Table 2.

The pathophysiologic interpretations of the 13 brain features in radiomics model

Brain features	Physiological function of the brain region	Reported changes of the brain region in CD	Clinical significance of the MRI parameter	Reported changes of the MRI parameter in CD	Speculative interpretation of brain features in CD
Left-Hippocampus- R2Star-p10	Hippocampus: The brain limbic system, responsible for adult neurogenesis, emotional control, and cognition. (PMID: 31969694)	Alterations in gray matter volume and functional activity of the hippocampus in CD patients compared to healthy volunteers. (PMID: 29204113) Experimental colitis in animals with IBD affects hippocampal neurogenesis and innate immune cell responses. (PMID: 31969694)	R2 Star: In vivo detection of iron deposition in brain tissue. (PMID: 26445114)	--*	The R2 Star in hippocampus may serve as a biomarker for detecting cognitive dysfunction or neurogenesis as well as innate immune cell responses in CD, by reflecting iron deposition.
Left-Putamen-fMRI-ReHo-p10	Putamen: Part of the striatum, the major input source of the basal ganglia; associated with integrating multiple sensory modalities and coordinating behavioral responses. (PMID: 35185768)	Inactive CD patients exhibited lower ReHo values in the putamen compared with healthy controls. (PMID: 35185768)	ReHo: The synchronization of fluctuations among adjacent voxels of blood oxygenation level-dependent signals to provide information about local activity. (PMID: 35185768)	As described in the section of “Reported changes of the brain region in CD” of this brain feature.	Lower ReHo values in CD patients may be related to psychological distress in these patients as this region is known to play a role in affective disorders.
Ctx-Lh-Caudal-Anterior-Cingulate- DKI-KFA-std	Caudal anterior cingulate gyrus: Part of a distributed attentional network; a crucial region in sensory and cognitive research, involving pain modulation and related emotional processing, such as anxiety, depression, and fear. (PMID: 37286175)	Peripheral inflammation of animal colitis model induced microglial and glutamatergic neuronal activation in the anterior cingulate cortex. Inhibition of glutamatergic neurons or depletion of microglia in the anterior cingulate cortex mitigates visceral pain, and the latter can also prevent depressive-like behaviors. (PMID: 37286175)	DKI KFA: Provides a concise representation of the directional variation in the degree of non-Gaussian diffusion; reflects tissue-diffusion complexity indicated injured white matter fiber integrity. (PMID: 27041679)	--*	The increased KFA in caudal anterior cingulate indicates a stronger connection among brain areas. Pain and related emotional processing, such as anxiety, depression and fear can cause sustained tension on this brain lobe.
Ctx-Lh-Middle-Temporal-CBF-p90	Temporal middle gyrus: Speech and hearing processing. (PMID: 35185768)	Active CD patients exhibited higher ReHo values in the temporal middle compared with HCs. (PMID: 35185768)	CBF: Provides brain oxygen information, which is essential to brain metabolism. Abnormal CBF may indicate cerebral microvascular dysfunction. (PMID: 30358242)	--*	The increased CBF in middle temporal may represent increased activity of these regions in an effort to bolster cognitive performance, and may suggest the adjustment to reduced nociceptive input or reflect an inherent susceptibility to heightened disease activity.
Ctx-Rh-Postcentral- fMRI-ReHo-p90	Cortex of Postcentral gyrus: A sensory area that explains various sensory stimuli; a primary receptor for general bodily feeling of touch, such as temperature and pain. (PMID: 35185768)	Compared with the HCs, CD patients exhibited lower ReHo values in the postcentral gyrus. The involvement of this brain region may contribute to the development of CD. (PMID: 35185768)	ReHo: As described in the section of “Clinical significance of the MRI parameter” of brain feature namely “Left-Putamen-fMRI-ReHo- p10”.	As described in the section of “Reported changes of the brain region in CD” of this brain feature.	Decreased ReHo values in the postcentral gyri cortex in CD patients may associated with the abnormal bodily feeling such as abdominal pain.
