Crohn’s disease (CD), a chronic transmural inflammatory condition of the gastrointestinal tract, frequently manifests during adolescence with distinctive complications with rising global incidence (Vernier-Massouille et al., 2008; Rosen et al., 2015; Piovani et al., 2020; Ng et al., 2017). Adolescents CD patients face unique challenges, including growth retardation, severe disease phenotypes, and psychosocial burdens such as academic disruptions and social isolation (Engel et al., 2021; Turner et al., 2021). Critically, these stressors contribute to a high prevalence of emotional dysregulation, with 5 to 33% of pediatric CD patients developing comorbid mental health’s—a rate significantly exceeding the general population (Stapersma et al., 2018). Population study indicated strong associations between early-onset CD and depression, anxiety, suicidal behaviors, and neurodevelopmental conditions (Butwicka et al., 2019; Mikocka-Walus et al., 2016), while disease-specific factors, such as fatigue (Bevers et al., 2023) and symptom stigma, further impair quality of life (Cooney et al., 2024; Ross et al., 2011). Despite evidence linking CD pathophysiology to gut-brain axis dysregulation, the neurofunctional mechanisms underlying emotional comorbidities in adolescents remain uncharacterized.

Resting-state functional magnetic resonance imaging (rs-fMRI), as a reliable and non-invasive method for assessing brain functions, has become one of the commonly used neuroimaging techniques in brain science research in recent years (Yabluchanskiy et al., 2021). Amplitude of low-frequency fluctuation (ALFF) is an rs-fMRI index used to detect the regional strength of spontaneous fluctuations in Blood Oxygen Level Dependent signals, which can precisely locate spontaneous neural activities in specific brain regions and physiological states (Zang et al., 2007). Changes in ALFF have been reported in CD patients (Huang et al., 2024; Li et al., 2021; Bao et al., 2018). Fractional ALFF (fALFF), derived from ALFF, measures the proportion of low-frequency oscillations within a specific frequency range (typically 0.01–0.08 Hz), thereby representing spontaneous neuronal activity during rest. To a certain extent, it avoids the drawbacks of ALFF, such as being easily affected by cerebrospinal fluid and physiological noise in the ventricle. It can effectively inhibit the non-specific signal components in the resting state fMRI and significantly improve the sensitivity and specificity of local spontaneous brain activity detection (Zou et al., 2008).

Functional connectivity (FC) characterizes the temporal synchronization of spontaneous fluctuations between distinct brain regions, providing insights into the functional integrity of neural networks (Fox and Raichle, 2007). The combined application of these metrics enables comprehensive evaluation of both regional intrinsic activity and disease-associated network alterations. These approaches have been widely employed in functional gastrointestinal disorders and neurological conditions, demonstrating significant potential in resting-state brain function research (Thomann et al., 2025; Langhammer et al., 2025). Consequently, they may prove instrumental in elucidating resting-state neural signatures in adolescents with CD and advancing our understanding of the pathophysiological mechanisms underlying pediatric CD. However, these study cohorts primarily comprised adult CD populations, with observed inconsistencies predominantly confined to adult patients. Specifically, Bao et al. (2018) reported hippocampal hyperactivity in adults, whereas Li et al. (2021) documented hypoactivity in a separate adult cohort. Similarly, Mallio et al. (2020) identified cerebellar connectivity alterations in adults, contrasting with Huang et al.’s (Huang et al., 2024) null findings in another adult sample. These contradictory findings underscore the necessity for further investigation into neural patterns in adolescent CD.

