fundamental responsibility of the brain is to keepitself, with the rest of the body, alive. The braincoordinates the regulation of vital inner processes,including blood pressure, digestion, and breathing,by flexibly reacting to external and internal changes.Interoception refers to the sensing of the internalstate of the body,1 providing the afferent channelof the interplay between body and brain that allowshomeostasis (i.e., maintenance of physiologicalstability) through covert reflexes (e.g., baroreflex),motivational drivers (e.g., hunger and thirst), andexplicit bodily sensations (e.g., breathlessness,bladder distension, or gastric pain). Interoceptionis differentiated by this inward bodily focus fromexteroceptive senses (e.g., vision and audition)2 thatprocess information about the outer world, andmore proximate senses (e.g., proprioception, touch,and taste) that use the body to describe the external

environment and its relation to it. Interoceptiveinformation is communicated through a set ofdistinct neural and humoral (i.e., blood-borne)pathways with different modes of signaling, whichthe brain represents, integrates, and prioritizes.How these central representations of the inner bodyare generated and interact is an important focusof interoception research, not least because of theimplications for a range of cognitive and behav-ioral processes and disorders. A comprehensiveunderstanding of cognition, emotion, and overallwell-being must incorporate an understanding ofinteroception. The same questions are conse-quently integral to the field of health neuroscience.3

Interoceptive processing has a key role in health anddisease, and research is systematically delineatingthe ways in which brain–body relations can alter aperson’s well-being.

Interoception involves a relatively restricted setof classes and channels of information (e.g.,

doi: 10.1111/nyas.13915

112 Ann. N.Y. Acad. Sci. 1428 (2018) 112–128 C© 2018 New York Academy of Sciences.

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Quadt et al. Neuroscience of interoception

cardiovascular, gastric, and respiratory).These dif-fer with respect to the generation of the signal(organ stretching, mechanoreceptive, and chemore-ception) and their afferent pathway (neural andhumoral).4 Complexity within interoceptive signal-ing arises more from the need to parse and integrateinformation originating from multiple organs andacross wide temporal domains than from the needto differentiate, uniquely characterize, and encodecomplex novel stimuli (even in the generalizationof immunological responses). Nevertheless, con-tinuous, dynamic, and diverse information aboutinternal bodily function is integrated within sharedneural substrates supporting distributed intero-ceptive representations and associated experiences(feeling states). Together, these shape the generative(autonomic or hormonal) control of bodily statesand steer adaptive behaviors (e.g., a drop in bloodsugar levels leads to foraging).

One theoretical framework to frame the dynam-ics and dimensions of interoception is predictive pro-cessing (PP).5–7 PP is a hitherto mainly hypotheticalmodel (with growing evidence) of neural functionthat assumes a functional and cortical hierarchy,where models about incoming signals are gener-ated, compared with, and lastly improved by, actualsensory input. Originally developed as a princi-ple for exteroception (e.g., vision), PP was recentlyapplied to interoception (interoceptive predictiveprocessing; IPP).2,8,9 IPP describes the hierarchicalprocessing schemes that may underlie brain–bodyinteraction. For IPP, where informational parame-ters are arguably more restricted, yet under moredirect neural control, the cerebral cortex mightdominate only at higher order representationallevels.

In this article, we review the dimensional natureof interoception, approaches to their quantifica-tion, discuss the neurobiological basis of interocep-tion, and how these findings can be framed withinIPP. We offer our perspective on the implicationsfor both physical and mental health, and scruti-nize the contributing role of interoception to dif-ferent health conditions. Finally, we suggest howinteroception research can further enhance healthneuroscience.

Dimensions of interoception

Interoception is defined by both its origin within,and reference to, the inner state of the body. This

single term generalizes communication throughmultiple distinct physical axes, and representationsthat unfold at different anatomical and psycholog-ical levels, on different timescales. Interoception isa concept that implicitly suggests the integrationof different types of sensory information. How-ever, inconsistency within the physiological andpsychological literature regarding the definition ofinteroception, and use of terms such as interocep-tive awareness, led to proposed dimensional frame-works for understanding and studying this set ofsenses.10,11 Within such a framework, interoceptioncan be described from the physical responses in bodyand brain representation up to (and beyond) inte-roceptive metacognitive (i.e., available for explicitawareness and reflection) insight and consciousawareness.

The first dimension of interoception refers to theafferent, interoceptive signal that is communicatedto the brain from one or more internal organs,which can be measured, for example, by evokedchanges in central neural activity, for example, as achange in neuroimaging signal or heartbeat evokedpotential (HEP).12 HEPs refer to a change in neuralactivity (measured using magnetoencephalography,electroencephalography, or intracranial neuralrecordings) that occurs after a heartbeat. Interest-ingly, HEP amplitude typically correlates with theability of an individual to detect and report theirheartbeats.13

The second dimension reflects the impact of vis-ceral afferent signals on other forms of central sen-sory or cognitive processing and behaviors. Thislevel does not necessitate (or preclude) perceptualawareness (i.e., consciousness) of the interoceptivesignal or other processes. Illustrations of this inte-roceptive dimension are found, for example, in car-diac timing experiments where afferent heartbeatsignals affect decisions, emotional processing, andmemory.14–16

Three “psychological” dimensions refer moredirectly to the perception of interoceptive signals:interoceptive accuracy, sensibility, and awareness.10

These dimensions developed from the use of tests ofinteroceptive sensitivity/ability, such as heartbeat-detection tasks.a These tasks are designed to rate

aClassic methods to assess interoceptive accuracy includeheartbeat tracking17 and heartbeat-discrimination

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Neuroscience of interoception Quadt et al.

