Emotional Processing, Interoception, and Illness Cognitions
1 Garfinkel2015 — Knowing Your Own Heart: Interoceptive Accuracy vs Awareness
Full Citation:: Garfinkel SN, Seth AK, Barrett AB, Suzuki K, Critchley HD. Knowing your own heart: distinguishing interoceptive accuracy from interoceptive awareness. Biological Psychology. 2015;104:65–74. (Garfinkel et al. 2015) DOI:: 10.1016/j.biopsycho.2014.11.004 Key Findings::
- Established tripartite interoceptive model: accuracy (objective performance), sensibility (self-reported), and awareness (metacognitive insight)
- Accuracy and sensibility are frequently dissociated in clinical populations — key for interpreting patient-reported body awareness vs objective deficitsConclusion:: Foundational framework for understanding interoceptive dysfunction in clinical conditions. The accuracy-sensibility dissociation has direct relevance to ME/CFS where patients may report heightened body awareness while showing objective interoceptive deficits. Limitations:: Healthy volunteers; non-clinical sample; heartbeat detection task may not generalize to other interoceptive channels. Certainty:: 0.75
2 Quadt2018 — The Neurobiology of Interoception in Health and Disease
Full Citation:: Quadt L, Critchley HD, Garfinkel SN. The neurobiology of interoception in health and disease. Annals of the New York Academy of Sciences. 2018;1428(1):112–128. (Quadt, Critchley, and Garfinkel 2018) DOI:: 10.1111/nyas.13915 Key Findings::
- Comprehensive review establishing interoception as transdiagnostic mechanism in psychiatric and neurological disorders
- Insula identified as hub of interoceptive processing with predictive coding architecture
- Links interoceptive dysfunction to anxiety, depression, autism, and functional disordersConclusion:: Provides the theoretical framework for applying interoceptive models to chronic fatigue states. Directly relevant to ME/CFS interoceptive predictive processing content. Limitations:: Narrative review; no new empirical data; comprehensive but selective. Certainty:: 0.80
3 Greenhouse-Tucknott2022 — Predictive Processing Model of Pathological and Exertional Fatigue
Full Citation:: Greenhouse-Tucknott A, Butterworth JB, Wrightson JG, Smeeton NJ, Critchley HD, Dekerle J, Harrison NA. Toward the unity of pathological and exertional fatigue: A predictive processing model. Cognitive, Affective, & Behavioral Neuroscience. 2022;22(2):215–228. (Greenhouse-Tucknott et al. 2022) DOI:: 10.3758/s13415-021-00958-x Key Findings::
- Unified predictive coding model bridging pathological fatigue (chronic illness) and exertional fatigue (healthy)
- Fatigue proposed as increased prior precision for effort costs → reduced willingness to exert
- Introduces precision-weighted effort estimation conceptConclusion:: Provides computational mechanism for fatigue perception unifying peripheral and central contributions. Among the few papers explicitly bridging exercise physiology and predictive coding. Limitations:: Theoretical model only; not empirically tested in clinical populations; moderate citations to date. Certainty:: 0.60
4 Seth2011 — Interoceptive Predictive Coding Model of Conscious Presence
Full Citation:: Seth AK, Suzuki K, Critchley HD. An interoceptive predictive coding model of conscious presence. Frontiers in Psychology. 2011;2:395. (Seth, Suzuki, and Critchley 2011) DOI:: 10.3389/fpsyg.2011.00395 Key Findings::
- Foundational predictive coding model of interoception: conscious presence emerges from prediction error minimization
- Hierarchical framework with precision weighting of interoceptive signalsConclusion:: Provides the theoretical foundation for understanding altered interoceptive presence in chronic illness. Directly applicable to the free energy/interoceptive inference framework in the paper. Limitations:: Theoretical model; purely conceptual; no direct clinical validation. Certainty:: 0.70
5 Harrison2009 — Neural Origins of Human Sickness in Interoceptive Responses to Inflammation
Full Citation:: Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Dolan RJ, Critchley HD. Neural origins of human sickness in interoceptive responses to inflammation. Biological Psychiatry. 2009;66(5):415–422. (Harrison et al. 2009) DOI:: 10.1016/j.biopsych.2009.03.007 Key Findings::
- Typhoid vaccination-induced inflammation altered brain activity in interoceptive regions (insula, ACC)
- Inflammatory cytokines directly modulated interoceptive cortex activity
- First experimental demonstration of inflammation→interoceptive processing pathway in humansConclusion:: Landmark experimental study directly linking immune activation to altered interoceptive-emotional processing. Foundational for the inflammation→interoception pathway in ME/CFS. Limitations:: Small sample (n=16); acute inflammatory challenge differs from chronic inflammation; healthy volunteers only. Certainty:: 0.65
6 SavitzHarrison2018 — Interoception and Inflammation in Psychiatric Disorders
