Functional outcome in people at high risk for psychosis predicted by thalamic glutamate levels and prefronto-striatal activation

Abstract

Little is known about the neurobiological factors that determine functional outcome in people at high risk for psychosis. We use multimodal neuroimaging to investigate whether cortical responses during a cognitive task and thalamic glutamate levels were associated with subsequent functional outcome. Sixty subjects participated: 27 healthy controls (CTRL) and 33 at ultrahigh risk (UHR) for psychosis. At baseline, cortical responses during a verbal fluency task were measured using functional Magnetic Resonance Imaging (fMRI) and proton Magnetic Resonance Spectroscopy (1H-MRS) was used to measure thalamic glutamate levels. The UHR subjects were then followed clinically for a mean duration of 18 months, and subdivided into "good" and "poor" functional outcome subgroups according to their Global Assessment of Function score at follow-up. UHR subjects with a poor functional outcome showed greater cortical and subcortical activation than UHR subjects with a good functional outcome. They also had lower levels of thalamic glutamate and showed a negative relationship between thalamic glutamate levels and prefrontal-striatal activation that was not present in the good functional outcome or control groups. In people at high risk for psychosis, their subsequent level of functioning may depend on the extent to which neurophysiological and neurochemical function is perturbed when they first present to clinical services.

Keywords: functional MRI; functional outcomes; glutamate; psychosis; spectroscopy; ultra-high risk.

Fig. 1.

GAF scores at baseline and follow-up for each UHR subject in the good (a) and poor (b) outcome subgroups.

Fig. 2.

(A) Statistical parametric maps showing activation during verbal fluency task in all subjects. Areas in yellow/red and blue represent VF task related activation and activation negatively correlated with GAF scores, respectively. The left side of the brain is on the left side of the image. (B) Brain areas where UHR subjects with a poor functional outcome showed greater activation than those with a good outcome and controls. (C) Plots of mean parameter estimates (PE) in each group from foci in the left insula/left inferior frontal gyrus (−36, 13, 4), left insula/putamen (−30, −8, 14), and left thalamus (−20, −10, 8).

Fig. 3.

(A) Bar chart showing reduced thalamic glutamate levels in the UHR subgroup with a poor outcome. (B) Scatter plot showing association between thalamic glutamate levels and activation in cortico-striatal-midbrain circuit. (C) Statistical parametric maps showing a positive correlation between right PFC activation and thalamic glutamate levels in CTRL group (D) interaction between group activation and thalamic glutamate levels in frontal polar cortex bilaterally. (E) Plot showing interaction between frontopolar activation (8, 64, 0) and thalamic glutamate (driven by negative interaction effect in UHR-PFO group).