Abstract
Background
Functional connectivity (FC) during the resting-state is reduced in schizophrenia, especially within the Default Mode Network (DMN) (Dong 2018), and between the hippocampus, striatum and ventral tegmental area (VTA), which together conform a Midbrain Network (Gangadin 2019). Cross-sectional studies in adult samples have reported altered FC between dopamine synthesizing centers in midbrain and cortical areas in schizophrenia (Martino 2018). Conceptualizing schizophrenia as a neurodevelopmental disorder, we hypothesize that these changes may take place in early ages, prior to the clinical onset of psychosis. Therefore, we aim to examine FC of the DMN and Midbrain networks longitudinally in adolescents at increased risk of developing psychosis compared with youth with early onset psychosis and healthy volunteers (HV).
Methods
This longitudinal case-control study encompassed adolescents (12.6–18.9 years old) with psychosis risk syndrome (PRS; n=47), first episode of psychosis (FEP; n=59), and age and sex-matched HV (n=34). Fourteen out of the 30 PRS with follow-up assessment developed psychosis (t-PRS). Resting-state fMRI data was available for 88 subjects at baseline and follow-up [no significant differences in relation to drop-outs]: 10 t-PRS re-scanned at 3–12 months (at transition), and 14 PRS who did not transited (nt-PRS), 35 FEP; and 29 HV re-scanned at 10–36 month follow-up. After exclusion due to poor acquisition or excess movement, the final sample encompassed: 27 FEP, 9 t-PRS, 12 nt-PRS and 28 HV. Individual time series were extracted from Regions of Interest (ROI): for the DMN, the medial Prefrontal Cortex (mPFC), precuneus (PC), and bilateral temporo-parietal junction (Schilbach 2016); and for the Midbrain Network, the associative and limbic striatum, VTA and subiculum (Gangadin 2019). The orthogonal parameters of movement, white matter and cerebrospinal fluid (and their derivatives) and head motion scrubbing regressors were regressed out before performing the correlations. Multivariate mixed-effect models were estimated, including group (4), time and group by time interaction as fixed effects; and time and individual variability as random effects.
Results
There were no significant differences within-network FC. There was a significant group by time interaction in FC between the two networks (p = .02), driven by VTA-PC (pFDR = .02) and VTA-mPFC (pFDR = .04). Post-hoc analyses showed a significant reduction in FC in nt-PRS over time (psFDR ≤ .03), with FEP and t-PRS showing an opposite pattern (psFDR ≤ .01) in both networks. There was a trend-level reduction in FC over time in HV (ps ≤ .09), which showed significant differences relative to FEP (ps ≤ .04) in the VTA-PC and VTA-mPFC, and with t-PRS in the VTA-PC (p = .02). There was no significant difference between HV and nt-PRS. Cumulative dose of antipsychotics was negatively correlated with FC between mPFC-VTA in FEP at follow-up (r = -.41; p = .04); yet group by time effects survived when used as covariable. Sex, socio-economic status or global intelligence quotient did not exert significant effects.
Discussion
Our findings suggest that the onset of psychosis during adolescence impacts on the age-normative reduction of FC between the DMN and Midbrain networks, characteristic of the network segregation which takes place during typical brain functional development (Satterthwaite 2013). Antipsychotic medication on cortico-subcortical FC appear to have a reversing effect on these findings, although longitudinal group differences in network connectivity persist despite controlling for this effect. Our data sheds light on the changes in the organization of brain function taking place in the early stages of psychosis, coinciding with a key developmental period.
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