individual differences in the ability to sense internalbodily signals, which might account for variationin emotional temperament or psychosomaticvulnerability.33 Typically, an interoceptive taskrequires a participant, at rest (i.e., usually sittingor lying down in a laboratory setting), to report“felt” interoceptive sensations (e.g., the timingof a heartbeat): Interoceptive accuracy refers toobjective performance on such behavioral tests, forexample, how accurately they perform a heartbeat-tracking task.17 Next, interoceptive sensibilitydescribes subjective belief about one’s own abilityto consciously perceive bodily signals, ascertainedvia self-report measures, such as questionnaires(e.g., body perception questionnaire; BPQ),34 orreflected in their rated confidence in their perfor-mance accuracy on an interoceptive task. Since

tasks.18–20 Indeed, these two tasks are widely and prin-cipally used to indicate accuracy, although empiricalassessments often use only one of the methods as asole proxy for interoceptive ability, with the majority ofthe current work dependent on the heartbeat-trackingtask.21–24 The two cardiac interoceptive tasks tap intodifferent processes,25 with the tracking task based on thesensing of internal physiological information, but alsopotentially amenable to higher order influences such asknowledge about heartrate;26 and the discriminationtask requiring coupling information proceeding fromexteroceptive and interoceptive channels.10,27 Both tasksshare similar and distinct functional architecture.28

Beliefs about heartrate have been shown to influence per-formance on the tracking task, leading some researchersto question its validity.29 Moreover, performance onthese two cardiac tasks can diverge,30 and the relationshipbetween heartbeat perception and other bodily axesof interoception, such as respiration and gut, is scarceand inconsistent.25,31,32 Therefore, the generalizabilityof findings derived from the heartbeat-tracking task isquestionable. From an IPP perspective, sensory evidenceor predictions related to certain modalities may beweighted more heavily than that of other modalities.Conditions in which cardiovascular sensations may be ofless relevance than sensations from other modalities (e.g.,eating disorders) suggest that this may be indeed the case.Thus, the assumption that the heartbeat-tracking taskcan serve as a valid proxy and the potential differentialweighing of interoceptive sources needs to be treated withcaution. Further research using additional interoceptivetests, covering a wide range of visceral signals, is neededto comprehensively understand the role of interoceptionin health and disease.

subjective and objective rating can diverge, a level ofconscious insight can be calculated: Metacognitiveinteroceptive awareness expresses this insight intointeroceptive performance aptitude and is derivedfrom confidence–accuracy correspondence.10 Thismetacognitive dimension of interoception is a mostappropriate use of the word “awareness” in thecontext of interoception.

A further “executive” dimension on this intero-ceptive dimensional framework attempts to capturethe degree to which an individual is able to flex-ibly attend to, and utilize, interoceptive informa-tion or can adaptively switch between interoceptiveand exteroceptive representations.11 The consciousperception of bodily sensations is an important yetbroad topic. Most theoretical approaches to intero-ception and consciousness focus on the role of bod-ily processes for phenomenal selfhood,8,35–37 whereinteroceptive events provide a bodily anchor forexperiences of selfhood.38 A more pressing ques-tion, however, is which circumstances elicit con-scious awareness of internal signals, such as thesudden awareness of heartbeats in fear-related sce-narios. The subjective impression of body percep-tion and actual accuracy in perceiving interoceptivesignals can diverge,10 raising the issue of how andwhen precise bodily signals are consciously repre-sented.

The neurobiology of interoception

Convergent evidence identifies the insular cortex(IC) (Fig. 1) as the brain substrate underpin-ning higher order interoceptive representations: forexample, the left posterior IC is reliably engagedwhen attention is directed to one’s heartbeat, rel-ative to an exteroceptive focus.39 Also, anterior IC(AIC) activity predicts objective performance accu-racy on interoceptive tasks. In particular, right AICfunctional reactivity predicts interoceptive accu-racy on a heartbeat discrimination task and itsvolume predicts interoceptive sensibility.1 The ICis buried between the adjacent frontal and tem-poral lobes. The architecture of insula changes(including progressive loss of the granule cell layer)from the posterior to AIC, with other subregionaldifferences in cellular organization. The ICs arebidirectionally connected to the cingulate, pre-frontal, parietal, and medial temporal corticesand subcortically to basal ganglia:40 The AIC isstrongly connected with the anterior cingulate



Figure 1. Diagram of insula connectivity. The insular cortex divides into the posterior (PIC) and anterior (AIC) insula. ThePIC receives afferent input from the thalamus (THAL) and is reciprocally connected with the primary somatosensory cortex(SI). Within the insula, the PIC projects interoceptive information to the AIC. The AIC strongly connects bidirectionally withthe anterior cingulate cortex (ACC), amygdala (AMY), prefrontal cortex (PFC), and the orbitofrontal cortex (OFC), forming afunctional network.

cortex (ACC), arguably forming a functional unitwith the amygdala and ventromedial/orbitofrontalcortex (VMPFC/OFC), to which they are mutu-ally linked. The posterior insula (PI) has strongerreciprocal connections to the second somatosensorycortex, and receives direct afferent input fromthe interoceptive thalamus (posterior ventromedialnucleus, which has a lighter corollary projectionto the ACC), relaying interoceptive and nocicep-tive information. Interoceptive information is pro-jected within the PI (i.e., primary viscerosensorycortex implicated in primary, objective representa-tions of bodily signals), and rostrally to the AIC,which serves to rerepresent and integrate intero-ceptive signals with exteroceptive and motivationalinformation.41

The higher order representation of interocep-tive information within the AIC and its pro-jection regions underpin consciously accessiblefeelings that inform emotions and motivate behav-iors. This representation also shapes the operationalfunctioning of the brain, as it continuously receivesand responds to such homeostatic afferent signals.An important aspect of this higher order represen-tation is the integration across distinct categoriesof signals that possess distinct temporal responsecharacteristics and encode hormonal, metabolic,thermal, immunological, nociceptive, and viscero-

motor information. This information reaches thebrain through humoral and neural pathways.42