While rs-fMRI has been widely used to investigate neuropsychiatric conditions, no studies to date have systematically examined functional brain alterations in adolescents with CD. Based on emerging evidence of brain-gut interactions in inflammatory bowel disease, we hypothesize that adolescent CD patients exhibit distinct patterns of altered ALFF, fALFF and FC in key brain regions involved in emotion regulation and social cognition. We further hypothesize that these neurofunctional changes correlate significantly with both validated measures of emotional dysregulation and clinically relevant disease characteristics. The primary objective of this study is to examine neural correlates of emotional symptoms changes in adolescent CD patients and explore potential associations between aberrant spontaneous brain activity and emotional symptoms. Additionally, we employed regions exhibiting altered activity in adolescent CD as seed points to map brain functional connectivity patterns using both ALFF and fALFF analyses. This will aid in early intervention and personalized care, and offer a new perspective for guiding the diagnosis, treatment, and prognostic evaluation of the condition.

Our study demonstrates that adolescents with CD exhibit significantly lower IBDQ and SSRS scores compared to HCs, while demonstrating significantly higher SCL-90 scores. Abnormal ALFF values are found in the left superior temporal gyrus, left inferior temporal gyrus, and left precuneus gyrus. Abnormal fALFF values were identified in the left calcarine fissure and surrounding cortex, vermis, and the left superior frontal gyrus, medial of the brain regions in adolescent CD patients. Furthermore, ALFF and fALFF value exhibited significant correlations with intestinal inflammation and nutritional indicators, and emotional symptoms scores in adolescent CD patients.

Our study found that adolescents with CD exhibited significantly impaired quality of life and diminished social support relative to HCs, concurrently presenting with elevated emotional symptom scores. These findings are consistent with previous research on adult CD patients (Huang et al., 2023), emphasizing the multifaceted nature of CD. Previous studies have shown that male and IBD patients aged 12 to 17 are at the highest risk of developing mental health conditions (McCartney et al., 2022), and children IBD patients are associated with higher prevalence of anxiety and depression (Loftus et al., 2011). The decline in quality of life and social support may stem from the unique behavioral issues associated with adolescent CD (Griffiths, 2004), such as perianal disease, abdominal pain, and fatigue (Greenley et al., 2010; Mackner et al., 2013). The embarrassing nature of IBD symptoms (such as frequent bowel movements, diarrhea etc.) can lead to social isolation, strained family relationships (Cushman et al., 2020), and academic difficulties among adolescent patients with CD, all of which contribute to a decrease in overall quality of life. Higher emotional symptoms scores, including symptoms of obsessive compulsive, depression, and anxiety, indicate that adolescent CD often coexists with other mental health conditions. This comorbidity can further complicate the treatment and management of adolescent CD, as addressing one aspect may require a comprehensive consideration of the interplay between behavioral and emotional symptoms.

Most prior studies included adult CD patients in remission or active stages, whereas our study focuses on adolescents, a population with unique neurodevelopmental and psychosocial challenges. In terms of resting-state ALFF and fALFF, we found that the ALFF values in the left precuneus gyrus, left superior temporal gyrus, and left inferior temporal gyrus were abnormally altered in the adolescent CD group. Reduced ALFF in the left precuneus aligns with Li et al. (2021), suggesting a consistent role of the default mode network in CD-related emotional dysregulation. The fALFF values were changed in the left calcarine fissure and surrounding cortex, left superior frontal gyrus, medial, and Vermis brain regions. The temporal gyrus is involved in auditory processing, language comprehension (Gernsbacher and Kaschak, 2003), social cognition (Jou et al., 2010), memory and learning (Jou et al., 2010), all of which are crucial for normal social interaction. Early-onset CD may confer greater neurodevelopmental risk, as inflammation during puberty could disrupt limbic system maturation. The relatively limited sample size in the age less than 16 years subgroup may constrain certain age-stratified analyses. However, we incorporated age as a covariate in all comparative analyses of ALFF and fALFF parameters between CD patients and healthy controls, thereby effectively controlling for potential confounding effects of age-related variation.