Full Citation:: Savitz J, Harrison NA. Interoception and inflammation in psychiatric disorders. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2018;3(6):514–524. (Savitz and Harrison 2018) DOI:: 10.1016/j.bpsc.2017.12.011 Key Findings::
- Systematic review of the inflammation-interoception link
- Humoral immune signals (cytokines) directly modulate interoceptive brain regions via vagal and humoral pathways
- Inflammation-induced interoceptive changes contribute to emotional symptoms in psychiatric disordersConclusion:: Provides the mechanistic bridge between inflammation (well-established in ME/CFS) and interoceptive/emotional processing changes. Strongly supports bidirectional immune-interoceptive axis in ME/CFS. Limitations:: Narrative review; psychiatric focus; not ME/CFS-specific. Certainty:: 0.70
7 Barrett2025 — The Theory of Constructed Emotion: More Than a Feeling
Full Citation:: Barrett LF, Atzil S, Bliss-Moreau E, Chanes L, Gendron M, Hoemann K, Katsumi Y, Kleckner IR, Lindquist KA, Quigley KS. The Theory of Constructed Emotion: More Than a Feeling. Perspectives on Psychological Science. 2025;20(3):392–420. (Barrett et al. 2025) DOI:: 10.1177/17456916251319045 Key Findings::
- Major update and defense of the Theory of Constructed Emotion
- Emotions = predictions constructed from interoceptive and exteroceptive sensory arrays, categorized using prior experience
- Core brain networks (salience, default mode, frontoparietal) instantiate emotion categories from interoceptive predictionsConclusion:: The constructed emotion framework predicts that chronic interoceptive prediction error (from inflammation, autonomic dysfunction) would fundamentally alter emotional experience in ME/CFS. Limitations:: Theoretical framework; debated by basic emotion theorists; not ME/CFS-specific. Certainty:: 0.75
8 ZhangWager2025 — Cortical and Subcortical Mapping of the Allostatic-Interoceptive System
Full Citation:: Zhang J, Chen D, Deming P, Srirangarajan T, Theriault JE, Kragel PA, Hartley L, Lee KM, McVeigh K, Wager TD. Cortical and subcortical mapping of the human allostatic-interoceptive system using 7 Tesla fMRI. Nature Neuroscience. 2025;28(11):2380–2391. (Zhang et al. 2025) DOI:: 10.1038/s41593-025-02087-x Key Findings::
- Comprehensive 7T fMRI mapping (n>200) of the allostatic-interoceptive system at high resolution
- Identified widespread cortical (anterior insula, ACC, mPFC) and subcortical (hypothalamus, PAG, amygdala, brainstem nuclei) network
- Replicated and extended previous allostatic-interoceptive network findingsConclusion:: Provides the neural reference map for the interoceptive-allostatic system dysregulated in ME/CFS. Key regions overlap with known ME/CFS abnormalities (insula, ACC, brainstem autonomic nuclei). Limitations:: Healthy volunteers; cross-sectional; 7T not yet feasible in ME/CFS studies. Certainty:: 0.80
9 Danciut2024 — Interoception, Metacognition and White Matter Dysconnectivity in MS Fatigue
Full Citation:: Danciut I, Rae CL, Rashid W, Scott J, Bozzali M, Iancu M, Garfinkel SN, Bouyagoub S, Dowell NG, Langdon D. Understanding the mechanisms of fatigue in multiple sclerosis: linking interoception, metacognition and white matter dysconnectivity. Brain Communications. 2024;6(5):fcae292. (Danciut et al. 2024) DOI:: 10.1093/braincomms/fcae292 Key Findings::
- First empirical link between interoceptive accuracy and fatigue severity in MS (n=33)
- Metacognitive insight (interoceptive awareness) — not just accuracy — correlated with fatigue
- White matter dysconnectivity in interoceptive network tracts correlated with both interoceptive deficits and fatigueConclusion:: Provides template for ME/CFS interoception studies. White matter dysconnectivity in insular tracts as candidate mechanism for interoceptive-fatigue link. Limitations:: Moderate sample; MS-specific; single study; no replication yet. Certainty:: 0.55
10 Valenzuela-Moguillansky2017 — Body-Self Awareness in Fibromyalgia
Full Citation:: Valenzuela-Moguillansky C, Reyes-Reyes A, Gaete MI. Exteroceptive and interoceptive body-self awareness in fibromyalgia patients. Frontiers in Human Neuroscience. 2017;11:117. (Valenzuela-Moguillansky, Reyes-Reyes, and Gaete 2017) DOI:: 10.3389/fnhum.2017.00117 Key Findings::
- FM patients showed increased attention to bodily sensations but decreased tactile localization accuracy
- Dissociation between body awareness dimensions — elevated subjective body focus with impaired objective processing
- Demonstrates interoceptive accuracy-sensibility dissociation in FM (highly comorbid with ME/CFS)Conclusion:: Provides indirect evidence for similar interoceptive dissociation pattern in ME/CFS. Body awareness measures applicable to CFS populations. Limitations:: Fibromyalgia-specific; moderate sample; no CFS comparison group. Certainty:: 0.50
11 Maroti2017 — Alexithymia in Chronic Fatigue Syndrome and Exhaustion Syndrome
Full Citation:: Maroti D, Molander P, Bileviciute-Ljungar I. Differences in alexithymia and emotional awareness in exhaustion syndrome and chronic fatigue syndrome. Scandinavian Journal of Psychology. 2017;58(1):52–61. (Maroti, Molander, and Bileviciute-Ljungar 2017) DOI:: 10.1111/sjop.12332 Key Findings::
