Diseases, Disorders, and Comorbidities of Interoception

Study at a glance

• Authors: Bruno Bonaz, Richard D. Lane, Michael L. Oshinsky, Paul J. Kenny, Rajita Sinha, Emeran A. Mayer, Hugo D. Critchley
• Year: 2021
• Journal: Trends in Neurosciences 44(1):39-51
• DOI: 10.1016/j.tins.2020.09.009
• Design: Review (clinical/translational); no new data. Arising from the NIH Blueprint workshop ‘The Science of Interoception and Its Roles in Nervous System Disorders’, Bethesda, 16-17 April 2019

Key findings

• Extends the interoception-and-illness argument out of psychiatry and into somatic medicine — IBS and the disorders of brain-gut interaction, chronic pain, urological chronic pelvic pain syndrome, arthritis and joint hypermobility, dysautonomia — the wiki’s first source treating gastroenterology, urology and rheumatology as interoceptive conditions.
• Organizes all of it under one hierarchical model: Stephan/Petzschner’s allostatic self-efficacy circuit (its Figure 1), where homeostatic reflex arcs are enslaved by descending allostatic policies from agranular visceromotor cortex, and ‘interoceptive dysfunction’ is a lightning bolt that can strike at any level of the neuraxis and perturb the whole bidirectional system.
• Claims the level at which the failure occurs, not the diagnosis, determines the symptom: higher-order cognitive ‘beliefs’ or emotional dysfunction drive maladaptive responses expressed through endocrine, immune, inflammatory, somatic, cardiovascular and neurological channels — and conversely peripheral dysfunction propagates upward.
• Reports that neuroimaging across these unrelated-looking brain-body disorders reveals similar alterations in cortical/subcortical reactivity and network connectivity, proposed as the shared interoceptive mechanism behind three recurring clinical features: anticipatory symptom-related anxiety, central sensory amplification, and aberrant autonomic activation.
• Uses lesion evidence to dissociate interoceptive dimensions neurologically: bilateral ischemic damage to insula and ACC can leave residual somatosensory but not viscerosensory heartbeat experience; fronto-insular-temporal stroke links heartbeat-detection deficits to deficits in emotion recognition and theory of mind; focal insular lesions produce disgust insensitivity, acquired alexithymia, psychopathy, and loss of drug-craving.
• Introduces the microbiota-gut-brain axis as an interoceptive signalling channel — short-chain fatty acids and bacterial lipopolysaccharides acting on enteroendocrine cells and toll-like receptors on vagal afferents — while conceding that causality for dysbiosis in IBS ‘is elusive’ and that microbiome-targeted therapy has ‘generally mixed results’.
• Names early adverse life events (EALs) as a cross-cutting determinant of symptom expression, with a rodent maternal-deprivation model producing stress-induced visceral hypersensitivity, gut-mucosal dysfunction, raised HPA response and heightened anxiety in one animal.
• Sets out the translational agenda — interoceptive biomarkers, and bioelectronic medicine (VNS, spinal cord stimulation, TMS, tDCS, DBS) as ‘electroceutical’ intervention — while stating plainly that of the markers currently used in research, ‘few of these measures have yet found broad clinical application’.

Limitations

• A narrative review with no data, no systematic search and no meta-analysis, assembled from a workshop; the seven authors write largely about their own clinical territories (Bonaz on vagus/gut, Mayer on brain-gut, Sinha on stress/addiction, Kenny on nicotine/habenula, Critchley on hypermobility), so the section boundaries track author expertise rather than an argued taxonomy.
• The unifying claim is asserted more than demonstrated. ‘Similar alterations in cortical and subcortical functional neural reactivity and network connectivity’ across brain-body disorders rests on one citation (Icenhour et al. 2017 on IBS) and is exactly the kind of shared-network finding that reverse inference makes cheap — the wiki’s locationist debate problem transposed to clinical populations.
• Causal direction is unestablished nearly everywhere, and the paper mostly says so: dysbiosis causality ‘elusive’, ‘more research is needed to link causally hypothesized interoceptive deficits to fatigue in MS’, chronic-pain sensibility/awareness data ‘less conclusive’. The correlational deficit-to-mechanism step is taken repeatedly regardless.
• Depends heavily on the resting cardiac tasks to establish ‘interoceptive deficits’ in MS, Parkinson’s, Alzheimer’s, Tourette’s, autism and chronic pain, with none of the validity caution that Quadt/Critchley (2018) and Petzschner et al. (2021) supply — despite Critchley co-authoring this paper too. See Is the heartbeat-counting task a valid measure of cardiac perception?.
• Species and evidence grade are mixed without flagging: the pelvic-disorder section runs on rodent micturition and urine-marking work, the addiction/metabolism section on mouse habenular circuitry, and both sit in the same prose as human patient findings.

