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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.

Neuromelanin-sensitive MRI is a burgeoning non-invasive neuroimaging method with an increasing number of applications in psychiatric research. This MRI modality is sensitive to the concentration of neuromelanin, which is synthesized from intracellular catecholamines and accumulates in catecholaminergic nuclei including the dopaminergic substantia nigra and the noradrenergic locus coeruleus. Emerging data suggest the utility of neuromelanin-sensitive MRI as a proxy measure for variability in catecholamine metabolism and function, even in the absence of catecholaminergic cell loss. Given the importance of catecholamine function to several psychiatric disorders and their treatments, neuromelanin-sensitive MRI is ideally positioned as an informative and easy-to-acquire catecholaminergic index. In this review paper, we examine basic aspects of neuromelanin and neuromelanin-sensitive MRI and focus on its psychiatric applications in the contexts of mechanistic research and biomarker development. We discuss ongoing debates and state-of-the-art research into the mechanisms of the neuromelanin-sensitive MRI contrast, standardized protocols and optimized analytic approaches, and application of cutting-edge methods such as machine learning and artificial intelligence to enhance the feasibility and predictive power of neuromelanin-sensitive-MRI-based tools. We finally lay out important future directions to allow neuromelanin-sensitive-MRI to fulfill its potential as a key component of the research, and ultimately clinical, toolbox in psychiatry., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects millions of seniors in the United States. Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to study neurophysiology in AD and its prodromal condition, mild cognitive impairment (MCI). The intrinsic neural timescale (INT), which can be estimated through the magnitude of the autocorrelation of neural signals from rs-fMRI, is thought to quantify the duration that neural information is stored in a local circuit. Such heterogeneity of the timescales forms a basis of the brain functional hierarchy and captures an aspect of circuit dynamics relevant to excitation/inhibition balance, which is broadly relevant for cognitive functions. Given that, we applied rs-fMRI to test whether distinct changes of INT at different hierarchies are present in people with MCI, those progressing to AD (called Converter), and AD patients of both sexes. Linear mixed-effect model was implemented to detect altered hierarchical gradients across populations followed by pairwise comparisons to identify regional differences. High similarities between AD and Converter were observed. Specifically, the inferior temporal, caudate, and pallidum areas exhibit significant alterations in both AD and Converter. Distinct INT-related pathological changes in MCI and AD were found. For AD/Converter, neural information is stored for a longer time in lower hierarchical areas, while higher levels of hierarchy seem to be preferentially impaired in MCI leading to a less pronounced hierarchical gradient. These results inform that the INT holds great potential as an additional measure for AD prediction, even a stable biomarker for clinical diagnosis., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

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., Competing Interests: Drs. Wengler, Cassidy, and Horga are inventors on patents for analysis and use of NM-MRI, licensed to Terran Biosciences, but have received no royalties. Drs. Cassidy and Horga have an investigator-initiated sponsored research agreement and a licensing agreement with Terran Biosciences. The other authors report no financial relationships with commercial interests.

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.)

