First-Episode Psychosis Associated With Lower Functional Connectivity

Brain connections
Brain connections
Connectivity between the anterior hippocampus and cortical areas that are typically associated with schizophrenia was found to be lower in individuals with first-episode psychosis.

Individuals who experience first-episode psychosis show lower functional connectivity between the anterior hippocampus and cortical areas that are traditionally associated with schizophrenia, according to study results published in Schizophrenia Bulletin. Identifying this pattern of abnormal functional connectivity may be useful in predicting a patient’s response to antipsychotics.

The investigators of this study analyzed whether resting-state functional connectivity can characterize anterior hippocampal abnormalities and predict treatment response in patients who were untreated with first-episode psychosis.

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The study included patients who were antipsychotic-naive with first-episode psychosis (n=61) and healthy control participants matched by gender and age (n=27) who underwent baseline neuroimaging assessment of subregional hippocampal-whole brain functional connectivity. The investigators used masked-hippocampal-group–independent component analysis with dual regression to contrast functional connectivity results between healthy controls and patients with first-episode psychosis. The analysis was repeated in a subsample of patients with first-episode psychosis (FEP A, n=27) after they received 8 weeks of second-generation antipsychotic treatment; random forest analysis was used to explore whether baseline functional connectivity predicted treatment response. A subsample of patients with first-episode psychosis (FEP B, n=34) was used that did not undergo follow up after the 8 weeks. 

Compared with healthy controls, participants with first-episode psychosis who were untreated demonstrated significantly lower functional connectivity between the left anteromedial hippocampus and cortical regions at baseline. This group effect was highly reproducible between the 2 subgroups of patients with first-episode psychosis (FEP A and FEP B; P <.05). Following the 8-week treatment period, there was no difference between patients with first-episode psychosis vs healthy controls in which anteromedial hippocampal functional connectivity increased among the participants with first-episode psychosis (P <.005). Random forest analysis accurately predicted responder vs nonresponder membership with an ROC area under the curve of 0.95; the 4 features in anteromedial hippocampal function connectivity that predicted treatment response included the right superior frontal gyrus, left precentral gyrus, right posterior insular-opercular cortex, and left postcentral gyrus.

Limitations to the study included the small sample size and lack of a replication sample and that a univariate approach used to test group differences further prevented the investigators’ ability to detect nonlinear interactions.

The researchers of the study concluded that untreated first-episode psychosis is associated with lower functional connectivity between the anterior hippocampus and the cortical regions implicated in schizophrenia, which was validated by the reproducibility of these findings. Hippocampal functional connectivity may be a useful biomarker in predicting treatment response to antipsychotics in patients with first-episode psychosis.


Blessing EM, Murty VP, Zeng B, Wang J, Davachi L, Goff DC. Anterior hippocampal-cortical functional connectivity distinguishes antipsychotic naïve first-episode psychosis patients from controls and may predict response to second-generation antipsychotic treatment [published online August 21, 2019]. Schizophr Bull. doi: 10.1093/schbul/sbz076