Connections

• Methods: Heartbeat detection task, Event-related potentials
• Concepts: Interoception, Central autonomic network, Functional disorders, Disorders of brain-gut interaction, Microbiota-gut-brain axis, Chronic pain, Joint hypermobility, Early adverse life events, Craving, Interoceptive psychopathology, Allostasis, Homeostasis (and feelings as homeostatic sensations), Insular cortex, Anterior cingulate cortex (ACC), Alexithymia, Sickness behaviors, HPA axis, computational psychosomatics, Interoceptive taxonomy (Farb et al. Box 1), Age-related interoceptive decline, Polyvagal theory, Psychopathy
• Debates: Is more interoceptive awareness better?, Is the heartbeat-counting task a valid measure of cardiac perception?, inferential?
• Related studies: Chen et al. (2021), Quadt et al. (2018), Khalsa et al. (2018), Petzschner et al. (2021), Craig (2002), Oldroyd et al. (2019), Kolk (1994), Quigley et al. (2021), Jones et al. (2010)

The third paper the wiki has read from the Trends in Neurosciences January 2021 interoception special issue, and the one that takes the field furthest from where the rest of this wiki lives. Almost everything here is about emotion, self, and mental health. This review is about gastroenterology, urology, rheumatology and neurology — IBS, bladder pain, hypermobile joints, multiple sclerosis, Parkinson’s, Alzheimer’s — argued to be interoceptive conditions in the same sense that panic and depression are.

Its natural companion is Weng et al. (2021), the issue’s intervention review, which cites this paper (their reference 4) for the premise that clinical disorders involve disrupted interoceptive processes across one or more physiological systems. Read together the pair is a diagnosis-and-treatment pairing: Bonaz et al. supply the conditions and the neuraxis-wide failure model, Weng et al. supply the three levels at which one might intervene — and neither supplies a rule for matching a patient to a level. The Bioelectronic medicine material introduced here is substantially extended there (taVNS, RAVANS).

It contradicts nothing in the wiki. Its value is coverage: it is the first source here to treat interoception as a medical rather than psychological subject, and the first to make the whole neuraxis, not just cortex, the site where interoception can fail.

The organizing claim: dysfunction at any level, expressed at every level

The frame is worth stating precisely because it is what licenses the review’s range. Interoception is a bidirectional predictive system running from receptor to cortex; therefore:

Perturbed interoceptive representation, integration, and predictive control can originate at any level of the neuraxis and impact distinct component processes or affect the whole bidirectional system.

Downward: “higher-order cognitive ‘beliefs’ or emotional dysfunction can drive maladaptive responses expressed through endocrine, immune, inflammatory, somatic, cardiovascular, and neurological channels.” Upward: peripheral pathology propagates into representation. The review’s Figure 1 is Stephan, Petzschner and colleagues’ allostatic self-efficacy circuit reproduced directly (adapted from their Figure 7), with a lightning bolt drawn onto it marking where interoceptive dysfunction strikes — and arrows radiating out to psychiatric disorders, neurological disorders, addiction, chronic visceral pain, neurodegenerative disease, autism, pelvic disorders, arthritis and comorbid conditions.

That is a strong architectural commitment and the wiki should record it as such: the same diagram the computational psychosomatics page holds as a theory of fatigue and depression is here made the general theory of psychosomatic medicine. See Allostasis, where allostatic self-efficacy already sits, and Central autonomic network, the anatomical layer the review adds beneath it.

Three clinical features are proposed as the shared surface expression across these disorders: anticipatory symptom-related anxiety, central sensory amplification, and aberrant autonomic activation. If the unifying claim has empirical content, it is here.

The neurological section: interoception dissociated by lesion

The most evidentially solid material in the paper, and new to the wiki, because it is the one place where interoceptive dimensions come apart through damage rather than through psychometrics.