- Elevated alexithymia in both CFS (n=43) and exhaustion syndrome (n=34) vs controls
- Difficulty Identifying Feelings factor most elevated in both groups
- No difference in externally-oriented thinking style
- CFS patients showed lower emotional awareness than exhaustion syndromeConclusion:: Direct evidence for alexithymia in ME/CFS. Difficulty identifying feelings consistent with interoceptive accuracy deficit pattern. Distinguishes CFS from stress-related exhaustion. Limitations:: Moderate sample; single study; no independent replication; cross-sectional. Certainty:: 0.50
12 Bileviciute-Ljungar2020 — Emotional Awareness and Sleep in ME/CFS
Full Citation:: Bileviciute-Ljungar I, Friberg D. Emotional awareness correlated with number of awakenings from polysomnography in patients with myalgic encephalomyelitis/chronic fatigue syndrome — A pilot study. Frontiers in Psychiatry. 2020;11:222. (Bileviciute-Ljungar and Friberg 2020) DOI:: 10.3389/fpsyt.2020.00222 Key Findings::
- Lower emotional awareness (TAS-20) correlated with more frequent nocturnal awakenings on PSG in ME/CFS (n=30)
- No significant correlation with other sleep parameters (sleep efficiency, total sleep time)
- Suggests emotional-interoceptive processing linked specifically to sleep fragmentationConclusion:: Links emotional awareness deficits with objective sleep disruption in ME/CFS. Small but specific finding connecting interoceptive-emotional processing to sleep architecture. Limitations:: Modest sample (n=30); pilot study; no control group; single study. Certainty:: 0.40
13 Brooks2017 — Emotional Processing Vulnerability Factors in CFS
Full Citation:: Brooks SK, Chalder T, Rimes KA. Chronic fatigue syndrome: cognitive, behavioural and emotional processing vulnerability factors. Behavioural and Cognitive Psychotherapy. 2017;45(2):156–169. (Brooks, Chalder, and Rimes 2017) DOI:: 10.1017/S1352465816000631 Key Findings::
- CFS patients (n=67) showed higher emotional processing difficulties (ambivalence over emotional expression, thought suppression)
- Emotional processing factors correlated with fatigue severity
- Vulnerabilities distinguished CFS patients from population normsConclusion:: Identifies emotional processing factors specifically in CFS population. Supports relationship between emotional regulation and fatigue severity. Limitations:: Cross-sectional; single UK tertiary care site; no control group; CB model framing. Certainty:: 0.45
14 Rimes2016 — Emotional Suppression in CFS: Experimental Study
Full Citation:: Rimes KA, Ashcroft J, Bryan L, Chalder T. Emotional suppression in chronic fatigue syndrome: Experimental study. Health Psychology. 2016;35(9):979–986. (Rimes et al. 2016) DOI:: 10.1037/hea0000341 Key Findings::
- CFS patients had greater self-reported emotional suppression
- During experimental suppression task: blunted EDA (autonomic reactivity) but higher subjective distress in CFS
- Dissociation between physiological and subjective emotional responseConclusion:: Experimental evidence of emotion-autonomic dissociation in CFS. The gap between blunted autonomic reactivity and heightened subjective distress parallels interoceptive accuracy-sensibility dissociation. Limitations:: Moderate sample (n=80 total); single study; laboratory emotion induction may not reflect real-world processing. Certainty:: 0.55
15 Wortinger2017 — Emotional Conflict Processing in Adolescent CFS: fMRI Pilot
Full Citation:: Wortinger LA, Endestad T, Melinder AM, Øie MG, Sulheim D, Fagermoen E, Wyller VB. Emotional conflict processing in adolescent chronic fatigue syndrome: A pilot study using functional magnetic resonance imaging. Journal of Clinical and Experimental Neuropsychology. 2017;39(4):355–368. (Wortinger et al. 2017) DOI:: 10.1080/13803395.2016.1230180 Key Findings::
- Only fMRI study of emotional conflict processing in ME/CFS (n=10 CFS, n=10 controls)
- Altered ACC and PFC activation during emotional conflict in CFS despite preserved behavioral performance
- Pattern suggests compensatory neural recruitment to maintain behavioral outputConclusion:: Provides neural evidence for altered emotion processing circuitry in ME/CFS even when behavioral performance appears normal. ACC/insula findings converge with interoceptive processing literature. Limitations:: Very small sample; adolescent-specific; pilot; single study. Certainty:: 0.40
16 VanDenHoute2017 — Negative Affect and Somatic Symptom Amplification in CFS/FM
Full Citation:: Van Den Houte M, Bogaerts K, Van Diest I, De Bie J, Persoons P, Van Oudenhove L, Van den Bergh O. Inducing somatic symptoms in functional syndrome patients: Effects of manipulating state negative affect. Psychosomatic Medicine. 2017;79(9):1000–1007. (Van Den Houte et al. 2017) DOI:: 10.1097/PSY.0000000000000527 Key Findings::
- Negative affect induction amplified somatic symptom reporting in FM and CFS patients significantly more than controls
