Neuromelanin-Sensitive MRI as Candidate Marker for Treatment Resistance in First-Episode Schizophrenia.

OBJECTIVE: Markers for treatment resistance in schizophrenia are needed to reduce delays in effective treatment. Nigrostriatal hyperdopaminergic function plays a critical role in the pathology of schizophrenia, yet antipsychotic nonresponders do not show increased dopamine function. Neuromelanin-sensitive MRI (NM-MRI), which indirectly measures dopamine function in the substantia nigra, has potential as a noninvasive marker for nonresponders. Increased NM-MRI signal has been shown in psychosis, but has not yet been assessed in nonresponders. In this study, the authors investigated whether nonresponders show lower NM-MRI signal than responders. METHODS: NM-MRI scans were acquired in 79 patients with first-episode psychosis and 20 matched healthy control subjects. Treatment response was assessed at a 6-month follow-up. An a priori voxel-wise analysis within the substantia nigra tested the relation between NM-MRI signal and treatment response in patients. RESULTS: Fifteen patients were classified as nonresponders and 47 patients as responders. Seventeen patients were excluded, primarily because of medication nonadherence or change in diagnosis. Voxel-wise analysis revealed 297 significant voxels in the ventral tier of the substantia nigra that were negatively associated with treatment response. Nonresponders and healthy control subjects had significantly lower NM-MRI signal than responders. Receiver operating characteristic curve analysis showed that NM-MRI signal separated nonresponders with areas under the curve between 0.62 and 0.85. In addition, NM-MRI signal in patients did not change over 6 months. CONCLUSIONS: These findings provide further evidence for dopaminergic differences between medication responders and nonresponders and support the potential of NM-MRI as a clinically applicable marker for treatment resistance in schizophrenia.

Endocannabinoid levels in plasma and neurotransmitters in the brain: a preliminary report on patients with a psychotic disorder and healthy individuals.

BACKGROUND: Interactions between the endocannabinoid system (ECS) and neurotransmitter systems might mediate the risk of developing a schizophrenia spectrum disorder (SSD). Consequently, we investigated in patients with SSD and healthy controls (HC) the relations between (1) plasma concentrations of two prototypical endocannabinoids (N-arachidonoylethanolamine [anandamide] and 2-arachidonoylglycerol [2-AG]) and (2) striatal dopamine synthesis capacity (DSC), and glutamate and y-aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC). As anandamide and 2-AG might reduce the activity of these neurotransmitters, we hypothesized negative correlations between their plasma levels and the abovementioned neurotransmitters in both groups. METHODS: Blood samples were obtained from 18 patients and 16 HC to measure anandamide and 2-AG plasma concentrations. For all subjects, we acquired proton magnetic resonance spectroscopy scans to assess Glx (i.e. glutamate plus glutamine) and GABA + (i.e. GABA plus macromolecules) concentrations in the ACC. Ten patients and 14 HC also underwent [18F]F-DOPA positron emission tomography for assessment of striatal DSC. Multiple linear regression analyses were used to investigate the relations between the outcome measures. RESULTS: A negative association between 2-AG plasma concentration and ACC Glx concentration was found in patients (p = 0.008). We found no evidence of other significant relationships between 2-AG or anandamide plasma concentrations and dopaminergic, glutamatergic, or GABAergic measures in either group. CONCLUSIONS: Our preliminary results suggest an association between peripheral 2-AG and ACC Glx levels in patients.

Glutamate and GABA levels in the anterior cingulate cortex in treatment resistant first episode psychosis patients.

BACKGROUND: Around 30 % of schizophrenia patients do not respond sufficiently to conventional antipsychotic treatment. Glutamate and γ-aminobutyric acid (GABA) may be implicated in treatment resistant (TR) patients. Some data indicate that TR patients show increased glutamate levels compared to responders, but findings are inconclusive and limited in the early disease stage. Furthermore, the two neurotransmitters have rarely been assessed in conjunction. We therefore aimed to investigate the role of GABA+ and glutamate in first episode TR patients and explore whether these neurometabolites could be potential predictive markers for TR schizophrenia. STUDY DESIGN: We used proton magnetic resonance spectroscopy (MRS) to assess glutamate + glutamine (Glx) and GABA including macromolecules (GABA+) in the anterior cingulate cortex (ACC) of 58 first episode psychosis patients. At six months follow-up treatment response was determined and in a subgroup of 33 patients a follow-up MRS scan was acquired. STUDY RESULTS: Glx and GABA+ levels were not significantly different between TR patients and responders at baseline and the levels did not change at six months follow-up. The groups differed in voxel fractions, which could have influenced our results even though we corrected for these differences. CONCLUSIONS: Our findings do not provide evidence that ACC Glx or GABA+ levels are potential biomarkers for TR in first episode psychosis. Future research needs to take in to account voxel fractions and report potential differences. Comparison with previous literature suggests that illness duration, clozapine responsiveness and medication effects may partly explain the heterogeneous results on Glx and GABA+ levels in TR.

