Generalizability and Out-of-Sample Predictive Ability of Associations Between Neuromelanin-Sensitive Magnetic Resonance Imaging and Psychosis in Antipsychotic-Free Individuals.

Importance: The link between psychosis and dopaminergic dysfunction is established, but no generalizable biomarkers with clear potential for clinical adoption exist. Objective: To replicate previous findings relating neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a proxy measure of dopamine function, to psychosis severity in antipsychotic-free individuals in the psychosis spectrum and to evaluate the out-of-sample predictive ability of NM-MRI for psychosis severity. Design, Setting, and Participants: This cross-sectional study recruited participants from 2019 to 2023 in the New York City area (main samples) and Mexico City area (external validation sample). The main samples consisted of 42 antipsychotic-free patients with schizophrenia, 53 antipsychotic-free individuals at clinical high risk for psychosis (CHR), and 52 matched healthy controls. An external validation sample consisted of 16 antipsychotic-naive patients with schizophrenia. Main Outcomes and Measures: NM-MRI contrast within a subregion of the substantia nigra previously linked to psychosis severity (a priori psychosis region of interest [ROI]) and psychosis severity measured using the Positive and Negative Syndrome Scale (PANSS) in schizophrenia and the Structured Interview for Psychosis-Risk Syndromes (SIPS) in CHR. The cross-validated performance of linear support vector regression to predict psychosis severity across schizophrenia and CHR was assessed, and a final trained model was tested on the external validation sample. Results: Of the 163 included participants, 76 (46.6%) were female, and the mean (SD) age was 29.2 (10.4) years. In the schizophrenia sample, higher PANSS positive total scores correlated with higher mean NM-MRI contrast in the psychosis ROI (t37 = 2.24, P = .03; partial r = 0.35; 95% CI, 0.05 to 0.55). In the CHR sample, no significant association was found between higher SIPS positive total score and NM-MRI contrast in the psychosis ROI (t48 = -0.55, P = .68; partial r = -0.08; 95% CI, -0.36 to 0.23). The 10-fold cross-validated prediction accuracy of psychosis severity was above chance in held-out test data (mean r = 0.305, P = .01; mean root-mean-square error [RMSE] = 1.001, P = .005). External validation prediction accuracy was also above chance (r = 0.422, P = .046; RMSE = 0.882, P = .047). Conclusions and Relevance: This study provided a direct ROI-based replication of the in-sample association between NM-MRI contrast and psychosis severity in antipsychotic-free patients with schizophrenia. In turn, it failed to replicate such association in CHR individuals. Most critically, cross-validated machine-learning analyses provided a proof-of-concept demonstration that NM-MRI patterns can be used to predict psychosis severity in new data, suggesting potential for developing clinically useful tools.

Effects of acute N-acetylcysteine challenge on cortical glutathione and glutamate in schizophrenia: A pilot in vivo proton magnetic resonance spectroscopy study.

Findings from in vivo brain proton magnetic resonance spectroscopy (1H MRS) and preclinical studies have suggested region- and medication status-dependent increases in glutamate (Glu) levels and deficiencies in glutathione (GSH) levels in schizophrenia. N-acetylcysteine (NAC), a GSH synthesis precursor, has demonstrated modest clinical benefit in schizophrenia. The objective of this study was to examine the effects of acute administration of NAC on GSH and Glu levels measured with 1H MRS in 19 patients with schizophrenia and 20 healthy control subjects. Levels of GSH were acquired in dorsal anterior cingulate cortex (dACC), and those of Glu in dACC and medial prefrontal cortex (mPFC), at baseline and 60 min following acute oral administration of 2400 mg of NAC. No differences in the levels of GSH or Glu were found at baseline or following NAC administration between patients with schizophrenia and control subjects in either of the targeted brain regions. Future studies measuring GSH levels in brain regions previously found to exhibit glutamatergic abnormalities or using genetic polymorphisms, while controlling for the age and medication status of the cohorts, are warranted to better identify groups of patients more likely to respond to NAC and its mode of action and mechanisms.

Enhanced Striatal Dopamine Release to Expectation of Alcohol: A Potential Risk Factor for Alcohol Use Disorder.

