Alterations in resting-state functional connectivity of the salience network in patients with schizophrenia with and without cannabis use disorder comorbidity.

Schizophrenia (SCZ) is a mental disorder with as yet undefined aetiology and pathogenesis, with a prevalence of approximately 1%. About one in four individuals with SCZ is diagnosed with comorbid Cannabis Use Disorder (CUD) (1). The neural mechanisms linking cannabis use to worse prognosis in SCZ are poorly understood. Aberrations in brain connectivity have been identified as contributing to the pathophysiology of schizophrenia. Three large-scale networks have shown abnormalities in patients with SCZ, i.e., the Default Mode Network (DMN), which is involved in internal modes of cognition, the Central Executive Network (CEN), involved in higher cognitive and executive functions, and the Salience Network (SN), which selects behaviourally relevant stimuli prioritizing them and feeding them to brain neural hubs to respond homoeostatically to the environment (2). To our knowledge, no rs-fMRI study has examined the contribution of continued cannabis use in patients with SCZ and CUD compared to patients with SCZ without cannabis use. We hypothesized that continued cannabis use in patients with SCZ and CUD could result in greater impairment of clinical and cognitive symptoms compared to SCZ without CUD and in altered connectivity in striate-cortical areas and those involved in planning and emotional control. Study Design: In this study, we included schizophrenia patients (SCZ) 14 with and 20 without comorbidity with cannabis use disorder (CUD) and assessed them cross-sectionally using psychometric tools, cognitive tests, and resting-state functional imaging (rs-fMRI) for brain connectivity study. The sample was subdivided according to the presence or absence of CUD. Patients were consecutively enrolled during voluntary hospitalization at the neuropsychiatric hospital in Genzano di Roma from October 2022 to July 2023. SCZ CUD+ patients answered a questionnaire on cannabis addiction, THC use patterns, age of onset, and years of continuous use. Assessment: Patients were all evaluated through the Neurological Evaluation Scale (NES), the Brief Assessment of Cognition in Schizophrenia (BACS) , and the Positive And Negative Syndrome Scale (PANSS). Imaging protocol:All patients underwent a brain MRI examination at 1.5 T scanner (GE Signa Voyager) with 32-channel phased-array head coil. Neuroimaging data analysis were performed using the SPM-based software Conn functional connectivity toolbox (version 22a) and run on MATLAB 2023. Clinical Variables results: We enrolled 34 patients diagnosed with schizophrenia, including 20 SCZ (CUD+) and 14 SCZ (CUD-). The age of our sample ranged 19-38 years (mean = 26.32, SD = 4.903). The SCZ CUD+ group was significantly younger (p = 0.011907) and had an earlier age of onset (p = 0.004615) compared to the SCZ CUD- group. SCZ CUD+ patients had a mean of 6.95 years of continuous THC use. There were no differences in PANSS scores between the two groups. SCZ CUD+ patients scored higher on the "poor impulse control" and "excitement" items compared to the control group (p = 0.001). On the NES scale, SCZ CUD- patients scored higher than the other group (p = 0.037). The two groups did not differ in cognitive performance assessed using the BACS scale except for the Symbol Coding test, where SCZ CUD+ patients performed worse (p = 0.033). Functional Imaging Results: Seed based analysis: SCZ CUD+ patients showed reduced functional connectivity of the right insular cortex with the Precuneous Cortex compared to SCZ CUD- (Fig. 1). Comparing to SCZ CUD-, patients with SCZ CUD+ showed reduced functional connectivity of the left Accumbens with the bilateral Frontal Pole cortex and with the left Fronto-Orbital cortex; and an increased functional connectivity with the left mesolimbic system (particularly left hippocampus, amygdala) (Fig.2). Roi-to-Roi analysis: Comparing to SCZ CUD-, patients with SCZ CUD+ showed a reduced functional connectivity between the Anterior Cingulate Cortex and the left Rostral Prefrontal Cortex (Fig.3). Using resting-state fMRI, the analysis has revealed differences in connectivity within the Salience Network and the Nucleus Accumbens between SCZ CUD- and SCZ CUD+ subgroups. We have highlighted that continuous cannabis use compromises functional connectivity in cortico-limbic, cortico-cortical, and striatal circuits, impacting connections which are already impaired in schizophrenia. This study supports the hypothesis of a disconnected network model in schizophrenia, where network dysfunction is closely linked to deficits in regulating salient information and maintaining the integrated self. Contrary to our hypothesis, we did not find significant effects of THC on resting-state functional connectivity in the default mode network. In our view, larger studies should explore the role of the precuneus in psychotic conditions comorbid with CUD.