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The kappa opioid receptor (KOR) and its endogenous agonist dynorphin have been implicated in multiple psychiatric conditions including psychotic disorders. We tested the hypotheses that kappa expression is elevated and associated with psychotic symptoms in schizophrenia. We measured kappa expression in unmedicated patients with schizophrenia (7 female, 6 male) and matched controls (7 female, 6 male) with positron emission tomography (PET). We also acquired a measurement of cumulative dopamine activity over the life span in the same subjects using neuromelanin sensitive MRI. We hypothesized that neuromelanin accumulation would be higher in patients than controls and that in patients there would be a positive association between KOR availability and neuromelanin accumulation. Fourteen patients and thirteen controls were enrolled. Whole brain dynamic PET imaging data using the KOR selective tracer [ 18 F]LY245998 were acquired. Distribution volume (V T ) was measured with region of interest analysis in 14 brain regions. Neuromelanin accumulation in midbrain dopaminergic nuclei was assessed in the same subjects. Positive and negative symptoms were measured by a clinical psychologist. We did not observe group level differences in KOR expression, neuromelanin accumulation or relationships of these to positive symptoms. Unexpectedly, we did observe strong positive associations between KOR expression and symptoms of anhedonia in the patients (Pearson r > 0.7, uncorrected p < 0.01 in 8 cortical brain regions). We also observed moderate associations between KOR expression and neuromelanin levels in patients. In conclusion, we did not observe a relationship between kappa and symptoms of psychosis but the observed relationship to the negative symptom of anhedonia is in line with recent work testing kappa antagonism as a therapy for anhedonia in depression., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Objective: Midbrain dopamine function plays a key role in translational models of substance use disorders. Whether midbrain dopamine function is associated with substance use frequency and severity or reward function in 20-24 year-olds remains a critical gap in knowledge. The authors collected neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a validated index of lifetime dopamine function in the substantia nigra/ventral tegmentum area (SN-VTA) complex, to characterize altered dopamine function., Method: Midbrain NM-MRI contrast-to-noise ratio (CNR) was acquired in 135 20-24 year-olds (105 women and 30 men). A composite measure of cumulative substance use was derived from factor analysis of lifetime alcohol intoxications, lifetime cannabis use, use of nicotine in heaviest month, number of classes of drugs used, and ever meeting DSM-5 criteria for a SUD. Trait reward function was assessed by self-report., Results: Cumulative substance use was significantly positively associated with NM-MRI CNR in a large area of the bilateral SN-VTA complex, an effect which was driven by women (who comprised most of the sample) and by voxels with greater NM-MRI CNR, including the ventral tegmentum area. NM-MRI CNR was not associated with individual differences in trait reward function., Conclusions: History of substance use is associated with greater NM signal in NM-rich areas of the midbrain, especially in women. Future longitudinal studies with repeated NM-MRI assessments, especially in younger cohorts and while including more men, are warranted to evaluate whether aberrant dopamine function predates, follows, or is modulated by substance use., Competing Interests: Dr. Abi-Dargham serves on the Scientific Advisory Board for Neurocrine, Sunovion, and Abbvie; on the Data Safety Monitoring Board for Merck; and as the Deputy Editor of Biological Psychiatry; holds stock options in Herophilus and Terran Life Sciences; and has received consulting fees/honoraria from Boehringer Ingelheim, Merck, Neurocrine, Otsuka, Roche, and Sunovion. Dr Horga reports an investigator-initiated sponsored research agreement from Terran Biosciences outside the submitted work and having filed patents for the analysis and use of neuromelanin-sensitive magnetic resonance imaging in central nervous system disorders licensed to Terran Biosciences with no royalties received (WO2021034770A1, WO2022192728A3, AU2021377338A1, AU2019359377A1). Dr Wengler reports having filed patents for the analysis and use of neuromelanin-sensitive magnetic resonance imaging in central nervous system disorders licensed to Terran Biosciences with no royalties received (WO2021034770A1, WO2022192728A3, AU2021377338A1). The remaining authors report no financial relationships with commercial interests.