Transdiagnostic Ecological Momentary Intervention for Improving Self-Esteem in Youth Exposed to Childhood Adversity: The SELFIE Randomized Clinical Trial.

Importance: Targeting low self-esteem in youth exposed to childhood adversity is a promising strategy for preventing adult mental disorders. Ecological momentary interventions (EMIs) allow for the delivery of youth-friendly, adaptive interventions for improving self-esteem, but robust trial-based evidence is pending. Objective: To examine the efficacy of SELFIE, a novel transdiagnostic, blended EMI for improving self-esteem plus care as usual (CAU) compared with CAU only. Design, Setting, and Participants: This was a 2-arm, parallel-group, assessor-blinded, randomized clinical trial conducted from December 2018 to December 2022. The study took place at Dutch secondary mental health services and within the general population and included youth (aged 12-26 years) with low self-esteem (Rosenberg Self-Esteem Scale [RSES] <26) exposed to childhood adversity. Interventions: A novel blended EMI (3 face-to-face sessions, email contacts, app-based, adaptive EMI) plus CAU or CAU only. Main Outcomes and Measures: The primary outcome was RSES self-esteem at postintervention and 6-month follow-up. Secondary outcomes included positive and negative self-esteem, schematic self-beliefs, momentary self-esteem and affect, general psychopathology, quality of life, observer-rated symptoms, and functioning. Results: A total of 174 participants (mean [SD] age, 20.7 [3.1] years; 154 female [89%]) were included in the intention-to-treat sample, who were primarily exposed to childhood emotional abuse or neglect, verbal or indirect bullying, and/or parental conflict. At postintervention, 153 participants (87.9%) and, at follow-up, 140 participants (80.5%), provided primary outcome data. RSES self-esteem was, on average, higher in the experimental condition (blended EMI + CAU) than in the control condition (CAU) across both postintervention and follow-up as a primary outcome (B = 2.32; 95% CI, 1.14-3.50; P < .001; Cohen d-type effect size [hereafter, Cohen d] = 0.54). Small to moderate effect sizes were observed suggestive of beneficial effects on positive (B = 3.85; 95% CI, 1.83-5.88; P < .001; Cohen d = 0.53) and negative (B = -3.78; 95% CI, -6.59 to -0.98; P = .008; Cohen d = -0.38) self-esteem, positive (B = 1.58; 95% CI, 0.41-2.75; P = .008; Cohen d = 0.38) and negative (B = -1.71; 95% CI, -2.93 to -0.48; P = .006; Cohen d = -0.39) schematic self-beliefs, momentary self-esteem (B = 0.29; 95% CI, 0.01-0.57; P = .04; Cohen d = 0.24), momentary positive affect (B = 0.23; 95% CI, 0.01-0.45; P = .04; Cohen d = 0.20), momentary negative affect (B = -0.33; 95% CI, -0.59 to -0.03, P = .01, Cohen d = -0.27), general psychopathology (B = -17.62; 95% CI, -33.03 to -2.21; P = .03; Cohen d = -0.34), and quality of life (B = 1.16; 95% CI, 0.18-2.13; P = .02; Cohen d = 0.33) across postintervention and follow-up. No beneficial effects on symptoms and functioning were observed. Conclusions and Relevance: A transdiagnostic, blended EMI demonstrated efficacy on the primary outcome of self-esteem and signaled beneficial effects on several secondary outcomes. Further work should focus on implementing this novel EMI in routine public mental health provision. Trial Registration: Dutch Trial Register Identifier:NL7129(NTR7475).

The association between clinical, sociodemographic, familial, and environmental factors and treatment resistance in schizophrenia: A machine-learning-based approach.