Increased ALFF in the left superior and inferior temporal gyri is a novel finding. These regions mediate auditory processing (Sun et al., 2025), language comprehension (Xu et al., 2020), and social cognition (Li et al., 2025), which may explain the social withdrawal and interpersonal sensitivity observed in adolescent CD patients. Abnormal ALFF values in the left superior temporal gyrus and left inferior temporal gyrus may disrupt these functions, thereby leading to social and behavioral deficits in patients with adolescent CD (Gamwell et al., 2018). The precuneus gyrus is associated with self-awareness processing and episodic memory (Cavanna and Trimble, 2006), which may be related to the self-regulation and emotional dysregulation issues commonly seen in adolescent CD. The left calcarine fissure and surrounding cortex are associated with visual processing, while the Vermis of the cerebellum is involved in motor control and cognitive functions (Devita et al., 2025; Chao et al., 2023). Although research on the function of the Vermis is relatively limited at present, as part of the cerebellar vermis, it has become a key node in the integrated network that connects different functions such as sensory, motor, emotional, and cognitive functions (Bostan and Strick, 2018; Stoodley and Tsai, 2021). While not directly mediating gastrointestinal function, dysregulation in visual and cerebellar networks may amplify symptom awareness and compromise emotional-motor adaptation, thereby contributing to the subjective burden of CD. Abnormal fALFF values in these regions may indicate a more widespread disruption of the neural networks that integrate sensory, motor, and cognitive processes, which may underlie the complex behavioral and emotional symptoms of adolescent CD. These findings provide new insights into the neurobiological basis of adolescent CD patients. Prior adult studies have not emphasized temporal lobe alterations, possibly due to age-related neural plasticity differences. The current results highlight age-dependent changes in brain regions critical for emotional regulation (e.g., temporal gyrus) and self-awareness (precuneus), whereas adult studies focus more on sensorimotor and frontal lobe networks. This underscores the need for age-stratified CD neuroimaging research. The discrepancy between adult and adolescent ALFF patterns suggests that CD-related brain alterations may emerge during critical neurodevelopmental stages, influencing long-term emotional comorbidity risk.

In this study, the ALFF-derived connectivity maps demonstrated significantly enhanced functional coupling between the PCUN. L and both STG. L and ITG. L. The PCUN. L is a hub of the default mode network (DMN), governing self-referential processing and episodic memory. Its hyperconnectivity with STG. L and ITG. L—regions critical for social cognition and auditory-emotional integration (Gernsbacher and Kaschak, 2003)—suggests maladaptive coupling between self-focused rumination and socioemotional processing. This may underpin excessive symptom monitoring and interpersonal sensitivity observed in CD adolescents. Meanwhile, the fALFF-derived connectivity maps demonstrated significantly enhanced functional coupling between the SFGmed. L and both CAL. L, and Vermis_10. The SFGmed. L supports executive control and emotion regulation (Devita et al., 2025). Its hyperconnectivity with visual cortex and cerebellar vermis—a region implicated in visceromotor and affective modulation (Stoodley and Tsai, 2021)—indicates dysregulated integration of sensory input with top-down cognitive control, potentially contributing to anxiety and somatic preoccupation. Moreover, FC in these brain regions has also been altered in adolescent CD patients, which is partly consistent with previous studies (Mallio et al., 2020; Thapaliya et al., 2023). This suggests that changes in underlying neural activity (reflected by ALFF and fALFF) may potentially drive the observed FC changes. Alterations in FC across multiple brain regions may manifest as heightened sensitivity to visceral sensory information (Langhammer et al., 2025), such as increased symptom monitoring, heightened vigilance, and anxiety about anticipated abdominal pain, cramps, and diarrhea.

