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Major depressive disorder (MDD) is characterized by behavioral and neural abnormalities in processing both rewarding and aversive stimuli, which may impact motivational and affective symptoms. Learning paradigms have been used to assess reinforcement encoding abnormalities in MDD and their association with dysfunctional incentive-based behavior, but how the valence and context of information modulate this learning is not well understood. To address these gaps, we examined responses to positive and negative reinforcement across multiple temporal phases of information processing. While undergoing functional magnetic resonance imaging (fMRI), 47 participants (23 unmedicated, predominantly medication-naive participants with MDD and 24 demographically-matched HC participants) completed a probabilistic, feedback-based reinforcement learning task that allowed us to separate neural activation during motor response (choice) from reinforcement feedback and monetary outcome across two independent conditions: pursuing gains and avoiding losses. In the gain condition, MDD participants showed overall blunted learning responses (prediction error) in the dorsal striatum when receiving monetary outcome, and reduced responses in ventral striatum for positive, but not negative, prediction error. The MDD group showed enhanced sensitivity to negative information, and symptom severity was associated with better behavioral performance in the loss condition. These findings suggest that striatal responses during learning are abnormal in individuals with MDD but vary with the valence of information.

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, T1 -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, BPND , 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). BPND values from MTL-generated segmentations were shown to correlate well with manual segmentations with R2 ≥ 0.91 in all caudate and putamen subregions, and R2 = 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.

PURPOSE This study proposes a novel Maximum Likelihood Expectation Maximization (MLEM) based positron emission tomography (PET) image reconstruction approach, designed to provide improved signal recovery, specifically in small structures. This proposed technique, termed GPSF-MLEM, utilizes a gradually decreasing full-width-half-maximum (FWHM) point spread function (PSF), designed to yield increased spatial details in progressing iterations when measured and estimated projection data are in closer consensus. METHODS GPSF-MLEM was compared with the analytical filtered back projection (FBP) and the iterative reconstruction techniques of standard MLEM and PSF incorporated into MLEM (PSF-MLEM). Simulated phantoms as well as cylindrical and brain phantoms were used to evaluate performance, contrast recovery and for visual assessment of image quality. The performance of GPSF-MLEM and PSF-MLEM with various FWHM kernel sizes was also investigated. This work presents evidence that the choice of reconstruction technique and parameters for the best quantification of reconstructed PET images should be based on the purpose (task-based optimization). RESULTS Quantitatively, across all reconstructions tested, the image intensity estimated using GPSF-MLEM terminated at an intermediate FWHM was in closest agreement to the raw image intensity in the simulated phantom. Qualitative analysis of reconstructed images with physical phantoms suggested that irrespective of the FWHM at the terminal iteration, GPSF-MLEM provided robust image contrast and increased suppression of background hotspot artifacts compared to MLEM and PSF-MLEM. Further, across all FWHM combinations tested, GPSF-MLEM yielded fewer artifacts inherent to PSF-MLEM images reconstructed with an overestimated FWHM. CONCLUSIONS Emphasizing common task scenarios frequently encountered in medical imaging: A) GPSF-MLEM is recommended for tasks requiring a low background noise; B) PSF-MLEM is recommended for tasks that require good image segmentation; C) GPSF-MLEM with a larger terminal FWHM is recommended for obtaining high contrast recovery in small image structures.

Patients at clinical high-risk (CHR) for psychosis show elevations in [18F]DOPA uptake, an estimate of dopamine (DA) synthesis capacity, in the striatum predictive of conversion to schizophrenia. Intrasynaptic DA levels can be inferred from imaging the change in radiotracer binding at D2 receptors due to a pharmacological challenge. Here, we used methylphenidate, a DA reuptake inhibitor, and [11C]-(+)-PHNO, to measure synaptic DA availability in CHR both in striatal and extra-striatal brain regions. Fourteen unmedicated, nonsubstance using CHR individuals and 14 matched control subjects participated in the study. Subjects underwent two [11C]-(+)-PHNO scans, one at baseline and one following administration of a single oral dose (60 mg) of methylphenidate. [11C]-(+)-PHNO BPND, the binding potential relative to the nondisplaceable compartment, was derived using the simplified reference tissue model with cerebellum as reference tissue. The percent change in BPND between scans, ΔBPND, was computed as an index of synaptic DA availability, and group comparisons were performed with a linear mixed model. An overall trend was found for greater synaptic DA availability (∆BPND) in CHR than controls (p = 0.06). This was driven entirely by ∆BPND in ventral striatum (-34 ± 14% in CHR, -20 ± 12% in HC; p = 0.023). There were no significant group differences in any other brain region. There were no significant differences in DA transmission in any striatal region between converters and nonconverters, although this finding is limited by the small sample size (N = 2). There was a strong and negative correlation between ΔBPND in VST and severity of negative symptoms at baseline in the CHR group (r = -0.66, p

