Positive psychotic symptoms are associated with divergent developmental trajectories of hippocampal volume during late adolescence in patients with 22q11DS


Low hippocampal volume is a consistent finding in schizophrenia and across the psychosis spectrum. However, there is a lack of studies investigating longitudinal hippocampal development and its relationship with psychotic symptoms. The 22q11.2 deletion syndrome (22q11DS) has proven to be a remarkable model for the prospective study of individuals at high risk of schizophrenia to unravel the pathophysiological processes predating the onset of psychosis. Repeated cerebral MRIs were acquired from 140 patients with 22q11DS (53 experiencing moderate-to-severe psychotic symptoms) and 135 healthy controls aged from 6 to 35 years and with up to 5 time points per participant. Hippocampal subfield analysis was conducted using FreeSurfer-v.6 and FIRST-FSL. Then, whole hippocampal and subfield volumes were compared across the groups. Relative to controls, patients with 22q11DS showed a remarkably lower volume of all subfields except for CA2/3. No divergent trajectories in hippocampal development were found. When comparing patients with 22q11DS exhibiting psychotic symptoms to those without psychosis, we detected a volume decrease during late adolescence, starting in CA1 and spreading to other subfields. Our findings suggested that hippocampal volume is consistently smaller in patients with 22q11DS. Moreover, we have demonstrated that patients with 22q11DS and psychotic symptoms undergo a further decrease in volume during adolescence, a vulnerable period for the emergence of psychosis. Interestingly, CA2/3, despite being affected in patients with psychotic symptoms, was the only area not reduced in patients with 22q11DS relative to controls, thus suggesting that its atrophy exclusively correlates with the presence of positive psychotic symptoms.

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Code availability

The code employed to model hippocampal developmental trajectories is available upon request.


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We would like to thank all the families who contributed to the study, as well as the family associations (Génération 22, Connect 22, Relais 22) for their ongoing support. Special thanks go to Léa Chambaz and Virginie Pouillard for coordinating the project and to the MRI operators at the Center of Biomedical Imaging (CIBM), François Lazeyras, Lydia Dubourg, Maëlle Chambaz, Laura Juan Galmes, and Joëlle van der Molen for their help in scanning.


This work was supported by research grants from the Swiss National Science Foundation (grant numbers 324730_121996, 324730_144260 to SE) and The National Centre of Competence in Research (NCCR) “Synapsy—The Synaptic Bases of Mental Diseases” (grant number 51NF40-158776 to SE). Personal grants by the Swiss National Science Foundation (grant numbers PZ00P1_174206 to M.Schn. and 163859 to M.Scha.) also supported the present work.

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Mancini, V., Sandini, C., Padula, M.C. et al. Positive psychotic symptoms are associated with divergent developmental trajectories of hippocampal volume during late adolescence in patients with 22q11DS. Mol Psychiatry 25, 2844–2859 (2020). https://doi.org/10.1038/s41380-019-0443-z

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