2026 ECNP Congress

PS04-4169

Intranasal oxytocin transiently normalises amygdala-centered functional connectivity during facial emotion recognition in psychosis

Beatriz Maria Das Neves Barros — V. Sá Diogo, D. Prata · University of Lisbon, Instituto de Biofísica e Engenharia Biomédica Faculdade de Ciências da Universidade de Lisboa, Lisboa, Portugal

2026 ECNP Congress

Introduction

Impairments in social cognition, particularly facial emotion recognition, are a core feature of psychosis and a major determinant of poor functional outcomes [1], yet remain largely unresponsive to current pharmacological treatments. Oxytocin (OT), a neuromodulator involved in social salience and affective regulation, has emerged as a promising candidate to target these deficits [2,3]. However, its effects on large-scale brain networks, specifically amygdala-centered functional connectivity, remain insufficiently characterised in this population.

Aims

This study primarily aimed to assess the potential of a single-dose intranasal oxytocin (IN-OT) intervention for transiently normalising whole-brain amygdala-seeded functional connectivity (FC) during emotion (fear and happiness) recognition in patients with psychosis. Secondarily, it sought to replicate previously reported baseline connectivity abnormalities in these patients. Additionally, associations between FC outcomes and demographic, clinical, and biochemical variables were examined to support the interpretation of the findings.

Methods

In this double-blind, randomised, placebo-controlled functional magnetic resonance imaging (fMRI) study, 57 males were included: healthy controls (HC; n = 21) receiving placebo, and patients with psychosis receiving either IN-OT (24 IU; n = 18) or placebo (PBO; n = 18). Participants performed a facial emotion recognition task during a 13-minute scan on a 3T MRI system, identifying the displayed fearful, neutral, or happy faces using a joystick. Functional connectivity was analysed using a generalized psychophysiological interaction (gPPI) model [4], as implemented in the CONN toolbox, with seeds in the whole amygdala and its subregions: laterobasal (BLA), centromedial (CMA), and superficial (SFA). Group-level effects were assessed using general linear models (GLMs), thresholded at voxel-level p < 0.005 and cluster-level p-FWE < 0.05. Post-hoc pairwise comparisons were performed on extracted cluster peak values. Exploratory associations with clinical measures, including the Positive and Negative Syndrome Scale (PANSS) and Brief Negative Symptom Scale (BNSS), were analysed using rank-based linear models with two-stage false discovery rate (FDR) correction.

Results

Patients under placebo exhibited significant functional dysconnectivity compared to controls. During fearful face recognition, patients showed hypoconnectivity between the left amygdala/subregions and bilateral frontal poles and middle frontal gyri. IN-OT significantly shifted these connections toward control levels; for instance, connectivity between the left BLA and right frontal pole was no longer significantly different from controls. During happy face recognition, patients displayed hyperconnectivity between amygdala subregions and the left inferior lateral occipital cortex. IN-OT reduced this exaggerated coupling toward control levels. Just one non-beneficial effect was found in the right CMA-left posterior supramarginal gyrus coupling, where oxytocin increased connectivity beyond control levels. Overall, IN-OT normalised most of the identified baseline abnormalities. Exploratory analyses revealed that greater symptom severity (PANSS and BNSS scores) was significantly associated with reduced amygdala–frontal and increased amygdala–occipital connectivity.

Conclusions

A single dose of intranasal oxytocin can transiently reshape amygdala-centered networks in psychosis, suggesting modulation of both deficient top-down prefrontal regulatory control and excessive bottom-up occipital salience processing. While the results highlight the translational relevance of oxytocin, its single-dose nature suggests a transient impact. Further longitudinal research is required to determine if these network restorations lead to sustained improvements in functional outcomes.

References

  1. Green, M. F., Horan, W. P., & Lee, J. (2015). Social cognition in schizophrenia. Nature Reviews. Neuroscience, 16(10), 620–631. https://doi.org/10.1038/nrn4005
  2. Shamay-Tsoory, S. G., & Abu-Akel, A. (2016). The Social Salience Hypothesis of Oxytocin. Biological Psychiatry, 79(3), 194–202. https://doi.org/10.1016/j.biopsych.2015.07.020
  3. Meyer-Lindenberg, A., Domes, G., Kirsch, P., & Heinrichs, M. (2011). Oxytocin and vasopressin in the human brain: Social neuropeptides for translational medicine. Nature Reviews Neuroscience, 12(9), 524–538. https://doi.org/10.1038/nrn3044
  4. McLaren, D. G., Ries, M. L., Xu, G., & Johnson, S. C. (2012). A generalized form of context-dependent psychophysiological interactions (gPPI): a comparison to standard approaches. NeuroImage, 61(4), 1277–1286. https://doi.org/10.1016/j.neuroimage.2012.03.068