Microglial transduction pathways additionallyinform about, and even engage the brain in, inflam-matory status, where inflammatory mediators leadto waves in microglial activation that is propagatedacross the brain.43 However, the loss of anatomi-cal specificity, temporal structure, and perceptualdistinctiveness may be obligatory characteristicsof a dynamic higher order integrative interocep-tive representation, from which may emerge anamorphous affective feeling state that is the pre-dictive platform for motivational behavior, emo-tional experience, and internal homeostatic control.Hypothetical models of brain function state thathigher order representations require nonspecificityto enable abstract and future-directed predictions toensure flexible adaptation to potentially disruptiveevents.2

Nevertheless, well before the IC, conscious access,and affective feeling states, afferent viscerosensoryinformation is processed within subcortical andbrain stem regions supporting homeostasis (Fig. 2).The nucleus of the solitary tract (NTS) is themain region where visceral neural (spinal lami-nar 1 and vagus nerve) inputs converge within thebrain stem44 and is of critical importance for thecontrol of physiological state (e.g., blood pressure



Figure 2. Schematic depiction of interoceptive brain centers and pathways in the human brain. Schematically depicted areinteroceptive brain centers (A) and viscerosensory pathways (B) in the human brain. The circumventricular organs area postrema(L), organum vasculosum (C), and subfornical organ (D) provide access to the brain for chemicals circulating in the blood stream.Visceral afferents (blue arrows) enter the spinal cord (lamina 1) and spinothalamic tract, with outputs in the nucleus of the solitarytract (NTS; J), parabrachial nucleus (I), and periaqueductal gray (H), terminating in the thalamus (E). Viscerosensory inputs (greenarrows) ascend mainly from the vagus nerve (M) and terminate in the nucleus of the solitary tract (J). The NTS projects to theventrolateral medulla (K), parabrachial nucleus (I), periaqueductal gray (H), and the thalamus (E), from where inputs (green andorange arrows) are relayed to the hypothalamus (F), amygdala (G), insula (B), and the anterior cingulate cortex (A).

control). The NTS consists of a series of purely sen-sory nuclei and is organized viscerotopically, whereneurons that receive input from distinct organs andtypes of visceral receptor are in close proximity. Thisspecific organization hints to early integration ofviscerosensory signals across related modalities.45

The NTS projects to the hypothalamus, ventrolat-eral medulla, and parabrachial nucleus, and throughthese regions provides a first level of control of hor-monal, immune, and autonomic outputs.46 Chemi-cals circulating in the blood stream access the brainvia specialist circumventricular organs (the areapostrema, organum vasculoscum of laminae termi-nae, and subfornical organ). The humoral infor-mation is projected to the hypothalamus and NTS,contributing the negative feedback control andcross-modal homeostatic responses mediatedthrough pituitary hormones and the autonomicnervous system.

The NTS receives from spinal visceral affer-ent neurons with cell bodies in the dorsalroot ganglion containing motivational informa-tion from cranial nerves, notably the vagusnerve. Viscerosensory inputs with cell bodies invagus nerve ganglia terminate in the NTS andproject onto the pontine parabrachial nucleusand periaqueductal gray before an obligatoryrelay within the posterior ventromedial thalamus.These prethalamic midbrain pathways project fur-

ther to the hypothalamus and amygdala, andcomplement the main viscerosensory thalamo-cortical projection to the IC (and the ACC).47

Nevertheless, all levels of the neuroaxis represent-ing interoceptive information are implicated in theautonomic control of internal physiological stateand processes that shape emotions, feelings, behav-ior, and cognition.8,35,41,42,47–49 Ultimately, the inter-play of body and brain depends on bi-directionalsignal messaging, where higher level brain regionsmight influence bodily processes in a top-downmanner, and afferent signals influence brain pro-cesses from the bottom-up. This complex anddynamic interaction is theoretically captured by anincreasingly prominent framework, PP, or, morespecifically, IPP.

Interoceptive predictive processing

General predictive processingPP5,6 is an algorithmic theory about neural functionand cortical organization.b The rationale is that thebrain only has an approximate access to external

bAlthough PP is praised as a very promising theory6

that aims to provide a unifying framework for cogni-tion, action, and perception,5,7 critics voice concerns50

about key assumptions of the theory being untested51 oreven untestable.52 Most empirical demonstrations of PP



(e.g., environmental and bodily) states, requiringit to infer the most probable hidden cause of themultitude of sensory signals it receives. In order tosteer the organism in an adaptive manner, a majorgoal of brain function is to filter out regularitieson different spatial and temporal scales, and cancelout noise and irregularities.7 PP suggests that theneural system achieves this by generating predictivemodels about the likelihood of incoming signals,whose probability is improved by feedback loopsthat are driven by the mismatch between signaland prediction (i.e., prediction error). Error signalsserve to either update the model, perhaps gener-ating a perception (i.e., perceptual inference), orby eliciting changes in behavior to improve world-model fit (i.e., active inference).59 External signalsthusly fundamentally alter predictive representa-tions; causal regularities of brain–external matterare “folded into” predictions.53 PP thereby allowsfor the influence of multiple factors, both from thetop-down (e.g., environmental, social, cultural, andprior experience) and the bottom-up (e.g., geneticdispositions and hormone levels).

Although PP integrates these brain–externalcomponents into its theoretical horizon, it is mainlyan account of neural function. The basic assumptionis that predictive models are generated within corti-cal hierarchies whose representational array rangesfrom highly abstract regularities at higher levels toconcrete sensory signal properties at lower levels.Timescales putatively differ from slow to fast as thedegree of abstraction decreases.60 Along this hierar-chical organization, generative models travel down-ward, carrying predictions about the state of thelevel below, and are met by, and compared with,signals that are propagated back up to improve pre-dictive power. The result is a dynamic and flexiblecascade of top-down and bottom-up informationcanceling out prediction error. PP states that preci-sion estimations of error signals (i.e., the probabil-ity of carrying valid signals with little noise) factorin this process. By reducing or increasing synaptic

in the brain remain indirect53 and appear in the formof, for example, computational simulations54,55 or repeti-tion suppression effects.56 However, new evidence keepsaccumulating.39,57,58 In this paper, PP is treated as a modelof neural functioning, parts of which are rather specula-tive, or are inferred from existing evidence.

gain, prediction errors are weighed low or high. Onlyerror signals that are deemed precise will be prop-agated back up and alter predictions.6 Accordingto PP, prediction error minimization is the brain’sprimary task in efficiently navigating behavior andexperience.