BACKGROUND: Prediction of treatment resistance in schizophrenia (TRS) would be helpful to reduce the duration of ineffective treatment and avoid delays in clozapine initiation. We applied machine learning to identify clinical, sociodemographic, familial, and environmental variables that are associated with TRS and could potentially predict TRS in the future. STUDY DESIGN: Baseline and follow-up data on trait(-like) variables from the Genetic Risk and Outcome of Psychosis (GROUP) study were used. For the main analysis, we selected patients with non-affective psychotic disorders who met TRS (n = 200) or antipsychotic-responsive criteria (n = 423) throughout the study. For a sensitivity analysis, we only selected patients who met TRS (n = 76) or antipsychotic-responsive criteria (n = 123) at follow-up but not at baseline. Random forest models were trained to predict TRS in both datasets. SHapley Additive exPlanation values were used to examine the variables' contributions to the prediction. STUDY RESULTS: Premorbid functioning, age at onset, and educational degree were most consistently associated with TRS across both analyses. Marital status, current household, intelligence quotient, number of moves, and family loading score for substance abuse also consistently contributed to the prediction of TRS in the main or sensitivity analysis. The diagnostic performance of our models was modest (area under the curve: 0.66-0.69). CONCLUSIONS: We demonstrate that various clinical, sociodemographic, familial, and environmental variables are associated with TRS. Our models only showed modest performance in predicting TRS. Prospective large multi-centre studies are needed to validate our findings and investigate whether the model's performance can be improved by adding data from different modalities.

The substantia nigra in the pathology of schizophrenia: A review on post-mortem and molecular imaging findings.

Dysregulation of striatal dopamine is considered to be an important driver of pathophysiological processes in schizophrenia. Despite being one of the main origins of dopaminergic input to the striatum, the (dys)functioning of the substantia nigra (SN) has been relatively understudied in schizophrenia. Hence, this paper aims to review different molecular aspects of nigral functioning in patients with schizophrenia compared to healthy controls by integrating post-mortem and molecular imaging studies. We found evidence for hyperdopaminergic functioning in the SN of patients with schizophrenia (i.e. increased AADC activity in antipsychotic-free/-naïve patients and elevated neuromelanin accumulation). Reduced GABAergic inhibition (i.e. decreased density of GABAergic synapses, lower VGAT mRNA levels and lower mRNA levels for GABAA receptor subunits), excessive glutamatergic excitation (i.e. increased NR1 and Glur5 mRNA levels and a reduced number of astrocytes), and several other disturbances implicating the SN (i.e. immune functioning and copper concentrations) could potentially underlie this nigral hyperactivity and associated striatal hyperdopaminergic functioning in schizophrenia. These results highlight the importance of the SN in schizophrenia pathology and suggest that some aspects of molecular functioning in the SN could potentially be used as treatment targets or biomarkers.

Acceleration of neuromelanin-sensitive MRI sequences in the substantia nigra using standard MRI options.

PURPOSE: Neuromelanin MRI (NM-MRI) is applied as a proxy measurement of dopaminergic functioning of the substantia nigra pars compacta (SN). To increase its clinical applicability, a fast and easily applicable NM-MRI sequence is needed. This study therefore compared accelerated NM-MRI sequences using standard available MRI options with a validated 2D gradient recalled echo NM-MRI sequence with off-resonance magnetization transfer (MT) pulse (2D-MToffRes). METHODS: We used different combinations of compressed sense (CS) acceleration, repetition times (TR), and MT pulse to accelerate the validated 2D-MToffRes. In addition, we compared a recently introduced 3D sequence with the 2D-MToffRes. RESULTS: Our results show that the 2D sequences perform best with good to excellent reliability. Only excellent intraclass correlation coefficients were found for the CS factor 2 sequences. CONCLUSION: We conclude that there are several reliable approaches to accelerate NM-MRI, in particular by using CS.

Imaging of the dopamine system with focus on pharmacological MRI and neuromelanin imaging.

