Background & Aims
Interoceptive fear is shaped by associative learning and memory processes and plays a central role in abnormal interoception, with implications for chronic visceral pain (1-4). Acute inflammation has been shown to induce brain alterations in the central fear network as a putative trajectory to both, pain chronicity and psychiatric comorbidity (5-9). Experimental research into pain-related learning and memory processes further demonstrates acute inflammation to alter fear network responses to interoceptive threat predictors (5,9). However, the role of chronic inflammation in neural underpinnings of visceral pain-related fear learning and memory remains unclear, especially in conditions involving the gut-brain axis and chronic visceral pain. We implemented an interoceptive fear conditioning paradigm to elucidate fear network reactivity in patients with quiescent ulcerative colitis (UC), compared to patients with irritable bowel syndrome (IBS) and healthy controls (HC).
Methods
A total of 20 women with quiescent inflammatory bowel disease (UC), 25 female patients with IBS and 25 healthy women (HC) included in this functional magnetic resonance imaging (fMRI) study underwent a multiple threat conditioning paradigm previously established in a healthy cohort (10). We herein focused on the acquisition and extinction of conditioned interoceptive fear of distension-induced visceral pain applied as unconditioned stimulus (US). During acquisition, visceral US were consistently preceded by a distinct visual cue as conditioned stimulus (CS+VISC) while a second visual CS- was repeatedly presented unpaired. During the extinction phase, all CS presentations were accomplished without any US. Differential neural responses to CS+VISC vs. CS- assessed during acquisition and extinction phases in UC were compared to those in IBS and HC, with a focus on key regions of the central fear network, and CS valence served as a behavioral indicator of learned emotional responses.
Results
In contrast to HC and IBS, UC patients demonstrated distinctly altered engagement of key regions of the central fear network, including amygdala and hippocampus as well as putamen and anterior insula, during differential interoceptive fear learning. Interestingly, while HC and IBS showed greater CS+VISC relative to CS- activation, differential neural response patterns were reversed in UC, with enhanced activation to conditioned safety relative to pain-predictive cues. Aberrant hippocampal responses correlated with chronic stress exclusively in IBD. During extinction, differential engagement was observed in UC compared to IBS patients within amygdala, anterior insula, and thalamus. Analyses of cue valence indicated comparable interoceptive fear acquisition and extinction on a behavioral level in all groups.
Conclusions
This is the first conditioning study assessing central fear network reactivity during interoceptive fear learning and extinction in patients with UC as a chronic inflammatory disease compared not only to HC but also to IBS as a functional visceral pain comparison group. Together, our findings of disease-specific alterations in neural responses during interoceptive pain-related fear conditioning in patients with quiescent colitis suggest persisting effects of recurring intestinal inflammation on central fear network reactivity. Given the crucial role of interoceptive fear in abnormal interoception and visceral pain, these findings point towards inflammation-related brain alterations as one trajectory to pain chronicity and psychological burden in inflammatory bowel disease.
References
1.Bhatt RR, Gupta A, Labus JS, Liu C, Vora PP, Jean S, et al. A neuropsychosocial signature predicts longitudinal symptom changes in women with irritable bowel syndrome. Mol Psychiatry. 2022;27(3):1774-91.
2.Mayer EA, Ryu HJ, Bhatt RR. The neurobiology of irritable bowel syndrome. Mol Psychiatry. 2023;28:1451-65.
3.Icenhour A, Langhorst J, Benson S, Schlamann M, Hampel S, Engler H, et al. Neural circuitry of abdominal pain-related fear learning and reinstatement in irritable bowel syndrome. Neurogastroenterol Motil. 2015;27:114-27.
4.Keefer L, Ballou SK, Drossman DA, Ringstrom G, Elsenbruch S, Ljotsson B. A Rome working team report on brain-gut behavior therapies for disorders of gut-brain interaction. Gastroenterology. 2021;162(1):300-15.
5.Benson S, Labrenz F, Kotulla S, Brotte L, Rödder P, Tebbe B, et al. Amplified gut feelings under inflammation and depressed mood: A randomized fMRI trial on interoceptive pain in healthy volunteers. Brain, Behavior, and Immunity. 2023;112:132-137.
6.Davies KA, Cooper E, Voon V, Tibble J, Cercignani M, Harrison NA. Interferon and anti-TNF therapies differentially modulate amygdala reactivity which predicts associated bidirectional changes in depressive symptoms. Mol Psychiatry. 2021;26(9):5150-60.
7.Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry. 2009;66(5):407-14.
8.Kraynak TE, Marsland AL, Wager TD, Gianaros PJ. Functional neuroanatomy of peripheral inflammatory physiology: a meta-analysis of human neuroimaging studies. Neurosci Biobahv Rev. 2018;94:76-92.
9.Pawlik RJ, Petrakova L, Cueillette A, Krawczyk K, Theysohn N, Elsenbruch S, et al. Inflammation shapes neural processing of interoceptive fear predictors during extinction learning in healthy humans. Brain Behav Immun. 2023;108:328-39.
10.Koenen LR, Pawlik RJ, Icenhour A, Petrakova L, Forkmann K, Theysohn N, et al. Associative learning and extinction of conditioned threat predictors across sensory modalities. Commun Biol. 2021;4:1-17.
11.Fairbrass KM, Costantino SJ, Gracie DJ, Ford AC. Prevalence of irritable bowel syndrome-type symptoms in patients with inflammatory bowel disease in remission: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020;5(12):1053-62.
12.Wils P, Caron B, D’Amico F, Danese S, Peyrin-Biroulet L. Abdominal pain in inflammatory bowel diseases: a clinical challenge. J Clin Med. 2022;11(15).
13.Robertson N, Gunn S, Piper R. Psychological and social factors associated with pain in inflammatory bowel disease : a systematic literature review of the evidence in adult and pediatric studies. Crohn’s and Colitis 360. 2019;1(1):1-19.
14.Hetterich L, Stengel A. Psychotherapeutic interventions in irritable bowel syndrome. Front Psychiatry. 2020;11:286.
15.Gracie DJ, Hamlin PJ, Ford AC. The influence of the brain – gut axis in inflammatory bowel disease and possible implications for treatment. Lancet Gastroenterol Hepatol. 2019;4(8):632-42.
16.Peppas S, Pansieri C, Piovani D, Danese S, Peyrin-Biroulet L, Tsantes AG, et al. The brain-gut axis: psychological functioning and inflammatory bowel diseases. J Clin Med. 2021;10(3).
Presenting Author
Adriane Icenhour
Poster Authors
Adriane Icenhour, PhD
PhD
Ruhr University Bochum
Lead Author
Laura Ricarda Lanters
PhD
University Hospital Essen, Germany
Lead Author
Hanna Öhlmann
PhD
Ruhr University Bochum
Lead Author
Jost Langhorst
MD
University Hospital Essen, Germany
Lead Author
Nina Theysohn
MD
University Hospital Essen, Germany
Lead Author
Harald Engler
Prof. Dr.
University Hospital Essen, Germany
Lead Author
Sigrid Elsenbruch
Prof. Dr.
Ruhr University Bochum
Lead Author
Topics
- Pain Imaging