Relapsing-remitting multiple sclerosis (RRMS) is associated with persistent blood-brain barrier (BBB) dysfunction. The impact of this persistent dysfunction in both active and chronic MS lesions has yet to be investigated due to technological challenges associated with invasive assessment of BBB water transportation (e.g. 15 O-PET). The purpose of this study was to test if persistent BBB dysfunction in RRMS manifests as lower BBB water exchange in chronic lesions using a recently developed noninvasive MRI paradigm. Patients with relapsing-remitting MS and healthy subjects were recruited for this prospective study. The novel Intrinsic Diffusivity Encoding of Arterial Labeled Spins (IDEALS) MRI method was used to map BBB water extraction fraction (E w ) and water permeability surface area product (PS w ), as well as cerebral blood flow (CBF). Regional differences in BBB water exchange were evaluated between MS patients (normal appearing white matter [NAWM] and normal appearing gray matter [NAGM]) and healthy subjects (white matter [WM] and gray matter [GM]) and within MS subjects in non gadolinium-based contrast-agent (GBCA) enhancing chronic lesions, perilesional areas, and NAWM. Significantly lower PS w and E w were observed in NAWM compared to WM (ΔPS w : -11.9 mL/100 g/min, p < .05; ΔE w : -4.3%, p < .01). Significantly lower E w was observed in NAGM compared to GM (ΔE w : -12.1%, p < .01). Significantly lower PS w and CBF were observed in non-GBCA contrast enhancing lesions compared to NAWM (ΔPS w  = -11.5 mL/100 g/min, p < .05; ΔCBF = -8.1 mL/100 g/min, p < .05). E w was significantly higher in non-GBCA enhancing chronic MS lesions compared to NAWM (ΔE w  = 1.6%, p < .05). The lower BBB water exchange in chronic MS lesions is consistent with previously reported observations and may demonstrate metabolic changes associated with MS., Competing Interests: Declaration of Competing Interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Neuromelanin-sensitive MRI (NM-MRI) provides a noninvasive measure of the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). NM-MRI has been validated as a measure of both dopamine neuron loss, with applications in neurodegenerative disease, and dopamine function, with applications in psychiatric disease. Furthermore, a voxelwise-analysis approach has been validated to resolve substructures, such as the ventral tegmental area (VTA), within midbrain dopaminergic nuclei thought to have distinct anatomical targets and functional roles. NM-MRI is thus a promising tool that could have diverse research and clinical applications to noninvasively interrogate in vivo the dopamine system in neuropsychiatric illness. Although a test-retest reliability study by Langley et al. using the standard NM-MRI protocol recently reported high reliability, a systematic and comprehensive investigation of the performance of the method for various acquisition parameters and preprocessing methods has not been conducted. In particular, most previous studies used relatively thick MRI slices (~3 ​mm), compared to the typical in-plane resolution (~0.5 ​mm) and to the height of the SN (~15 ​mm), to overcome technical limitations such as specific absorption rate and signal-to-noise ratio, at the cost of partial-volume effects. Here, we evaluated the effect of various acquisition and preprocessing parameters on the strength and test-retest reliability of the NM-MRI signal to determine optimized protocols for both region-of-interest (including whole SN-VTA complex and atlas-defined dopaminergic nuclei) and voxelwise measures. Namely, we determined a combination of parameters that optimizes the strength and reliability of the NM-MRI signal, including acquisition time, slice-thickness, spatial-normalization software, and degree of spatial smoothing. Using a newly developed, detailed acquisition protocol, across two scans separated by 13 days on average, we obtained intra-class correlation values indicating excellent reliability and high contrast, which could be achieved with a different set of parameters depending on the measures of interest and experimental constraints such as acquisition time. Based on this, we provide detailed guidelines covering acquisition through analysis and recommendations for performing NM-MRI experiments with high quality and reproducibility. This work provides a foundation for the optimization and standardization of NM-MRI, a promising MRI approach with growing applications throughout clinical and basic neuroscience., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Existing ultrashort echo time magnetic resonance imaging (UTE MRI) methods require prohibitively long acquisition times (~ 20-40 min) to quantitatively assess the clinically relevant fast decay T 2 * component in ligaments and tendons. The purpose of this study was to evaluate the feasibility and clinical translatability of a novel abbreviated quantitative UTE MRI paradigm for monitoring graft remodeling after anterior cruciate ligament (ACL) reconstruction., Methods: Eight patients who had Graftlink™ hamstring autograft reconstruction were recruited for this prospective study. A 3D double-echo UTE sequence at 3.0 Tesla was performed at 3- and 6-months post-surgery. An abbreviated UTE MRI paradigm was established based on numerical simulations and in vivo validation from healthy knees. This proposed approach was used to assess the T 2 * for fast decay component ([Formula: see text]) and bound water signal fraction (f bw ) of ACL graft in regions of interest drawn by a radiologist., Results: Compared to the conventional bi-exponential model, the abbreviated UTE MRI paradigm achieved low relative estimation bias for [Formula: see text] and f bw over a range of clinically relevant values for ACL grafts. A decrease in [Formula: see text] of the intra-articular graft was observed in 7 of the 8 ACL reconstruction patients from 3- to 6-months (- 0.11 ± 0.16 ms, P = 0.10). Increases in [Formula: see text] and f bw from 3- to 6-months were observed in the tibial intra-bone graft ([Formula: see text]: 0.19 ± 0.18 ms, P < 0.05; Δf bw : 4% ± 4%, P < 0.05). Lower [Formula: see text] (- 0.09 ± 0.11 ms, P < 0.05) was observed at 3-months when comparing the intra-bone graft to the graft/bone interface in the femoral tunnel. The same comparisons at the 6-months also yielded relatively lower [Formula: see text] (- 0.09 ± 0.12 ms, P < 0.05)., Conclusion: The proposed abbreviated 3D UTE MRI paradigm is capable of assessing the ACL graft remodeling process in a clinically translatable acquisition time. Longitudinal changes in [Formula: see text] and f bw of the ACL graft were observed.

