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Considering the wide range of outcomes following sport-related concussions, biomarkers are needed to detect underlying pathological changes. The objective was to analyze the use of plasma phosphorylated tau 181 (pTau181) as a non-invasive measure of underlying brain changes in a cohort of retired contact sports athletes at risk of neurodegeneration.Fifty-four retired contact sport athletes and 27 healthy controls whose blood plasma was analyzed for pTau181 were included. A portion (N = 21) of retired athletes had a 2-years follow-up visit. All participants had completed a neuropsychological battery and MRI imaging.Plasma pTau181 was significantly higher in retired athletes compared to healthy controls (8.94 ± 5.08 pg/mL vs. 6.00 ± 2.53 pg/mL, respectively; 95% BCa CI 1.38-4.62; p = 0.02); and was significantly associated with fornix fractional anisotropy values only in the athletes group (β = - 0.002; 95% BCa CI - 0.003 to - 0.001; p = 0.002). When the retired athletes cohort was divided into high vs. normal pTau181 groups, the corpus callosum (CC) volume and white-matter integrity was significantly lower in high pTau181 compared to older healthy controls (CC volume: 1.57 ± 0.19 vs. 2.02 ± 0.32, p = 0.002; CC medial diffusivity: 0.96 ± 0.04 × 10Although high plasma pTau181 levels were associated with abnormalities in CC and fornix, baseline pTau181 did not predict longitudinal changes in regional brain volumes or white-matter integrity in the athletes. pTau181 may be useful for identifying those with brain abnormalities related to repeated concussion but not for predicting progression.

Stimuli previously paired with drugs of dependence can produce cravings that are associated with increased dopamine (DA) levels in limbic and striatal brain areas. Positron Emission Tomography (PET) imaging with [11C]-(+)-PHNO allows for a sensitive measurement of changes in DA levels. The purpose of the present study was to investigate changes in DA levels, measured with PET imaging with [11C]-(+)-PHNO, in regions of interest in smokers who had maintained abstinence for 7–10 days. Participants (N = 10) underwent two PET scans on separate days, during which they viewed either smoking-related or neutral images, in counterbalanced order. Craving was measured with the 12-item Tobacco Craving Questionnaire (TCQ) and the Questionnaire on Smoking Urges-Brief (QSU-B). Compared to neutral cues, smoking cues did not increase craving. There were no changes in [11C]-(+)-PHNO binding in the cue condition compared to the neutral condition for most regions of interest (ventral pallidum, globus pallidus, limbic striatum, associative striatum, sensorimotor striatum). However, binding potential in the substantia nigra was greater in the smoking-cue condition, indicating decreased synaptic dopamine. There is a potential change of DA level occurring in midbrain following the presentation of smoking-related cues. However, this preliminary finding would need to be validated with a larger sample.

Background Gliosis is common among neuropsychiatric diseases, but the relationship between gliosis and response to therapeutics targeting effects of gliosis is largely unknown. Translocator protein total distribution volume (TSPO VT), measured with positron emission tomography, mainly reflects gliosis in neuropsychiatric disease. Here, the primary objective was to determine whether TSPO VT in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) predicts reduction of depressive symptoms following open-label celecoxib administration in treatment-resistant major depressive disorder. Methods A total of 41 subjects with treatment-resistant major depressive disorder underwent one [18F]FEPPA positron emission tomography scan to measure PFC and ACC TSPO VT. Open-label oral celecoxib (200 mg, twice daily) was administered for 8 weeks. Change in symptoms was measured with the 17-item Hamilton Depression Rating Scale (HDRS). Results Cumulative mean change in HDRS scores between 0 and 8 weeks of treatment was plotted against PFC and ACC TSPO VT, showing a significant nonlinear relationship. At low TSPO VT values, there was no reduction in HDRS scores, but as TSPO VT values increased, there was a reduction in HDRS scores that then plateaued. This was modeled with a 4-parameter sigmoidal model in which PFC and ACC TSPO VT accounted for 84% and 92% of the variance, respectively. Conclusions Celecoxib administration in the presence of gliosis labeled by TSPO VT is associated with greater reduction of symptoms. Given the predictiveness of TSPO VT on symptom reduction, this personalized medicine approach of matching a marker of gliosis to medication targeting effects of gliosis should be applied in early development of novel therapeutics, in particular for treatment-resistant major depressive disorder.