Previous research has suggested that schizotypal personality disorder (SPD), a condition that shares clinical and cognitive features with schizophrenia, may be associated with elevated striatal dopamine functioning; however, there are no published studies of dopamine release within subregions of the striatum in SPD. To characterize dopamine release capacity in striatal subregions and its relation to clinical and cognitive features in SPD. We used positron emission tomography with [11C]raclopride and an amphetamine challenge to measure dopamine D2-receptor availability (binding potential, BPND), and its percent change post-amphetamine (∆BPND) to index amphetamine-induced dopamine release, in subregions of the striatum in 16 SPD and 16 healthy control participants. SPD participants were evaluated with measures of schizotypal symptom severity and working memory. There were no significant group differences in BPND or ∆BPND in any striatal subregion or whole striatum. Among SPD participants, cognitive-perceptual symptoms were associated at trend level with ∆BPND in the ventral striatum, and disorganized symptoms were significantly negatively related to ∆BPND in several striatal subregions. In contrast to previous findings, SPD was not associated with elevated striatal dopamine release. However, in SPD, there was a moderate positive association between ventral striatal dopamine release and severity of cognitive-perceptual symptoms, and negative associations between striatal dopamine release and severity of disorganized symptoms. Future larger scale investigations that allow for the separate examination of subgroups of participants based on clinical presentation will be valuable in further elucidating striatal DA functioning in SPD.

Background Declining function in dopamine circuits is implicated in normal aging and late-life depression (LLD). Dopamine augmentation recently has shown therapeutic promise, but predictors of response are unknown. Methods Depressed elders with slowed gait underwent baseline magnetic resonance imaging (MRI) and [11C]raclopride positron emission tomography (PET). Subjects then received open treatment with carbidopa/levodopa (L-DOPA) for three weeks. Linear regressions examined relationships between baseline MRI measures, [11C]raclopride binding, and behavioral outcomes. Results Among N = 16 participants aged 72.5 ± 6.8 years, higher left superior temporal gyrus volume was associated with higher processing speed at baseline, while cortical thinning in a processing speed network was associated with greater improvement following L-DOPA. Greater volume and cortical thickness in brain regions associated with mobility were associated with higher baseline gait speed. Higher baseline white matter hyperintensity volume predicted less post-L-DOPA improvement on dual task gait speed and IDS-SR scores. Higher [11C]raclopride binding in the associative striatum was associated with cortical thickness in some, but not all, processing speed brain regions, while higher binding in sensorimotor striatum was significantly associated with left caudate volume. Limitations Limiting the conclusions drawn from this pilot study are the small sample size and open administration of L-DOPA. Conclusions Greater baseline brain volumes and cortical thickness in regions supporting cognition and gait were associated with higher behavioral performance, while lower structural integrity was associated with increased responsivity to L-DOPA. If substantiated in larger studies, these findings could facilitate the targeting of dopaminergic treatments to those LLD patients most likely to respond.