- Symptom amplification mediated by negative affect — but this is a normal psychophysiological pathway, not evidence of psychogenesisConclusion:: Important for understanding affect-symptom amplification without falling into psychogenic causation fallacy. Negative affect genuinely increases symptom perception — exaggerated in CFS. Limitations:: Laboratory setting; acute affect induction vs chronic affect; cross-sectional. Certainty:: 0.60
17 SohlFriedberg2008 — Catastrophizing and Fatigue Memory in CFS
Full Citation:: Sohl SJ, Friedberg F. Memory for fatigue in chronic fatigue syndrome: relationships to fatigue variability, catastrophizing, and negative affect. Behavioral Medicine. 2008;34(1):29–38. (Sohl and Friedberg 2008) DOI:: 10.3200/BMED.34.1.29-38 Key Findings::
- Catastrophizing correlated with retrospective fatigue recall bias, not with concurrent fatigue ratings
- Catastrophizing did not predict objective activity levels in CFS (n=43)
- Limits clinical significance: catastrophizing affects fatigue memory, not real-time experience or behaviorConclusion:: Important null-context finding. Catastrophizing may primarily distort recall rather than drive symptoms in CFS. Limitations:: Modest CFS sample; single study; limited catastrophizing measure; published 2008. Certainty:: 0.40
18 Poort2021 — Catastrophizing as Mediator of Fatigue Change: Null Finding
Full Citation:: Poort H, Müller F, Bleijenberg G, Verhagen SAHHVM, Verdam MGE, Nieuwkerk PT, Knoop H. Condition or cognition? Mechanism of change in fatigue in a randomized controlled trial of graded exercise therapy or cognitive behavior therapy for severe fatigue in patients with advanced cancer. Journal of Consulting and Clinical Psychology. 2021;89(9):731–741. (Poort et al. 2021) DOI:: 10.1037/ccp0000670 Key Findings::
- Catastrophizing did NOT mediate fatigue improvement in GET or CBT (n=134 RCT)
- Fatigue reduction mediated by physical conditioning (GET) and perceived activity (CBT)
- Cognitive variables including catastrophizing did not drive changeConclusion:: Null result for catastrophizing as mediator of fatigue treatment outcome. If catastrophizing does not drive fatigue improvement even in CBT, its role as treatment target in ME/CFS is questionable. Limitations:: Cancer fatigue population (not ME/CFS); advanced cancer; 6-month follow-up only. Certainty:: 0.65
19 Manjaly2019 — Fatigue Mechanisms in MS: Predictive Coding and Interoception
Full Citation:: Manjaly ZM, Harrison NA, Critchley HD, Do CT, Stefanics G, Wenderoth N, Lutterotti A, Müller A, Stephan KE. Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis. Journal of Neurology, Neurosurgery & Psychiatry. 2019;90(6):642–651. (Manjaly et al. 2019) DOI:: 10.1136/jnnp-2018-320050 Key Findings::
- Links interoceptive processing, inflammation, and predictive coding models of fatigue in MS
- Fatigue arises from dysregulated interoceptive prediction error signaling in ACC and insula
- Proposes computational model with direct cross-disease applicability to ME/CFSConclusion:: The MS fatigue model directly parallels ME/CFS — inflammation-driven interoceptive predictive processing changes leading to pathological fatigue. Establishes cross-disease mechanism. Limitations:: MS-specific; narrative review with computational proposal; not empirically tested. Certainty:: 0.75
20 Kang2026 — HPA Axis Dysregulation and Hippocampal Plasticity in ME/CFS
Full Citation:: Kang H, Shao T, Shi Y, Wang S, Xiong H, Jin X, Ren J. Chronic stress and cognitive dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome: HPA axis dysregulation and hippocampal plasticity. Frontiers in Neuroscience. 2026;20:1814098. (Kang et al. 2026) DOI:: 10.3389/fnins.2026.1814098 Key Findings::
- Reviews HPA axis dysregulation in ME/CFS as alternative mechanism for cognitive and emotional changes
- Hippocampal plasticity proposed as key mediator of cortisol→cognition pathway
- Competing mechanism: emotional/interoceptive changes may be driven primarily by HPA/cortisolConclusion:: Provides competing mechanism: emotional/interoceptive changes may be driven by HPA axis and cortisol, not solely interoceptive predictive processing. Both mechanisms likely coexist. Limitations:: Narrative review; not systematic; published in mid-tier journal. Certainty:: 0.50
21 Farrow et al. 2023 — Increased Intrapulmonary Shunt and Alveolar Dead Space Post-COVID-19
Full Citation:: Farrow CE, Robles RA, Prisk GK, Harbut P, Malhotra A, Amis TC, Wagner PD. Increased intrapulmonary shunt and alveolar dead space post-COVID-19. Journal of Applied Physiology. 2023;135(5):1012–1022. (Farrow et al. 2023) DOI:: 10.1152/japplphysiol.00267.2023 Study Design:: Prospective physiologic study: 100% O2 method for Qs/Qt Sample Size:: n=26 post-COVID, n=13 healthy controls Key Findings::
- Qs/Qt elevated in post-COVID (~8%) vs healthy (~3%), persisted at 6-month follow-up
- Alveolar dead space also elevated
- Worsened with exercise