The endocannabinoid enzyme, fatty acid amide hydrolase (FAAH), has been proposed as a therapeutic target for alcohol use disorder (AUD) and co-morbid psychiatric illnesses. Investigating this target in the living human brain and its relationship to clinical outcome is a critical step of informed drug development. Our objective was to establish whether brain FAAH levels are low in individuals with AUD and related to drinking behavior. In this pilot study, treatment-seeking patients with AUD completed two PET scans with the FAAH radiotracer [C-11]CURB after 3–7 days (n = 14) and 2–4 weeks (n = 9) of monitored abstinence. Healthy controls (n = 25) completed one scan. FAAH genetic polymorphism (rs324420) and blood concentrations of anandamide and other N-acylethanolamines metabolized by FAAH were determined and AUD symptoms assessed. In AUD, brain FAAH levels were globally lower than controls during early abstinence (F(1,36) = 5.447; p = 0.025)) and FAAH substrates (anandamide, oleoylethanolamide, and N-docosahexaenoylethanolamide) were significantly elevated (30–67%). No significant differences in FAAH or FAAH substrates were noted after 2–4 weeks abstinence. FAAH levels negatively correlated with drinks per week (r = −0.57, p = 0.032) and plasma concentrations of the three FAAH substrates (r > 0.57; p

Dysregulation of hippocampus glutamatergic neurotransmission and reductions in hippocampal volume have been associated with psychiatric disorders. The endocannabinoid system modulates glutamate neurotransmission and brain development, including hippocampal remodeling. In humans, elevated levels of anandamide and lower activity of its catabolic enzyme fatty acid amide hydrolase (FAAH) are associated with schizophrenia diagnosis and psychotic symptom severity, respectively (Neuropsychopharmacol, 29(11), 2108-2114; Biol. Psychiatry 88 (9), 727-735). Although preclinical studies provide strong evidence linking anandamide and FAAH to hippocampus neurotransmission and structure, these relationships remain poorly understood in humans. We recruited young adults with and without psychotic disorders and measured FAAH activity, hippocampal glutamate and glutamine (Glx), and hippocampal volume using [

Greater activation of glia, a key component of neuroinflammation, is an important process to target in neuropsychiatric illnesses. However, the magnitude of gliosis varies across cases so low-cost predictors are needed to stratify subjects for clinical trials. Here, several such blood serum measures were assessed in relation to TSPO V(T), an index of translocator protein density, measured with positron emission tomography. Blood serum concentration of several products known to be synthesized by activated microglia (and to some extent astroglia) [prostaglandin E(2) (PGE(2)), prostaglandin F(2) alpha (PGF(2α)), and tumor necrosis factor alpha (TNF(α))], controlled by an index of peripheral inflammation [C-reactive protein (CRP)] and TSPO V(T) were measured in 3 cohorts: prefrontal cortex TSPO V(T) of 20 subjects with major depressive episodes (MDEs) from major depressive disorder (MDD); and 56 subjects with treatment resistant MDEs from MDD; and dorsal caudate TSPO V(T) of 20 subjects with obsessive-compulsive disorder. Ln(PGE(2)/CRP) and ln(TNF(α)/CRP) consistently correlated with TSPO V(T) (R(2) = 0.36 to 0.11, p = 0.0030 to p = 0.0076). Assessment of threshold serum values to predict highly elevated TSPO V(T), demonstrated that a positive predictive value (PPV) of 80% was possible while retaining 40% of participant samples and that receiver operating curves (ROC) ranged from 75 to 81%. Post-hoc selection of ln(CRP) was more predictive (R(2) = 0.23 to 0.39, p = 0.0058 to p = 0.00013; ROC > 80%). Systematic assessment of selected peripheral inflammatory markers is promising for developing low cost predictors of TSPO V(T). Marker thresholds with high PPV will improve subject stratification for clinical trials of glial targeting therapeutics.

