Aberrant Frontostriatal Connectivity in Negative Symptoms of Schizophrenia

Abstract

Negative symptoms represent a distinct component of psychopathology in schizophrenia (SCZ) and are a stable construct over time. Although impaired frontostriatal connectivity has been frequently described in SCZ, its link with negative symptoms has not been carefully studied. We tested the hypothesis that frontostriatal connectivity at rest may be associated with the severity of negative symptoms in SCZ. Resting state functional connectivity (rsFC) data from 95 mostly medicated patients with SCZ and 139 healthy controls (HCs) were acquired. Negative symptoms were assessed using the Brief Negative Symptom Scale. The study analyzed voxel-wise rsFC between 9 frontal "seed regions" and the entire striatum, with the intention to reduce potential biases introduced by predefining any single frontal or striatal region. SCZ showed significantly reduced rsFC between the striatum and the right medial and lateral orbitofrontal cortex (OFC), lateral prefrontal cortex, and rostral anterior cingulate cortex compared with HCs. Further, rsFC between the striatum and the right medial OFC was significantly associated with negative symptom severity. The involved striatal regions were primarily at the ventral putamen. Our results support reduced frontostriatal functional connectivity in SCZ and implicate striatal connectivity with the right medial OFC in negative symptoms. This task-independent resting functional magnetic resonance imaging study showed that medial OFC-striatum functional connectivity is reduced in SCZ and associated with severity of negative symptoms. This finding supports a significant association between frontostriatal connectivity and negative symptoms and thus may provide a potential circuitry-level biomarker to study the neurobiological mechanisms of negative symptoms.

Keywords: functional connectivity; negative symptoms; schizophrenia.

Fig. 1.

Surface rendering of frontal cortical regions (only left hemisphere shown) used for the functional connectivity driven striatal parcellation. dlPFC, dorsolateral prefrontal cortex; SFC, superior frontal cortex; mOFC, medial orbitofrontal cortex ; lPFC, lateral prefrontal cortex; iFC, inferior frontal cortex; lOFC, lateral orbitofrontal cortex; SMA, supplementary motor area; rACC, rostral anterior cingulate cortex; and dACC, dorsal anterior cingulate cortex.

Fig. 2.

Significant group differences in the functional connectivity between the striatum and frontal cortical regions: medial orbitofrontal cortex (OFC), lateral OFC, lateral prefrontal cortex (PFC), and rostral cingulate. z score comparisons between healthy control (HC) and schizophrenia (SCZ) groups are also shown (corrected P < .05).

Fig. 3.

Pearson correlations between Brief Negative Symptom Scale (BNSS) total score (A) and Brief Psychiatric Rating Scale (BPRS) withdrawal symptom subscale (B), and the mean functional connectivity z score for the right medial orbitofrontal cortex (OFC) and the right striatum. Between-group comparison for the right medial OFC–right striatum functional connectivity z score is also shown (C).