The objective of this study (NCT01854944) was to assess D(2)/D(3), 5-HT(1A), 5-HT(2A) and serotonin transporter (SERT) occupancies of brexpiprazole in adult subjects with schizophrenia in order to identify the in vivo pharmacologic profile that may be relevant to the antipsychotic, antidepressant, and side effect profiles of the drug. Subjects were grouped into three independent cohorts of four subjects each. All subjects underwent positron emission tomography (PET) scans with two different radiotracers at baseline prior to brexpiprazole administration, and again on Day 10 after daily doses of either 4 mg (Cohorts 1 and 2), or 1 mg (Cohort 3). Cohort 1 received scans with [(11)C]-(+)-PHNO to measure D(2) and D(3) receptor occupancy and [(11)C]CUMI101 to measure 5-HT(1A) occupancy; Cohort 2 received [(11)C]MDL100907 for 5-HT(2A) occupancy and [(11)C]DASB for SERT occupancy; Cohort 3 underwent scanning with [(11)C]-(+)-PHNO and [(11)C]MDL100907. Five female and seven male subjects, aged 42 ± 8 years (range, 28–55 years), participated in this study. Dose dependency was observed at D(2) receptors, with occupancies reaching 64 ± 8% (mean +/− SD) following 1 mg/day and 80 ± 12% following 4 mg/day. D(3) receptor availability increased following 1 mg brexpiprazole treatment and did not change with 4 mg. Robust and dose-related occupancy was also observed at 5-HT(2A) receptors. Negligible occupancy (

F17464, a dopamine D3 receptor antagonist with relatively high D3 selectivity (70 fold vs D2 in vitro), exhibits an antipsychotic profile in preclinical studies, and therapeutic efficacy was demonstrated in a randomized placebo-controlled clinical trial in patients with schizophrenia (Bitter et al. Neuropsychopharmacology 44(11):1917–1924, 2019). This open-label study in healthy male subjects aimed at characterizing F17464 binding to D3/D2 receptors and the time course of receptor occupancy using positron emission tomography (PET) imaging with a D3-preferring tracer, [11C]-(+)-PHNO. PET scans were performed at baseline and following a single 30 mg or 15 mg dose of F17464 (3 subjects/dose), and blood samples were collected for pharmacokinetic analysis. Receptor occupancy was calculated based upon reduction in binding potential of the tracer following F17464 administration. The relationship between plasma F17464 concentration and D3/D2 receptor occupancy was modeled and the plasma concentration corresponding to 50% receptor occupancy (EC50) calculated. Both doses of F17464 robustly blocked [11C]-(+)-PHNO D3 receptor binding, with substantial occupancy from 1 h post-administration, which increased at 6–9 h (89–98% and 79-87% for the 30 mg and 15 mg groups, respectively) and remained detectable at 22 h. In contrast, D2 binding was only modestly blocked at all time points (< 18%). F17464 exhibited a combination of rapid peripheral kinetics and hysteresis (persistence of binding 22 h post-dose despite low plasma concentration). The best estimate of the EC50 was 19 ng ml−1 (~ 40 nM). Overall, F17464 was strongly D3-selective in healthy volunteers, a unique profile for an antipsychotic candidate drug.

Background Neuroinflammation has long been theorized to arise from exposures to fine particulate matter and to be modulated when individuals experience chronic stress, both of which are also though to cause cognitive decline in part as a result of neuroinflammation. Objectives Hypothesizing that neuroinflammation might be linked to experiences at the World Trade Center (WTC) events, this study explored associations between glial activation and neuropsychological measures including post-traumatic stress disorder (PTSD) symptom severity and WTC exposure duration. Methods Translocator protein 18-kDa (TSPO) is overexpressed by activated glial cells, predominantly microglia and astrocytes, making TSPO distribution a putative biomarker for neuroinflammation. Twenty WTC responders completed neuropsychological assessments and in vivo PET brain scan with [18F]-FEPPA. Generalized linear modeling was used to test associations between PTSD, and WTC exposure duratiioni as the predictor and both global and regional [18F]-FEPPA total distribution volumes as the outcomes. Result Responders were 56.0 ​± ​4.7 years-old, and 75% were police officers on 9/11/2001, and all had at least a high school education. Higher PTSD symptom severity was associated with global and regional elevations in [18F]-FEPPA binding predominantly in the hippocampus (d ​= ​0.72, P ​= ​0.001) and frontal cortex (d ​= ​0.64, P ​= ​0.004). Longer exposure duration to WTC sites was associated with higher [18F]-FEPPA binding in the parietal cortex. Conclusion Findings from this study of WTC responders at midlife suggest that glial activation is associated with PTSD symptoms, and WTC exposure duration. Future investigation is needed to understand the important role of neuroinflammation in highly exposed WTC responders., Highlights • We examined the theory that glial activation is associated with 9/11 exposures. • TSPO-Vt was examined using PET in 20 responders adjusting for TSPO genotype. • Responders with PTSD had increased TSPO distribution volume in the hippocampus. • Heavily exposed responders had increased TSPO distribution in the parietal cortex.

