Altered Hierarchical Gradients of Intrinsic Neural Timescales in Mild Cognitive Impairment and Alzheimer's Disease.

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.

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

Obsessive-compulsive disorder (OCD) is an impairing psychiatric condition, which often onsets in childhood. Growing research highlights dopaminergic alterations in adult OCD, yet pediatric studies are limited by methodological constraints. This is the first study to utilize neuromelanin-sensitive MRI as a proxy for dopaminergic function among children with OCD. N = 135 youth (6-14-year-olds) completed high-resolution neuromelanin-sensitive MRI across two sites; n = 64 had an OCD diagnosis. N = 47 children with OCD completed a second scan after cognitive-behavioral therapy. Voxel-wise analyses identified that neuromelanin-MRI signal was higher among children with OCD compared to those without (483 voxels, permutation-corrected p = 0.018). Effects were significant within both the substania nigra pars compacta (p = 0.004, Cohen's d = 0.51) and ventral tegmental area (p = 0.006, d = 0.50). Follow-up analyses indicated that more severe lifetime symptoms (t = -2.72, p = 0.009) and longer illness duration (t = -2.22, p = 0.03) related to lower neuromelanin-MRI signal. Despite significant symptom reduction with therapy (p < 0.001, d = 1.44), neither baseline nor change in neuromelanin-MRI signal associated with symptom improvement. Current results provide the first demonstration of the utility of neuromelanin-MRI in pediatric psychiatry, specifically highlighting in vivo evidence for midbrain dopamine alterations in treatment-seeking youth with OCD. Neuromelanin-MRI likely indexes accumulating alterations over time, herein, implicating dopamine hyperactivity in OCD. Given evidence of increased neuromelanin signal in pediatric OCD but negative association with symptom severity, additional work is needed to parse potential longitudinal or compensatory mechanisms. Future studies should explore the utility of neuromelanin-MRI biomarkers to identify early risk prior to onset, parse OCD subtypes or symptom heterogeneity, and explore prediction of pharmacotherapy response.

Does the change in glutamate to GABA ratio correlate with change in depression severity? A randomized, double-blind clinical trial.

Previous proton magnetic resonance spectroscopy (1H-MRS) studies suggest a perturbation in glutamate and/or GABA in Major Depressive Disorder (MDD). However, no studies examine the ratio of glutamate and glutamine (Glx) to GABA (Glx/GABA) as it relates to depressive symptoms, which may be more sensitive than either single metabolite. Using a within-subject design, we hypothesized that reduction in depressive symptoms correlates with reduction in Glx/GABA in the anterior cingulate cortex (ACC). The present trial is a randomized clinical trial that utilized 1H-MRS to examine Glx/GABA before and after 8 weeks of escitalopram or placebo. Participants completed the 17-item Hamilton Depression Rating Scale (HDRS17) and underwent magnetic resonance spectroscopy before and after treatment. Two GABA-edited MEGA-PRESS acquisitions were interleaved with a water unsuppressed reference scan. GABA and Glx were quantified from the average difference spectrum, with preprocessing using Gannet and spectral fitting using TARQUIN. Linear mixed models were utilized to evaluate relationships between change in HDRS17 and change in Glx/GABA using a univariate linear regression model, multiple linear regression incorporating treatment type as a covariate, and Bayes Factor (BF) hypothesis testing to examine strength of evidence. No significant relationship was detected between percent change in Glx, GABA, or Glx/GABA and percent change in HDRS17, regardless of treatment type. Further, MDD severity before/after treatment did not correlate with ACC Glx/GABA. In light of variable findings in the literature and lack of association in our investigation, future directions should include evaluating glutamate and glutamine individually to shed light on the underpinnings of MDD severity. Advancing Personalized Antidepressant Treatment Using PET/MRI, ClinicalTrials.gov, NCT02623205.

Individual Differences in Cerebral Perfusion as a Function of Age and Loneliness.

