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Original Investigation
December 2018

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

Author Affiliations
  • 1Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento
  • 2Department of Psychology, The University of Texas at Austin
  • 3Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, Sacramento
  • 4Department of Psychology, University of Oregon, Eugene
  • 5Department of Psychology, UCLA (University of California, Los Angeles), Westwood
  • 6Department of Psychology, University of California, Davis, Sacramento
  • 7MIND Institute, University of California, Davis, Sacramento
  • 8Center for Neuroscience, University of California, Davis, Sacramento
JAMA Psychiatry. 2018;75(12):1252-1260. doi:10.1001/jamapsychiatry.2018.2538
Key Points

Question  Do young patients with recent-onset schizophrenia show a pattern of improvement or deterioration of prefrontal cognitive control processes during the first 2 years after illness onset compared with age-matched healthy controls?

Findings  In this naturalistic, longitudinal, functional magnetic resonance imaging study, 87 young patients early in the course of schizophrenia showed stable behavioral and functional deficits in cognitive control that paralleled the pattern of 93 age-matched healthy control individuals across the age span.

Meaning  In support of the neurodevelopmental hypothesis of schizophrenia, no evidence was found of (1) differential impairment related to earlier age at onset or (2) deterioration of cognitive control processes in young patients with recent-onset schizophrenia.


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.