Research suggests decreased cortical dopamine is a neural correlate of cognitive deficits in schizophrenia. Evidence of impaired cognitive task-induced cortical dopamine release was demonstrated in patients with psychosis. However, whether cortical dopamine release in response to a cognitive task in clinical high risk for psychosis (CHR) is also impaired, is currently unknown. We aimed to test dopamine release in the dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC) in antipsychotic-free CHR participants and healthy controls (HC) performing the Wisconsin Card Sorting Task (WCST). Two [11C]FLB457 PET scans were conducted for 13 CHR and 15 HC while performing the WCST and the sensorimotor control task (SMCT), respectively. A magnetic resonance image was acquired for anatomical delineation. Percentage change in binding potential (ΔBPND) in ACC and DLPFC in WCST were compared with the SMCT between CHR and HC. Mixed model analysis revealed no statistically significant differences in the cognitive task induced ΔBPND in any ROIs. There were no main effect of group (F(1, 26) = 0.348; p = 0.560) or ROI (F(1, 26) = 1.080; p = 0.308) and no significant Group x ROI interaction (F(1, 26) = 0.049; p = 0.826). Our findings suggest no statistically significant difference between CHR and HC in cognitive task-induced cortical dopamine release. This is the first in vivo study to illustrate that the cortical hypodopaminergic state observed in schizophrenia may not be present in its putative high-risk state.

Beta-amyloid (Aβ) in the brain is a key pathological feature of certain neurodegenerative diseases. Recent studies using graph theory have shown that Aβ brain networks are of pathological significance in Alzheimer's disease (AD). However, the characteristics of Aβ brain networks in Parkinson's disease (PD) are unknown. In the present study using positron emission tomography (PET) with [11C]-Pittsburgh compound B (PiB), we applied a graph theory-based analysis to assess the topological properties of Aβ brain network in PD patients with and without Aβ burden (PiB-positive and PiB-negative, respectively) and healthy controls with Aβ burden. We found that the PD PiB-positive group demonstrated significantly lower value in global efficiency and modularity compared with PD PiB-negative group. The less robust modular structure indicates the tendency of having increased inter-modular connections than intra-modular connectivity (i.e., reduced segregation). Results of hub organization showed that relative to PD PiB-negative group, different hubs were identified in the PiB-positive group, which were located mainly within the default mode network. Overall, our findings suggest disturbances in Aβ topological organization characterized by abnormal network integration and segregation in PD patients with Aβ burden. The stronger inter-modular connectivity observed in the PD PiB-positive group may suggest the spreading pattern of Aβ between modules in those PD patients with elevated PiB burden, thus providing insight into the beta-amyloidopathy of PD.

To date, the contribution of the nigropallidal pathway degeneration to Parkinson's disease (PD) motor symptoms has received little attention and is generally poorly understood in spite of solid evidence that the globus pallidus (GP) receives a dense neuronal projection from the substantia nigra. To explore the dopaminergic (DA) changes of the GP in PD, we measured the availability of vesicular monoamine transporter 2 (VMAT2) using [11C]DTBZ and positron emission tomography in 30 PD patients and 12 controls. PD patients were classified in two groups based on severity of disease. VMAT2 reduction was found to be significant in the external GP (GPe) regardless of the disease stage, while the internal GP (GPi) showed reduction only in more severe patients. Pallidal VMAT2 binding correlated with dopaminergic changes in the striatum, with the GPe showing a stronger association than GPi. Our findings showed DA terminals in the GPe and GPi may be differentially vulnerable in different stages of the disease, possibly playing a distinctive role in the development of motor complications with GPi DA deficiency contributing more to later-stage symptoms.

In this Viewpoint, we highlight the history of positron emission tomography (PET) radiotracer development to quantify changes in monoamine oxidase (MAO)-A and -B enzyme expression or activity. MAO-A and MAO-B are critical for understanding monoaminergic pathways in psychiatric addiction disorders, and more recently in neurodegenerative disorders with MAO-B expression in astrogliosis. Unique radiochemical innovations have been shown for neuroimaging of MAOs including the clinical translation of irreversible propargylamine-based suicide inhibitors, application of deuterium-substitution to slow down metabolism, development of trapped metabolite imaging agents, and unique 11C-carbonylation chemistry toward novel high-affinity reversibly binding inhibitors.