Loneliness is defined as the subjective feeling that one's social needs are not satisfied by both quantity and quality of one's social relationships. Loneliness has been linked to a broad range of adverse physical and mental health consequences. There is an interest in identifying the neural and molecular processes by which loneliness adversely affects health. Prior imaging studies reported divergent networks involved in cognitive, emotional, and social processes associated with loneliness. Although loneliness is common among both younger and older adults, it is experienced differently across the lifespan and has different antecedents and consequences. The current study measured regional cerebral blood flow (CBF) using pulsed arterial spin labeling imaging. Forty-five older (Mage = 63.4) and forty-four younger adults (Mage = 20.9) with comparable degrees of loneliness were included. Whole-brain voxel-wise analysis revealed a main effect of age (in superior temporal and supramarginal gyri), but no main effect of loneliness. Furthermore, the age effect was only observed among people who reported higher level of loneliness. These regions have previously been implicated in social- and attention-related functions. The moderation of loneliness on age and regional CBF suggests that younger and older individuals present differential neural manifestations in response to loneliness, even with comparable levels of loneliness.

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.

Reproducibility assessment of neuromelanin-sensitive magnetic resonance imaging protocols for region-of-interest and voxelwise analyses.

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 â€‹mm), compared to the typical in-plane resolution (~0.5 â€‹mm) and to the height of the SN (~15 â€‹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.

In vivo evaluation of human patellar tendon microstructure and microcirculation with diffusion MRI.

BACKGROUND: Patellar tendon (PT) microstructure integrity and microcirculation status play a crucial role in the progression of tendinopathy and tendon repair. PURPOSE: To assess the feasibility and robustness of stimulated-echo based diffusion-weighted MRI with readout-segmented echo-planar imaging (ste-RS-EPI) for noninvasive assessment of microstructure and microcirculation of human PT. STUDY TYPE: Prospective. SUBJECTS: Fifteen healthy volunteers. FIELD STRENGTH/SEQUENCE: PT diffusion tensor imaging (DTI) and intravoxel incoherent motion (IVIM) were acquired with an ste-RS-EPI protocol on a 3T MRI scanner. ASSESSMENT: Subjects were positioned with their PT at the magic angle. DTI-derived parameters including axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), and fractional anisotropy (FA) were estimated with b-values of 0 and 800 s/mm2 and 12 diffusion directions. IVIM-derived parameters, f p , D* × f p , V b , and D* × V b were assessed in the central-third and the outer-two thirds of the PT with b-values of 0, 20, 30, 60, 80, 120, 200, 400, and 600 s/mm2 in three orthogonal directions. STATISTICAL TESTS: Paired t-tests were used to evaluate differences in IVIM parameters between the central-third and outer-two thirds regions of the patellar tendon. Paired t-tests and within-subject coefficient of variation were used to assess the intra- and intersession reproducibility of PT DTI and IVIM parameters. RESULTS: DTI parameters for healthy PT were 1.54 ± 0.09 × 10-3 mm2 /s, 1.01 ± 0.05 × 10-3 mm2 /s, 1.18 ± 0.06 × 10-3 mm2 /s, and 0.30 ± 0.04 for AD, RD, MD, and FA, respectively. Significantly higher (P < 0.05) IVIM parameters f p and D* × f p were observed in the outer-two thirds (6.1% ± 2.4% and 95.2 ± 49.6, respectively) compared with the central-third (3.8% ± 2.3% and 48.6 ± 35.2, respectively) of the PT. DATA CONCLUSION: Diffusion MRI of PT with an ste-RS-EPI protocol is clinically feasible. Both DTI- and IVIM-derived parameters of the PT demonstrated good test-retest reproducibility and interrater reliability. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:780-790.

3D MRI of whole-brain water permeability with intrinsic diffusivity encoding of arterial labeled spin (IDEALS).

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 (Ew) and water permeability surface area product (PSw) were estimated. The feasibility and sensitivity of this method was evaluated in healthy subjects at baseline and after caffeine challenge. The estimated baseline Ew and PSw maps showed contrast among gray matter (GM) and white matter (WM). GM Ew was significantly lower than that of WM (78.8% ±â€¯3.3% in GM vs. 83.9% ±â€¯4.6% in WM; p < 0.05) and GM PSw was significantly higher than that of WM (131.7 ±â€¯29.5 mL/100  g/min in GM vs. 76.2 ±â€¯18.4 mL/100  g/min in WM; p < 0.05). BBB Ew was significantly lower for females than males (74.9% ±â€¯3.7% for females vs. 81.3% ±â€¯3.3% for males in GM; 80.5% ±â€¯4.7% for females vs. 86.1 ±â€¯3.0 for males in WM; p < 0.05 for both), while significant PSw differences were only observed in WM (143.8 ±â€¯34.4 mL/100  g/min for females vs. 123.6 ±â€¯24.4 mL/100  g/min for males in GM; 91.6 ±â€¯15.0 mL/100  g/min for females vs. 65.9 ±â€¯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 Ew and CBF (r = -0.32, p < 0.05) and between PSw and CBF (r = 0.89, p < 0.05) were observed, consistent with 15O-H2O PET findings. After caffeine challenge, reduced CBF, Ew and PSw were observed, demonstrating the sensitivity of IDEALS approach.