BACKGROUND: We used positron emission tomography imaging with [11C]raclopride to examine the effects of consumption of alcohol or placebo beverage by participants with alcohol use disorder (AUD) compared with healthy participants with and without family history of AUD. We sought to assess dopamine release following alcohol exposure in relation to AUD risk. METHODS: Three groups were enrolled: participants with AUD (n = 15) and healthy participants with family history negative (n = 34) or positive (n = 16) for AUD. Participants consumed a placebo (n = 65) or alcohol (n = 63) beverage in counterbalanced order before positron emission tomography scanning (128 scans). Binding potential (BPND) in the two drink conditions and the percent change in BPND between conditions were evaluated across striatal subregions. Subjective effects of beverage consumption were rated. Effects of group, drink order, and sex were evaluated. RESULTS: Alcohol resulted in greater dopamine release than did placebo in the ventral striatum (p < .001). There were no main effects of group, drink order, or sex on ventral striatum BPND or percent change in BPND. However, there was a drink order-by-group interaction (p = .02) whereby family history-positive participants who received placebo first had both lower placebo BPND and less difference between placebo and alcohol BPND than all other groups, consistent with expectation of alcohol powerfully evoking dopamine release in this group. Subjective responses showed the same order-by-group interaction. CONCLUSIONS: Hyper-responsivity of the dopaminergic system in family history-positive participants to expectation of alcohol may contribute to the expression of familial risk for AUD.

Mechanisms of Working Memory Impairment in Schizophrenia.

BACKGROUND: The neural correlates of working memory (WM) impairment in schizophrenia remain a key puzzle in understanding the cognitive deficits and dysfunction of dorsolateral prefrontal cortex observed in this disorder. We sought to determine whether patients with schizophrenia exhibit an alteration in the inverted-U relationship between WM load and activation that we recently observed in healthy individuals and whether this could account for WM deficits in this population. METHODS: Medicated (n = 30) and unmedicated (n = 21) patients with schizophrenia and healthy control subjects (n = 45) performed the self-ordered WM task during functional magnetic resonance imaging. We identified regions exhibiting an altered fit to an inverted-U relationship between WM load and activation that were also predictive of WM performance. RESULTS: A blunted inverted-U response was observed in left dorsolateral prefrontal cortex in patients and was associated with behavioral deficits in WM capacity. In addition, suppression of medial prefrontal cortex during WM was reduced in patients and was associated with poorer WM capacity in patients. Finally, activation of visual cortex in the cuneus was elevated in patients and associated with improved WM capacity. Together, these findings explained 55% of the interindividual variance in WM capacity when combined with diagnostic and medication status, which alone accounted for only 22% of the variance in WM capacity. CONCLUSIONS: These findings identify a novel biomarker and putative mechanism of WM deficits in patients with schizophrenia, a reduction or flattening of the inverted-U relationship between activation and WM load observed in healthy individuals in left dorsolateral prefrontal cortex.

Antipsychotic binding to the dopamine-3 receptor in humans: A PET study with [(11)C]-(+)-PHNO.

BACKGROUND: All currently available antipsychotic medications bind to both the dopamine-2 (D2) and dopamine-3 (D3) receptors in vitro. However, there is conflicting evidence from in vivo studies about whether or not antipsychotic medications bind to the D3 receptor (D3R). The purpose of this study was to determine whether acute doses of risperidone bind to the D3R in humans. METHODS: We performed PET scans on an mCT scanner with [(11)C]-(+)-PHNO injected as a bolus, before and after a 2mg oral dose of risperidone in five medication free subjects with schizophrenia. The subjects were scanned for 120min and underwent an MRI scan for region of interest delineation and coregistration. Cerebellum was used as a reference region. Simplified reference tissue modeling (SRTM) was used to calculate BPND. RESULTS: We observed binding to the D3R receptor by risperidone as evidenced by observable occupancy in regions in which the [(11)C]-(+)-PHNO signal is almost exclusively from the D3R (i.e., substantia nigra/ventral tegmental area). Using a regression model to estimate D2R:D3R selectivity, we observed a D2R:D3R selectivity of 2.1 for risperidone. CONCLUSION: Our preliminary results provide further support that acute doses of antipsychotic medications bind to the D3R and provide additional support for the further development of this receptor as a treatment target in schizophrenia.

Deficits in prefrontal cortical and extrastriatal dopamine release in schizophrenia: a positron emission tomographic functional magnetic resonance imaging study.