Interoceptive inferenceInteroceptive inference,2,8 or IPP, takes up thegeneral PP framework and applies it to internalbody–brain interactions. Here, high-level predic-tions about the internal state of the body aregenerated within cortex (AIC is most strongly impli-cated) within a neural hierarchy, proximately involv-ing the PI. Descending predictions are comparedagainst incoming afferents, creating an error sig-nal that serves to improve predictions and reducesubsequent prediction error through both percep-tual inference (change in feeling state) and activeinference (autonomic and behavioral response). It isassumed that these generative predictions cascade toearlier levels of control (including brain stem auto-nomic centers, which operate along similar negativecontrol feedback principles), ultimately serving tokeep bodily states within their expected range foradaptive behavior, thereby keeping the physiologi-cal integrity.

The Embodied Predictive Interoceptive Coding(EPIC) model2 relates IPP and prediction error min-imization more specifically to cortical architecture,offering a hypothetical model of IPP. By analogyto predictive coding within the motor system,61–63

EPIC proposes that interoceptive predictions origi-nate in the deep layers of the agranular (i.e., less lam-inar differentiation) visceromotor regions withinthe prefrontal (caudal VMPFC/OFC), anterior/midcingulate cortices, and AIC. Back-projecting pre-dictions are deemed to terminate within the super-ficial layers of dysgranular and granular corticalcolumns, where they alter an ongoing pattern ofactivity by changing the firing range of neurons inanticipation of viscerosensory input. These intero-ceptive inputs ascend from the NTS, parabrachialnucleus, via the thalamus to primary dysgranularand granular regions of the mid- and posteriorIC.64 Therefore, it is assumed that cortical predic-tion errors (i.e., difference between predicted andactual signal) are computed. The resulting predic-tion error signal is then projected onto the deep lay-ers of the agranular visceromotor cortices, where the



prediction originated.c At this point, the error sig-nal can trigger the generation of new descendingpredictions that are ultimately expressed as theautonomic/visceromotor outputs. This process isinteroceptive active inference minimizing futureprediction error through generating interoceptiveinputs that confirm predictions. Alternatively, theerror may trigger a reduction of further signal sam-pling to reduce subsequent prediction error (affect-ing feeling state). Lastly, another option is that theerror signal adjusts the precision of prediction unitswithin the visceromotor cortices thereby modu-lating sensory sampling and viscerosensory inputthrough adjusting the gain on the thalamo–corticalcommunication.

The EPIC model of IPP also suggests, in linewith the general principle of PP, that interocep-tive sensations are largely driven by predictions.This means that the perception of bodily signalsis weighed toward mostly top-down, rather thanbottom-up, cortical processes. The perception ofbodily sensations is thus determined by predictionsthat are informed by prior experience and kept incheck by actual bodily states. The extent to whichthese predictions lead to perception also depends onprecision weighing across the interoceptive hierar-chy, where precision units reflect both the reliabil-ity of predictions and prediction errors to increaseor decrease the gain on error signals in order tochange predictions. PP claims that precision instan-tiates attention, as estimates of reliability determinethe impact of error signals on prediction units.Attention is thus thought to be the consequenceof an increase in gain on prediction errors, ren-dering them apt to drive responses, behavior, andlearning.66 A well-functioning precision-weighingsystem is paramount for healthy functioning, as willbecome more obvious later in this paper.

EPIC assumes that interoceptive predictionsinteract with other sensory modalities, projectingonto visual, auditory, and somatosensory networks,

c EPIC, IPP, and PP assume brain function to be imple-mented in a hierarchical manner. This hierarchy does notrepresent rigid step-by-step processing, but rather a highlycontext-sensitive, reconfigurable dynamical system whosepatterns of effective connectivity change on a moment-to-moment basis depending on task, and internal andexternal contexts.61,65

to provide an embodied representational contextfor perception, cognition, and action. This way,interoceptive representations modulate responsesacross the brain, which serves as a referencefor exteroceptive process and enables a dynamicmultisensory representation of the body in itsenvironment. Interoceptive predictions may thuslydetermine behavioral and perceptual patternssteered toward enabling and maintaining overallintegrity. The agranular cortices, the putative ori-gin of interoceptive predictions, are likely less con-strained by incoming signals from the body.2 Thisin turn may permit abstract and future-orientedpredictions, enabling the system to flexibly adaptto and anticipate ever-changing demands (allosta-sis), instead of merely maintaining fixed set pointsin a reactive manner (homeostasis). IPP thereforeencapsulates the flexible interplay between top-down and bottom-up processes that supports a sta-ble, yet dynamic, internal environment.

In a healthy brain, predictions are informed byprior experience, situational context and state ofthe system, the comparison between prediction andactual incoming bodily signal, and precision esti-mation that results in a well-balanced interaction ofbrain and body. The goal of this complex process isto keep bodily states within a functional range thatpermits flexible adaptation to both internal changesand external challenges. The interoceptive sys-tem balances anticipated demands and deviations,efficiently regulating needs and resources. Thisprocess was conceptualized as “allostasis” or “pre-dictive regulation”67 and it underpins the well-beingof body and mind.

Interoception in health and disease

The processing of interoceptive signals in thebrain informs central control processes involved inmaintaining physiological integrity. Interoceptionis tightly related to the predictive control of bodilysignals that contribute to a system being able tomaintain homeostatic set points, and a flexibleallostatic regulation of more complex demands.When the system fails to respond to demands in anadaptive manner, or when predictive fluctuationsfail to foresee necessary demands, the organism mayreach allostatic overload and succumb to sicknessand disease. Interoception research is increasinglydemonstrating that the signaling and detection ofinternal bodily signals is important for physical and



mental well-being.68 Interoceptive and emotionalprocesses share underlying neural substrates,11 andprominent theories of emotion even suggest thatemotional feeling states arise through the sensingof bodily signals.69–72 Emotional impairmentsaccompany the majority of mental disorders,37

acting as one potential route linking interoceptionto mental health.