• Viscerosensory vs somatosensory heartbeat experience dissociate. Patients with bilateral ischemic damage to insula and ACC may retain residual somatosensory but not viscerosensory experience of their own heartbeats, tested under pharmacologically induced tachycardia (García-Cordero et al. 2016; Khalsa et al. 2009’s isoproterenol method). The felt heartbeat is not one thing.
• Cardiac interoception, emotion recognition and theory of mind fall together. After fronto-insular-temporal ischemic stroke, heartbeat-detection deficits are linked to deficits in emotion recognition and mentalizing — read as confirming that network’s role in integrating interoceptive information into emotional and social representation.
• Focal insular lesions produce specific affective losses: disgust insensitivity, acquired Alexithymia, Psychopathy, and loss of drug-craving — the last being a striking convergence with the addiction material later in the same paper.
• Alzheimer’s disease shows a four-way interoceptive deficit that maps cleanly onto the wiki’s taxonomy: impaired accuracy (imprecise fingertap tracking of own heartbeats), abnormal heartbeat-evoked potential modulation, impaired interoceptive learning (negligible gain from feedback), and impaired metacognitive awareness (confidence-accuracy mismatch). Prolonged vagus somatosensory evoked-potential latencies distinguish AD from major depression.
• Tourette syndrome: interoceptive deficits linked to the premonitory urge-to-tic — an interoceptive account of a symptom usually described motorically.
• Multiple sclerosis and Parkinson’s: structural insula abnormality and altered cardiac-interoception responses; interoceptive processing deficit proposed as a behavioural marker for subtyping Parkinson’s.

Also here: functional (psychogenic) neurological disorders — functional motor disorders and functional seizures — where interoceptive abnormalities predict dissociative symptoms and seizure frequency. See Functional disorders.

The caution the wiki should attach: nearly all of this rests on the resting cardiac tasks, and Critchley co-authored both the review that flags those tasks’ generalizability problem and this one, which uses them without the flag. See Is the heartbeat-counting task a valid measure of cardiac perception?.

The somatic-visceral sections: medicine as interoception

This is the review’s distinctive payload, and none of it existed in the wiki before.

IBS — the most common disorder of brain-gut interaction, 5–20% of people worldwide, still diagnosed on symptom criteria in the absence of agreed biomarkers or organic pathology. IBS patients score high on interoceptive sensibility (subjective self-report), consistent with a strong focus on gut symptoms, while deficits in interoceptive processing increase risk. That accuracy-low/sensibility-high shape is the same signature the ITPE literature reports for autism and anxiety, reached independently in gastroenterology — the wiki’s best evidence that the discrepancy profile is not an artefact of one measurement tradition.

The microbiota-gut-brain axis — an interoceptive channel the wiki did not have, and one that does not run through neurons at the periphery at all. Bacterial metabolites reach the CNS via systemic circulation or via enteroendocrine cells relaying luminal signals to vagal afferents; short-chain fatty acids stimulate EECs to release neurotransmitters activating those afferents; bacterial lipopolysaccharides directly activate toll-like receptors (TLR4) on vagal afferents. This is the humoral channel Quadt et al. flagged, extended to a signalling source that is not the body’s own.

Chronic pain — deficits in objective interoceptive accuracy predict symptom severity; sensibility and metacognitive awareness data are “less conclusive.”

Pelvic disorders — urological chronic pelvic pain syndrome as chronic idiopathic visceral (i.e. interoceptive) pain, with functional abnormality in a bladder–pontine micturition centre–locus coeruleus–forebrain pathway, linked to EALs and exacerbated by stress. ~60% of women with pelvic floor disorders have overlapping bladder and bowel symptoms, and experimental bladder filling and rectal distension both activate the insula — offered as a partial account of the overlap.

Joint hypermobility — Critchley’s own line, and the most surprising item in the review. Variant connective tissue (the Ehlers-Danlos spectrum) is associated with higher interoceptive sensitivity, heightened insula reactivity, and anxiety symptoms; postural orthostatic tachycardia syndrome is a common comorbidity mediating affective symptoms; and both hypermobility and PoTS are increasingly recognized in autism and ADHD. A connective-tissue variant with an interoceptive and psychiatric phenotype is the strongest single case for the review’s bottom-up limb.

Comorbidity, adversity, and the addiction thread

The review’s account of why these conditions cluster is early adverse life events. The animal evidence is specific — maternal deprivation in rats produces long-term central CRF changes and predisposes adults to stress-induced visceral hypersensitivity, with increased defecation, intestinal mucosal dysfunction under stress, greater colitis sensitivity, raised HPA response and heightened anxiety in the same animal — which is the clearest demonstration in the paper that one early perturbation can express across organ systems. The human side is correlational: childhood trauma negatively correlates with interoceptive ability (heartbeat detection after cold pressor), and maltreatment is associated with lower cardiovascular and HPA responses alongside higher subjective distress. Maternal nurture is named as the protective factor, with a mother’s reading of her child’s bodily needs laying the foundation for mentalization — Fotopoulou & Tsakiris’s “mentalizing homeostasis,” which is Social origins of interoception arriving from a second direction. Compare Oldroyd et al. (2019).