Mapping hepatic blood oxygenation by quantitative BOLD (qBOLD) MRI.

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 (Yv ) 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 T2* decay profile from the simulated signal due to high hepatic blood volume fraction. Small relative estimation bias for hepatic Yv 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 Yv 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 Yv 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.

MRI biomarkers in osseous tumors.

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.

Abbreviated quantitative UTE imaging in anterior cruciate ligament reconstruction.

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 T2* 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 T2* for fast decay component ([Formula: see text]) and bound water signal fraction (fbw) 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 fbw 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 fbw from 3- to 6-months were observed in the tibial intra-bone graft ([Formula: see text]: 0.19 ± 0.18 ms, P < 0.05; Δfbw: 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 fbw of the ACL graft were observed.

Diffusion sensitivity of 3D-GRASE in arterial spin labeling perfusion.

PURPOSE: To evaluate the role of true diffusion and flow-related pseudodiffusion in cerebral blood flow (CBF) quantification using arterial spin labeling (ASL) with single-shot or segmented 3D gradient and spin echo (GRASE) readouts. THEORY: The extended phase graph (EPG) algorithm, originally designed to model the effects of T1 /T2 relaxation and true diffusion in MRI acquisitions utilizing multiple refocusing RF pulses, was augmented (aEPG). This augmentation accounted for flow-related pseudodiffusion attenuation of intravascular MRI signal in the k-space domain during 3D-GRASE acquisition, which leads to blur along the partition direction in the image domain. Blurring of ASL signal into neighboring voxels can lead to underestimation of CBF in small, high-flow structures such as cortical gray matter (GM). METHODS: The diffusion sensitivity of 3D-GRASE was evaluated through aEPG simulations and in vivo experiments in 13 healthy subjects. The CBF estimation bias for different postlabeling delays, crusher gradient strengths, and segmentation factors along the partition (PAR) and phase-encoding (PE) directions was numerically assessed by simulations and experimentally validated. RESULTS: In vivo experiments demonstrated systematic underestimation of mean GM CBF measured with segmented 3D-GRASE. The GM CBF underestimation depended on ASL preparation and imaging parameters; it reached up to 25% at low-segmentation schemes (1PAR × 2PE ) but was considerably lower at high-segmentation schemes (4PAR × 2PE or 8PAR × 2PE ). Theoretical predictions showed that conventional T1 /T2 relaxation and true diffusion may account for at most ∼25% of GM CBF estimation bias, whereas the pseudodiffusion effect constituted the major fraction in a typical ASL experiment. CONCLUSION: The pseudodiffusion effect leads to considerable estimation bias in ASL-based CBF quantification using 3D-GRASE readouts. This bias can be substantially reduced by increasing the segmentation factors. Magn Reson Med 80:736-747, 2018. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Diffusion tensor imaging of human Achilles tendon by stimulated echo readout-segmented EPI (ste-RS-EPI).