Ctx-Lh-Superior- Temporal-vol	Superior temporal gyrus: Associated with auditory processing, including language. As an important structure in the pathway, which are involved in social cognition processes and the perception of emotions in facial stimuli. (PMID: 26843641 PMID: 12724168 PMID: 19699306)	Joint independent component analysis detected structural alterations of temporal regions with voxel-based morphometry. It may act as one part of controls and patients point toward key hubs of the so-called default mode network (DMN), which is thought to mediate several discrete functions, including processing of self-referential information and affect, internal mentation and memory. (PMID: 33368950)	Vol: Cortical volume has been identified as a significant marker of brain pathology. (PMID: 29212177)	Negative correlations were found between the gray matter volumes in several brain regions (e.g., the insula and caudal anterior cinaulate) and the severity of abdominal pain in CD patients. (PMID: 29212177)	The alterations of volume in superior-temporal gyrus may contribute to the social anxiety disorder of CD patients. In general, the mechanism underlying cortical volume changes may be attributed to frequent and chronic nociceptive input and the subsequent functional reorganization and plasticity of the brain. The lower volumes could be related to a decrease in the size of neuronal somata, cell atrophy, or a decrease in intra-cortical axonal architecture (i.e., synaptic loss)
Brain-Stem-fMRI- ALFF-p90	Brain stem: The vital center for physiological activities in the human body, encompassing a multitude of functions, including the regulation of digestive systems.	--*	fMRI ALFF: The amplitude of low‐frequency fluctuations (ALFF) reflects the level of spontaneous activity at each voxel. ALFF is a classic metric that has mostly been calculated to determine abnormal brain activity precisely, with the energy of a time series being broken down into sets of stationary sinusoidal functions of different frequencies. (PMID: 31451898)	Patients with the active CD exhibited higher ALFF in several brain regions (e.g., the caudal anterior cingulate hippocampus, insula, superior-frontal cortex, precuneus, and parahippocampus). (PMID: 35600612 PMID: 29464530)	The development and progression of intestinal inflammation or abdominal pain in CD patients may contribute to the increased level of spontaneous activity in the brain stem, as indicated by an increase in ALFF.
Left-Thalamus-Proper- CBF-std	Thalamus: a nuclear complex and relay center between the cerebral cortex and several subcortical brain regions located in the diencephalon, supporting both sensory and motor mechanisms. (PMID: 12192499)	CD patients had significantly stronger activations than controls in the thalamus. The volume of thalamus in IBD patients was smaller than that in control group. (PMID: 27132547 PMID: 34734248)	CBF: As described in the section of “Clinical significance of the MRI parameter” of brain feature namely “Ctx-Lh-Middle-Temporal-CBF- p90”.	--*	The increased CBF in thalamus may indicate heightened activity in this region, which is recognized for its involvement in processing and regulating sensory, cognitive, emotional aspects of pain, as well as threat assessment.
Ctx-Lh-Cuneus-fMRI- ReHo-std	Cuneus: Correlates with sympathetic nervous system activity and processing of the autonomic subdimension. Plays a role in the perceptions of bodily expressions, threatening or fear-inducing signals. Interconnected with the default mode network (regions involved in resting-state brain activity) and limbic regions for vigilance, attention, motivation and arousal. (PMID: 20723605 PMID: 21255659)	The reduction of nodal betweenness centrality was detected in the cuneus in CD patients through the building of topological properties of networks, suggesting that CD is accompanied by alterations in both global network organization and regional connectivity. (PMID: 35111602)	fMRI ReHo: As described in the section of “Clinical significance of the MRI parameter” of brain feature namely “Left-Putamen-fMRI-ReHo- p10”.	As described in the section of “Reported changes of the brain region in CD” of brain feature namely “Ctx-Rh-Postcentral-fMRI-ReHo- p90”.	Higher ReHo values in the cuneus of CD patients may be related to affective disorders, such as vigilance, arousal, attention, perceptions of fear, sensory and visuospatial transformation.