The dopamine system in the brain is involved in a variety of neurologic and psychiatric disorders, such as Parkinson's disease, attention-deficit/hyperactivity disorder and psychosis. Different aspects of the dopamine system can be visualized and measured with positron emission tomography (PET) and single photon emission computed tomography (SPECT), including dopamine receptors, dopamine transporters, and dopamine release. New developments in MR imaging also provide proxy measures of the dopamine system in the brain, offering alternatives with the advantages MR imaging, i.e. no radiation, lower costs, usually less invasive and time consuming. This review will give an overview of these developments with a focus on the most developed techniques: pharmacological MRI (phMRI) and neuromelanin sensitive MRI (NM-MRI). PhMRI is a collective term for functional MRI techniques that administer a pharmacological challenge to assess its effects on brain hemodynamics. By doing so, it indirectly assesses brain neurotransmitter function such as dopamine function. NM-MRI is an upcoming MRI technique that enables in vivo visualization and semi-quantification of neuromelanin in the substantia nigra. Neuromelanin is located in the cell bodies of dopaminergic neurons of the nigrostriatal pathway and can be used as a proxy measure for long term dopamine function or degeneration of dopaminergic neurons. Both techniques are still primarily used in clinical research, but there is promise for clinical application, in particular for NM-MRI in dopaminergic neurodegenerative diseases like Parkinson's disease.

Cross-Scanner Harmonization of Neuromelanin-Sensitive MRI for Multisite Studies.

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.

Reliability and Reproducibility of Neuromelanin-Sensitive Imaging of the Substantia Nigra: A Comparison of Three Different Sequences.

BACKGROUND: Neuromelanin-sensitive MRI (NM-MRI) of the substantia nigra provides a noninvasive way to acquire an indirect measure of dopamine functioning. Despite the potential of NM-MRI as a candidate biomarker for dopaminergic pathology, studies about its reproducibility are sparse. PURPOSE: To assess the test-retest reproducibility of three commonly used NM-MRI sequences and evaluate three analysis methods. STUDY TYPE: Prospective study. POPULATION: A total of 11 healthy participants age between 20-27 years. FIELD STRENGTH/SEQUENCE: 3.0T; NM-MRI gradient recalled echo (GRE) with magnetization transfer (MT) pulse; NM-MRI turbo spin echo (TSE) with MT pulse; NM-MRI TSE without MT pulse. ASSESSMENT: Participants were scanned twice with a 3-week interval. Manual analysis, threshold analysis, and voxelwise analysis were performed for volume and contrast ratio (CR) measurements. STATISTICAL TESTS: Intraclass correlation coefficients (ICCs) were calculated for test-retest and inter- and intrarater variability. RESULTS: The GRE sequence achieved the highest contrast and lowest variability (4.9-5.7%) and showed substantial to almost perfect test-retest ICC (0.72-0.90) for CR measurements. For volume measurements, the manual analysis showed a higher variability (10.7-17.9%) and scored lower test-retest ICCs (-0.13-0.73) than the other analysis methods. The threshold analysis showed higher test-retest ICC (0.77) than the manual analysis for the volume measurements. DATA CONCLUSION: NM-MRI is a highly reproducible measure, especially when using the GRE sequence and CR measurements. Volume measurements appear to be more sensitive to inter/intrarater variability and variability in placement and orientation of the NM-MRI slab. The threshold analysis appears to be the best alternative for volume analysis. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Plasma dopa decarboxylase activity in treatment-resistant recent-onset psychosis patients.

Treatment resistance (TR) in psychosis is a major clinical problem. A biomarker predicting TR against conventional antipsychotic drugs would be relevant, potentially reducing unnecessary delay to adequate treatment with clozapine. Dopa decarboxylase (DDC) activity in the striatum, measured with positron emission tomography, is elevated in responders, but not in treatment-resistant patients. Plasma DDC activity could be a surrogate marker for DDC brain activity, and thus a potential biomarker that could be used in daily clinical practice. Therefore, we determined plasma DDC activity in 40 male patients with recent-onset psychosis, of whom the majority had started treatment, whereby 21 turned out to be treatment responders and 19 treatment resistant during follow up. We observed no significant group differences. Furthermore, symptom severity was not associated with plasma DCC activity. We did observe a trend level difference in the distribution of plasma DDC activity across categories of medication, with subsequent post hoc analysis showing lower DDC activity in risperidone-using patients. This may suggest that risperidone could influence plasma DDC activity. Based on these results, plasma DDC activity does not appear to be a promising biomarker for TR in recent-onset psychosis patients who are already receiving antipsychotic treatment.

Influence of muscarinic M1 receptor antagonism on brain choline levels and functional connectivity in medication-free subjects with psychosis: A placebo controlled, cross-over study.

