The novel coronavirus (Severe acute respiratory syndrome-2 (SARS-CoV-2)) which caused the coronavirus disease 2019 (Covid-19) pandemic led to 757 million confirmed cases and 6.8 million deaths world-wild by February 2023 (“WHO Coronavirus (COVID-19) Dashboard,” 2023). A recent meta-analysis showed that approximately one in two survivors of SARS-CoV-2 suffer from physical and mental sequelae for up to 12 months after infection (Zeng et al., 2023). The pooled prevalence of neuropsychiatric symptoms among SARS-CoV-2 survivors within 12 months was reported as 41.2% mild/moderate anxiety, 6% severe/very severe anxiety, 18.3% depression, 17.9% post-traumatic stress disorders, 13.5% sleep disturbance, 17.5% memory impairment, and 15.7% lost of taste or smell infection (Zeng et al., 2023).

In addition, concerns have been raised regarding a possible link between SARS-CoV-2 and new-onset psychosis, though the validity of this association is still questioned (Moccia et al., 2023). Although the annual incidence of first-episode psychosis ranges from 24.6 to 40.9 per 100.000 inhabitants (Fearon et al., 2006; Kirkbride et al., 2012), its estimated incidence in SARS-CoV-2 survivors over six months reported as 0.42% in a recent retrospective cohort study (Taquet et al., 2021). Moreover, Oh et al. (2021) found that the risk of first-episode psychosis in the SARS-CoV-2 group (0.17%) was 2.49 times higher than that in the control group (0.04%) within six months. However, this observed increase in the incidence of psychosis could also be attributed to the possible confounders such as misdiagnosis of delirium, undocumented previous mental illness, iatrogenic factors (e.g., steroids), or stress related to the pandemic (e.g., quarantine, uncertainty regarding SARS-CoV-2 infection) (Moccia et al., 2023).

Several shared risk factors, including genetic risk, migration, adverse childhood experiences, peer bullying, substance use, perinatal events, neuroanatomical and neurocognitive changes, depressive/anxiety symptoms and self-harm/suicide have been reported between psychosis and psychotic-like experiences (PLEs) (Staines et al., 2022; van Os and Reininghaus, 2016). In addition, peripheral inflammation as a result of infections or auto-immune diseases may trigger PLEs (Khandaker et al., 2014) and psychosis (Fraguas et al., 2017). Thus, because of the assumption of a clinical continuum and several shared risk factors, especially peripheral inflammation, between PLEs and psychotic disorder, several studies have also begun to examine whether PLEs are associated with SARS-CoV-2 infection (Fraguas et al., 2017; Khandaker et al., 2014; van Os and Reininghaus, 2016). A large-scale epidemiological study confirmed that COVID-19 infection was associated with significantly greater odds of having PLEs (H. Oh et al., 2021). Yilmaz Kafali et al. (2022) also showed that PLEs were more frequently and severely experienced by SARS-CoV-2 adolescent survivors than controls. Moreover, the authors showed an association between the severity of SARS-CoV-2 infection and PLE frequency, which was fully mediated by anxiety/depressive symptoms (Yilmaz Kafali et al., 2022). Despite the possible association between SARS-CoV-2 and PLEs, to our knowledge, the neural correlates of PLEs among adolescents exposed to SARS-CoV-2 have not been investigated yet.

Various studies have examined functional connectivity (FC) changes in the brain among individuals who experience PLEs. Data from 3,434 9–11-year-olds in the Adolescent Brain Cognitive Development (ABCD) study demonstrated that children experiencing PLEs had decreased FC in the salience network (SN), default mode network (DMN), and fronto-parietal network (also known as central executive network (CEN)) than controls (Karcher et al., 2019). Similar to Karcher et al.’s study, reduced global efficiency of DMN and SN (Sheffield et al., 2016); higher connectivity within DMN and lower connectivity within CEN (Blain et al., 2020); and hypoconnectivity between dorsal striatum, dorsolateral prefrontal, anterior cingulate, and primary motor cortices (Sabaroedin et al., 2019) were reported. Thus, we assumed that SARS-CoV-2 infection may cause dysconnectivity within DMN, SN, and CEN which may provide a basis for PLEs.

Abnormal FC findings among SARS-CoV-2 survivors without neurological manifestations have been documented since the beginning of the Covid-19 pandemic. A recent resting-state functional magnetic resonance imaging (rs-fMRI) study revealed that SARS-CoV-2 survivors had an increased amplitude of low-frequency fluctuation (ALFF) values in the limbic system, striatum, and left frontal, parietal, and temporal lobes than controls (Du et al., 2022). Hafiz et al. (2022) showed an enhanced FC within basal ganglia and precuneus networks, while a reduced FC in the language network (LN). In addition, an increase in FC was observed in SARS-CoV-2 survivors within DMN and dorsal attention network (DAN) compared to healthy controls (Niroumand Sarvandani et al., 2021) (Fu et al. (2021) reported an increased occurrence of a dynamic FC state with heterogeneous patterns between sensorimotor network (SMN) and visual network (VN) in Covid-19 survivors compared to controls. In a multi-model MRI study, Benedetti et al. (2021) found that the severity of inflammation during the acute phase of SARS-CoV-2 infection was associated with a reduction of resting-state FC between DMN, language network and CEN; and SN and DAN. Despite these abnormal FC findings, little is known regarding the effect of Covid-19 disease on the developing brain.

In the current study, we first aimed to investigate the alterations of the neural circuits of the brain among adolescents exposed to SARS-CoV-2 compared to healthy controls, using rs-fMRI. Considering the possible association between PLEs and the SARS-CoV-2 infection, our second aim was to examine the effect of the Community Assessment of Psychotic Experiences-42 (CAPE-42) score on the group differences in resting-state FC. Moreover, since inflammation markers were found to be related to more severe PLEs (Edmondson-Stait et al., 2022), thirdly, we aimed to investigate the brain correlates associated with SARS-CoV-2-related inflammation response during the acute infection. We considered the following hypothesis: (1) Adolescents who were exposed to SARS-CoV-2 show alterations within DMN, SMN, VN, LN, and DAN compared to controls. (2) When PLEs are included as a covariate, adolescents exposed to SARS-CoV-2 have dysconnectivity within DMN, CEN, and SN compared to controls. (3) The severity of inflammation during the acute infection period is associated with a reduced FC of DMN, SN, CEN, LN, and DAN.