Posttraumatic stress disorder (PTSD) is a debilitating mental health condition that results from exposure to traumatic event(s). Decreased astrocyte-related proteins (e.g., glial fibrillary acidic protein, GFAP) and atrophic astrocytes in corticolimbic brain areas implicated in PTSD have been reported in experimental models suggesting that astrocyte pathology may be a feature of this disorder. We used positron emission tomography (PET) of the monoamine oxidase (MAO)-B probe [

Background: Upregulation of the endocannabinoid enzyme fatty acid amide hydrolase (FAAH) has been linked to abnormal activity in frontoamygdalar circuits, a hallmark of posttraumatic stress disorder. We tested the hypothesis that FAAH levels in the amygdala were negatively correlated with functional connectivity between the amygdala and prefrontal cortex, subserving stress and affect control. Methods: Thirty-one healthy participants completed positron emission tomography (PET) imaging with the FAAH probe [C-11]CURB, and resting-state functional MRI scans. Participants were genotyped for the FAAH polymorphism rs324420, and trait neuroticism was assessed. We calculated amygdala functional connectivity using predetermined regions of interest (including the subgenual ventromedial prefrontal cortex [sgvmPFC] and the dorsal anterior cingulate cortex [dACC]) and a seed-to-voxel approach. We conducted correlation analyses on functional connectivity, with amygdala [C-11]CURB binding as a variable of interest. Results: The strength of amygdala functional connectivity with the sgvmPFC and dACC was negatively correlated with [C-11]CURB binding in the amygdala (sgvmPFC: r = −0.38, q = 0.04; dACC: r = –0.44; q = 0.03). Findings were partly replicated using the seed-to-voxel approach, which showed a cluster in the ventromedial prefrontal cortex, including voxels in the dACC but not the sgvmPFC (cluster-level, family-wise error rate corrected p < 0.05). Limitations: We did not replicate earlier findings of a relationship between an FAAH polymorphism (rs324420) and amygdala functional connectivity. Conclusion: Our data provide preliminary evidence that lower levels of FAAH in the amygdala relate to increased frontoamygdalar functional coupling. Our findings were consistent with the role of FAAH in regulating brain circuits that underlie fear and emotion processing in humans.

Antisocial personality disorder (ASPD) imposes a high societal burden given the repetitive reactive aggression that affected individuals perpetrate. Since the brain endocannabinoid system (ECS) has been implicated in ASPD and aggressive behavior, we utilized [11C]CURB positron emission tomography to investigate fatty acid amide hydrolase (FAAH), an enzyme of the ECS that degrades anandamide, in 16 individuals with ASPD and 16 control participants. We hypothesized that FAAH density would be lower in the amygdala for several reasons. First, decreased FAAH expression is associated with increased cannabinoid receptor 1 stimulation, which may be responsible for amygdala hyper-reactivity in reactive aggression. Second, the amygdala is the seat of the neural circuit mediating reactive aggression. Third, other PET studies of externalizing populations show reduced brain FAAH density. Conversely, we hypothesized that FAAH expression would be greater in the orbitofrontal cortex. Consistent with our hypothesis, we found that amygdala FAAH density was lower in the amygdala of ASPD (p = 0.013). Cerebellar and striatal FAAH expression were inversely related with impulsivity (cerebellum: r = −0.60, p = 0.017; dorsal caudate: r = −0.58, p = 0.023; dorsal putamen: r = −0.55, p = 0.034), while cerebellar FAAH density was also negatively associated with assaultive aggression (r = −0.54, p = 0.035). ASPD presents high levels of disruptive behavior with few, if any, efficacious treatment options. Novel therapeutics that increase FAAH brain levels in a region-specific manner could hold promise for attenuating certain symptom clusters of ASPD, although our results require replication.

