2026 ECNP Congress

PS01-1090

Left hippocampal connectivity links Toxoplasma gondii seropositivity to depression severity in hospitalised major depression

Edoardo Venturelli — F. Colombo, M. Palladini, G. Semeraro, S. Spadini, C. Lorenzi, C. Colombo, R. Zanardi, F. Benedetti, S. Poletti · IRCCS San Raffaele Hospital, Psychiatry and Clinical Psychobiology Unit - Division of Neuroscience, Milan, Italy

2026 ECNP Congress

Introduction: Latent Toxoplasma gondii (T. gondii) infection has been associated with neuropsychiatric phenotypes and may influence brain function through immune, neurotropic, and neurotransmitter-related mechanisms [1]. Experimental models indicate that chronic infection affects limbic and cortico-limbic regions involved in emotion and behavioural regulation, suggesting a potential mechanistic link with mood dysregulation [2]. However, epidemiological evidence linking T. gondii seropositivity to Major Depressive Disorder (MDD) remains inconsistent [3,4], and whether latent parasitic exposure is associated with altered functional brain connectivity in MDD has not been directly investigated.

Objectives: We investigated whether T. gondii seropositivity is associated with altered resting-state functional connectivity in MDD inpatients, and whether regional connectivity mediates the association between T. gondii serostatus and depressive symptom severity.

Methods: Blood samples of 42 MDD patients were collected to detect and quantify anti-T. gondii IgG antibodies using ELISA kits. Based on the manufacturer-defined cut-off, patients were classified as seronegative (N=25) or seropositive (N=17). Depressive symptom severity was assessed at recruitment using the Hamilton Depression Rating Scale (HDRS-21), and group differences between seronegative and seropositive patients for HDRS-21 total scores were assessed using t-tests. Resting-state fMRI data were acquired on the same day as blood sampling. Functional connectivity analyses were performed using AAL atlas regions, excluding the cerebellum. Nodal strength was computed for each region as the sum of weighted functional connections. Partial correlations examined associations between T. gondii serostatus and regional functional strength, controlling for age and sex. High-dimensional mediation analysis (HIMA) tested whether regional nodal strength mediated the association between T. gondii serostatus and HDRS-21 total score, adjusting for multiple comparisons using the False Discovery Rate (FDR).

Results: Seropositive patients showed significantly lower HDRS-21 total scores than seronegative patients (18.18±6.06 vs. 23.56±5.82; t(33.53)= -2.87, p=0.007). Partial correlations revealed widespread functional connectivity alterations involving cortical and subcortical regions, encompassing nodes of the cortico-limbic circuit (all p<0.05). In the mediation analysis, left hippocampal strength was the only regional mediator surviving FDR correction (pFDR<0.001). T. gondii seropositivity was associated with lower left hippocampal strength (α= -0.285), and lower left hippocampal strength was in turn associated with higher HDRS-21 total scores (β= -1.860). The indirect effect was positive (α×β=0.530), indicating that hippocampal functional strength opposed the negative total association between seropositivity and depressive symptom severity.

Conclusion: Our findings provide preliminary evidence that T. gondii seropositivity is associated with altered functional connectivity in patients with MDD, suggesting that latent exposure may be linked to differences in brain functional organisation. The mediation model suggests that reduced connectivity strength in the left hippocampus may constitute a potential neurobiological pathway linking latent parasitic exposure to depressive symptomatology, consistent with previous evidence of altered hippocampal functioning in mouse models of toxoplasmosis [5]. Although seropositive patients showed lower HDRS-21 scores, their need for inpatient care may indicate broader clinical vulnerability not fully captured by depressive symptom severity. Taken together, these findings suggest that T. gondii exposure may be associated with increased vulnerability to hospitalisation in MDD patients, potentially through alterations in hippocampal functional connectivity.

References

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  2. Gatkowska, J., Wieczorek, M., Dziadek, B., Dzitko, K., & Dlugonska, H. (2012). Behavioral changes in mice caused by Toxoplasma gondii invasion of brain. Parasitology research, 111(1), 53-58.
  3. Nayeri Chegeni, T., Sharif, M., Sarvi, S., Moosazadeh, M., Montazeri, M., Aghayan, S. A., … & Daryani, A. (2019). Is there any association between Toxoplasma gondii infection and depression? A systematic review and meta-analysis. PloS one, 14(6), e0218524.
  4. Gale, S. D., Erickson, L. D., Brown, B. L., & Hedges, D. W. (2021). Examining the relationship between Toxoplasma Gondii and Seropositivity and Serointensity and Depression in adults from the United Kingdom and the United States: a cross-sectional study. Pathogens, 10(9), 1101.
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