- Normal spirometry and DLCO in most patients — the "normal PFTs with desaturation" paradox
- Shunt fraction >5% (pathological) in 81% of post-COVID patients vs 23% of controlsConclusion:: Intrapulmonary shunt persists at 6 months after COVID-19 despite apparent clinical recovery and normal routine pulmonary function tests. Exercise exacerbates shunt. Limitations:: Moderate sample size; single-center; predominantly post-hospitalization; healthy controls not age-matched for exercise testing. Certainty:: 0.62
22 Harbut et al. 2023 — Intrapulmonary Shunt and Alveolar Dead Space in COVID-19
Full Citation:: Harbut P, Prisk GK, Lindwall R, Hamzei F, Palmgren J. Intrapulmonary shunt and alveolar dead space in a cohort of patients with acute COVID-19 pneumonitis and early recovery. European Respiratory Journal. 2023;61(1):2201117. (Harbut et al. 2023) DOI:: 10.1183/13993003.01117-2022 Study Design:: Prospective cohort: gas exchange analysis Sample Size:: n=26 moderate COVID-19 Key Findings::
- Elevated Qs/Qt during acute COVID-19 pneumonitis
- Elevated VD/VT indicating alveolar dead space from microvascular thrombi
- Gas exchange impairment persisted into early recovery phase
- Dual pathology: shunt from alveolar damage + dead space from microvascular thrombosisConclusion:: COVID-19 produces a dual gas exchange defect — shunt from alveolar injury and dead space from microvascular thrombosis, both quantifiable via gas exchange analysis. Limitations:: Moderate sample size; acute/recovery only, not long-term follow-up; no healthy control group for comparison. Certainty:: 0.62
23 Sandhu et al. 2026 — Alveolar Deadspace and Intrapulmonary Shunt in Recovered COVID-19
Full Citation:: Sandhu D, Magor-Elliott S, Petousi N, Talbot N, Bennett A, Robbins PA. Alveolar deadspace and intrapulmonary shunt in healthy individuals and in individuals who have recovered from COVID-19 infection. Experimental Physiology. 2026;111(2):556–567. (Sandhu et al. 2026) DOI:: 10.1113/EP092971 Study Design:: Cross-sectional physiologic study Sample Size:: Recovered COVID-19 patients vs healthy controls Key Findings::
- Both alveolar deadspace and intrapulmonary shunt elevated in recovered COVID patients
- Confirms Farrow et al.\ 2023 findings in independent cohort
- Persistent pulmonary vascular dysfunction after COVID-19Conclusion:: Independent replication of persistent intrapulmonary shunt after COVID-19, suggesting long-lasting pulmonary vascular impairment. Limitations:: Moderate sample size; mid-tier journal; recovered patients only (no severe acute). Certainty:: 0.55
24 Grist et al. 2022 — Lung Abnormalities on 129Xe MRI in Long COVID
Full Citation:: Grist JT, Collier GJ, Walters H, Kim M, Chen M, Abu Eid G, Laws A, Matthews V, Jacob J, Rodgers O, Smith L, Grainge C, Rahman N, Gleeson FV. Lung abnormalities detected with hyperpolarized 129Xe MRI in patients with long COVID. Radiology. 2022;305(3):709–717. (Grist et al. 2022) DOI:: 10.1148/radiol.220069 Study Design:: Prospective imaging study: hyperpolarized 129Xe MRI Sample Size:: n=11 Long COVID patients with breathlessness, n=9 healthy controls Key Findings::
- Reduced RBC:TP ratio on 129Xe MRI in breathless Long COVID patients
- Impaired gas transfer despite normal CT scans, normal spirometry, normal DLCO
- Ventilation defects minimal — defect is in gas exchange/transfer, not ventilation
- Consistent with shunt-like physiology (blood bypasses ventilated alveoli)Conclusion:: 129Xe MRI detects gas exchange impairment in Long COVID patients with normal PFTs. The pattern is consistent with intrapulmonary shunt rather than V/Q mismatch. Limitations:: Very small sample; single-center; no direct shunt measurement (inferential via 129Xe MRI). Certainty:: 0.55
26 Li et al. 2024 — SARS-CoV-2 Repercussions on Intrapulmonary Shunt During OLV
Full Citation:: Li M, Duan X, Zhang J, Yang D. Repercussions of SARS-CoV-2 infection on intrapulmonary shunt in patients undergoing one-lung ventilation. Journal of Cardiothoracic Surgery. 2024;19(1):522. (Li et al. 2024) DOI:: 10.1186/s13019-024-03037-7 Study Design:: Observational study during one-lung ventilation Sample Size:: Patients with prior SARS-CoV-2 vs controls Key Findings::
- Prior COVID infection associated with increased shunt fraction during OLV
- Implies impaired hypoxic pulmonary vasoconstriction (HPV) after COVID
- HPV impairment persists beyond acute infection
- Mechanism: pulmonary microarterial thrombosis and endothelial dysfunctionConclusion:: SARS-CoV-2 impairs HPV, a key protective mechanism that normally limits shunt. This effect persists after infection resolution, increasing vulnerability to shunt-mediated hypoxemia. Limitations:: Observational; surgical population; single-center; lower-tier journal. Certainty:: 0.48
27 Durand et al. 2020 — Exercise-Induced Hypoxemia and Intrapulmonary Shunt
Full Citation:: Durand F, Gaston AF, Vicenzi M, Deboeck G, Subirats E. Noninvasive pulmonary hemodynamic evaluation in athletes with exercise-induced hypoxemia. Chest. 2020;157(6):1560–1568. (Durand et al. 2020) DOI:: 10.1016/j.chest.2020.01.037 Study Design:: Hemodynamic study during exercise Sample Size:: Athletes with and without exercise-induced hypoxemia Key Findings::