Antisocial personality disorder (ASPD) imposes a high societal burden given the repetitive reactive aggression that affected individuals perpetrate. Since the brain endocannabinoid system (ECS) has been implicated in ASPD and aggressive behavior, we utilized [11C]CURB positron emission tomography to investigate fatty acid amide hydrolase (FAAH), an enzyme of the ECS that degrades anandamide, in 16 individuals with ASPD and 16 control participants. We hypothesized that FAAH density would be lower in the amygdala for several reasons. First, decreased FAAH expression is associated with increased cannabinoid receptor 1 stimulation, which may be responsible for amygdala hyper-reactivity in reactive aggression. Second, the amygdala is the seat of the neural circuit mediating reactive aggression. Third, other PET studies of externalizing populations show reduced brain FAAH density. Conversely, we hypothesized that FAAH expression would be greater in the orbitofrontal cortex. Consistent with our hypothesis, we found that amygdala FAAH density was lower in the amygdala of ASPD (p = 0.013). Cerebellar and striatal FAAH expression were inversely related with impulsivity (cerebellum: r = −0.60, p = 0.017; dorsal caudate: r = −0.58, p = 0.023; dorsal putamen: r = −0.55, p = 0.034), while cerebellar FAAH density was also negatively associated with assaultive aggression (r = −0.54, p = 0.035). ASPD presents high levels of disruptive behavior with few, if any, efficacious treatment options. Novel therapeutics that increase FAAH brain levels in a region-specific manner could hold promise for attenuating certain symptom clusters of ASPD, although our results require replication.

Anxiety is a very common yet poorly understood symptom of Parkinson's disease. We investigated whether Parkinson's disease patients experiencing anxiety share neural mechanisms described in the general population with involvement of critical regions for the control of behaviour and movement. Thirty-nine patients with PD were recruited for this study, 20 with higher anxiety scores and 19 with lower anxiety scores. They all underwent a resting-state fMRI scan, while they were on medication. The amplitude of low-frequency fluctuation (ALFF) and seed-based connectivity were investigated to reveal the changes of the spontaneous activity and the interaction among different related regions. The results provided evidence that anxiety in Parkinson's disease is associated with the over-activation of the amygdala and impaired inter-relationship of regions involved in behavior (i.e. medial prefrontal cortex, insula) and motor control (i.e. basal ganglia).

We have recently shown that levels of fatty acid amide hydrolase (FAAH), the enzyme that metabolises the endocannabinoid anandamide, are lower in the brains of adult cannabis users (34±11 years of age), tested during early abstinence. Here, we examine replication of the lower FAAH levels in a separate, younger cohort (23±5 years of age). Eighteen healthy volunteers (HV) and fourteen cannabis users (CU) underwent a positron emission tomography scan using the FAAH radioligand [(11)C]CURB. Regional [(11)C]CURB binding was calculated using an irreversible two-tissue compartment model with a metabolite-corrected arterial plasma input-function. The FAAH C385A genetic polymorphism (rs324420) was included as a covariate. All CU underwent a urine screen to confirm recent cannabis use and had serum cannabinoids measured. One CU screened negative for cannabinoids via serum and was removed from analysis. All HV reported less than five lifetime cannabis exposures more than a month prior to study initiation. There was a significant effect of group (F(1, 26)=4.31; p=0.048) when two A/A (rs324420) HV were removed from analysis to match the genotype of the CU group (n=16 HV, n=13 CU). Overall, [(11)C]CURB λk(3) was 12% lower in CU compared to HV. Exploratory correlations showed that lower brain [(11)C]CURB binding was related to greater use of cannabis throughout the past year. We confirmed our previous report and extended these findings by detecting lower [(11)C]CURB binding in a younger cohort with less cumulative cannabis exposure.

There has been considerable interest in the development of dopamine D3 receptor (DRD3) partial agonists and antagonists for the treatment of substance use disorders. Pre-clinical evidence overwhelmingly supports the use of these drugs, but translation to humans has remained elusive due to the lack of selective compounds that are suitable for use in humans. Although it has been established for full antagonists, little in vivo occupancy data are available with DRD3 partial agonists. Here we investigate for the first time in healthy controls, the in vivo occupancy of a novel D3 partial agonist (BP1.4979) at the DRD3 and DRD2. Participants received either a single dose (1, 3, 10 or 30 mg) or a subchronic regimen (5-7 days, q.d. or b.i.d) of BP1.4979, with the last dose given at 1, 12 or 24 h prior to scanning with [11C]-(+)-PHNO. Single and subchronic administration of BP1.4979 dose-dependently occupied the DRD3 and DRD2, and this occupancy was preferential for the DRD3, notably at longer time points after administration of BP1.4979. Also consistent with preference for the DRD3, prolactin levels were minimally increased, and no subjective effects of BP1.4979 were reported. Serum levels of BP1.4979 were higher than its active metabolite, BP1.6239, while no notable increases in the inactive metabolite, BP1.6197, were found. These findings indicate the range of doses that can be used to occupy selectively the DRD3 over the DRD2 with BP1.4979 and speak to the use of in vivo imaging approaches in dose finding studies.

