Structural and Functional Default Mode Network Connectivity and Antipsychotic Treatment Response in Medication-Naïve First Episode Psychosis Patients

Abstract

Introduction Only a few studies have comprehensively characterized DMN pathology on a structural and functional level, and definite conclusions cannot be drawn due to antipsychotic medication exposure and illness chronicity. The objective of this study was to characterize DMN pathology in medication-naïve first episode psychosis patients (FEP), and determine if DMN structural and functional connectivity (FC) have potential utility as a predictor for subsequent antipsychotic treatment response. Methods Diffusion imaging and resting state FC data from 42 controls and 52 FEP were analyzed. Patients then received 16 weeks of antipsychotic treatment. Using region of interest analyses, we quantified FC of the DMN and structural integrity of the white matter tracts supporting DMN function. We then did linear regressions between DMN structural and FC indices and antipsychotic treatment response. Results We detected reduced DMN fractional anisotropy and axial diffusivity in FEP compared to controls. No DMN FC abnormalities nor correlations between DMN structural and FC were found. Finally, DMN fractional anisotropy and radial diffusivity were associated with response to treatment. Conclusion Our study highlights the critical role of the DMN in the pathophysiology suggesting that axonal damage may already be present in FEP patients. We also demonstrated that DMN pathology is clinically relevant, as greater structural DMN alterations were associated with a less favorable clinical response to antipsychotic medications.

fMRI connectivity as a biomarker of antipsychotic treatment response: A systematic review

“…Study characteristics are shown in Table 1a , Table 1b , Table 1c . Q1) seventeen studies reported on baseline fMRI-FC and AP-R at follow-up ( Anticevic et al, 2015 , Blazer et al, 2022 , Cadena et al, 2019 , Deng et al, 2022 , Doucet et al, 2020 , Hadley et al, 2014 , Han et al, 2020 , Kraguljac et al, 2016 , Kraguljac et al, 2016 , Li et al, 2020 , Maximo et al, 2021 , Nelson et al, 2022 , Sarpal et al, 2016 , Wang et al, 2019 , Zhang et al, 2019 , Blessing et al, 2020 , Zong et al, 2019 ), Q2) eighteen studies investigated associations between changes in fMRI-FC characteristics before and after treatment related to AP-R ( Anticevic et al, 2015 , Blazer et al, 2022 , Cadena et al, 2019 , Chopra et al, 2021 , Deng et al, 2022 , Duan et al, 2020 , Hadley et al, 2014 , Hadley et al, 2016 , Han et al, 2020 , Kraguljac et al, 2016 , Li et al, 2016 , Li et al, 2020 , Liu et al, 2022 , Sarpal et al, 2015 , Shan et al, 2021 , Wang et al, 2019 , Blessing et al, 2020 , Zong et al, 2019 ), Q3) nine studies investigated the prediction of AP-R based on fMRI-FC ( Cao et al, 2018 , Li et al, 2020 , Li et al, 2020 , Liu et al, 2022 , Sarpal et al, 2016 , Shan et al, 2021 , Zhu et al, 2018 , Blessing et al, 2020 , Nejad et al, 2013 ).…”

“…Seventeen studies reported a difference in baseline FC between AP-R and AP-NR ( Nelson et al, 2022 , Anticevic et al, 2015 , Blessing et al, 2020 , Cadena et al, 2019 , Doucet et al, 2020 , Hadley et al, 2014 , Han et al, 2020 , Kraguljac et al, 2016 , Kraguljac et al, 2016 , Sarpal et al, 2016 , Li et al, 2020 , Wang et al, 2019 , Zhang et al, 2019 , Zong et al, 2019 , Deng et al, 2022 , Blazer et al, 2022 , Maximo et al, 2021 ). Studies included 585 patients of which 408 FE patients and 177 chronic patients.…”

“…Three studies defined AP-R as a priori set percentage (i.e., 20, 30 and, 35%) reduction in symptom score ( Blessing et al, 2020 , Deng et al, 2022 , Sarpal et al, 2016 ). Treatment consisted of risperidone monotherapy (N = 9 studies ( Nelson et al, 2022 , Cadena et al, 2019 , Hadley et al, 2014 , Han et al, 2020 , Kraguljac et al, 2016 , Kraguljac et al, 2016 , Zong et al, 2019 , Maximo et al, 2021 ) monotherapy with variable AP-agents (N = 4 ( Blessing et al, 2020 , Doucet et al, 2020 , Wang et al, 2019 , Blazer et al, 2022 ), monotherapy or multitherapy with variable AP-agents ( Deng et al, 2022 ) or 1:1 randomization between risperidone and aripiprazole ( Sarpal et al, 2016 ). Two studies did not specify the type of AP-treatment ( Anticevic et al, 2015 , Zhang et al, 2019 ).…”

A Whole-Brain Neuromark Resting-State Fmri Analysis of First-Episode and Early Psychosis: Evidence of Aberrant Cortical-Subcortical-Cerebellar Functional Circuitry

“…Wang et al, 2023;Wilson et al, 2020; from the onset of illness, while EP samples (also referred to as early-phase or earlyonset psychosis) typically include individuals within a duration of five years from the onset of illness (Deakin et al, 2018;Holmes et al, 2023;Koshiyama et al, 2018;Vanes et al, 2019;. Some studies define FEP and EP based on the first emergence of psychotic symptoms (Fornito et al, 2013;, while others define FEP and EP based on when treatment began, which may be considered the individual's first contact with a clinician (Breitborde et al, 2009;Flaum et al, 1992;O'Connor et al, 2017;Reid et al, 2019), but may also account for when the individual began taking antipsychotic medication (Dempster et al, 2020;Iwashiro et al, 2016;Jauhar et al, 2018;Lencz et al, 2022;Maximo et al, 2021;Salisbury et al, 2022;Wen et al, 2023). An advantage of basing the definition for FEP or EP on the emergence of symptoms is that one can examine individuals in the earliest stages of illness by accounting for untreated psychosis.…”

Cortical Network Disruption is Minimal in Early Stages of Psychosis

“…Previous dMRI studies in first-episode psychosis (FEP) have thus far converged on a report of reduced fractional anisotropy (FA) in FEP, 25 but the location and scale of these findings vary across studies. [26][27][28][29][30][31][32][33][34][35][36][37] Other reports have studied changes in the number of streamlines connecting cortical regions, a metric that gives insight into the anatomical makeup of the structural connectome. Results from such analyses have been relatively modest compared to FA.…”