Fatigue in Crohn’s disease maps onto folding of temporal and frontal cortex

Fatigue is one of the most disabling symptoms of Crohn’s disease, an inflammatory bowel condition marked by chronic, relapsing inflammation of the gastrointestinal tract. It drains quality of life whether the gut itself is flaring or in remission, and researchers have repeatedly flagged it as a top research priority. Yet its biology remains stubbornly opaque. A new study published in Frontiers in Neuroimaging by Theresa McIver, Jennifer Kornelsen, and colleagues at the University of Manitoba and Dalhousie University now offers a structural clue: the severity of fatigue in Crohn’s disease is tied to how intricately folded specific regions of the cortex are, and different flavors of fatigue leave different structural fingerprints.

The team recruited 49 adults with Crohn’s disease and 49 healthy controls from a larger longitudinal study of psychiatric comorbidity in immune-mediated inflammatory disease. Every participant completed the Fatigue Impact Scale, a validated 40-item questionnaire that separates the burden of fatigue into three domains: physical functioning, cognitive functioning, and psychosocial functioning. Participants rated how much fatigue had caused problems in each area, from no problem to extreme problem. As expected, the Crohn’s disease group reported substantially higher fatigue than controls across all domains, with mean physical scores of 10.63 versus 2.84, cognitive scores of 11.18 versus 3.96, and psychosocial scores of 18.57 versus 4.53. Crucially, depression scores on the Hospital Anxiety and Depression Scale fell below the clinical threshold in both groups, meaning the findings could not be explained away by mood symptoms.

Each participant then underwent whole-brain T1-weighted magnetic resonance imaging on a 3 Tesla Siemens scanner using a high-resolution MPRAGE sequence with roughly one-millimeter spatial resolution. Rather than measuring grey matter volume, the researchers analyzed cortical complexity, a surface-based morphometry metric computed with the Computational Anatomy Toolbox 12. Cortical complexity, closely related to the fractal dimension of the cortical surface, estimates gyrification by combining sulcal depth, the frequency of cortical folding, and the convolution of gyral shape. It is a sensitive but understudied measure: previous work by the same group found differences in cortical complexity among people with inflammatory bowel disease even when grey matter volumes looked normal, and reduced complexity has been linked to a range of neurological disorders.

The results were striking in their consistency. Among people with Crohn’s disease, greater fatigue across all three domains was associated with lower cortical complexity in the right superior temporal gyrus, a temporal region previously implicated in experimentally induced cognitive fatigue in chronic fatigue syndrome. The psychosocial domain produced the largest cluster, with a t-statistic of 4.8 spanning 204 vertices, while the physical and cognitive domains yielded smaller but significant clusters in the same region. In other words, the more severely fatigue impaired daily functioning, the less intricately folded this part of the temporal cortex appeared.

But the domains diverged in the frontal and parietal lobes. Higher physical fatigue was associated with lower complexity in the right superior frontal gyrus, a region involved in impulse control and motor urgency, and paradoxically with greater complexity in the right supramarginal gyrus, a parietal area linked to motor impairment after stroke. Higher cognitive fatigue, by contrast, was associated with greater complexity in the left superior frontal gyrus, which supports working memory and executive function. The authors suggest this increased left frontal folding might reflect compensatory structural changes, given that people with inflammatory bowel disease have shown executive function deficits, particularly in working memory, in prior research.

The healthy control group told a different story. Cortical complexity in controls was related exclusively to the physical impact of fatigue, and only positively: regions including the right pars triangularis, the left superior temporal gyrus, and the left cuneus showed greater folding among those reporting more physical fatigue burden. Between-group contrasts confirmed that these fatigue-related complexity relationships in frontal and visual regions were significantly stronger in controls than in patients. The authors interpret this cautiously, noting the limited variability and low fatigue scores in the healthy sample, but suggest these regions may participate in normative processing of fatigue perception.

The most consequential finding emerged from post-hoc moderation analyses. Disease activity, measured with the Harvey-Bradshaw Index, is a known risk factor for fatigue, but the strength of that link varied dramatically depending on cortical structure. In the right superior temporal gyrus, cortical complexity explained an additional 6.2 percent of variance in the relationship between disease activity and total fatigue impact (ΔR² = 0.062, F = 5.558, p = 0.023). The right superior frontal gyrus showed a similar moderating effect (ΔR² = 0.058, F = 4.059, p = 0.050).

Simple slope analyses revealed the pattern in detail. When complexity in the right superior temporal gyrus was lowest, at the 16th percentile, greater disease activity was strongly associated with greater fatigue (b = 9.257, p = 0.0001), and the association remained significant at the median. But when complexity was highest, at the 84th percentile, the relationship between disease activity and fatigue vanished entirely (b = 0.453, p = 0.857). The right superior frontal gyrus showed the same moderating signature: disease activity predicted fatigue only when frontal complexity was lowest and negative. In effect, intricate cortical folding appeared to buffer patients against the fatigue that gut inflammation would otherwise produce.

These findings expand the emerging picture of the brain-gut axis in Crohn’s disease. The axis is a bidirectional communication system in which the gut influences the brain through neurotransmitter production, sensory nerve modulation, and mucosal immune regulation, while the brain alters gut motility, permeability, and immune function. Prior work from the same laboratory found that fatigue-related differences in resting-state functional connectivity, particularly involving the temporal lobe, similarly moderated the disease activity-fatigue link. The new study shows that stable structural features of the cortex carry comparable weight, suggesting that both the wiring and the folding of temporal and frontal cortex shape how enteric pathology is translated into the perception of extraintestinal symptoms.

The authors are careful about limits. The cross-sectional design cannot establish whether reduced cortical complexity precedes or follows disease activity and fatigue, and the results rest on self-reported fatigue, a single clinical activity index, and one composite morphometry metric. Medication use varied widely across participants, from thiopurines to anti-TNF antibodies, and could contribute unstudied variability. Future research should incorporate physiological inflammatory markers such as C-reactive protein and fecal calprotectin, objective physical and cognitive performance measures, and longitudinal designs to test whether cortical structure operates as a mechanism mediating the disease-fatigue relationship. Given that reduced cortical fractal dimension predicts disability worsening in multiple sclerosis, another immune-mediated inflammatory disease, the authors propose that decreased cortical complexity should be explored as a potential risk factor for compromised cognitive and physical performance in Crohn’s disease, and possibly as a target for novel therapies along the brain-gut axis.

Subject of Research: Neuroscience

Article Title: Physical, cognitive, and psychosocial fatigue are differently related to cortical complexity of superior temporal and frontal brain regions in Crohn’s disease

Article References: McIver, T. A., Bernstein, C. N., Marrie, R. A., Fisk, J. D., Figley, C. R., & Kornelsen, J. (2026). Physical, cognitive, and psychosocial fatigue are differently related to cortical complexity of superior temporal and frontal brain regions in Crohn’s disease. Frontiers in Neuroimaging, 5, Article 1814006. https://doi.org/10.3389/fnimg.2026.1814006

Image Credits: AI Generated

DOI: 10.3389/fnimg.2026.1814006

Keywords: Crohn's disease, fatigue, cortical complexity, brain-gut axis, MRI, inflammatory bowel disease, neuroimaging, disease activity, Physical, cognitive, psychosocial, differently