An increasing number of studies implicate the muscarinic cholinergic system in cognitive dysfunction associated with psychosis. This study examined the effect of muscarinic M1 receptor modulation on anterior cingulate cortex (ACC) and striatal choline concentrations and the relation with cognitive performance, as well as functional connectivity of cognitive networks. Thirty medication-free subjects with a psychosis spectrum disorder and 30 gender, age and IQ-matched healthy control subjects underwent 1H-proton magnetic resonance spectroscopy (1H-MRS) twice, once after placebo and once after a single dose of biperiden (M1 receptor antagonist, 4 mg). A subset of 19 psychotic subjects and 28 controls underwent resting-state functional magnetic resonance imaging (rs-fMRI) as well. No significant differences were found in ACC and striatal choline levels, nor in functional connectivity, between the two groups after placebo. Moreover, M1 antagonism did not significantly affect choline levels or functional connectivity. No correlations were found between choline levels and cognition as well as psychotic symptoms. Our findings do not support an association between the cholinergic system and cognition and psychotic symptoms. However, the lack of group differences in choline concentrations and functional connectivity, both after biperiden and placebo, may indicate that there were no severe cholinergic abnormalities present in our sample.

Can we use neuroimaging data to differentiate between subgroups of children with ADHD symptoms: A proof of concept study using latent class analysis of brain activity.

BACKGROUND: Multiple pathway models of ADHD suggest that multiple, separable biological pathways may lead to symptoms of the disorder. If this is the case, it should be possible to identify subgroups of children with ADHD based on distinct patterns of brain activity. Previous studies have used latent class analysis (LCA) to define subgroups at the behavioral and cognitive level and to then test whether they differ at the neurobiological level. In this proof of concept study, we took a reverse approach. We applied LCA to functional imaging data from two previously published studies to explore whether we could identify subgroups of children with ADHD symptoms at the neurobiological level with a meaningful relation to behavior or neuropsychology. METHODS: Fifty-six children with symptoms of ADHD (27 children with ADHD and 29 children with ASD and ADHD symptoms) and 31 typically developing children performed two neuropsychological tasks assessing reward sensitivity and temporal expectancy during functional magnetic resonance imaging. LCA was used to identify subgroups with similar patterns of brain activity separately for children with ADHD-symptoms and typically developing children. Behavioral and neuropsychological differences between subgroups were subsequently investigated. RESULTS: For typically developing children, a one-subgroup model gave the most parsimonious fit, whereas for children with ADHD-symptoms a two-subgroup model best fits the data. The first ADHD subgroup (n = 49) showed attenuated brain activity compared to the second subgroup (n = 7) and to typically developing children (n = 31). Notably, the ADHD subgroup with attenuated brain activity showed less behavioral problems in everyday life. CONCLUSIONS: In this proof of concept study, we showed that we could identify distinct subgroups of children with ADHD-symptoms based on their brain activity profiles. Generalizability was limited due to the small sample size, but ultimately such neurobiological profiles could improve insight in individual prognosis and treatment options.

First in human evaluation of [18F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors.

BACKGROUND: Efforts to develop suitable positron emission tomography (PET) tracers for the ion channel site of human N-methyl-D-aspartate (NMDA) receptors have had limited success. [18F]PK-209 is a GMOM derivative that binds to the intrachannel phencyclidine site with high affinity and selectivity. Primate PET studies have shown that the volume of distribution in the brain was reduced by administration of the NMDA receptor antagonist MK-801, consistent with substantial specific binding. The purpose of the present study was to evaluate [18F]PK-209 in 10 healthy humans by assessing test-retest reproducibility and binding specificity following intravenous S-ketamine administration (0.5 mg âˆ™ kg-1). Five healthy subjects underwent a test-retest protocol, and five others a baseline-ketamine protocol. In all cases dynamic, 120-min PET scans were acquired together with metabolite-corrected arterial plasma input functions. Additional input functions were tested based on within-subject and population-average parent fractions. RESULTS: Best fits of the brain time-activity curves were obtained using an irreversible two-tissue compartment model with additional blood volume parameter. Mean test-retest variability of the net rate of influx Ki varied between 7 and 24% depending on the input function. There were no consistent changes in [18F]PK-209 PET parameters following ketamine administration, which may be a consequence of the complex endogenous ligand processes that affect channel gating. CONCLUSIONS: The molecular interaction between [18F]PK-209 and the binding site within the NMDA receptor ion channel is insufficiently reproducible and specific to be a reliable imaging agent for its quantification. TRIAL REGISTRATION: EudraCT 2014-001735-36. Registered 28 April 2014.