Decades of research have highlighted the importance of optimal stimulation of cortical dopaminergic receptors, particularly the D1R receptor (D1R), for prefrontal-mediated cognition. This mechanism is particularly relevant to the cognitive deficits in schizophrenia, given the abnormalities in cortical dopamine (DA) neurotransmission and in the expression of D1R. Despite the critical need for D1R-based therapeutics, many factors have complicated their development and prevented this important therapeutic target from being adequately interrogated. Challenges include determination of the optimal level of D1R stimulation needed to improve cognitive performance, especially when D1R expression levels, affinity states, DA levels, and the resulting D1R occupancy by DA, are not clearly known in schizophrenia, and may display great interindividual and intraindividual variability related to cognitive states and other physiological variables. These directly affect the selection of the level of stimulation necessary to correct the underlying neurobiology. The optimal mechanism for stimulation is also unknown and could include partial or full agonism, biased agonism, or positive allosteric modulation. Furthermore, the development of D1R targeting drugs has been complicated by complexities in extrapolating from in vitro affinity determinations to in vivo use. Prior D1R-targeted drugs have been unsuccessful due to poor bioavailability, pharmacokinetics, and insufficient target engagement at tolerable doses. Newer drugs have recently become available, and these must be tested in the context of carefully designed paradigms that address methodological challenges. In this paper, we discuss how a better understanding of these challenges has shaped our proposed experimental design for testing a new D1R/D5R partial agonist, PF-06412562, renamed CVL-562.

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 Multi-Task 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: 87 total data sets from patients with schizophrenia and matched controls. FIELD STRENGTH/SEQUENCE: 1.5T and 3.0T, 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. PET imaging: 60min of emission data were acquired using [11C]raclopride. Data were reconstructed by filtered back projection (FBP) with computed tomography (CT) used for attenuation correction. Binding potential values, BP(ND), and ROI time-series and whole-brain connectivity using 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 assessment, 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 3D striatal subregion segmentation with results comparable to manually segmented ROIs.

Background A high-risk subgroup of older patients with depression has slowed processing and gait speeds. This study examined whether carbidopa/levodopa (L-DOPA) monotherapy increased dopamine availability, increased processing/gait speed, and relieved depressive symptoms. Methods Adult outpatients with depression >59 years old underwent baseline [11C]raclopride positron emission tomography followed by open L-DOPA for 3 weeks (1 week each of 150 mg, 300 mg, and 450 mg). Generalized estimating equations tested the pre- and post-L-DOPA differences in processing and gait speed measures, depressive symptoms, and reported side effects. The decrease in binding potential between the pre- and posttreatment scans indexed enhanced synaptic dopamine availability induced by L-DOPA treatment. Results Thirty-six subjects participated (age, 75.3 ± 7.5 years; 44.4% male). Significant, dose-dependent increases in processing and gait speed were observed with L-DOPA (450-mg dose: processing speed factor score effect size = 0.41, p = .001; dual-task gait speed effect size = 0.43, p = .002). [11C]raclopride decrease in binding potential was significantly different from 0 in sensorimotor (t24 = −4.85, p Conclusions By enhancing availability of dopamine, L-DOPA improved processing and gait speed in older adults with depression and significantly decreased [11C]raclopride binding in selected striatal subregions.

Background Mesolimbic dopamine system dysfunction is believed to contribute to major depressive disorder (MDD), but molecular neuroimaging of striatal dopamine neurotransmission has yielded mixed results, possibly owing to limited sensitivity of antagonist radioligands used with positron emission tomography to assess dopamine release capacity. This study used an agonist radioligand with agonist challenge to assess dopamine release capacity and D2/D3 receptor availability in MDD. Methods Twenty-six treatment-naive adults with MDD and 26 healthy comparison participants underwent functional magnetic resonance imaging during a probabilistic reinforcement task, and positron emission tomography with the D3-preferring ligand [11C]-(+)-PHNO, before and after oral dextroamphetamine. MDD participants then received pramipexole treatment for 6 weeks. Results MDD participants had trend-level greater dopamine release capacity in the ventral striatum, as measured by percent change in baseline binding potential relative to nondisplaceable compartment (ΔBPND) (−34% vs. −30%; p = .072, d = 0.58) but no difference in D2/D3 receptor availability (BPND). Striatal and extrastriatal BPND and percent change in baseline BPND were not significantly associated with blood oxygen level–dependent response to reward prediction error in the ventral striatum, severity of depression and anhedonia, or antidepressant response to pramipexole (response rate = 72.7%). Conclusions [11C]-(+)-PHNO demonstrated high sensitivity to displacement by amphetamine-induced dopamine release, but dopamine release capacity and D2/D3 availability were not associated with ventral striatal activation to reward prediction error or clinical features, in this study powered to detect large effects. While a preponderance of indirect evidence implicates dopaminergic dysfunction in MDD, these findings suggest that presynaptic dopamine dysregulation may not be a feature of MDD or a prerequisite for treatment response to dopamine agonists.