Health and disease have distinct behavioral andexperiential profiles that can be characterized bythe presence or absence of reported symptoms andchanges in behavior. PP claims that conscious per-ception is the product of prediction error min-imization where the hypothesis with the highestposterior probability populates consciousness.73

Probability distributions depend on prior expe-rience (predictions), sensory effects (predictionerrors), and the flexible weighing of theirprecision.74 An important consequence is that per-ceptual content is determined by the estimated relia-bility of both prior knowledge and sensory input.75

Under this assumption, prediction errors need tobe precise or unsuppressed to determine consciousperception. Van den Bergh and colleagues76 offer aplausible account of the role of interoceptive infer-ence in the occurrence of reported symptoms. Theysuggest that interoceptive signals rarely reach aware-ness in the state of health, as interoceptive eventsare within the expected range (i.e., low predictionerror). Interoceptive sensations are considered toarise only when signals are unexpected, thus elicit-ing prediction errors that are sufficiently precise toreach awareness. Interoceptive sensations are inter-preted as symptoms when the hypothesis with thehighest posterior probability contains informationrepresenting aberrant, disease-related, causes.76

Below, we review the role of interoception andinteroceptive inference in several health conditionswhose symptomatic profile shows that mental andphysical health are often inextricable.

Sickness behaviorsThe human immune system communicates imm-unological and inflammatory states to the brain viainteroceptive pathways.42 Peripheral states of infec-tion and inflammation are transmitted to the brainvia vagus nerve pathways, cytokines that circulatehumorally, and via immune cells.42 Responses tothese insults include the activation of cardiovascu-lar and gastrointestinal reflexes, the regulation of

peripheral immune reactions,77 and also a stereo-typed pattern of responses called sickness behaviors(SBs).78 These entail fatigue, reduced calorie and flu-ids intake, social isolation, anhedonia, and fever.79

SBs potentially facilitate counteracting responses toinfection and inflammation by inducing behavioralpatterns that reduce bodily strain (e.g., fatigue moti-vates rest), and risk of additional infection (e.g.,social isolation). This narrow repertoire of behav-iors is evoked as a response to a wide range of infec-tious and inflammatory conditions, which suggeststhat they may form a coordinated general physiolog-ical and motivational reaction to a particular typeof interoceptive challenge for the protection of thebody’s integrity.80

Experimentally, these mechanisms can be explo-red by administration of substances that cause abrief spike in inflammation, for example, typhoidvaccine,81 infusion of endotoxin,82 or inhalationof antigens.83 A neurally mediated interoceptivepathway, recruiting the basal and posterior ven-tromedial thalamus, and dorsal mid- and PI, isactivated after typhoid vaccination.84 Specific com-ponents of SBs are associated with functionalchanges within interoceptive brain regions, includ-ing the mid-insula (fatigue),84 subgenual cingu-late (mood change),81 and the midbrain substantianigra (psychomotor slowing).85 The insula is fur-ther implicated in the expression of inflammation-induced subjective experiences of fatigue, malaise,and social disconnect.86 Increase in the right ante-rior insula (AI) metabolism tracks the loss ofinterest in social interaction,87 while heightenedconnectivity between the AI and middle cingulatecortex predicts subjective malaise and discomfortafter induction of inflammation.88 These findingsindicate a role for the insula in mediating the expe-riential side of SBs, a hypothesis that is in linewith the theoretical proposal and emerging evi-dence implicating the IC in subjective experience ofconscious motivational and emotional states arisingfrom IPP.35,70

The same brain regions that support emotionsand affective regulation are thus involved in SBs(and their origin in IPP), highlighting a connectionbetween inflammation, SB, and mood disorders.86

Changes in motivation are a hallmark of both SBsand major depressive disorder.89 Low motivationto move can be adaptive in the context of physi-cal illness, as it enables energy conservation while



prioritizing resources for fighting off inflammationand infection. In the case of prolonged or very severeinflammation, however, these motivational changescan mark the onset of a depressive episode.86 Moti-vational changes ultimately influence processingof reward-stimuli;18,19 correspondingly, responseto reward outcomes is altered following inflam-mation. This is reflected on both the neural andbehavioral level; reactivity within the ventral stria-tum, a center of (predictive) reward processing90

is decreased, and both subjective and objectivemeasures of anhedonia (the absence of reactivityto positive stimuli) are increased.82 Distinct brainareas connected with interoceptive processing playa major role in the regulation of homeostaticallyrelevant behavioral motivations.47,91 To maintainthe organism’s integrity, information about aber-rant bodily states is conveyed by interoceptive path-ways, ultimately enabling behavior to balance outequilibrium through motivational changes result-ing in the necessary action.42 Social withdrawal isanother symptom that SBs and depression share.Not participating in social interaction often leads tofeelings of isolation and loneliness, and contributesto the maintenance of depressed mood.92 Inflam-mation, through interoception, thus facilitates pro-cesses that underlie and enhance feelings of socialisolation; induce feelings of social disconnect;93 andimpair the processing of social cues.94

Taken together, SBs illustrate how perturbationof internal bodily states affects neural representa-tions, emotional states, and executive behaviors.These reactive patterned responses are mediatedvia interoceptive pathways that typically supportadaptive social, emotional, and motivational behav-iors. The next section focusses on fatigue as an SB,chronic condition, and symptom of inflammatoryor immunological diseases. Both SBs and fatigue canbe conceptualized under the IPP principle, as willbe detailed in the following.

