Functional Dysconnectivity of Corticostriatal Circuitry as a Risk Phenotype for Psychosis

Abstract

IMPORTANCE Dysregulation of corticostriatal circuitry has long been thought to be critical in the etiology of psychotic disorders, although the differential roles played by dorsal and ventral systems in mediating risk for psychosis have been contentious.OBJECTIVE To use resting-state functional magnetic resonance imaging to characterize disease-related, risk-related, and symptom-related changes of corticostriatal functional circuitry in patients with first-episode psychosis and their unaffected first-degree relatives. DESIGN, SETTING, AND PARTICIPANTSThis case-control cross-sectional study was conducted at a specialist early psychosis clinic, GlaxoSmithKline Clinical Unit, and magnetic resonance imaging facility. Nineteen patients with first-episode psychosis, 25 of their unaffected first-degree relatives, and 26 healthy control subjects were included in this study. MAIN OUTCOMES AND MEASURESVoxelwise statistical parametric maps testing differences in the strength of functional connectivity between 6 striatal seed regions of interest (3 caudate and 3 putamen) per hemisphere and all other brain regions.RESULTS Disease-related changes, reflecting differences between patients and control subjects, involved widespread dysregulation of corticostriatal systems characterized most prominently by a dorsal-to-ventral gradient of hypoconnectivity to hyperconnectivity between striatal and prefrontal regions. A similar gradient was evident in comparisons between relatives and control subjects, identifying it as a genetically inherited risk phenotype. In patients, functional connectivity in risk-affected and disease-affected dorsal frontostriatal circuitry correlated with the severity of both positive and negative symptoms.CONCLUSIONS AND RELEVANCE First-episode psychosis is associated with pronounced dysregulation of corticostriatal systems, characterized most prominently by hypoconnectivity of dorsal and hyperconnectivity of ventral frontostriatal circuits. These changes correlate with symptom severity and are also apparent in unaffected first-degree relatives, suggesting that they represent a putative risk phenotype for psychotic illness.

Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia

“…ARMS individuals display hypoconnectivity (as compared with control subjects) in the circuit involving dorsal caudate, right DLPFC, medial PFC, and thalamus, but hyperconnectivity between ventral putamen, frontoinsular cortex, and superior temporal gyrus (Dandash et al, 2014). Similarly, in individuals with first-episode psychosis (FEP) and their first-degree relatives, functional connectivity is enhanced for the ventral circuit and reduced for the dorsal circuit (Fornito et al, 2013). These findings, together with the assumed importance of striatal networks for treatment response and the growing evidence for a dissociable neurophysiologic foundation for treatmentresistant schizophrenia, guided our interest in clarifying whether treatment-resistant individuals are differentiable from other individuals with schizophrenia on the basis of their striatal connectivity.…”

“…Second, frontostriatal disruptions observed when comparing patients with healthy individuals (Quide et al, 2013;Sarpal et al, 2015) would differ as a function of treatment resistance. In addition, as the persistence of positive symptoms is fundamental to treatment resistance, and with the aim of building on previous FEP observations (Fornito et al, 2013), we assessed the extent to which current positive symptom severity predicted striatal FC in treatment-resistant and non-refractory patients.…”

Reduced specialized processing in psychotic disorder: a graph theoretical analysis of cerebral functional connectivity

“…The thus far more frequently used traditional methods (seed‐based correlation, ICA) consistently showed that unaffected siblings/first‐degree relatives share functional connectivity network alterations with their affected siblings (e.g., Whitfield‐Gabrieli and Ford 2012; Fornito et al. 2013; Su et al. 2013), with only a few exceptions, for example, (Repovs et al.…”

Copy number deletion burden is associated with cognitive, structural, and resting-state network differences in patients with schizophrenia

“…Interestingly, functional connectivity between the right DLPFC region and a cluster predominantly in the right putamen was negatively correlated with total deletion burden. Altered prefrontal-striatal connectivity has been identified in schizophrenia in both the ventral and dorsal circuits during rest [13] and during a working memory task [63]. As grey-matter within the striatum (putamen and A c c e p t e d M a n u s c r i p t 17 left caudate nucleus) was also correlated with total deletion burden, the reduced connectivity between the right DLPFC and right putamen further implicates these structures in the role of deletions in schizophrenia risk.…”

“…Studies of resting-state functional connectivity have primarily identified global hypoconnectivity in patients compared with controls [12] although some studies have provided evidence for distinct patterns of hypo and hyperconnectivity in certain networks, including between striatal and prefrontal regions [13].…”