The human striatum is a collection of subcortical nuclei that serves as a critical node in an information processing network. Recent studies have established a clear topographical and functional organization of projections to and from striatal regions that involves detailed and complex subdivisions of the striatum. Manual segmentation of these functional subdivisions is labor-intensive and time-consuming, yet automated methods have also been a challenging computational problem. Recently, deep learning has emerged as a powerful tool for various tasks, including semantic segmentation. Multi-Task Learning (MTL) is a machine learning technique that allows latent representations between related tasks to be shared during model prediction of multiple tasks with better accuracy. We utilized MTL 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). Dice similarity coefficients (DSC) demonstrate excellent spatial agreement between manual and MTL-generated segmentations (≥ 0.72 across all striatal subregions). Further quantitative task-based analysis was also conducted. Binding potential values, BPND, of [11C]raclopride PET, and ROI time-series and whole-brain connectivity using fMRI images were compared between results generated from manual segmentations and MTL-generated segmentations. BPND values from MTL-generated segmentations were shown to correlate well with manual segmentations with R2 ≥ 0.91 in all caudate and putamen subregions, and R2=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. We conclude that the MTL approach is a fast, robust and reliable method for 3D striatal subregion segmentation with results comparable to manually segmented ROIs.

Patients at clinical high-risk (CHR) for psychosis show elevations in [

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis. ispartof: JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM vol:40 issue:8 pages:1576-1585 ispartof: location:United States status: published

BACKGROUND: We used positron emission tomography imaging with [(11)C]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 (BP(ND)) in the two drink conditions and the percent change in BP(ND) 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 BP(ND) or percent change in BP(ND). However, there was a drink order-by-group interaction (p = .02) whereby family history–positive participants who received placebo first had both lower placebo BP(ND) and less difference between placebo and alcohol BP(ND) 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.

The efficacy of dopamine agonists in treating major depressive disorder has been hypothesized to stem from effects on ventrostriatal dopamine and reward function. However, an important question is whether dopamine agonists are most beneficial for patients with reward-based deficits. This study evaluated whether measures of reward processing and ventrostriatal dopamine function predicted response to the dopamine agonist, pramipexole (ClinicalTrials.gov Identifier: NCT02033369). Individuals with major depressive disorder (n = 26) and healthy controls (n = 26) (mean ± SD age = 26.5 ± 5.9; 50% female) first underwent assessments of reward learning behaviour and ventrostriatal prediction error signalling (measured using functional MRI). 11C-(+)-PHNO PET before and after oral amphetamine was used to assess ventrostriatal dopamine release. The depressed group then received open-label pramipexole treatment for 6 weeks (0.5 mg/day titrated to a maximum daily dose of 2.5 mg). Symptoms were assessed weekly, and reward learning was reassessed post-treatment. At baseline, relative to controls, the depressed group showed lower reward learning (P = 0.02), a trend towards blunted reward-related prediction error signals (P = 0.07), and a trend towards increased amphetamine-induced dopamine release (P = 0.07). Despite symptom improvements following pramipexole (Cohen’s d ranging from 0.51 to 2.16 across symptom subscales), reward learning did not change after treatment. At a group level, baseline reward learning (P = 0.001) and prediction error signalling (P = 0.004) were both associated with symptom improvement, albeit in a direction opposite to initial predictions: patients with stronger pretreatment reward learning and reward-related prediction error signalling improved most. Baseline D2/3 receptor availability (P = 0.02) and dopamine release (P = 0.05) also predicted improvements in clinical functioning, with lower D2/3 receptor availability and lower dopamine release predicting greater improvements. Although these findings await replication, they suggest that measures of reward-related mesolimbic dopamine function may hold promise for identifying depressed individuals likely to respond favourably to dopaminergic pharmacotherapy.