FatigueFatigue is a disorder that is characterized in the ICD-10 as a long-term condition that includes severe andconstant feelings of tiredness, trouble concentrat-ing and carrying out daily activities, generalizedaches and pains, fever, and sleep disturbances.95

It can be part of SBs, and as such have adaptiveeffects in that it prioritizes rest to save resourcesand may facilitate the role of fever in fighting off

infections.96 Fatigue can also appear on its own asa chronic condition (chronic fatigue syndrome),97

which affects approximately 20% of the generalpopulation.98 Its prevalence increases to 50%, how-ever, as a symptom in conditions that are associ-ated with a compromised immune system,99 suchas cancer,100 autoimmune diseases like multiplesclerosis,101 and fibromyalgia.102 Fatigue is stronglyassociated with depression,103 and listed in bothDSM-5 and ICD-10 as a core criterion for majordepression.95,104

Fatigue is a multidimensional construct thatinvolves impairment of motor and cognitive pro-cesses, the subjective experience of fatigue, andbehavioral changes affecting every day activities.105

Research on fatigue emphasizes approaches thatassociate the condition with peripheral inflamma-tion and its influence on brain structures involved insteering immunological responses.79,106 Brain struc-tures involved in fatigue include the insula andthe frontostriatal network, most notably the ventralstriatum.107 In this context, signals of peripheralinflammation reach the frontostriatal network viaimmune-to-brain communication pathways thatinvolve activation of microglia. This network under-lies response to reward, which supports anticipa-tion and motivation, both of which are reduced infatigue.108 An altered frontostriatal network due toinflammation is thus one strong candidate for theneurobiology of fatigue.107 AIC has been associatedwith the experiential quality of emotions and feel-ings, and is thought to play a key role in the experi-ence of fatigue.108 After the experimental inductionof inflammation via typhoid vaccine, fatigue waspredicted by altered reactivity within the mid- andPI, and the ACC.81 This suggests that interoceptivesignaling of inflammatory states, and their impacton brain regions that are associated with process-ing interoceptive input, is an important factor insubjective experience of fatigue and vitality/agency.

Newly emerging views on fatigue are turn-ing toward approaches that do not only considerthe bottom-up effects leading to fatigue, but thatalso take into account possible top-down influ-ences. From a Bayesian perspective, SBs in general,and fatigue in particular, may occur as a con-sequence of aberrant metacognitive beliefs aboutthe brain’s capacity to predictively control bod-ily states.109 These aberrant beliefs could bethe product of immunological and metabolic



disturbances that remain unresolved, or mayresult from the chronic exposure to environ-mental or social stress. Chronic stress mani-fests physiologically,110 for example, as increasedcortisol levels,111 or as impaired hypothalamus–pituitary–adrenal (HPA) axis activation.112 Theresulting disturbances feed back into cerebralcircuits, where increased cortisol levels disruptN-methyl-D-aspartate receptor function,14 whichhas been claimed to be involved in the generationand updating of belief representations.113 This posi-tive feedback loop may be the basis for the metacog-nitive belief that the system is unable to regulatebodily states, due to a chronically occurring dis-crepancy (i.e., prediction error) between predicted(i.e., belief based) and sensed internal states. Resort-ing to SBs and fatigue may thus be an adaptiveresponse to a metacognitive evaluation of the sys-tem’s dysfunctional regulatory capacities that aremanifested in the failure to reduce interoceptive pre-diction error.109

Further research is needed to determine if distinctlevels of interoceptive processing accuracy are com-promised in individuals with high levels of fatigue,which would indicate another possible source ofmaladaptive regulation of bodily states.

DepressionMajor depressive disorder is associated with affec-tive symptoms such as low mood, and negativecognitions such as pervasive negative thoughts andintense feelings of hopelessness.114 In addition,somatic symptoms, including aches and pains, dis-ordered sleep, loss of appetite, and fatigue are just asfrequent and occur universally across cultures.115,116

Recognition that somatic alterations are an impor-tant factor for changes in emotion and cognition hasgrown over the past decade.22,117 Depression is asso-ciated with autonomic dysfunction, manifesting asdecreased baroreflex sensitivity,112,113 reduced pha-sic skin conductance responses,14,118 and reducedheart rate variability.118 In addition to autonomicalterations, signs of heightened inflammation havebeen documented in depression.39 In a subsetof individuals with depression, cumulative meta-analyses demonstrate raised inflammatory markers,particularly IL-6 and C-reactive protein.40 Distur-bances in brain function are linked to increases inperipheral inflammatory markers, where, for exam-ple, reduced functional connectivity of corticostri-

atal reward circuitry is observed in depressed indi-viduals with elevated C-reactive protein.58

Healthy controls demonstrate a correlationbetween interoceptive accuracy and intensity ofexperienced emotions, where better accuracy corre-lates with reports of more intense feelings,33 raisingthe possibility of an impairment in interoceptiveaccuracy in depression where emotional “numb-ness” is often reported. However, the experimentsdetailing patterns of altered interoceptive accuracyassociated with depression present a more com-plex relationship.22 The ability to accurately per-ceive one’s heartbeat is negatively correlated withdepression symptoms in healthy controls, an effectonly found to manifest when coupled with highanxiety.117 In an experiment that contrasted inte-roceptive accuracy across three groups (healthycontrols, community sample with moderate depres-sion, and a more severely depressed clinical sample),only the moderately depressed sample had signifi-cantly impaired interoception.22 Interestingly, andcounter to predictions, the more depressed groupdisplayed levels of interoceptive accuracy compa-rable to the control group,117 though this effectmay have been influenced, in part, by medicationstatus.22 Increasingly, nuanced investigation of inte-roceptive behavioral impairments linked to specificclusters of symptoms (e.g., differentiating negativeeffect from emotional numbness) may reveal clearerassociations in depression.

Decreased heartbeat perception accuracy isaccompanied by significantly reduced HEP ampli-tudes in depressed individuals.62 The neurocircuitryunderlying attention to visceral interoceptive sensa-tions was assessed in unmedicated individuals withmajor depressive disorder (MDD) relative to con-trols. Activity in the dorsal mid-insula and a networkof brain regions involved in emotion and visceralcontrol were decreased in the MDD group. More-over, resting state functional connectivity betweenthe amygdala and the dorsal mid-insula cortex wasincreased in MDD and predictive of depressionseverity.46 Together, these results suggest that thebrain representation of interoceptive focus may bealtered in MDD.