On addiction, Craving is framed as an interoceptive motivational feeling that varies with drug state (intoxication, tolerance, withdrawal, abstinence, recovery), with alcohol acting partly through a humoral interoceptive route (HPA stress-hormone release, glucocorticoid receptor upregulation in limbic forebrain and mPFC), and stress hormones themselves serving as conditioned interoceptive cues motivating consumption. The eating sections run the same logic through satiety: reduced interoceptive sensitivity in obesity, distorted interoceptive prediction in anorexia, leptin resistance of vagal afferents accompanying hyperphagia.

Kenny’s molecular section is the finest-grained mechanism in the paper — nicotine activating GLP-1 neurons in the NTS, exciting medial habenular projections to the interpeduncular nucleus, attenuating nicotine reward and hyperglycemia in mice — and also the furthest from anything else in the wiki. Recorded as mouse circuit work with an interoceptive framing, not as a human finding.

The translational close

Two deliverables are proposed. Interoceptive biomarkers — questionnaires, heartbeat-detection performance, autonomic measures (baroreflex sensitivity, HRV), neuroendocrine response (salivary cortisol, NPY), neuroimaging, M/EEG — with the concession that “few of these measures have yet found broad clinical application in this role.” That is the same empty cupboard the roadmap reported in 2018 and Petzschner et al. report in the same issue, now stated a third time.

And Bioelectronic medicine — VNS, spinal cord stimulation, TMS, tDCS, DBS as “electroceutical” intervention on brain-body communication, alongside the psychological route (biofeedback, interoceptive exposure of panic). This is the wiki’s first translational thread that treats the interoceptive pathway rather than interoceptive attention as the target — a genuinely different intervention logic from the contemplative and exposure material the wiki otherwise holds. Bonaz’s own VNS/anti-inflammatory work is the evidence base cited.

Sex and gender differences in interoceptive sensitivity and neural reactivity are flagged as an under-handled consideration for biomarker development.

Placement, and the vagus

The issue’s anatomical quadrant, Berntson & Khalsa (2021), is the wiring this review’s argument presupposes — and it cites this paper (as reference 79) for the CAN’s cardiovascular pathology. Two things it adds here. The CAN’s cortical top row is now traced rather than inferred (retrograde rabies from adrenal medulla and stomach), which strengthens the “dysfunction at any level” claim by showing the levels really are connected — but the same tracing finds the monkey’s three prefrontal adrenal networks largely absent in rat, which weakens every rodent-derived step in the argument. And the immune reflex this review runs through the vagus gets its efferent limb specified (NTS → DMN/nucleus ambiguus/RVLM, cholinergic suppression of splenic cytokines) alongside the authors’ admission that the role of the ascending targets in immune regulation “is unclear.”

A fourth quadrant joined the issue with the Quigley et al. (2021) ingest — the functional one, asking what interoception is for. Two direct points of contact: their lower-urinary-tract physiology is the normal-function counterpart to this review’s pelvic-pain section, and their reading of homeostasis as retaining local autonomy sits against this paper’s “enslaved” reflex arcs (recorded on Homeostasis (and feelings as homeostatic sensations)).

Read as the clinical-medicine quadrant, standing beside Quadt et al. (2018) (psychiatric conditions, same Critchley lineage, more careful about measurement) and Petzschner et al. (2021) (the computational quadrant, cited here as reference 118). Where Quadt et al. work six psychiatric conditions through one inferential mechanism, Bonaz et al. work twenty-odd conditions across all of medicine through one architectural diagram — broader, shallower, and more useful for knowing that the claim has been made than for knowing it is true.

One structural note. The vagus nerve carries this paper: immune-to-brain signalling, the microbiota axis, VNS as therapy, vagal SEP latencies in Alzheimer’s. The wiki’s only vagus page is Polyvagal theory, held at one remove through Somatic Experiencing and flagged as contested. Bonaz is a vagus researcher writing about the vagus, and nothing here depends on or endorses Porges’s three-branch scheme — so the wiki now holds mainstream vagal-interoceptive material that is entirely independent of the polyvagal framework. Worth keeping separate.