Probing midbrain dopamine function in pediatric obsessive-compulsive disorder via neuromelanin-sensitive magnetic resonance imaging

Pagliaccio, David; Wengler, Kenneth; Durham, Katherine; Fontaine, Martine; Rueppel, Meryl; Becker, Hannah; Bilek, Emily L.; Pieper, Sarah; Risdon, Catherine; Horga, Guillermo; Fitzgerald, Kate D.; Marsh, Rachel

doi:10.1038/s41380-023-02105-z

Cited by 6 publications

(4 citation statements)

References 91 publications

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“…Finally, while NM-MRI provides a biologically grounded and validated proxy for dopamine function, it is less direct than molecular imaging. However, NM-MRI affords a higher-resolution measure of presynaptic dopamine nuclei that can be readily acquired noninvasively in most MRI scanners, including in pediatric populations …”

Section: Discussionmentioning

confidence: 99%

“…See eTable 3 in Supplement 1 for control analyses excluding NT and GT. As in prior work, 14,[39][40][41][42] exploratory voxelwise univariate analyses within the overinclusive SN/VTA mask used robust multiple-linear regression (eMethods in Supplement 1).…”

Section: Mri Data Processing and Analysismentioning

confidence: 99%

“…However, NM-MRI affords a higher-resolution measure of presynaptic dopamine nuclei that can be readily acquired noninvasively in most MRI scanners, including in pediatric populations. 39…”

Section: Limitationsmentioning

confidence: 99%

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

Wengler,

Baker,

Velikovskaya

et al. 2024

JAMA Psychiatry

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ImportanceThe link between psychosis and dopaminergic dysfunction is established, but no generalizable biomarkers with clear potential for clinical adoption exist.ObjectiveTo 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 ParticipantsThis 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 MeasuresNM-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.ResultsOf 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 RelevanceThis 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.

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Section: Discussionmentioning

confidence: 99%

Section: Mri Data Processing and Analysismentioning

confidence: 99%

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

Wengler,

Baker,

Velikovskaya

et al. 2024

JAMA Psychiatry

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“…Emerging evidence in broader psychiatry suggests that diminished neuromelanin may be evident in disorders of impulsivity (Cassidy et al., 2019 ). Moreover, studies of OCD—a disorder highly comorbid with AN—suggest that greater symptom severity and illness duration are independently linked to greater perturbations in midbrain neuromelanin (Pagliaccio et al., 2023 ). As such, the assessment of midbrain neuromelanin and both illness duration and symptom severity in AN—a disorder highly linked to dopaminergic perturbations and altered hedonic drive—is warranted.…”

Section: Introductionmentioning

confidence: 99%

Assessing midbrain neuromelanin and its relationship to reward learning in anorexia nervosa: Stage 1 of a registered report

Murray,

Diaz‐Fong,

Mak

et al. 2024

Brain and Behavior

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IntroductionAnorexia nervosa (AN) is a debilitating and potentially chronic eating disorder, characterized by low hedonic drive toward food, which has been linked with perturbations in both reward processing and dopaminergic activity. Neuromelanin‐sensitive magnetic resonance imaging (MRI) is an emerging method to index midbrain neuromelanin—a by‐product of dopaminergic synthesis. The assessment of midbrain neuromelanin, and its association with AN psychopathology and reward‐related processes, may provide critical insights into reward circuit function in AN.MethodsThis study will incorporate neuromelanin‐sensitive MRI into an existing study of appetitive conditioning in those with AN. Specifically, those with acute and underweight AN (N = 30), those with weight‐restored AN (N = 30), and age‐matched healthy controls (N = 30) will undergo clinical assessment of current and previous psychopathology, in addition to structural neuromelanin‐sensitive MRI, diffusion MRI, and functional MRI (fMRI) during appetitive conditioning.ConclusionThis study will be among the first to interrogate midbrain neuromelanin in AN—a disorder characterized by altered dopaminergic activity. Results will help establish whether abnormalities in the midbrain synthesis of dopamine are evident in those with AN and are associated with symptomatic behavior and reduced ability to experience pleasure and reward.

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Neurobiology of Obsessive–Compulsive Disorder from Genes to Circuits: Insights from Animal Models

Zhang,

Shi,

Wang

2024

Neurosci. Bull.

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Probing midbrain dopamine function in pediatric obsessive-compulsive disorder via neuromelanin-sensitive magnetic resonance imaging

Cited by 6 publications

References 91 publications

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

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

Assessing midbrain neuromelanin and its relationship to reward learning in anorexia nervosa: Stage 1 of a registered report

Neurobiology of Obsessive–Compulsive Disorder from Genes to Circuits: Insights from Animal Models

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