Background Individuals at clinical high-risk (CHR) who progress to fully psychotic symptoms have been observed to show a steeper rate of cortical gray matter reduction compared with those without symptomatic progression and with healthy controls. Whether such changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotic drugs is unknown. Methods In this multisite study, 274 CHR cases, including 35 who converted to psychosis, and 135 healthy comparison subjects were scanned with MRI at baseline, 12-month follow-up, and/or the point of conversion for those who developed fully psychotic symptoms. Results In a traveling subjects sub-study, we observed excellent reliability for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR converters showed a steeper rate of gray matter loss in right superior frontal, middle frontal, and medial orbitofrontal cortical regions, as well as a greater rate of expansion of the third ventricle, compared with CHR non-converters and healthy controls. Differential tissue loss was present among cases who had not received antipsychotic medications during the inter-scan interval and was predicted by baseline levels of an aggregate measure of pro-inflammatory cytokines in plasma. Conclusions These findings demonstrate that the brain changes are not explained by exposure to antipsychotic drugs, but likely play a role in psychosis pathophysiology. Given that the cortical changes were more pronounced among cases with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acute-onset forms of psychosis.

N-methyl-D-aspartate glutamate receptor (NMDA-R) antagonists produce schizophrenia-like positive and negative symptoms in healthy human subjects. Preclinical research suggests that NMDA-R antagonists interfere with the function of gamma-aminobutyric acid (GABA) neurons and alter brain oscillations. These changes have been hypothesized to contribute to psychosis. In this investigation, we evaluated the hypothesis that the NMDA-R antagonist ketamine produces alterations in cortical functional connectivity during rest that are related to symptoms. We administered ketamine to a primary sample of twenty-two subjects and to an additional, partially overlapping, sample of twelve subjects. Symptoms before and after the experimental session were rated with the Positive and Negative Symptom Scale (PANSS). In the primary sample, functional connectivity was measured via functional magnetic resonance imaging almost immediately after infusion began. In the additional sample, this assessment was repeated after 45 minutes of continuous ketamine infusion. Global, enhanced functional connectivity was observed at both timepoints and this hyperconnectivity was related to symptoms in a region-specific manner. This study supports the hypothesis that pathological increases in resting brain functional connectivity contribute to the emergence of positive and negative symptoms associated with schizophrenia.

Preclinical research suggests that N-methyl-D-aspartate glutamate receptors (NMDA-Rs) have a crucial role in working memory (WM). In this study, we investigated the role of NMDA-Rs in the brain activation and connectivity that subserve WM. Because of its importance in WM, the lateral prefrontal cortex, particularly the dorsolateral prefrontal cortex and its connections, were the focus of analyses. Healthy participants (n=22) participated in a single functional magnetic resonance imaging session. They received saline and then the NMDA-R antagonist ketamine while performing a spatial WM task. Time-course analysis was used to compare lateral prefrontal activation during saline and ketamine administration. Seed-based functional connectivity analysis was used to compare dorsolateral prefrontal connectivity during the two conditions and global-based connectivity was used to test for laterality in these effects. Ketamine reduced accuracy on the spatial WM task and brain activation during the encoding and early maintenance (EEM) period of task trials. Decrements in task-related activation during EEM were related to performance deficits. Ketamine reduced connectivity in the DPFC network bilaterally, and region-specific reductions in connectivity were related to performance. These results support the hypothesis that NMDA-Rs are critical for WM. The knowledge gained may be helpful in understanding disorders that might involve glutamatergic deficits such as schizophrenia and developing better treatments.

Multi-site longitudinal neuroimaging designs are used to identify differential brain structural change associated with onset or progression of disease. The reliability of neuroanatomical measurements over time and across sites is a crucial aspect of power in such studies. Prior work has found that while within-site reliabilities of neuroanatomical measurements are excellent, between-site reliability is generally more modest. Factors that may increase between-site reliability include standardization of scanner platform and sequence parameters and correction for between-scanner variations in gradient nonlinearities. Factors that may improve both between- and within-site reliability include use of registration algorithms that account for individual differences in cortical patterning and shape. In this study 8 healthy volunteers were scanned twice on successive days at 8 sites participating in the North American Prodrome Longitudinal Study (NAPLS). All sites employed 3 Tesla scanners and standardized acquisition parameters. Site accounted for 2 to 30% of the total variance in neuroanatomical measurements. However, site-related variations were trivial (<1%) among sites using the same scanner model and 12-channel coil or when correcting for between-scanner differences in gradient nonlinearity and scaling. Adjusting for individual differences in sulcal-gyral geometries yielded measurements with greater reliabilities than those obtained using an automated approach. Neuroimaging can be performed across multiple sites at the same level of reliability as at a single site, achieving within- and between-site reliabilities of 0.95 or greater for gray matter density in the majority of voxels in the prefrontal and temporal cortical surfaces as well as for the volumes of most subcortical structures.

BACKGROUND: Disruptive behaviors are prevalent in children with autism spectrum disorder (ASD) and often cause substantial impairments. However, the underlying neural mechanisms of disruptive behaviors remain poorly understood in ASD. In children without ASD, disruptive behavior is associated with amygdala hyperactivity and reduced connectivity with the ventrolateral prefrontal cortex (vlPFC). This study examined amygdala reactivity and connectivity in children with ASD with and without co-occurring disruptive behavior disorders. We also investigated differential contributions of externalizing behaviors and callous-unemotional traits to variance in amygdala connectivity and reactivity. METHODS: This cross-sectional study involved behavioral assessments and neuroimaging in three groups of children 8 to 16 years of age: 18 children had ASD and disruptive behavior, 20 children had ASD without disruptive behavior, and 19 children were typically developing control