Cortical stress regulation is disrupted in schizophrenia but not in clinical high risk for psychosis

Abstract

While alterations in striatal dopamine in psychosis and stress have been well studied, the role of dopamine in prefrontal cortex is poorly understood. To date, no study has investigated the prefrontocortical dopamine response to stress in the psychosis spectrum, even though the dorsolateral and medial prefrontal cortices are key regions in cognitive and emotional regulation, respectively. The present study uses the high-affinity dopamine D2/3 receptor radiotracer 11C-FLB457 and PET together with a validated psychosocial stress challenge to investigate the dorsolateral and medial prefrontocortical dopamine response to stress in schizophrenia and clinical high risk for psychosis. Forty participants completed two 11C-FLB457 PET scans (14 antipsychotic-free schizophrenia, 14 clinical high risk for psychosis and 12 matched healthy volunteers), one while performing a Sensory Motor Control Task (control) and another while performing the Montreal Imaging Stress Task (stress). Binding potential (BPND) was estimated using Simplified Reference Tissue Model with cerebellar cortex as reference region. Dopamine release was defined as per cent change in BPND between control and stress scans (ΔBPND) using a novel correction for injected mass. Salivary cortisol response (ΔAUCI) was assessed throughout the tasks and its relationship with dopamine release examined. 11C-FLB457 binding at control conditions was significantly different between groups in medial [F(2,37) = 7.98, P = 0.0013] and dorsolateral [F(2,37) = 6.97, P = 0.0027] prefrontal cortex with schizophrenia patients having lower BPND than participants at clinical high risk for psychosis and healthy volunteers, but there was no difference in ΔBPND among groups [dorsolateral prefrontal cortex: F(2,37) = 1.07, P = 0.35; medial prefrontal cortex: F(2,37) = 0.54, P = 0.59]. We report a positive relationship between ΔAUCI and 11C-FLB457 ΔBPND in dorsolateral and medial prefrontal cortex in healthy volunteers (r = 0.72, P = 0.026; r = 0.76, P = 0.014, respectively) and in participants at clinical high risk for psychosis (r = 0.76, P = 0.0075; r = 0.72, P = 0.018, respectively), which was absent in schizophrenia (r = 0.46, P = 1.00; r = 0.19, P = 1.00, respectively). Furthermore, exploratory associations between ΔBPND or ΔAUCI and stress or anxiety measures observed in clinical high risk for psychosis were absent in schizophrenia. These findings provide first direct evidence of a disrupted prefrontocortical dopamine-stress regulation in schizophrenia.

Stress‐induced cortical dopamine response is altered in subjects at clinical high risk for psychosis using cannabis

“…This suggests that those subjects with lower dopamine release had higher stress‐induced positive symptoms. This is in line with our recent findings that CHR individuals with higher distress and anxiety had lower PFC dopamine release and consistent with the suggestions that stress may precipitate psychosis in vulnerable individuals …”

“…Image acquisition and reconstruction were described in detail before . In brief, every subject underwent a MRI scan to acquire a proton density‐weighted image, used for delineation of individual regions of interest (ROIs) after coregistering with the PET image.…”

“…Right and left ROIs were pooled together to create a single TAC used to derive the BP ND . As quantifying [ 11 C]FLB457 is challenging, in part due to potential mass effects, a novel correction was applied in the current study, described in detail elsewhere . The corrected change in BP ND was calculated as first described by Gallezot et al:…”

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

“…Two other recent FLB‐457 studies adopted psychological challenges. One of these used a psychological stressor, which did not induce cortical tracer displacement in either patients or controls. The other used a cognitive test of executive function, which did show lower tracer displacement in patients, but interpretation was complicated by the fact that, again, the task did not consistently induce dopamine release.…”

Altered hypothalamic DNA methylation and stress-induced hyperactivity in a novel model of early life stress

“…Although the precise mechanisms linking preterm birth with ADHD are unknown, a number of hypotheses have been advanced, including early life environmental exposures, HPA axis dysregulation and perinatal inflammation [9]. Whether the ADHD phenotype in preterm infants is responsive to novel environments is not known, but abnormal responses to stress are certainly present in a number of other psychiatric and neurodevelopmental disorders including anxiety disorders [65], ASD [66], schizophrenia [67], bipolar disorder [68] and are well-described as a consequence of early life stress in humans [69].…”