The ALFF and fALFF indices in these brain regions are correlated with emotional symptoms scores, which also illustrate this point to some extent. In adolescent CD patients, the abnormal increase in FC in these regions may indicate compensatory mechanisms for underlying neuropathology. Understanding these relationships between neural activity and connectivity is crucial for deciphering the complex pathophysiology of CD. The hyperconnectivity between DMN nodes and social-cognitive regions may amplify salience attribution to visceral sensations, fostering catastrophic appraisals of symptoms. Concurrently, weakened connectivity between SFGmed. L and cerebellar vermis could impair downregulation of limbic arousal. Our study identifies ALFF values increased in left superior temporal gyrus and inferior temporal gyrus, but decreased in left precuneus gyrus. Reduced ALFF in the left precuneus aligns with Li et al. (2021), while Bao et al. (2018) reported default mode network alterations encompassing this region, suggesting a consistent role of the DMN in CD-related emotional dysregulation.

Furthermore, our correlation analyses revealed clinically meaningful associations between aberrant neural activity and both emotional symptoms and disease biomarkers. Specifically, the ALFF value in the ITG. L demonstrated a negative correlation with obsessive-compulsive symptoms, depression, and anxiety, while exhibiting a positive correlation with serum albumin levels. Similarly, the ALFF in the STG. L was negatively correlated with CRP and positively correlated with albumin. These findings suggest that increased inflammation (reflected by elevated CRP) and malnutrition (indicated by hypoalbuminemia) may contribute to dysregulated neural activity in temporal regions involved in social cognition and auditory processing. Conversely, reduced ALFF in these regions correlates with heightened psychopathological burden, reinforcing the role of the temporal cortex in mediating gut-brain interactions in adolescent CD. Inflammation in the gut may release cytokines and other immune mediators that can cross the blood brain barrier and affect neural function (Agirman et al., 2021). Additionally, medications used in CD can modulate inflammatory markers and brain activity, which were not controlled for in this cross-sectional design. Future longitudinal studies with detailed inflammatory profiling are needed to disentangle the specific contributions of gut-derived inflammation to neural alterations. Collectively, these results position the temporal gyri as critical neural interfaces bridging gastrointestinal pathophysiology and behavioral comorbidities, potentially implicating neuroinflammatory pathways in the gut-brain axis. The positive correlations between fALFF in Vermis and emotional symptoms scores, including interpersonal sensitivity, depression, paranoid, and psychoticism, further emphasize the link between brain function and emotional well-being in CD patients. The cerebellum is increasingly recognized for its role in emotional regulation and cognitive processing (Turner et al., 2007). This relationship also highlights the potential for targeting the cerebellum in the development of novel therapeutic interventions for CD, such as non-invasive brain stimulation techniques.

There are still some limitations of our study. Firstly, the cross-sectional design precludes temporal inferences; longitudinal investigations are required to delineate the evolution of observed changes. Secondly, our cohort exhibited pronounced male predominance, and heterogeneous pharmacotherapy regimens initiated prior to enrollment were present. These pharmacological interventions may confound normative cerebral metabolism through diverse pathways, consequently exerting differential effects on neurofunctional activity. Third, while we selected well-validated measures for adolescent populations, the IBDQ’s original validation in adolescent requires cautious interpretation of quality-of-life metrics in this transitional age group. Our findings reflect subclinical emotional symptoms measured by SCL-90, not diagnosed psychiatric symptoms. Future studies should incorporate structured clinical interviews to assess symptoms comorbidity. Methodologically, seed-based FC analyses identify temporal correlations between neural regions but cannot establish directional influences. Finally, the modest sample size inherently constrains statistical power to detect subtle neurofunctional alterations and precludes robust subgroup analyses (e.g., active vs. quiescent disease, depression comorbidity status) that might elucidate phenotype-specific neural signatures. Future expanded longitudinal cohorts, stratified by sex and medication status, should track neurofunctional trajectories alongside molecular profiling to establish mechanistic links between gut inflammation and neural circuit dysregulation.

In conclusion, our study found that adolescent CD patients showed altered emotional symptoms, and their intrinsic brain function, which may relate to behavioral issues, was also affected. Future research should focus on exploring the underlying mechanisms, and developing targeted interventions based on these insights.