Background: Individuals with substance use disorder show impaired self-awareness of ongoing behavior. This deficit suggests problems with metacognition, which has been operationalized in the cognitive neuroscience literature as the ability to monitor and evaluate the success of one's own cognition and behavior. However, the neural mechanisms of metacognition have not been characterized in a population with drug addiction., Methods: Community samples of participants with opioid use disorder (OUD) (n = 27) and healthy control participants (n = 29) performed a previously validated functional magnetic resonance imaging metacognition task (perceptual decision-making task along with confidence ratings of performance). Measures of recent drug use and addiction severity were also acquired., Results: Individuals with OUD had lower metacognitive sensitivity (i.e., disconnection between task performance and task-related confidence) than control individuals. Trial-by-trial analyses showed that this overall group difference was driven by (suboptimally) low confidence in participants with OUD during correct trials. In functional magnetic resonance imaging analyses, the task engaged an expected network of brain regions (e.g., rostrolateral prefrontal cortex and dorsal anterior cingulate/supplementary motor area, both previously linked to metacognition); group differences emerged in a large ventral anterior cluster that included the medial and lateral orbitofrontal cortex and striatum (higher activation in OUD). Trial-by-trial functional magnetic resonance imaging analyses showed group differences in rostrolateral prefrontal cortex activation, which further correlated with metacognitive behavior across all participants. Exploratory analyses suggested that the behavioral and neural group differences were exacerbated by recent illicit opioid use and unexplained by general cognition., Conclusions: With confirmation and extension of these findings, metacognition and its associated neural circuits could become new, promising therapeutic targets in addiction., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Recent studies have established a clear topographical and functional organization of projections to and from complex subdivisions of the striatum. Manual segmentation of these functional subdivisions is labor-intensive and time-consuming, and automated methods are not as reliable as manual segmentation., Purpose: To utilize multitask learning (MTL) as a method to segment subregions of the striatum consisting of pre-commissural putamen (prePU), pre-commissural caudate (preCA), post-commissural putamen (postPU), post-commissural caudate (postCA), and ventral striatum (VST)., Study Type: Retrospective., Population: Eighty-seven total data sets from patients with schizophrenia and matched controls., Field Strength/sequence: 1.5 T and 3.0 T, T 1 -weighted (SPGR SENSE, 3D BRAVO)., Assessment: MTL-generated segmentations were compared to the Imperial College London Clinical Imaging Center (CIC) atlas. Dice similarity coefficient (DSC) was used to compare the automated methods to manual segmentations. Positron emission tomography (PET) imaging: 60 minutes of emission data were acquired using [ 11 C]raclopride. Data were reconstructed by filtered back projection (FBP) with computed tomography (CT) used for attenuation correction. Binding potential values, BP ND , and region of interest (ROI) time series and whole-brain connectivity using functional magnetic resonance imaging (fMRI) images were compared between manual and both automated segmentations., Statistical Tests: Pearson correlation and paired t-test., Results: MTL-generated segmentations showed excellent spatial agreement with manual (DSC ≥0.72 across all striatal subregions). BP ND values from MTL-generated segmentations were shown to correlate well with manual segmentations with R 2  ≥ 0.91 in all caudate and putamen subregions, and R 2  = 0.69 in VST. Mean Pearson correlation coefficients of the fMRI data between MTL-generated and manual segmentations were also high in time series (≥0.86) and whole-brain connectivity (≥0.89) across all subregions., Data Conclusion: Across both PET and fMRI task-based assessments, results from MTL-generated segmentations more closely corresponded to results from manually drawn ROIs than CIC-generated segmentations did. Therefore, the proposed MTL approach is a fast and reliable method for three-dimensional striatal subregion segmentation with results comparable to manually segmented ROIs., Level of Evidence: 2 TECHNICAL EFFICACY STAGE: 1., (© 2021 International Society for Magnetic Resonance in Medicine.)

Background: Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) is a validated measure of neuromelanin concentration in the substantia nigra-ventral tegmental area (SN-VTA) complex and is a proxy measure of dopaminergic function with potential as a noninvasive biomarker. The development of generalizable biomarkers requires large-scale samples necessitating harmonization approaches to combine data collected across sites., Purpose: To develop a method to harmonize NM-MRI across scanners and sites., Study Type: Prospective., Population: A total of 128 healthy subjects (18-73 years old; 45% female) from three sites and five MRI scanners., Field Strength/sequence: 3.0 T; NM-MRI two-dimensional gradient-recalled echo with magnetization-transfer pulse and three-dimensional T1-weighted images., Assessment: NM-MRI contrast (contrast-to-noise ratio [CNR]) maps were calculated and CNR values within the SN-VTA (defined previously by manual tracing on a standardized NM-MRI template) were determined before harmonization (raw CNR) and after ComBat harmonization (harmonized CNR). Scanner differences were assessed by calculating the classification accuracy of a support vector machine (SVM). To assess the effect of harmonization on biological variability, support vector regression (SVR) was used to predict age and the difference in goodness-of-fit (Δr) was calculated as the correlation (between actual and predicted ages) for the harmonized CNR minus the correlation for the raw CNR., Statistical Tests: Permutation tests were used to determine if SVM classification accuracy was above chance level and if SVR Δr was significant. A P-value <0.05 was considered significant., Results: In the raw CNR, SVM MRI scanner classification was above chance level (accuracy = 86.5%). In the harmonized CNR, the accuracy of the SVM was at chance level (accuracy = 29.5%; P = 0.8542). There was no significant difference in age prediction using the raw or harmonized CNR (Δr = -0.06; P = 0.7304)., Data Conclusion: ComBat harmonization removes differences in SN-VTA CNR across scanners while preserving biologically meaningful variability associated with age., Level of Evidence: 2 TECHNICAL EFFICACY: 1., (© 2021 International Society for Magnetic Resonance in Medicine.)

Neuromelanin-sensitive MRI (NM-MRI) purports to detect the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). Interindividual variability in dopamine function may result in varying levels of NM accumulation in the SN; however, the ability of NM-MRI to measure dopamine function in nonneurodegenerative conditions has not been established. Here, we validated that NM-MRI signal intensity in postmortem midbrain specimens correlated with regional NM concentration even in the absence of neurodegeneration, a prerequisite for its use as a proxy for dopamine function. We then validated a voxelwise NM-MRI approach with sufficient anatomical sensitivity to resolve SN subregions. Using this approach and a multimodal dataset of molecular PET and fMRI data, we further showed the NM-MRI signal was related to both dopamine release in the dorsal striatum and resting blood flow within the SN. These results suggest that NM-MRI signal in the SN is a proxy for function of dopamine neurons in the nigrostriatal pathway. As a proof of concept for its clinical utility, we show that the NM-MRI signal correlated to severity of psychosis in schizophrenia and individuals at risk for schizophrenia, consistent with the well-established dysfunction of the nigrostriatal pathway in psychosis. Our results indicate that noninvasive NM-MRI is a promising tool that could have diverse research and clinical applications to investigate in vivo the role of dopamine in neuropsychiatric illness., Competing Interests: The authors declare no conflict of interest.