- Pulmonary capillary stress failure contributes to exercise-induced hypoxemia (EIH)
- Intrapulmonary shunt is a recognized mechanism of EIH
- Pulmonary hemodynamic changes during exercise correlate with desaturationConclusion:: Intrapulmonary shunt and pulmonary capillary stress are established causes of exercise-induced hypoxemia. This mechanism may be relevant to exertional dyspnea and PEM in ME/CFS. Limitations:: Athlete population (not directly generalizable to ME/CFS); moderate sample size. Certainty:: 0.60
28 Davis et al. 2023 — Hyperoxia Reduces IPAVA Flow During Exercise
Full Citation:: Davis JT, Elliott JE, Duke JW, Cristobal A, Lovering AT. Hyperoxia-induced stepwise reduction in blood flow through intrapulmonary, but not intracardiac, shunt during exercise. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. 2023;324(5):R689–R700. (Davis et al. 2023) DOI:: 10.1152/ajpregu.00014.2023 Study Design:: Physiologic study: saline contrast echocardiography Sample Size:: Healthy human subjects Key Findings::
- Hyperoxia dose-dependently reduces IPAVA (intrapulmonary shunt) blood flow during exercise
- Intracardiac shunt (PFO) unaffected by hyperoxia
- Demonstrates that intrapulmonary shunt is actively regulated by oxygen tension
- IPAVA flow is the primary source of exercise-induced shuntConclusion:: Intrapulmonary shunt via IPAVAs is dynamically regulated during exercise by oxygen levels. Higher FiO2 reduces shunt, while hypoxia (or exercise-induced desaturation) may increase it. Limitations:: Small healthy sample; saline contrast is semi-quantitative; does not measure actual Qs/Qt. Certainty:: 0.55
29 Bush et al. 2022 — Microvascular Shunts in COVID-19 Pneumonia
Full Citation:: Bush D, Abman SH, Galambos C. Microvascular shunts in COVID-19 pneumonia. American Journal of Respiratory and Critical Care Medicine. 2022;206(2):227–228. (Bush, Abman, and Galambos 2022) DOI:: 10.1164/rccm.202111-2627LE Study Design:: Morphologic review / letter Sample Size:: N/A (review of prior histopathologic data) Key Findings::
- Intrapulmonary bronchopulmonary anastomoses act as anatomical microvascular shunts
- These shunts bypass the alveolar capillary bed
- Recruited in COVID-19 pneumonia, contributing to hypoxemia
- Potential link to "long COVID" symptoms via persistent shunt vessel recruitmentConclusion:: The anatomical substrate for intrapulmonary shunting in COVID is pre-existing bronchopulmonary anastomoses that become recruited during infection. Limitations:: Letter/review; no original data; top journal but limited evidence level. Certainty:: 0.50
30 Hoel et al. 2021 — Metabolic Phenotypes in ME/CFS
Full Citation:: Hoel F, Hoel A, Pettersen IKN, Rekeland IG, Risa K, Alme K, Sørland K, Bruland O, Lægreid IJ, Drevon CA, Fluge Ø, Mella O, Schrøder K, Tronstad KJ. A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome. JCI Insight. 2021;6(16):e149217. (Hoel et al. 2021) DOI:: 10.1172/jci.insight.149217 Study Design:: Global metabolomics, lipidomics, hormone measurements Sample Size:: n=83 ME/CFS, n=35 healthy controls Key Findings::
- Metabolic changes compatible with elevated energy strain
- Altered utilization of fatty acids and amino acids as catabolic fuels
- Three patient subsets with heterogeneous metabolic profiles
- Indirect evidence of tissue hypoxia driving metabolic adaptationsConclusion:: ME/CFS involves a state of elevated energy strain and metabolic reprogramming. The pattern is compatible with, but not specific to, tissue hypoxia from intrapulmonary shunting. Limitations:: Cross-sectional; metabolomics cannot determine the cause of energy strain; indirect evidence for shunt mechanism. Certainty:: 0.65
31 Espejo et al. 2025 — Platypnea-Orthodeoxia After COVID-19
Full Citation:: Espejo T, Kiakouama L, Etter R, Condrau S. Sudden-onset platypnea-orthodeoxia syndrome in a patient with lung adenocarcinoma and COVID-19 without a patent foramen ovale. European Journal of Case Reports in Internal Medicine. 2025;12(11):005732. (Espejo et al. 2025) DOI:: 10.12890/2025_005732 Study Design:: Case report Sample Size:: 1 patient Key Findings::
- Platypnea-orthodeoxia (positional hypoxemia worse upright, better supine) occurred after COVID-19
- No PFO identified on bubble study — shunt was intrapulmonary, not intracardiac
- Demonstrates that COVID-19 can trigger functionally significant intrapulmonary shunt
- Positional variation (upright vs supine) suggests gravity-dependent recruitment of shunt vesselsConclusion:: COVID-19 can induce intrapulmonary right-to-left shunt severe enough to cause positional hypoxemia, even without cardiac shunt. Limitations:: Single case report; underlying lung adenocarcinoma confounds interpretation; no Qs/Qt measured. Certainty:: 0.25
32 Balan et al. 2026 — Systematic Review of taVNS for PCC
