Transdiagnostic Associations Between Functional Brain Network Integrity and Cognition

Abstract

Importance: Cognitive impairment occurs across the psychosis spectrum and is associated with functional outcome. However, it is unknown whether these shared manifestations of cognitive dysfunction across diagnostic categories also reflect shared neurobiological mechanisms or whether the source of impairment differs.

Objective: To examine whether the general cognitive deficit observed across psychotic disorders is similarly associated with functional integrity of 2 brain networks widely implicated in supporting many cognitive domains.

Design, setting, and participants: A total of 201 healthy control participants and 375 patients with psychotic disorders from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium were studied from September 29, 2007, to May 31, 2011. The B-SNIP recruited healthy controls and stable outpatients from 6 sites: Baltimore, Maryland; Boston, Massachusetts; Chicago, Illinois; Dallas, Texas; Detroit, Michigan; and Hartford, Connecticut. All participants underwent cognitive testing and resting-state functional magnetic resonance imaging. Data analysis was performed from April 28, 2015, to February 21, 2017.

Main outcomes and measures: The Brief Assessment of Cognition in Schizophrenia was used to measure cognitive ability. A principal axis factor analysis on the Brief Assessment of Cognition in Schizophrenia battery yielded a single factor (54% variance explained) that served as the measure of general cognitive ability. Functional network integrity measures included global and local efficiency of the whole brain, cingulo-opercular network (CON), frontoparietal network, and auditory network and exploratory analyses of all networks from the Power atlas. Group differences in network measures, associations between cognition and network measures, and mediation models were tested.

Results: The final sample for the current study included 201 healthy controls, 143 patients with schizophrenia, 103 patients with schizoaffective disorder, and 129 patients with psychotic bipolar disorder (mean [SD] age, 35.1 [12.0] years; 281 male [48.8%] and 295 female [51.2%]; 181 white [31.4%], 348 black [60.4%], and 47 other [8.2%]). Patients with schizophrenia (Cohen d = 0.36, P < .001) and psychotic bipolar disorder (Cohen d = 0.33, P = .002) had significantly reduced CON global efficiency compared with healthy controls. All patients with psychotic disorders had significantly reduced CON local efficiency, but the clinical groups did not differ from one another. The CON global efficiency was significantly associated with general cognitive ability across all groups (β = 0.099, P = .009) and significantly mediated the association between psychotic disorder status and general cognition (β = -0.037; 95% CI, -0.076 to -0.014). Subcortical network global efficiency was also significantly reduced in psychotic disorders (F3,587 = 4.01, P = .008) and positively predicted cognitive ability (β = 0.094, P = .009).

Conclusions and relevance: These findings provide evidence that reduced CON and subcortical network efficiency play a role in the general cognitive deficit observed across the psychosis spectrum. They provide new support for the dimensional hypothesis that a shared neurobiological mechanism underlies cognitive impairment in psychotic disorders.

Figure 1.. Group Differences in Global and Local Efficiency of Functional Networks

We observed an overall significant group difference in global efficiency (A) and local efficiency (B), controlling for sex, race/ethnicity, age, head motion, and Bipolar-Schizophrenia Network on Intermediate Phenotypes site. Cingulo-opercular network (CON) global efficiency and whole-brain global efficiency but not the frontoparietal network (FPN) or auditory network (AN) were significantly different across groups. Post hoc least significant difference tests revealed a significant reduction in CON global efficiency in the schizophrenia and bipolar disorder groups compared with healthy controls. A similar pattern was observed for local efficiency. A significant reduction in CON local efficiency was observed in all clinical groups compared with controls. ^aP < .001. ^bP < .01. ^cP < .05.

Figure 2.. Association Between Cingulo-Opercular Network (CON) Global Efficiency and General Cognition

Greater CON global efficiency predicted better general cognitive ability across all groups, suggesting that more globally efficient CON is related to better cognitive functioning across psychotic disorders. We observed a significant interaction for the schizophrenia and healthy control groups, reflecting a stronger association between CON global efficiency and general cognition in the schizophrenia group compared with the healthy control participants. No other significant interactions were observed, suggesting similar associations between cognition and CON global efficiency across groups. Diagonal lines represent the linear association between CON global efficiency and the residual of general cognitive ability after taking into account the diagnostic group.

Figure 3.. Cingulo-Opercular Network (CON) Global Efficiency Mediation

The CON global efficiency significantly mediated the association between clinical status (patient/control) and general cognitive ability, providing further evidence that the reduced CON global efficiency in psychotic disorders may underlie deficits in general cognition. Path C represents the variance in psychosis status associated with general cognitive ability, and Path C’ represents the association between psychosis status and general cognition after taking into account CON global efficiency as a mediator. Path AB is the mediation effect and is significant at P < .05 based on confidence intervals from bias-corrected bootstrapping of 1000 samples.