F17464, a dopamine D3 receptor antagonist with relatively high D3 selectivity (70 fold vs D2 in vitro), exhibits an antipsychotic profile in preclinical studies, and therapeutic efficacy was demonstrated in a randomized placebo-controlled clinical trial in patients with schizophrenia (Bitter et al. Neuropsychopharmacology 44(11):1917-1924, 2019).This open-label study in healthy male subjects aimed at characterizing F17464 binding to D3/D2 receptors and the time course of receptor occupancy using positron emission tomography (PET) imaging with a D3-preferring tracer, [PET scans were performed at baseline and following a single 30 mg or 15 mg dose of F17464 (3 subjects/dose), and blood samples were collected for pharmacokinetic analysis. Receptor occupancy was calculated based upon reduction in binding potential of the tracer following F17464 administration. The relationship between plasma F17464 concentration and D3/D2 receptor occupancy was modeled and the plasma concentration corresponding to 50% receptor occupancy (ECBoth doses of F17464 robustly blocked [Overall, F17464 was strongly D3-selective in healthy volunteers, a unique profile for an antipsychotic candidate drug.

Objective We hypothesized that DA and L-DOPA derived from nutritional tyrosine and the resultant observed postprandial plasma excursions of L-DOPA and DA might affect glucose tolerance via their ability to be taken-up by beta cells and inhibit glucose-stimulated β-cell insulin secretion. Methods To investigate a possible circuit between meal-stimulated 3,4-dihydroxy-L-phenylalanine (L-DOPA) and dopamine (DA) production in the GI tract and pancreatic β-cells, we: 1) mapped GI mucosal expression of tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC); 2) measured L-DOPA and DA content of GI mucosal tissues following meal challenges with different L-tyrosine (TYR) content, 3) determined whether meal TYR content impacts plasma insulin and glucose excursions; and 4) characterized postprandial plasma excursions of L-DOPA and DA in response to meal tyrosine content in rodents and a population of bariatric surgery patients. Next, we characterized: 1) the metabolic transformation of TYR and L-DOPA into DA in vitro using purified islet tissue; 2) the metabolic transformation of orally administrated stable isotope labeled TYR into pancreatic DA, and 3) using a nuclear medicine technique, we studied endocrine beta cells in situ release and binding of DA in response to a glucose challenge. Results We demonstrate in rodents that intestinal content and circulatory concentrations L-DOPA and DA, plasma glucose and insulin are responsive to the tyrosine (TYR) content of a test meal. Intestinal expression of two enzymes, Tyrosine hydroxylase (TH) and Aromatic Amino acid Decarboxylase (AADC), essential to the transformation of TYR to DA was mapped and the metabolism of metabolism of TYR to DA was traced in human islets and a rodent beta cell line in vitro and from gut to the pancreas in vivo. Lastly, we show that β cells secrete and bind DA in situ in response to glucose stimulation. Conclusions We provide proof-of-principle evidence for the existence of a novel postprandial circuit of glucose homeostasis dependent on nutritional tyrosine. DA and L-DOPA derived from nutritional tyrosine may serve to defend against hypoglycemia via inhibition of glucose-stimulated β-cell insulin secretion as proposed by the anti-incretin hypothesis., Graphical abstract Image 1Schematic of the proposed gut to pancreas blood glucose concentration regulatory circuit. Abbreviations used: TH, tyrosine hydroxylase; AADC, Aromatic l-amino acid decarboxylase; L-DOPA, L-3,4-dihydroxyphenylalanine; D2R, Dopamine receptor type 2, DA, Dopamine; LAAT, L-Type Amino Acid Transporter 1; DAT, dopamine active transporter; VMAT2, Vesicular monoamine transporter type 2; GSIS, glucose-stimulated insulin secretion. Grey boxes show tissue bypassed by GS, Sleeve Gastrectomy, and RYGB, Roux-en-Y Gastric Bypass surgeries., Highlights • Nutritional tyrosine is metabolized to L DOPA and DA in the foregut. • Postprandial L-DOPA and DA plasma concentrations rise in response to tyrosine. • Oral stable isotope labeled tyrosine is found postprandially in the pancreas as DA. • L-DOPA and DA are inhibitors of beta cell glucose-stimulated insulin secretion. • Postprandial L-DOPA and DA excursions are muted in certain bariatric surgery patients.