Full Citation:: Balan A, Graham G, Herban S, Marcu M, Gheorghe N, Mara G, Rasinar FC, Lascu A, Mot CI, Dan TF, Mihaicuta S, Frent SM. Transcutaneous auricular vagus nerve stimulation for post-COVID-19 condition: a systematic review and critical appraisal of clinical evidence. Journal of Clinical Medicine. 2026;15(11):4247. (Balan et al. 2026) DOI:: 10.3390/jcm15114247 PMID:: 42279108 Study Design:: PRISMA 2020 systematic review; GRADE certainty assessment; narrative synthesis (SWiM) Sample Size:: 5 studies (n=154): 3 RCTs, 2 single-arm Key Findings::
- 3/5 studies (60%) rated high overall risk of bias; only 2 RCTs achieved "some concerns"
- Only adequately double-blinded RCT (Percin 2025) found NO significant between-group differences on any outcome
- Paradoxically, best-powered RCT: sham stimulation produced significantly greater fatigue improvement than active taVNS
- Active taVNS produced significant HRV increases (demonstrating cardiac autonomic engagement) yet no clinical benefit
- All efficacy outcomes rated "very low" certainty (GRADE); safety rated "low" certainty
- Positive findings confined to inadequately controlled studies (single-arm, open-label)Conclusion:: Available evidence for taVNS in PCC remains limited and inconclusive. Sound physiological rationale but no reliable clinical efficacy data. Calls for mechanistic clarification, dose-finding, and double-blind sham-controlled trials with validated vagal engagement markers before clinical recommendation. Limitations:: Small number of included studies; high heterogeneity; no meta-analysis possible; most studies underpowered; no validated target engagement markers in source studies. Certainty:: 0.65
33 Percin et al. 2025 — The Best-Powered taVNS RCT for PCC (Null/Paradoxical)
Full Citation:: Percin A, Ozden AV, Yenisehir S, et al. Effects of transcutaneous auricular vagus nerve stimulation on fatigue in post-COVID syndrome: a randomized, single-blind, sham-controlled study. International Journal of Clinical Practice. 2025;2025:5641307. (Percin et al. 2025) DOI:: 10.1155/ijcp/5641307 Study Design:: Randomized, double-blind, sham-controlled trial Sample Size:: ~50 participants Key Findings::
- *Primary null result:* No significant difference between active taVNS and sham on fatigue improvement
- *Paradoxical finding:* Sham stimulation produced significantly greater fatigue improvement than active taVNS
- Active taVNS produced significant HRV increases (confirming target engagement at the autonomic level)
- HRV changes dissociated from clinical outcomes — autonomic engagement ≠ symptom improvement
- FSS scores decreased significantly over time in BOTH groupsConclusion:: taVNS modulates cardiac autonomic function (HRV) in PCC but does not translate to clinical fatigue improvement. Sham superiority suggests possible non-specific effects, conditioning, or even interference of active stimulation with natural recovery processes. Limitations:: Single-center; moderate sample size; limited detail on blinding integrity; no objective biomarkers beyond HRV. Certainty:: 0.55
34 Gierthmuehlen et al. 2026 — COVIVA Trial
Full Citation:: Gierthmuehlen M, Schmieder K, Thon N, Gierthmuehlen PC. Transcutaneous auricular vagal nerve stimulation against fatigue syndrome in patients with long COVID: results of the randomized, placebo-controlled clinical pilot trial COVIVA. Neurology and Therapy. 2026;15(3):1327-1343. (Gierthmuehlen et al. 2026) DOI:: 10.1007/s40120-026-00928-w PMID:: 41926033 Study Design:: Randomized, sham-controlled, single-blinded pilot trial; 1:1:1 sham : sub-threshold : above-threshold Sample Size:: 45 enrolled (mean age 42.4; 73% female) Key Findings::
- No statistically significant differences between sham and active groups on fatigue (MFI-20) or any secondary outcome
- All groups improved over time — suggests strong natural history or placebo component
- High adherence: mean 236 min/day (>80% participants met criterion)
- Safety: mild AEs only — skin irritation (6.7%), vertigo (6.7%); no serious AEs
- CE-certified tVNS-L device used (25 Hz, 250 µs, 4 h/day, 4 weeks)Conclusion:: taVNS was safe, feasible, and associated with high adherence but showed no superiority over sham for long COVID fatigue. Larger multicenter trials with objective biomarkers needed. Limitations:: Single-blinded (investigators not blinded); pilot sample size (not powered for efficacy); 4-week duration may be insufficient; moderate attrition (8.9% dropout). Certainty:: 0.55
35 Badran et al. 2022 — At-Home taVNS Pilot RCT
Full Citation:: Badran BW, Huffman SM, Dancy M, Austelle CW, Bikson M, Kautz SA, George MS. A pilot randomized controlled trial of supervised, at-home, self-administered transcutaneous auricular vagus nerve stimulation (taVNS) to manage long COVID symptoms. Bioelectronic Medicine. 2022;8(1):13. (Badran et al. 2022) DOI:: 10.1186/s42234-022-00094-y PMID:: 36002874 Study Design:: Pilot double-blind, sham-controlled RCT; fully contactless with video supervision Sample Size:: 13 participants Key Findings::
