Altered age-related trajectories of amygdala-prefrontal circuitry in adolescents at clinical high risk for psychosis: A preliminary study

Emotion processing deficits are prominent in schizophrenia and exist prior to the onset of overt psychosis. However, developmental trajectories of neural circuitry subserving emotion regulation and the role that they may play in illness onset have not yet been examined in patients at risk for psychosis. The present study employed a cross-sectional analysis to examine age-related functional activation in amygdala and prefrontal cortex, as well as functional connectivity between these regions, in adolescents at clinical high risk (CHR) for psychosis relative to typically developing adolescents. Participants (n=34) performed an emotion processing fMRI task, including emotion labeling, emotion matching, and non-emotional control conditions. Regression analyses were used to predict activation in the amygdala and ventrolateral prefrontal cortex (vlPFC) based on age, group, sex, and the interaction of age by group. CHR adolescents exhibited altered age-related variation in amygdala and vlPFC activation, relative to controls. Controls displayed decreased amygdala and increased vlPFC activation with age, while patients exhibited the opposite pattern (increased amygdala and decreased vlPFC activation), suggesting a failure of prefrontal cortex to regulate amygdala reactivity. Moreover, a psychophysiological interaction analysis revealed decreased amygdala-prefrontal functional connectivity among CHR adolescents, consistent with disrupted brain connectivity as a vulnerability factor in schizophrenia. These results suggest that the at-risk syndrome is marked by abnormal development and functional connectivity of neural systems subserving emotion regulation. Longitudinal data are needed to confirm aberrant developmental trajectories intra-individually and to examine whether these abnormalities are predictive of conversion to psychosis, and of later deficits in socioemotional functioning

Reliability of functional magnetic resonance imaging activation during working memory in a multi-site study: Analysis from the North American Prodrome Longitudinal Study

Multi-site neuroimaging studies offer an efficient means to study brain functioning in large samples of individuals with rare conditions; however, they present new challenges given that aggregating data across sites introduces additional variability into measures of interest. Assessing the reliability of brain activation across study sites and comparing statistical methods for pooling functional data is critical to ensuring the validity of aggregating data across sites. The current study used two samples of healthy individuals to assess the feasibility and reliability of aggregating multi-site functional magnetic resonance imaging (fMRI) data from a Sternberg-style verbal working memory task. Participants were recruited as part of the North American Prodrome Longitudinal Study (NAPLS), which comprises eight fMRI scanning sites across the United States and Canada. In the first study sample (n = 8), one participant from each home site traveled to each of the sites and was scanned while completing the task on two consecutive days. Reliability was examined using generalizability theory. Results indicated that blood oxygen level-dependent (BOLD) signal was reproducible across sites and was highly reliable, or generalizable, across scanning sites and testing days for core working memory ROIs (generalizability ICCs = 0.81 for left dorsolateral prefrontal cortex, 0.95 for left superior parietal cortex). In the second study sample (n = 154), two statistical methods for aggregating fMRI data across sites for all healthy individuals recruited as control participants in the NAPLS study were compared. Control participants were scanned on one occasion at the site from which they were recruited. Results from the image-based meta-analysis (IBMA) method and mixed effects model with site covariance method both showed robust activation in expected regions (i.e. dorsolateral prefrontal cortex, anterior cingulate cortex, supplementary motor cortex, superior parietal cortex, inferior temporal cortex, cerebellum, thalamus, basal ganglia). Quantification of the similarity of group maps from these methods confirmed a very high (96%) degree of spatial overlap in results. Thus, brain activation during working memory function was reliable across the NAPLS sites and both the IBMA and mixed effects model with site covariance methods appear to be valid approaches for aggregating data across sites. These findings indicate that multi-site functional neuroimaging can offer a reliable means to increase power and generalizability of results when investigating brain function in rare populations and support the multi-site investigation of working memory function in the NAPLS study, in particular

Reliability of an fMRI paradigm for emotional processing in a multisite longitudinal study

Multisite neuroimaging studies can facilitate the investigation of brain-related changes in many contexts, including patient groups that are relatively rare in the general population. Though multisite studies have characterized the reliability of brain activation during working memory and motor functional magnetic resonance imaging tasks, emotion processing tasks, pertinent to many clinical populations, remain less explored. A traveling participants study was conducted with eight healthy volunteers scanned twice on consecutive days at each of the eight North American Longitudinal Prodrome Study sites. Tests derived from generalizability theory showed excellent reliability in the amygdala ( Eρ2 = 0.82), inferior frontal gyrus (IFG; Eρ2 = 0.83), anterior cingulate cortex (ACC; Eρ2 = 0.76), insula ( Eρ2 = 0.85), and fusiform gyrus ( Eρ2 = 0.91) for maximum activation and fair to excellent reliability in the amygdala ( Eρ2 = 0.44), IFG ( Eρ2 = 0.48), ACC ( Eρ2 = 0.55), insula ( Eρ2 = 0.42), and fusiform gyrus ( Eρ2 = 0.83) for mean activation across sites and test days. For the amygdala, habituation ( Eρ2 = 0.71) was more stable than mean activation. In a second investigation, data from 111 healthy individuals across sites were aggregated in a voxelwise, quantitative meta-analysis. When compared with a mixed effects model controlling for site, both approaches identified robust activation in regions consistent with expected results based on prior single-site research. Overall, regions central to emotion processing showed strong reliability in the traveling participants study and robust activation in the aggregation study. These results support the reliability of blood oxygen level-dependent signal in emotion processing areas across different sites and scanners and may inform future efforts to increase efficiency and enhance knowledge of rare conditions in the population through multisite neuroimaging paradigms

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG