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

Abstract

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.

Figure 1. Task Design

The emotional faces fMRI task consisted of Emotion Labeling and Emotion Matching, as well as non-emotional control conditions of Gender Labeling, Gender Matching, and Shape Matching (adapted from Lieberman et al., 2007).

Figure 2. Regions of Interest

Regions of interest for the left amygdala (left) and right vlPFC (right) are shown. For the left amygdala, an anatomical ROI was used based on the probabilistic Harvard-Oxford Structural Atlas. The right vlPFC ROI mask was created using a spherical ROI centered at 56, 22, 8, a peak of activation for emotion labeling versus gender labeling in a study of healthy controls (Lieberman et al., 2007).

Figure 3. vlPFC Trajectories

Analysis of the right vlPFC revealed a significant interaction (F(4,29) = 5.43, p = .027) between age-related trajectories of functional activation during emotion labeling versus gender labeling for CHR patients and controls, such that controls showed increasing vlPFC activation whereas CHR patients showed decreasing vlPFC activation across development.

Figure 4. Amygdala Trajectories

Regression analysis demonstrated a significant interaction (F(4,28) = 4.84, p = .037) between age-related trajectories of left amygdala activation during emotion labeling versus emotion matching for CHR patients and controls, such that controls exhibited decreasing amygdala activation whereas CHR patients showed increasing amygdala activation with increasing age.

Figure 5. Amygdala-Prefrontal Functional Connectivity

CHR patients demonstrated weaker inverse task-dependent functional connectivity between the amygdala and prefrontal regions consisting of left orbitofrontal cortex and left inferior frontal gyrus, compared with controls (Z = 3.82, p = .027, corrected).