Deterioration in cognitive control related mPFC function underlying development of treatment resistance in early psychosis.

One third of people with psychosis become antipsychotic treatment-resistant and the underlying mechanisms remain unclear. We investigated whether altered cognitive control function is a factor underlying development of treatment resistance. We studied 50 people with early psychosis at a baseline visit (mean < 2 years illness duration) and follow-up visit (1 year later), when 35 were categorized at treatment-responsive and 15 as treatment-resistant. Participants completed an emotion-yoked reward learning task that requires cognitive control whilst undergoing fMRI and MR spectroscopy to measure glutamate levels from Anterior Cingulate Cortex (ACC). Changes in cognitive control related activity (in prefrontal cortex and ACC) over time were compared between treatment-resistant and treatment-responsive groups and related to glutamate. Compared to treatment-responsive, treatment-resistant participants showed blunted activity in right amygdala (decision phase) and left pallidum (feedback phase) at baseline which increased over time and was accompanied by a decrease in medial Prefrontal Cortex (mPFC) activity (feedback phase) over time. Treatment-responsive participants showed a negative relationship between mPFC activity and glutamate levels at follow-up, no such relationship existed in treatment-resistant participants. Reduced activity in right amygdala and left pallidum at baseline was predictive of treatment resistance at follow-up (67% sensitivity, 94% specificity). The findings suggest that deterioration in mPFC function over time, a key cognitive control region needed to compensate for an initial dysfunction within a social-emotional network, is a factor underlying development of treatment resistance in early psychosis. An uncoupling between glutamate and cognitive control related mPFC function requires further investigation that may present a future target for interventions.

The role of cognitive control in the positive symptoms of psychosis.

BACKGROUND: Positive symptoms of psychosis (e.g., hallucinations) often limit everyday functioning and can persist despite adequate antipsychotic treatment. We investigated whether poor cognitive control is a mechanism underlying these symptoms. METHODS: 97 patients with early psychosis (30 with high positive symptoms (HS) and 67 with low positive symptoms (LS)) and 40 healthy controls (HC) underwent fMRI whilst performing a reward learning task with two conditions; low cognitive demand (choosing between neutral faces) and high cognitive demand (choosing between angry and happy faces - shown to induce an emotional bias). Decision and feedback phases were examined. RESULTS: Both patient groups showed suboptimal learning behaviour compared to HC and altered activity within a core reward network including occipital/lingual gyrus (decision), rostral Anterior Cingulate Cortex, left pre-central gyrus and Supplementary Motor Cortex (feedback). In the low cognitive demand condition, HS group showed significantly reduced activity in Supplementary Motor Area (SMA)/pre-SMA during the decision phase whilst activity was increased in LS group compared to HC. Recruitment of this region suggests a top-down compensatory mechanism important for control of positive symptoms. With additional cognitive demand (emotional vs. neutral contrast), HS patients showed further alterations within a subcortical network (increased left amygdala activity during decisions and reduced left pallidum and thalamus activity during feedback) compared to LS patients. CONCLUSIONS: The findings suggest a core reward system deficit may be present in both patient groups, but persistent positive symptoms are associated with a specific dysfunction within a network needed to integrate social-emotional information with reward feedback.