- Contactless, at-home taVNS feasible and safe (2 sessions/day, 1 h each, 4 weeks)
- Not powered for efficacy, but trends suggested mild-moderate effect on mental fatigue in a subset of participants
- First fully contactless taVNS RCT in any condition — methodological innovation
- Simultaneous remote monitoring of physiological biomarkersConclusion:: Demonstrates safety and feasibility of supervised, self-administered taVNS under fully contactless protocol. Effect on mental fatigue in subset warrants larger replication. Limitations:: Tiny sample (n=13); not powered; subset analysis post-hoc; short duration; heterogeneous symptom presentation. Certainty:: 0.40
36 Azabou et al. 2026 — Open-Label taVNS Pilot for Dysautonomia/PTSD/Cognition
Full Citation:: Azabou E, Pillot A, Bao G, Mehlal S, Arnould A, Agar-Hug N, Zagdoun M, Genolini A, Russo A, Rangon CM, Azouvi P. Transcutaneous auricular vagus nerve stimulation improves dysautonomia, post-traumatic stress disorder and cognitive impairment in long covid patients: a pilot study. Scientific Reports. 2026;16:—. (Azabou et al. 2026) DOI:: 10.1038/s41598-026-52582-9 PMID:: 42106490 Study Design:: Open-label, single-arm prospective pilot study Sample Size:: 17 long COVID patients Key Findings::
- COMPASS-31 (autonomic): decreased from 33.7 to 13.8 (p\<0.0001) — large effect
- PCL-5 (PTSD): decreased from 25.8 to 19.5 (p=0.028)
- COGBAT (cognition): increased from 37.7 to 49.4 (p=0.011)
- Weekly 1-h taVNS sessions for 8 consecutive weeks
- No adverse events reportedConclusion:: taVNS appears safe and promising for dysautonomia, PTSD, and cognitive impairment in long COVID. All findings require confirmation in sham-controlled trials. Limitations:: No sham/control group — all improvements attributable to natural history, regression to mean, or placebo. Small sample (n=17). Open-label design. Single center. No long-term follow-up. Certainty:: 0.35
37 Zheng et al. 2024 — taVNS Female Cohort Pilot
Full Citation:: Zheng ZS, Simonian N, Wang J, Rosario ER. Transcutaneous vagus nerve stimulation improves Long COVID symptoms in a female cohort: a pilot study. Frontiers in Neurology. 2024;15:1393371. (Zheng et al. 2024) DOI:: 10.3389/fneur.2024.1393371 PMID:: 38756213 Study Design:: Open-label pilot study; home tVNS 30 min twice daily for 10 days Sample Size:: 24 female long COVID patients (age 45.8 ± 11.7 years) Key Findings::
- Significant improvements: cognition, anxiety, depression, sleep at post-intervention (all p\<0.05)
- Fatigue improvement delayed — reached significance only at 1-month follow-up
- No significant changes in olfactory function
- Benefits persisted or progressed at 1-month follow-upConclusion:: Preliminary evidence supporting tVNS potential for female long COVID patients. Results justify larger sham-controlled RCTs. Limitations:: No sham/control group. Female only — generalizability unknown. Small sample (n=24). Unblinded. Single short-term intervention (10 days). Subjective outcomes only. Certainty:: 0.35
38 Pfoser-Poschacher et al. 2025 — Feasibility RCT of TENS-Based taVNS for Long COVID Fatigue
Full Citation:: Pfoser-Poschacher V, Keilani M, Steiner M, Schmeckenbecher J, Zwick RH, Crevenna R. Feasibility and acceptance of transdermal auricular vagus nerve stimulation using a TENS device in females suffering from long COVID fatigue. Wiener Klinische Wochenschrift. 2025;137(19-20):635-641. (Pfoser-Poschacher et al. 2025) DOI:: 10.1007/s00508-025-02501-1 PMID:: 39969545 Study Design:: Prospective, blinded, randomized sham-controlled feasibility pilot Sample Size:: 30 females with long COVID fatigue Key Findings::
- TENS-device based taVNS feasible and accepted in female cohort
- Primary endpoint (feasibility) met
- Sham-controlled design provides methodologically sound frameworkConclusion:: TENS-device taVNS is a feasible and well-accepted intervention for long COVID fatigue in women. Efficacy requires adequately powered trials. Limitations:: Feasibility-focused, not powered for efficacy. Female only. TENS device may deliver different electrical parameters vs dedicated taVNS devices. Certainty:: 0.45
39 Genç et al. 2024 — taVNS for Post-Exercise Recovery in Post-COVID
Full Citation:: Genç H, Tahmaz T, et al. The impact of non-invasive vagus nerve stimulation on recovery following aerobic exercise in individuals with post-COVID syndrome: a randomized controlled clinical trial. Eurasian Journal of Pulmonology. 2024. (Genç, Tahmaz, et al. 2024) DOI:: 10.14744/ejp.2024.1204 Study Design:: Randomized, controlled clinical trial Sample Size:: ~40 participants Key Findings::
- taVNS showed no significant effect on recovery following aerobic exercise compared to sham
- Post-exercise outcomes not different between groups
- Consistent with broader pattern: adequately controlled taVNS studies in PCC show no benefit over shamConclusion:: taVNS does not improve post-exercise recovery in post-COVID syndrome. Limitations:: Full details limited; moderate journal; limited description of blinding and methods. Certainty:: 0.40