Rationale Second-generation antipsychotics occupy dopamine D2 receptors and act as antagonists or partial agonists at these receptors. While these drugs alleviate positive symptoms in patients with schizophrenia, they are less effective for treating cognitive deficits and negative symptoms. Dopamine D3 receptors are highly expressed in areas of the brain thought to play a role in the regulation of motivation and reward-related behavior. Consequently, the dopamine D3 receptor has become a target for treating negative symptoms in combination with D2 antagonism to treat positive symptoms in patients with schizophrenia. Objective The purpose of this study was to determine the cariprazine receptor occupancies in brain for D2 and D3 receptors in patients with schizophrenia. Methods Using [11C]-(+)-PHNO as a radioligand, positron emission tomography (PET) scans were performed in eight patients at baseline and postdose on days 1, 4, and 15. Plasma and cerebrospinal fluid (CSF) samples were analyzed for cariprazine concentrations. Results A monotonic dose-occupancy relationship was observed for both receptor types. After 2 weeks of treatment, near complete (∼100 %) occupancies were observed for both receptors at a dose of 12 mg/day. At the lowest cariprazine dose (1 mg/day), mean D3 and D2 receptor occupancies were 76 and 45 %, respectively, suggesting selectivity for D3 over D2 receptors at low doses. An exposure-response analysis found a ∼3-fold difference in EC50 (D3 = 3.84 nM and D2 = 13.03 nM) in plasma after 2 weeks of dosing. Conclusion This PET imaging study in patients with schizophrenia demonstrated that cariprazine is a D3-preferring dual D3/D2 receptor partial agonist.

Connectivity between brain networks may adapt flexibly to cognitive demand, a process that could underlie adaptive behaviors and cognitive deficits, such as those observed in neuropsychiatric conditions like schizophrenia. Dopamine signaling is critical for working memory but its influence on internetwork connectivity is relatively unknown. We addressed these questions in healthy humans using functional magnetic resonance imaging (during ann-back working-memory task) and positron emission tomography using the radiotracer [11C]FLB457 before and after amphetamine to measure the capacity for dopamine release in extrastriatal brain regions. Brain networks were defined by spatial independent component analysis (ICA) and working-memory-load-dependent connectivity between task-relevant pairs of networks was determined via a modified psychophysiological interaction analysis. For most pairs of task-relevant networks, connectivity significantly changed as a function of working-memory load. Moreover, load-dependent changes in connectivity between left and right frontoparietal networks (Δ connectivity lFPN-rFPN) predicted interindividual differences in task performance more accurately than other fMRI and PET imaging measures. Δ Connectivity lFPN-rFPN was not related to cortical dopamine release capacity. A second study in unmedicated patients with schizophrenia showed no abnormalities in load-dependent connectivity but showed a weaker relationship between Δ connectivity lFPN-rFPN and working memory performance in patients compared with matched healthy individuals. Poor working memory performance in patients was, in contrast, related to deficient cortical dopamine release. Our findings indicate that interactions between brain networks dynamically adapt to fluctuating environmental demands. These dynamic adaptations underlie successful working memory performance in healthy individuals and are not well predicted by amphetamine-induced dopamine release capacity.SIGNIFICANCE STATEMENTIt is unclear how communication between brain networks responds to changing environmental demands during complex cognitive processes. Also, unknown in regard to these network dynamics is the role of neuromodulators, such as dopamine, and whether their dysregulation could underlie cognitive deficits in neuropsychiatric illness. We found that connectivity between brain networks changes with working-memory load and greater increases predict better working memory performance; however, it was not related to capacity for dopamine release in the cortex. Patients with schizophrenia did show dynamic internetwork connectivity; however, this was more weakly associated with successful performance in patients compared with healthy individuals. Our findings indicate that dynamic interactions between brain networks may support the type of flexible adaptations essential to goal-directed behavior.