Psychosis is associated with abnormal structural changes in the brain including decreased regional brain volumes and abnormal brain morphology. However, the underlying causes of these structural abnormalities are less understood. The immune system, including microglial activation, has been implicated in the pathophysiology of psychosis. Although previous studies have suggested a connection between peripheral proinflammatory cytokines and structural brain abnormalities in schizophrenia, no in-vivo studies have investigated whether microglial activation is also linked to brain structure alterations previously observed in schizophrenia and its putative prodrome. In this study, we investigated the link between mitochondrial 18kDa translocator protein (TSPO) and structural brain characteristics (i.e. regional brain volume, cortical thickness, and hippocampal shape) in key brain regions such as dorsolateral prefrontal cortex and hippocampus of a large group of participants (N = 90) including individuals at clinical high risk (CHR) for psychosis, first-episode psychosis (mostly antipsychotic naïve) patients, and healthy volunteers. The participants underwent structural brain MRI scan and [(18)F]FEPPA positron emission tomography (PET) targeting TSPO. A significant [(18)F]FEPPA binding-by-group interaction was observed in morphological measures across the left hippocampus. In first-episode psychosis, we observed associations between [(18)F]FEPPA V(T) (total volume of distribution) and outward and inward morphological alterations, respectively, in the dorsal and ventro-medial portions of the left hippocampus. These associations were not significant in CHR or healthy volunteers. There was no association between [(18)F]FEPPA V(T) and other structural brain characteristics. Our findings suggest a link between TSPO expression and alterations in hippocampal morphology in first-episode psychosis.

Le present article revisite les donnees recueillies dans le cadre d’une recherche anterieure conduite par Hurteau et Houle (2008). A l’epoque, les chercheurs n’avaient pas ete en mesure de detailler la contribution des competences personnelles de l’evaluateur au pilotage d’une evaluation dont les resultats sont acceptables pour les parties prenantes et d’en effectuer une analyse exhaustive, faute d’un cadre theorique adequat. En introduisant le concept de sagesse pratique, House (2015) leur offre l’opportunite de le faire. Cet auteur definit le concept comme « …doing the right thing in the special circumstances of performing the job» (p. 88). De plus, Schwartz et Sharpe (2010) offrent des criteres qui permettent d’en etablir la presence. La demarche actuelle a consiste a analyser le temoignage d’un policier d’experience. Les resultats ont permis de bonifier notre comprehension du concept, tout en soulignant la contribution du Telos (valeurs morales) ainsi que de criteres supplementaires, tels que l’importance d’un temps de reflexion et la necessite de completer les informations lorsque cela s’avere necessaire. This article revisits data collected during previous research conducted by Hurteau and Houle (2008). At the time, the researchers were not able to account for the evaluator’s personal skills to pilot an evaluation, the results of which were acceptable to the stakeholders, and to conduct a comprehensive analysis, for lack of an appropriate theoretical framework. By introducing the concept of practical wisdom, House (2015) offers them the opportunity to do so. The author defines this concept as “… doing the right thing in the special circumstances of performing the job” (p. 88). In addition, Schwartz and Sharpe (2010) offer criteria used to establish its presence. The current approach consisted of analyzing the testimony of an experienced police officer. The results helped to improve our understanding of the concept, highlighting the contribution of Telos (moral values) as well as additional criteria such as the importance of time for reflection and the need to supplement the information where necessary.

