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

Abstract

IMPORTANCEThe 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 PARTICIPANTSThis 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. RESULTSAmong 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 cogniti...

Longitudinal studies of functional magnetic resonance imaging in first-episode psychosis: A systematic review

“…Taken together, most of the included studies reported findings of hypoactivation in several brain areas during the basal assessment. Different studies found hypoactivation in the prefrontal cortex (PFC) areas [23, 24, 27, 29, 30, 33, 34] and limbic regions, specifically the amygdala and hippocampus [24, 29, 32, 34]. Hypoactivation was also found in regions such as the basal ganglia, particularly the striatum [24, 26, 31], anterior cingulate cortex (ACC) [23, 24], thalamus [24, 29], bilateral precuneus [29] and posterior cingulate cortex (PCC) [34] (Fig.…”

“…Li et al [29] reported several hypoconnected areas across the brain in their global approach to image processing. Niendam et al [27] studied the DLPFC using a task, with a long interval between scans (15 months) and they reported the absence of deterioration during the first 2 years of the illness in a very young patients sample.In contrast, Anticevic et al reported stability of the DLPFC disfunctions starting with the youngest sample that we included in this review. The interpretation of these results is based on the neurodevelopmental hypothesis of schizophrenia, in which deficits emerge before illness onset.…”

“…According to the employed task, Snitz et al [23], Ikuta et al [25], and Niendam et al [27] implemented cognitive control paradigms and reported different findings (hypoactivation in the DLPFC and ACC versus hyperactivation in the basal ganglia and thalamus). Consequently, differences in the ROI approach (DLPFC and ACC versus the basal ganglia and thalamus), longer intervals between scans and different medication states at baseline (naïve versus prior antipsychotic exposure) must be considered for interpretation.…”

“…1. A total of 13 clinical studies were included [23][24][25][26][27][28][29][30][31][32][33][34][35]. By aggregating the included samples, a total of 290 FEP patients and 401 healthy volunteers were assessed.…”

“…One study was interpreted to support the disconnection syndrome [33]. One study was interpreted to support the neurodevelopmental hypothesis for schizophrenia [27]. The other 6 studies proposed design-specific interpretations related to treatment response.…”