Functional dysconnectivity of the limbic loop of frontostriatal circuits in first‐episode, treatment‐naive schizophrenia

Abstract

Frontostriatal circuits dysfunction has been implicated in the etiology and psychopathology of patients with schizophrenia (SZ). However, few studies have investigated SZ-related functional connectivity (FC) alterations in discrete frontostriatal circuits and their relationship with pathopsychology in first-episode schizophrenia (FESZ). The goal of this study was to identify dysfunctions in discrete frontostriatal circuits that are associated with key features of FESZ. To this end, a case-control, cross-sectional study was conducted, wherein resting-state (RS) functional magnetic resonance (fMRI) data were collected from 37 treatment-naïve FESZ patients and 29 healthy control (HC) subjects. Seed-based FC analyses were performed by placing six bilateral pairs of seeds within a priori defined subdivisions of the striatum. We observed significantly decreased FC for the FESZ group relative to the HC group [p < .05, family-wise error (FWE)-corrected] in the limbic loop, but not in the sensorimotor or associative loops, of frontostriatal circuitry. Moreover, bilaterally decreased inferior ventral striatum/nucleus accumbens (VSi)-dorsal anterior cingulate cortex (dACC) FC within the limbic loop correlated inversely with overall FESZ symptom severity and the disorganization factor score of PANSS. These findings provide new insight into the role of frontostriatal limbic loop hypoconnectivity in early-stage schizophrenia pathology and suggest potential novel therapeutic targets.

Abnormalities of intrinsic regional brain activity in first-episode and chronic schizophrenia: a meta-analysis of resting-state functional MRI

“…102 The putamen also has widespread connections with the frontal cortex, involved in motor sequence performance and habitual instrumental behaviour; executive function and goal-directed behaviour; emotion processing; and reinforcement learning. 103 In our metaanalysis, the increased cluster of putamen in patients with first-episode schizophrenia did not appear in patients with chronic schizophrenia; we speculate that increased ALFF in the putamen plays an important compensatory mechanism for maintaining normal cognitive performance in the early stages of schizophrenia. Interestingly, our study observed an inconsistent activation in the VN regions (occipital gyrus, including BA 17,18 and 19).…”

Hippocampal Hyperactivity as a Druggable Circuit-Level Origin of Aberrant Salience in Schizophrenia

“…Most prominently, the anterior cingulate cortex (ACC) encodes reward predictions and reward prediction errors ( Bissonette and Roesch, 2016 ), receives input not only from the VTA ( Decot et al, 2017 ) but also the LC ( Fillinger et al, 2017 ), and projects to the associative and—to a lesser extent—the ventral striatum ( Fillinger et al, 2018 ) ( Figure 2 ). The latter (ACC→NAc) connection is functionally reduced in first-episode schizophrenia ( Lin et al, 2018 ). The ACC also projects to further key structures of the extended vSub/VTA circuit, such as the amygdala and the vHC ( Figure 2 )—these connections are crucial for attribution of the appropriate levels of significance during associative learning ( Bian et al, 2019 ; Ortiz et al, 2019 ).…”

Evidence for Decreased Density of Calretinin-Immunopositive Neurons in the Caudate Nucleus in Patients With Schizophrenia

“…However, several indications point to the caudate nucleus (CN) as being a primary node of dysfunction in SCH (Li et al, 2018). For instance, functional hypo-connectivity was found between the frontal cerebral cortex and the CN in treatmentnaïve first-episode patients with SCH (Lin et al, 2018). Furthermore, reduced structural connectivity was observed between the frontal cerebral cortex and the CN in SCH (Levitt et al, 2017).…”