Ctx-Rh-Superior-Frontal-DKI-GA-std	Frontal regions: Involved in early auditory encoding. (PMID: 33368950)	Decreased gray matter volume in the frontal in CD patients. The structural alterations in superior-frontal gyrus in CD patients detected by ioint independent component analysis. (PMID: 22998431 PMID: 33368950)	DKI GA (Geodesic Anisotropy): Measures the distance of a diffusion tensor to the nearest isotropic tensor, computed intrinsically on the manifold of positive-definite symmetric diffusion tensors. (PMID: 30546820)	--*	The increased GA in superior frontal of CD patients may indicate the alteration of brain fiber microstructure and abnormal connection of fronto-temporal auditory networks.
Ctx-Rh-Precentral- fMRI-ALFF-p10	Precentral gyrus: The site of the premotor cortex, which is involved in the sensorimotor network and is responsible for the execution and control of voluntary movements through the corticospinal tract. Inextricably involved in emotion control. (PMID: 25001084)	Inactive CD patients exhibited lower ReHo values in the precentral. (PMID: 35185768)	fMRI ALFF: As described in the section of “Clinical significance of the MRI parameter” of brain feature namely “Brain-Stem-fMRI-ALFF-p90”.	As described in the section of “Reported changes of the MRI parameter in CD” of brain feature namely “Brain-Stem-fMRI- ALFF-p90”.	The decreased ALFF in precentral gyrus of CD patients may be associated with sensorimotor and emotional dysfunctions.
Ctx-Lh-Middle-Temporal-vol	As described in the section of “Physiological function of the brain region” of brain feature namely “Ctx-Lh-Superior- Temporal-vol”.	As described in the section of “Reported changes of the brain region in CD” of brain feature namely “Ctx-Lh-Superior-Temporal- vol”.	As described in the section of “Clinical significance of the MRI parameter” of brain feature namely “Ctx-Lh-Superior-Temporal-vol”.	As described in the section of “Reported changes of the MRI parameter in CD” of brain feature namely “Ctx-Lh-Superior- Temporal-vol”.	The volume in middle temporal was decreased in CD patients compared with healthy people, which may be related to a decrease in the size of neuronal somata, cell atrophy, or a decrease in intra-cortical axonal architecture (i.e., synaptic loss), and may have acted as the adaptations to decreased nociceptive input.
Ctx-Rh-Precentral- fMRI-ReHo-mean	As described in the section of “Physiological function of the brain region” of brain feature namely “Ctx-Rh-Precentral- fMRI-ALFF-p10”.	As described in the section of “Reported changes of the brain region in CD” of brain feature namely “Ctx-Rh-Precentral-fMRI-ALFF- p10”.	ReHo: As described in the section of “Clinical significance of the MRI parameter” of brain feature namely “Left-Putamen-fMRI-ReHo- p10”.	As described in the section of “Reported changes of the brain region in CD” of brain feature namely “Ctx-Rh-Postcentral-fMRI-ReHo- p90”.	The decreased ReHo in CD patients may indicate the lower activation of this region and may be associated with sensorimotor and emotional dysfunctions.

The brain feature names highlighted in bold represent novel features that have not been previously documented in the literature

p10 10th percentile, fMRI functional MRI, ctx cortex, ReHo regional homogeneity, DKI diffusion kurtosis imaging, KFA kurtosis fractional anisotropy, STD standard deviation, CBF cerebral blood flow, p90 90th percentile, vol volume, ALFF amplitude of low-frequency fluctuations, DKI diffusion kurtosis imaging, GA geodesic anisotropy, CD Crohn’s disease, HCs healthy controls

* The changes in these MRI parameters have not been reported in CD