From a theoretical approach, IPP (includingthe EPIC model) provides a potential insight intodepressive mechanisms, extending to the hypothe-sis that structural abnormalities and dysfunctionalmetabolism within the agranular visceromotor



cortices may be underlying causes of depressivestates, particularly when associated with inflam-mation and SBs.2 Visceromotor cortical dys-function causes imbalance between demand andresponse through overpredicting metabolic energydemands.119 This may engender overactivity of theHPA axis and thereby increasing levels of proin-flammatory cytokines,66 causing concomitant alter-ations in the immune and endocrine system.120

This aberrant process will compromise dependentcoupling of interoceptive predictions and inputs atthe thalamocortical level, leading to a speculatedincrease in interoceptive prediction errors. Down-regulation of these noisy error signals by preci-sion units leaves them less able to influence andinform predictions. To further reduce predictionerrors, the interoceptive network is left with twoprincipal options: maintaining the dysfunctionalpredictions, or generating afferents that match thesepredictions. The latter may lead to noisier sig-nals that fail to update predictive models. Thisinsensitivity to prediction errors might mean thatfaulty predictions will maintain metabolic energydemand, until the endocrine and immune systemhave reached their limit. Depression, according toEPIC, ensues when the error signals can finally nolonger be ignored and must be reduced, enlisting SBsto conserve energy.2 The insensitivity to predictionerrors in combination with ever-more demandingpredictions is hypothesized to lead to a “locked-in” (attractor state) brain that maintains a viciouscycle of faulty predictions and noisy error signals.121

Inefficient energy regulation may underlie negativeaffect, biasing the system more toward avoidancebehaviors and social withdrawal.110 A hypotheticalIPP model of depression (and fatigue) thus connectsaberrant allostatic processes to imbalanced affectiveprocessing, driving both somatic and experientialemotional symptoms of depression.

Autism spectrum conditionsAutism spectrum conditions (ASCs) are classifiedas neurodevelopmental conditions that are asso-ciated with stereotypical and restricted behavioralpatterns, altered sensory reactivity, and social andemotional difficulties.122

Research is currently investigating the nature ofinteroceptive deficits associated with ASCs. Workin children is divergent, with one study suggest-ing that interoceptive accuracy is intact in autis-

tic children and adolescents (aged 8–17),123 while asubsequent study found that interoceptive accuracy,ascertained using heartbeat tracking, was markedlyimpaired in a comparable child and adolescentautistic sample.52 Impaired interoceptive accuracyhas also been shown in autistic adults, demon-strated using the heart beat tracking task, where sig-nificantly lower interoceptive accuracy scores wereobserved relative to a matched control group.27

One study, however, demonstrates data to suggestthat autism per se does not necessarily lead tointeroceptive impairments, but instead alexithymia,which is highly comorbid with ASCs, is associ-ated with reduced interoceptive accuracy.124 Alex-ithymia is a subclinical condition characterized by areduced capacity to detect and identify emotionsin oneself and others,125 and thus the emotion-processing deficits in autism, characterized by highalexithymia, may be the principal driver for intero-ceptive impairments in ASC. A recent study revealedthat impaired interoceptive awareness, but not inte-roceptive sensitivity, is linked to autistic traits,alexithymia, and empathy.126 Other studies innonautistic populations have demonstrated a linkbetween high alexithymia and impairments ininteroceptive accuracy.127 Together, these resultssuggest that interoceptive accuracy may beimpaired in autistic individuals, and that this maybe particularly coupled with emotion-processingdeficits.

In contrast to behavioral performance on inte-roceptive tests, interoceptive sensibility, assessedvia self-report questionnaires, is elevated in autisticadults, despite these same individuals demon-strating a relative impairment in interoceptiveaccuracy.27 This is in line with research docu-menting that interoceptive aptitude ascertainedusing self-report does not necessarily predict actualperformance measures.10 Moreover, it suggests thatthese interoception dimensions may further divergein clinical populations, with autistic individualshaving an overinflated belief in their interoceptiveaptitude relative to their performance accuracy.This enlarged discrepancy between objective andsubjective interoceptive performance denotespotentially poor interoceptive sensory precisionin ASCs and is in line with accounts of autismconceptualized as a condition with an imbalance ofthe precision ascribed to sensory evidence relativeto prior beliefs.128



Altered insula reactivity has been observed inautistic individuals across a variety of distinctemotion-processing tasks, including response inhi-bition of emotional stimuli,129 processing ofbodily expressions,130 and the processing of incon-gruent emotional information.131 ASC is also asso-ciated with altered intrinsic functional connectivityof anterior and PI regions and specific brain regionsinvolved in emotion and sensory processing.132

Together, these results suggest that altered sensoryprecision marked by reduced interoceptive accu-racy underscored by aberrant insula activity andfunctional connectivity may contribute to emotion-processing deficits observed in ASC and alexithymiamore generally.

Anxiety disordersAnxiety disorders include panic disorder, agorapho-bia, social anxiety, generalized anxiety disorder, andspecific phobias.104 Investigations into interoceptivealterations in anxiety disorders are mixed, reflect-ing the diversity of anxiety conditions and alsothe range of methodological approaches.133 Stud-ies have reliably found that interoceptive sensibil-ity (i.e., self-report measures of interoception) iselevated in individuals with a variety of anxiety-related conditions.134,135 In accordance with this,interoceptive accuracy is also frequently elevatedin individuals with anxiety, indexed by height-ened performance on heartbeat perception tests inpatients with anxiety and elevated occurrence oftrait anxiety symptoms with heightened interocep-tive accuracy in nonclinical cohorts.22,136 However, astraightforward relationship between elevated inte-roception in anxiety is challenged by a number ofstudies that either do not show a relationship,54,56

or reveal a reverse relationship, with higher levels ofanxiety related to reduced interoceptive accuracy.50

