Development of MRI Techniques for Applications in Substance Use Disorders

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

1. Maturation of Dorsal Association Tracts during Preadolescence Links to Concurrent and Future Cognitive Performance and Transdiagnostic Psychopathology Many psychiatric disorders begin during adolescence, coinciding with the rapid development of brain white matter (WM). However, it remains unclear whether deviations from normal WM maturation during this age period contribute to the development of psychopathology. In this study, we developed and validated normative models of brain age based on specific WM tracts using three large-scale developmental datasets (a total of ∼10,000 subjects). We found that tract-specific deviations in WM development of association and limbic/subcortical systems were linked to concurrent cognition and psychopathology. The spatial pattern of the association system aligned closely with distributions of high-order brain networks, and with mitochondrial content and respiratory capacity. The maturation of the association system contributed significantly to better cognitive performance assessed two or three years later. Importantly, delayed WM development especially in dorsal association tracts predicted psychiatric disorders across diagnoses and disorder onset over a 2-year follow-up. By identifying tract-specific WM development during preadolescence as a predictor of cognitive capacity and psychiatric disorder risks, this study provides a valuable framework for tracking individualized brain maturation and understanding the neurobiological underpinnings of cognitive performance and transdiagnostic psychopathology. (Wang et al., manuscript under review) 2. Abnormal ventromedial-to-dorsolateral hierarchical topography of striatal circuits in cocaine use disorder and its modulations by brain stimulation Cocaine use disorder (CUD) has been linked to cortico-striatal dysfunctions, particularly within the prefrontal-striatal circuitry. However, previous studies have typically focused on discrete parcellations of the striatum, overlooking its continuous variations of neural organization. Moreover, while repetitive transcranial magnetic stimulation (rTMS) has shown benefits in CUD treatment, the neural effects of rTMS on striatal dysfunction in CUD remain poorly understood. Using connectome gradient-mapping techniques on three resting-state functional magnetic resonance imaging datasets, we derived the ventromedial-to-dorsolateral striatal functional topography. We identified specific alterations in this topography in the discovery cohort (41 CUD patients and 44 controls), validated findings in an independent cohort (53 CUD patients and 45 controls), and examined whether rTMS targeting the left dorsolateral prefrontal cortex (dlPFC) could normalize abnormalities in the rTMS-treatment cohort (44 patients). Across all datasets, we found a positive correlation between gradient variation and drug dependence severity in CUD. Compared to controls, CUD in both the discovery and replication cohorts exhibited elevated gradient values in the ventral striatum, while decreased values in the dorsal striatum were observed only in the discovery cohort. Furthermore, in the rTMS-treatment cohort, 5-Hz rTMS targeting the left dlPFC significantly normalized the aberrant gradient values in the ventral striatum, and these changes also related to cocaine craving changes. Overall, our study provides novel evidence of specific alterations in the ventromedial-to-dorsolateral functional topography of the striatum in CUD patients and highlights the impact of rTMS on striatal circuits through prefrontal modulation. (Zhang et al., Neuropsychopharmacology, 2025) 3. Response at the striatal-thalamic pathway to high- or low-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex Transcranial magnetic stimulation (TMS) over the dorsolateral prefrontal cortex (DLPFC) has been used in the treatment of major depressive disorder (MDD) and substance use disorders (SUDs). It has been hypothesized that when TMS is applied over the DLPFC it stimulates the cortical-striatal-thalamic pathway, affecting the dopaminergic circuitry that is dysregulated in patients with either MDD or SUDs. In this work, we aimed to evaluate TMS-induced changes in striatal-thalamic BOLD activity under two different frequencies when applied to the left DLPFC using the simultaneous TMS-fMRI technique. Twenty-two adult, healthy volunteers participated in the study. TMS was applied over the left DLPFC, using either low frequency (LF: 0.4 Hz) or (HF: 10Hz). General Linear Model was conducted by contrasting the TMS blocks with the rest blocks. Next, an independent component analysis was conducted on the individual beta-weights, using an ICA component that includes the striatum-thalamus regions. Finally, t-tests were conducted to evaluate frequency effects. Results of the study indicate that HF, but not LF, rTMS applied to the left DLPFC stimulates the cortical-striatum-thalamic pathway. These findings suggests that HF rTMS may regulate neuronal activity in these areas, therefore improving the treatment outcome as previously reported. (Caparelli et al., presented at ACNP 2024 conference). 4. Functional connectivity of orbitofrontal cortex predicts cocaine relapse: Protective and risk circuits, individual differences, and neuromodulation implications Substance use disorder (SUD) remains a significant public health problem as it is highly refractory with low treatment commitment and a high relapse rate. The human orbitofrontal cortex (OFC), a region involved in decision making, valuation and reward processing, has been implicated in multiple neuropsychiatric diseases and considered one of the potential therapeutic targets of SUD treatment using non-invasive neuromodulations. However, the OFC is a large, heterogeneous brain area and the precise location within OFC that could serve as an efficacious stimulation target is unknown. Moreover, exploring all possible loci within the OFC with clinical trials is operationally not feasible. Therefore, we propose a two-stage approach for target selection based on neuroimaging data and associated behavior relevant to SUD: Stage I is a systematic exploration of regions-of-interest (ROIs) for their relevance to the disease; and Stage II as testing a few of the most relevant loci with clinical trials. In the current study, we demonstrate an approach for Stage I by exploring the resting state functional connectivity in 20 ROIs covering the medial and lateral human OFC, using Cox regression based prediction modeling to identify OFC loci and their functional circuits that predict cocaine relapse in a cohort of treated CUD patients. We identified two left lateral OFC ROIs whose connectivity predicted relapse in a Cox regression model with high accuracy, and verified the results in an independent cohort. These functional circuits provide system-level insights into drug relapse, reveal specific disease endophenotypes, and offer potential neuromodulation targets to test under future clinical trials. (Zhai et al., manuscript under review)