Although radiography continues to play a critical role in osseous tumor assessment, there have been remarkable advances in cross-sectional imaging. MRI has taken a lead in this assessment due to high tissue contrast and spatial resolution, which are well suited for bone lesion assessment. More recently, although somewhat lagging other organ systems, quantitative parameters have shown promising potential as biomarkers for osseous tumors. Among these sequences are chemical shift imaging (CSI), apparent diffusion coefficient (ADC), and intravoxel incoherent motion (IVIM) from diffusion-weighted imaging (DWI), quantitative dynamic contrast enhanced (DCE)-MRI, and magnetic resonance spectroscopy (MRS). In this article, we review the background and recent roles of these quantitative MRI biomarkers for osseous tumors. Level of Evidence: 3 Technical Efficacy Stage: 3 J. MAGN. RESON. IMAGING 2019. J. Magn. Reson. Imaging 2019;50:702-718., (© 2019 International Society for Magnetic Resonance in Medicine.)

Purpose: Abnormalities in hepatic oxygen delivery and oxygen consumption may serve as a significant indicator of hepatic cellular dysfunction and may predict treatment response. However, conventional and oxygen-enhanced hepatic BOLD MRI can only provide semiquantitative assessment of hepatic oxygenation., Methods: A hepatic quantitative BOLD (qBOLD) model was proposed for noninvasive mapping of hepatic venous blood oxygen saturation (Y v ) and deoxygenated blood volume (DBV) in human subjects. The validity and the estimation bias of the proposed model were evaluated by Monte Carlo simulations. Eight healthy subjects were scanned after written consent with institutional review board approval., Results: Monte Carlo simulations demonstrated that the proposed single-compartment hepatic qBOLD model leads to significant deviation of the predicted T 2 * decay profile from the simulated signal due to high hepatic blood volume fraction. Small relative estimation bias for hepatic Y v and significant overestimation for hepatic DBV were observed, which can be corrected by applying the calibration curves established from simulations. After correction, the mean hepatic Y v in human subjects was 56.8 ± 6.8%, and the mean hepatic DBV was 0.190 ± 0.035, consistent with measurements from other invasive approaches. Except in regions with significant vascular contamination, the maps for hepatic Y v and DBV were relatively homogenous., Conclusions: With estimation bias correction, the hepatic qBOLD approach enables noninvasive mapping of hepatic blood volume and oxygenation in human subjects. The established protocol may be used to quantitatively assess hepatic tissue hypoxia in multiple liver diseases., (© 2019 International Society for Magnetic Resonance in Medicine.)

This work proposes a novel MRI method - Intrinsic Diffusivity Encoding of Arterial Labeled Spin (IDEALS) - for the whole-brain mapping of water permeability in the human brain without an exogenous contrast agent. Quantitative separation of the intravascular and extravascular labeled water MRI signal was achieved in arterial spin labeling experiments with segmented 3D-GRASE acquisition by modulating the relative sensitivity between relaxation, true diffusion, and pseudodiffusion. The intrinsic diffusivity encoding in k-space created different broadening of the image-domain point spread functions for intravascular and extravascular labeled spins, from which blood-brain barrier (BBB) water extraction fraction (E w ) and water permeability surface area product (PS w ) were estimated. The feasibility and sensitivity of this method was evaluated in healthy subjects at baseline and after caffeine challenge. The estimated baseline E w and PS w maps showed contrast among gray matter (GM) and white matter (WM). GM E w was significantly lower than that of WM (78.8% ± 3.3% in GM vs. 83.9% ± 4.6% in WM; p < 0.05) and GM PS w was significantly higher than that of WM (131.7 ± 29.5 mL/100  g/min in GM vs. 76.2 ± 18.4 mL/100  g/min in WM; p < 0.05). BBB E w was significantly lower for females than males (74.9% ± 3.7% for females vs. 81.3% ± 3.3% for males in GM; 80.5% ± 4.7% for females vs. 86.1 ± 3.0 for males in WM; p < 0.05 for both), while significant PS w differences were only observed in WM (143.8 ± 34.4 mL/100  g/min for females vs. 123.6 ± 24.4 mL/100  g/min for males in GM; 91.6 ± 15.0 mL/100  g/min for females vs. 65.9 ± 12.5 mL/100  g/min for males in WM; p = 0.20 and p < 0.05 for GM and WM respectively). Significant correlations between E w and CBF (r = -0.32, p < 0.05) and between PS w and CBF (r = 0.89, p < 0.05) were observed, consistent with 15 O-H 2 O PET findings. After caffeine challenge, reduced CBF, E w and PS w were observed, demonstrating the sensitivity of IDEALS approach., (Copyright © 2019 Elsevier Inc. All rights reserved.)