Recent work partly reconciles these divergent find-ings, by demonstrating that it is the relationshipbetween subjective and objective measures of intero-ception, which predict anxiety symptomatology (inboth an autistic population and healthy controls).27

Specifically, individuals with an elevated interocep-tive trait prediction error (ITPE), derived from apropensity to belief one is interoceptively profi-cient despite relatively poor interoceptive accuracy,had heightened trait anxiety scores.27 ITPE refers tothe specific discrepancy in interoceptive dimensionsdescribing low accuracy paired with perceived high

self-reported sensitivity to internal signals. Here,the self-report measure (such as the BPQ) is abelief about general interoceptive aptitude, poten-tially serving as a prior. In contrast, metacognitiveinteroceptive accuracy depends on the moment-to-moment divergence of interoceptive dimensions,such as confidence–accuracy correspondence. Thisinteroceptive predictive error is potentially consis-tent with theoretical work that has posited that thepathogenesis of anxiety is related to noisy intero-ceptive input in combination with noisily ampli-fied self-referential interoceptive predictive beliefstates.137

Eating disordersEating disorders (EDs) are characterized by atyp-ical food intake (e.g., restriction in anorexia ner-vosa, or binging and purging in bulimia nervosa),and are often accompanied by a distorted bodyimage.138 Poor interoception has been linked tobody image concerns,57 and a number of empir-ical findings converge to suggest potential distur-bances in the processing of interoceptive signals inindividuals with EDs. Interoceptive self-report inthis population has been primarily probed using theEating Disorder Inventory (EDI),139 which assessesthe subjectively reported ability to discriminate sen-sations of hunger and satiety, and to respond toemotional states. Patients with EDs report impair-ments in these abilities,140 which could reflect ageneralized deficit in interoceptive processing.Empirical findings support this in part, with studiesdemonstrating impaired interoceptive accuracy inanorexia nervosa patients relative to matched con-trols using a heartbeat perception test.76,141 Otherstudies, however, fail to show impaired interoceptiveaccuracy in anorexia nervosa,75 and instead docu-ment enhanced reported detection of interoceptivesensations.

To date, only few studies have investigatedwhether interoception is compromised in bulimianervosa, although it is suggested that interoceptiveprocessing deficits drive the symptoms and asso-ciated behaviors in bulimia.61 One study inves-tigating interoceptive accuracy in women with acurrent diagnosis of bulimia nervosa observed nodifferences in heartbeat-tracking task performancewhen correcting for the presence of covaryingcomorbid alexithymia, depressive symptoms, andanxiety.142 In contrast, women who had recovered



from bulimia nervosa (without a prior diagno-sis of anorexia nervosa) demonstrated significantlyreduced interoceptive accuracy compared withcontrols.91

Neural representation of bodily state is altered inEDs. During an interoceptive attention task (focus-ing on the heart, stomach, and bladder), the indi-viduals with anorexia nervosa display significantlyreduced activation in the AI during heartbeat per-ception, and significantly reduced activation in thedorsal mid-insula during stomach interoception,relative to a matched control group.143 Individualswith anorexia nervosa display reductions in func-tional connectivity in the thalamo−insula subnet-work, thought to reflect changes in the propagationof sensations that convey homeostatic imbalances.30

Bulimia nervosa is associated with increased graymatter volumes within the ventral AI,29 and bingeED is associated with increased insula activity whenviewing food images after an overnight fast.25

Interestingly, altered interoception is not onlyfound in patients who are currently suffering froman ED. Impairments in interoceptive self-report, asmeasured by the EDI, predict vulnerability to thedevelopment of EDs, as revealed in longitudinalstudies.144–146 It is not yet known whether otherdimensions of interoception, such as interoceptiveaccuracy or neural processing of bodily state,would also demonstrate premorbid alterations.Nevertheless, interoceptive measures, at leastascertained via self-report, may serve as a markerfor ED vulnerability, facilitating potential earlyintervention.

The exact nature of interoceptive impairmentin EDs remains unclear, as it varies across thetype of ED, and studies often do not take intoaccount comorbidities, such as anxiety, depres-sion, and alexithymia, which are also associatedwith aberrant interoception.125,147 Differences inmethodology also potentially contribute to furtherambiguity, with objective and subjective dimen-sions of interoception being used interchangeably,and the interoceptive axis (e.g., cardiac versusgastric) requiring further differentiation and sys-tematic evaluation. Behavioral, neuroimaging, andpsychophysiological studies nonetheless show thatseveral dimensions of interoception are affected indifferent types of EDs. Further research with ter-minological and methodological consistency couldhelp to create a more differentiated account of how

interoception contributes to, and maybe even pre-dict, the occurrence of EDs.

Conclusion

There is increasing evidence that the signaling, sens-ing, and detection of bodily states are implicated inphysical and mental well-being.45,148 Interoceptionresearch contributes an important dimension to thefield of health neuroscience, by providing a pow-erful explanatory understanding into the dynamicinteractions between body, brain, and mind thatunderlie pathophysiological disturbances acrossphysical and mental disorders. Capitalizing onstrengthening theoretical frameworks, includingIPP, further research needs to extend systematicinteroceptive investigation across different bodilyaxes, and include measures of interoception thatcover neural signaling, objective behavioral perfor-mance, subjective experiences and beliefs, alongsidemetacognitive measures, to delineate comprehen-sively interoceptive predictors of specific symptoms.Where aberrant interoceptive processing appearsrelated to symptoms, therapeutic efforts target-ing interoception could prove to alleviate specificconditions. Interventions based upon biofeedback,for example, could improve interoceptive accuracy.More accurate access to internal signals, in turn,may be helpful to contextualize them within a non-threatening setting, potentially decreasing anxietysymptoms.149 Understanding the precise nature ofinteroceptive deficits has important clinical impli-cations, as insight into interoceptive mechanismsmay reveal new therapeutic targets to promote novelinterventions.

Competing interests

The authors declare no competing interests.

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