Evidence from several lines of research suggests decreased dopamine release in the prefrontal cortex as the neurochemical correlates of cognitive deficits in schizophrenia (SCZ). However, in vivo examination of cortical hypodopaminergia using positron emission tomography (PET) during cognitive task performance in SCZ remains to be investigated. We examined dopamine release in anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC), using PET while participants were performing a cognitive task. Thirteen drug-free patients with SCZ and 13 healthy volunteers (HV) matched for age and sex participated in the study. Data were acquired between 2011 and 2015. Two PET scans with [(11)C]FLB 457 were acquired while the participants were performing the Wisconsin Card Sorting Test (WCST) and a sensorimotor control task (SMCT). A magnetic resonance image was acquired for anatomical delineation. Differences in cortical dopamine release between SCZ and HV, indexed as percentage change in binding potential between WCST and SMCT (ΔBP(ND)), were calculated in ACC and DLPFC. We observed significant differences in the ΔBP(ND) in ACC (HV = 4.40 ± 6.00; SCZ = −11.48 ± 15.08; t = 3.52; P = .003) and a trend-level difference in ΔBP(ND) in DLPFC (HV = −0.58 ± 8.45; SCZ = −7.79 ± 11.28; t = 1.84; P = .079), suggesting dopamine depletion in cortical brain regions in patients with SCZ while performing a cognitive task. These results provide the first in vivo evidence for reduced dopamine release or even dopamine depletion while performing cognitive task in ACC and DLPFC in patients with SCZ. The present results provide support for the frontal hypodopaminergia hypothesis of cognitive symptoms in SCZ.

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 D(2/3) receptor radiotracer (11)C-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 (11)C-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 (BP(ND)) was estimated using Simplified Reference Tissue Model with cerebellar cortex as reference region. Dopamine release was defined as per cent change in BP(ND) between control and stress scans (ΔBP(ND)) using a novel correction for injected mass. Salivary cortisol response (ΔAUC(I)) was assessed throughout the tasks and its relationship with dopamine release examined. (11)C-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 BP(ND) than participants at clinical high risk for psychosis and healthy volunteers, but there was no difference in ΔBP(ND) 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 ΔAUC(I) and (11)C-FLB457 ΔBP(ND) 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 ΔBP(ND) or ΔAUC(I) 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.

Altered neuroimmune response and oxidative stress have both been implicated in the pathophysiology of schizophrenia. While preclinical studies have proposed several pathways regarding potential interactions between oxidative stress and neuroimmune imbalance in the development of psychosis, the molecular mechanisms underlying this interaction are not yet understood. To date, no study has investigated this link in vivo in the human brain. We conducted the first in vivo study linking translocator protein 18 kDa (TSPO) expression and glutathione (a major brain antioxidant and a marker for redox status) in the medial prefrontal cortex (mPFC) of a relatively large sample of participants (N = 48) including 27 antipsychotic-naïve individuals at clinical high risk for psychosis and 21 matched healthy volunteers using high-resolution PET with TSPO radioligand, [(18)F]FEPPA, and 3T proton magnetic resonance spectroscopy ((1)H MRS). The omnibus model (including TSPO genotype as covariate) was significant (F((4, 43)) = 10.01, p

Background Identifying the biological basis of smoking cessation success is of growing interest. The rate of nicotine metabolism, measured by the nicotine metabolite ratio, affects multiple aspects of nicotine dependence. Fast nicotine metabolizers tend to smoke more, experience more withdrawal and craving, and have lower cessation rates compared with slow metabolizers. The nicotine metabolite ratio predicts treatment response, and differences in brain activation between fast metabolizers and slow metabolizers have been reported in fMRI studies. As reinforcing/rewarding effects of tobacco are associated with dopamine transmission, the purpose of the present study was to study the dopaminergic system in human smokers based on their nicotine metabolite ratio. Methods The first aim of the study was to explore if there were differences in D2 and D3 receptor binding between fast metabolizers and slow metabolizers during abstinence. The second aim was to explore smoking-induced dopamine release in both groups. Participants underwent 2 [11C]-(+)-PHNO PET scans: one scan during abstinence and the other after smoking a tobacco cigarette. Subjective measures were recorded and blood was drawn for measurement of nicotine and cotinine levels. Results During abstinence, slow metabolizers (n = 13) had lower [11C]-(+)-PHNO binding potential than fast metabolizers (n = 15) restricted to the D2 regions of the associative striatum and sensorimotor striatum. After smoking a cigarette, [11C]-(+)-PHNO binding potential was decreased in the limbic striatum and ventral pallidum, suggestive of increases in dopamine, but there were no nicotine metabolite ratio differences. Conclusions Further studies are required to delineate if differences in [11C]-(+)-PHNO binding between slow metabolizers and fast metabolizers at abstinence baseline are preexisting traits or induced by prolonged tobacco use.