Association of Age at Onset and Longitudinal Course of Prefrontal Function in Youth With Schizophrenia

Abstract

Importance: The extent of cognitive deterioration after schizophrenia (SZ) onset is poorly understood because prior longitudinal studies used small samples of older individuals with established illness.

Objective: To examine the association of age at onset and subsequent longitudinal course of prefrontal activity during the first 2 years of illness in youths with SZ and healthy control participants (HCs).

Design, setting, and participants: This naturalistic, longitudinal, functional magnetic resonance imaging (fMRI) study included patients with recent-onset SZ and HCs aged 12 to 25 years enrolled in an ongoing study of cognition in recent-onset psychosis in the Sacramento, California, area from October 13, 2004, through June 25, 2013. Participants completed clinical assessments and an established measure of cognitive control, the AX Continuous Performance Task (AX-CPT), during fMRI at baseline and at 6-, 12-, and 24-month follow-up. Whole-brain, voxelwise, and an a priori dorsolateral prefrontal cortex (DLPFC) region of interest analyses were performed. Group differences in developmental trajectories were examined by focusing on behavioral performance (d'-context) and cognitive control-associated brain activity. The association of antipsychotic medication and clinical factors were also examined. Data were analyzed from April 15, 2015, through August 29, 2017.

Main outcomes and measures: Primary outcomes included group differences (HC vs SZ) in behavioral performance (d'-context from AX-CPT) and brain activity for cue B-A trials of the AX-CPT in an a priori DLPFC region of interest at baseline and across the age span. Secondary analysis examined the influence of antipsychotics on behavioral performance and DLPFC activity.

Results: Among the sample of 180 participants (66.1% male; mean [SD] age at baseline, 19.2 [3.2] years), 87 patients with SZ (mean [SD] age, 19.6 [3.0] years) showed impaired performance compared with 93 HCs (mean [SD] age, 18.8 [3.4] years) across the age span (estimated difference [SE], -0.571 [0.12], d'-context; P < .001). Patients with SZ showed reduced activation in the DLPFC and parietal cortex (false discovery rate cluster corrected to P < .05) compared with HCs under conditions of high cognitive control at baseline. Region-of-interest analysis showed reduced activation in the DLPFC bilaterally for patients with SZ, with a trajectory that paralleled that of HCs across the age span (left DLPFC β [SE] estimates, 0.409 [0.165] for the HC group and -0.285 [0.130] for the SZ group [main effect of group, P = .03]; right DLPFC β [SE] estimates, 0.350 [0.103] for the HC group and -0.469 [0.157] for the SZ group [P = .003]). Antipsychotic medication, clinical symptoms, and global functioning were associated with SZ performance.

Conclusions and relevance: During the initial 1 to 2 years after illness onset, young individuals with SZ showed deficits in DLPFC activation and cognitive control, with developmental trajectories comparable to those of HCs. Younger age at onset was not associated with reduced cognition or activation. For individuals contributing to longitudinal analysis, results suggest that young patients do not show deterioration or disruption of ongoing brain development in the initial years after illness onset.

Figure 1.. AX Continuous Performance Task Parameters and Timing

Individuals make a target response to probe X only when it follows the cue A. Nontarget BX trials require increased cognitive control to prevent error.

Figure 2.. Estimated Trajectories in Behavioral Performance (d′-Context) on the AX Continuous Performance Task

Dots and connected lines show the longitudinal sequence for as many as 3 follow-up visits (at 6, 12, and 24 months). A dot alone indicates the participant performed the test at baseline only. Patients with schizophrenia (SZ) are stratified between those who received (medicated SZ group) and did not receive (nonmedicated SZ group) medications. HC indicates healthy control.

Figure 3.. Functional Activity

A, Between-group whole-brain activation maps from baseline data contrast healthy controls (HCs) vs patients with schizophrenia (SZ) for conditions of high cognitive control (cue B − A), displayed at height threshold of P < .001 (false discovery rate cluster corrected to P < .05). B and C, Estimated trajectories of a prior left dorsolateral prefrontal cortex (DLPFC) activation for conditions of high cognitive control (cue B − A) between HC and SZ groups and among HCs and patients with SZ receiving (medicated SZ group) vs not receiving (nonmedicated SZ group) medication. Dots and connected lines show the longitudinal sequence for as many as 3 follow-up visits (at 6, 12, and 24 months). A dot alone indicates the participant performed the test at baseline only. BOLD indicates blood oxygenation level–dependent; ROI, region of interest.