IMPORTANCE: Multiple lines of evidence suggest a deficit in dopamine release in the prefrontal cortex (PFC) in schizophrenia. Despite the prevalence of the concept of prefrontal cortical hypodopaminergia in schizophrenia, in vivo imaging of dopamine release in the PFC has not been possible until now, when the validity of using the positron emission tomographic D2/3 radiotracer carbon 11-labeled FLB457 in combination with the amphetamine paradigm was clearly established. OBJECTIVES: To (1) test amphetamine-induced dopamine release in the dorsolateral PFC (DLPFC) in drug-free or drug-naive patients with schizophrenia (SCZ) and healthy control (HC) individuals matched for age, sex, race/ethnicity, and familial socioeconomic status;(2) test blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging activation during a working memory task in the same participants; and (3) examine the relationship between positron emission tomographic and functional magnetic resonance imaging outcome measures. DESIGN, SETTING AND PARTICIPANTS: Positron emission tomographic imaging with carbon 11-labeled FLB457 before and following 0.5 mg/kg of amphetamine by mouth. Blood oxygenation level-dependent functional magnetic resonance imaging during the self-ordered working memory task. Twenty patients with schizophrenia recruited from the inpatient and outpatient research facilities at New York State Psychiatric Institute and 21 healthy control individuals participated, and data were acquired between June 16, 2011, and February 25, 2014. MAIN OUTCOMES AND MEASURE: The percentage change in binding potential (∆BPND) in the DLPFC following amphetamine, BOLD activation during the self-ordered working memory task compared with the control task, and the correlation between these 2 outcome measures. RESULTS: We observed significant differences in the effect of amphetamine on DLPFC BPND (mean [SD], ∆BPND in HC: -7.5% [11%]; SCZ: +1.8% [11%]; P = .01); a generalized blunting in dopamine release in SCZ involving most extrastriatal regions and the midbrain; and a significant association between ∆BPND and BOLD activation in the DLPFC in the overall sample including patients with SCZ and HC individuals. CONCLUSIONS AND RELEVANCE: To our knowledge, these results provide the first in vivo evidence for a deficit in the capacity for dopamine release in the DLPFC in SCZ and suggest a more widespread deficit extending to many cortical and extrastriatal regions including the midbrain. This contrasts with the well-replicated excess in dopamine release in the associative striatum in SCZ and suggests a differential regulation of striatal dopamine release in associative striatum vs extrastriatal regions. Furthermore, dopamine release in the DLPFC relates to working memory-related activation of this region, suggesting that blunted release may affect frontal cortical function.

Elevated prefrontal cortex γ-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy.

CONTEXT: Postmortem studies have found evidence of γ-aminobutyric acid (GABA) deficits in fast-spiking, parvalbumin-positive interneurons in the prefrontal cortex in schizophrenia. Magnetic resonance spectroscopy studies in unmedicated patients have reported glutamine or glutamate-glutamine (Glx) elevations in this region. Abnormalities in these transmitters are thought to play a role in cognitive impairments in the illness. OBJECTIVE: To measure GABA and Glx levels in vivo in 2 prefrontal brain regions in unmedicated and medicated patients with schizophrenia and healthy controls. DESIGN: Case-control study. SETTING: Inpatient psychiatric research unit and associated outpatient clinic. PARTICIPANTS: Sixteen unmedicated patients with schizophrenia, 16 medicated patients, and 22 healthy controls matched for age, sex, ethnicity, parental socioeconomic status, and cigarette smoking. METHODS: Proton magnetic resonance spectroscopy with a 3-T system and the J-edited spin-echo difference method. The GABA and Glx levels were measured in the dorsolateral and medial prefrontal cortex and normalized to the simultaneously acquired water signal. Working memory performance was assessed in all subjects. MAIN OUTCOME MEASURES: The GABA and Glx concentrations determined by proton magnetic resonance spectroscopy. RESULTS: In the medial prefrontal cortex region, 30% elevations were found in GABA (P = .02) and Glx (P = .03) levels in unmedicated patients compared with controls. There were no alterations in the medicated patients or in either group in the dorsolateral prefrontal cortex. Both regions showed correlations between GABA and Glx levels in patients and controls. No correlations with working memory performance were found. CONCLUSIONS: To our knowledge, this study presents the first GABA concentration measurements in unmedicated patients with schizophrenia, who showed elevations in both GABA and Glx levels in the medial prefrontal cortex but not the dorsolateral prefrontal cortex. Medicated patients did not show these elevations, suggesting possible normalization of levels with antipsychotic medication. The Glx elevations agree with prior magnetic resonance spectroscopy literature, but GABA elevations were unexpected and suggest possible involvement of classes of interneurons not found to show impairments in postmortem studies.