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 prefrontalstriatal 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.

Pattern of activation during delayed matching to sample task predicts functional outcome in people at ultra high risk for psychosis

“…In contrast, in the other half of the sample (UHRp), the mean GAF score did not improve, but remained at approximately the same low level (58.8 at baseline, and 57.8 at follow up; Figure 1b). These observations are consistent with previous findings (Allen et al, 2014), and highlight the importance of finding biomarkers that could be used to stratify UHR samples according to future clinical need (Reilly and McGuire, 2013). A large proportion (26.5%) of the overall UHR sample had a GAF score below 60 at follow up, which corresponds to a significant degree of functional impairment.…”

“…A relationship between neuroimaging measures and functional outcomes is consistent with data from studies in patients with first episode psychosis (Lappin et al, 2014), and in chronic schizophrenia (Mitelman et al, 2005). More recently, functional outcome in UHR subjects has been found to be linked to the level of activation in inferior frontal cortex, the hippocampus, putamen and thalamus (Allen et al, 2014), and to thalamic glutamate levels (Allen et al, 2014). These observations suggest that neuroimaging has the potential to facilitate the prediction of outcomes, which is difficult to do on the basis of clinical measures alone.…”

“…Our results provide further evidence that baseline fMRI measures can separate subgroups of UHR subjects according to outcomes at follow up (Allen et al, 2014;Fusar-Poli et al, 2011b), and extend this literature by illustrating that this applies to functional outcome, as well as the traditional outcome of transition to psychosis. A relationship between neuroimaging measures and functional outcomes is consistent with data from studies in patients with first episode psychosis (Lappin et al, 2014), and in chronic schizophrenia (Mitelman et al, 2005).…”

“…However, most of these studies did not examine how these findings related to outcomes, although one reported that a poor functional outcome was linked to increased left IFG activation (Allen et al, 2014). In the present study, we also found that UHR subjects with a poor functional outcome failed to deactivate the ACC and medial frontal gyrus.…”

Using neuroimaging to help predict the onset of psychosis

“…This partly reflects the logistical demands associated with acquiring multi-modal neuroimaging data in samples that are large enough to permit comparison of subgroups with different clinical outcomes 95 .…”