2026 ECNP Congress

PS02-2077

Associations between immuno-metabolic dysregulation and functional connectivity of corticostriatal and insular circuits in depressive and anxiety disorders

Simon Braak — L.K.M. Han, C. Vriend, T. Bastiaanssen, M.J. van Tol, N.J.A. van der Wee, B.W.J.H. Penninx · Amsterdam UMC, Psychiatry, Amsterdam, Netherlands

2026 ECNP Congress

Background

A growing body of research has identified a subgroup of individuals with depressive disorders characterized by systemic low-grade inflammation (e.g., elevated levels of C-reactive protein (CRP) and pro-inflammatory cytokines) and metabolic dysregulation (e.g., insulin resistance and altered lipid profiles) [1]. This immuno-metabolic profile is often accompanied by atypical energy-related symptoms and anhedonia [1]. Emerging evidence suggests that immuno-metabolic dysregulation may disrupt interoceptive processing in the insula and reward processing in corticostriatal circuits, potentially contributing to these symptom dimensions [2,3]. This study examined associations between corticostriatal and insular functional connectivity, peripheral immuno-metabolic markers, and relevant depressive symptoms across persons with and without depressive and anxiety disorders.

Methods

Data were drawn from the baseline (N = 211), two- (N = 140), and nine-year (N = 160) waves of the NESDA study, and from the baseline sample of the MOTAR study (N = 117) [4,5]. The analysis pipeline was preregistered (Open Science Framework: https://osf.io/9t6gu) and applied consistently across datasets. Resting-state fMRI data were preprocessed using fMRIPrep and postprocessed with XCP-D, including despiking, band-pass filtering, and denoising with 24 head-motion parameters plus eight physiological signals derived from white matter and cerebrospinal fluid. Seed-based analyses examined ventral striatum functional connectivity with the ventromedial prefrontal cortex and subgenual anterior cingulate cortex, as well as anterior-posterior insula connectivity. To maximize robustness, summary statistics were pooled using inverse-variance weighted random-effects meta-analysis (N = 628). Composite scores for atypical energy-related symptoms and anhedonia were derived from the Inventory of Depressive Symptomatology – Self Report. Immuno-metabolic markers included an inflammation composite (CRP, interleukin-6, tumor necrosis factor-alpha) and a metabolic syndrome index. Associations were tested using linear regression models adjusted for age, sex, and scanner site, with statistical significance set at p < 0.05.

Results

Meta-analytic pooling across the four samples revealed that more severe atypical energy-related symptoms were consistently associated with higher inflammation (β = 0.14, 95% confidence interval (CI) [0.06, 0.23], p = 0.0005) and metabolic syndrome scores (β = 0.20, 95% CI [0.07, 0.34], p = 0.004), whereas anhedonia did not relate to the immuno-metabolic indices (p > 0.05). Higher inflammation was associated with lower anterior-posterior insula functional connectivity (β = -0.09, 95% CI [-0.17, -0.01], p = 0.030). Additionally, lower functional connectivity between the ventral striatum and subgenual anterior cingulate cortex was associated with greater anhedonia (β = -0.10, 95% CI [-0.18, -0.02], p = 0.014).

Conclusions

These findings support the role of immuno-metabolic dysregulation in atypical energy-related depressive symptoms, with reduced anterior-posterior insula connectivity representing a neural correlate of peripheral inflammation. Anhedonia was specifically associated with reduced corticostriatal connectivity, pointing to a potential neurocircuit target for precision medicine. Future longitudinal and interventional studies are needed to clarify the directionality and specificity of these relationships and to evaluate their relevance in stratified treatment approaches.

References

  1. Miller, A. H. (2025). Advancing an Inflammatory Subtype of Major Depression. Am J Psychiatry, 182(6), 516–524. https://doi.org/10.1176/appi.ajp.20250289
  2. Felger, J. C., Li, Z., Haroon, E., Woolwine, B. J., Jung, M. Y., Hu, X., & Miller, A. H. (2016). Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry, 21(10), 1358–1365. https://doi.org/10.1038/mp.2015.168
  3. Stefanov, K., McLean, J., McColl, A., Basu, N., Cavanagh, J., & Krishnadas, R. (2020). Mild Inflammation in Healthy Males Induces Fatigue Mediated by Changes in Effective Connectivity Within the Insula. Biol Psychiatry Cogn Neurosci Neuroimaging, 5(9), 865–874. https://doi.org/10.1016/j.bpsc.2020.04.005
  4. Penninx, B., Eikelenboom, M., Giltay, E. J., van Hemert, A. M., Riese, H., Schoevers, R. A., & Beekman, A. T. F. (2021). Cohort profile of the longitudinal Netherlands Study of Depression and Anxiety (NESDA) on etiology, course and consequences of depressive and anxiety disorders. J Affect Disord, 287, 69–77. https://doi.org/10.1016/j.jad.2021.03.026
  5. Lever-van Milligen, B. A., Verhoeven, J. E., Schmaal, L., van Velzen, L. S., Revesz, D., Black, C. N., Han, L. K. M., Horsfall, M., Batelaan, N. M., van Balkom, A., van Schaik, D. J. F., van Oppen, P., & Penninx, B. (2019). The impact of depression and anxiety treatment on biological aging and metabolic stress: study protocol of the MOod treatment with antidepressants or running (MOTAR) study. BMC Psychiatry, 19(1), 425. https://doi.org/10.1186/s12888-019-2404-0