PURPOSE: Healing, regeneration, and remodeling of the injured Achilles tendon are associated with notable changes in tendon architecture. However, assessing Achilles microstructural properties with conventional diffusion tension imaging (DTI) remains a challenge because of very short T2 / T 2 * values of the tendon. Hence, the objective of this study was to develop a novel Achilles tendon DTI protocol for a non-invasive investigation of the changes of microstructural integrity in tendinopathy. METHODS: A novel stimulated echo readout-segmented EPI (ste-RS-EPI) DTI sequence was proposed to achieve a TE of ∼14-20 ms for typical b-values of 400-800 s/mm2 on clinical 3T MRI scanners. To further boost tendon MR signal, the Achilles was positioned at the magic angle (∼55 °) with respect to the scanner B0 field. The sensitivity of the developed protocol was evaluated in 19 healthy participants and 6 patients with clinically confirmed tendinopathy. RESULTS: Compared to spin echo RS-EPI DTI protocol, ste-RS-EPI provided an ∼100-200% increase in Achilles MR signal. Tendinopathic Achilles demonstrated a high degree of microstructural disruption based on DTI tractography analysis, with significantly lower (P < 0.05) axial diffusivity (1.20 ± 0.19 vs. 1.39 ± 0.10 × 10-3 mm2 /s), radial diffusivity (0.72 ± 0.11 vs. 0.81 ± 0.08 × 10-3 mm2 /s), and mean diffusivity (0.87 ± 0.14 vs. 1.00 ± 0.07 × 10-3 mm2 /s), but no significant difference in fractional anisotropy (0.38 ± 0.04 vs. 0.38 ± 0.05; P = 0.86). CONCLUSION: Achilles tendon ste-RS-EPI DTI can non-invasively detect the tendinopathy-induced changes to microstructural integrity, consistent with the disruption of collagen arrangement and increased cellularity. This study demonstrated the robustness and sensitivity of the proposed protocol in Achilles tendinopathy.

Intravoxel incoherent motion (IVIM) imaging in human achilles tendon.

BACKGROUND: Limited microcirculation has been implicated in Achilles tendinopathy and may affect healing and disease progression. Existing invasive and noninvasive approaches to evaluate tendon microcirculation lack sensitivity and spatial coverage. PURPOSE: To develop a novel Achilles tendon intravoxel incoherent motion (IVIM) MRI protocol to overcome the limitations from low tendon T2 /T2 * value and low intratendinous blood volume and blood velocity to evaluate tendon microcirculation. STUDY TYPE: Prospective. SUBJECTS: Sixteen healthy male participants (age 31.0 ± 2.1) were recruited. FIELD STRENGTH/SEQUENCE: A stimulated echo readout-segmented echo planar imaging (ste-RS-EPI) IVIM sequence at 3.0T. ASSESSMENT: The feasibility of the proposed ste-RS-EPI IVIM protocol combined with Achilles tendon magic angle effect was evaluated. The sensitivity of the protocol was assessed by an exercise-induced intratendinous hemodynamic response in healthy participants. The vascular origin of the observed IVIM signal was validated by varying the diffusion mixing time and echo time. STATISTICAL TESTS: Two-tailed t-tests were used to evaluate differences (P < 0.05 was considered significant). RESULTS: Consistent with known tendon hypovascularity, the midportion Achilles tendon at baseline showed significantly lower IVIM-derived perfusion fraction (fp ) (3.1 ± 0.9%) compared to the proximal and distal Achilles tendon (6.0 ± 1.8% and 6.1 ± 2.0%, respectively; P < 0.01). Similarly, the midportion Achilles tendon exhibited significantly lower baseline blood flow index (D*×fp ) (40.9 ± 19.2, 18.3 ± 5.3, and 32.0 ± 9.4 in proximal, midportion, and distal Achilles tendon, respectively; P < 0.01). Eccentric heel-raise exercise led to ∼2 times increase of Achilles tendon blood flow in healthy participants. Consistent with its vascular origin, the estimated fp demonstrated a high dependency to IVIM protocol parameters, while the T1 /T2 -corrected absolute intratendinous microvascular blood volume fraction (Vb ) did not vary. DATA CONCLUSION: Achilles tendon ste-RS-EPI IVIM noninvasively assessed baseline values and exercise-induced changes to tendon microcirculation in healthy tendon. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1690-1699.

Imaging the Vesicular Acetylcholine Transporter in Schizophrenia: A Positron Emission Tomography Study Using [18F]-VAT.

BACKGROUND: Despite longstanding interest in the central cholinergic system in schizophrenia (SCZ), cholinergic imaging studies with patients have been limited to receptors. Here, we conducted a proof-of-concept positron emission tomography study using [18F]-VAT, a new radiotracer that targets the vesicular acetylcholine transporter as a proxy measure of acetylcholine transmission capacity, in patients with SCZ and explored relationships of vesicular acetylcholine transporter with clinical symptoms and cognition. METHODS: A total of 18 adult patients with SCZ or schizoaffective disorder (the SCZ group) and 14 healthy control participants underwent a positron emission tomography scan with [18F]-VAT. Distribution volume (VT) for [18F]-VAT was derived for each region of interest, and group differences in VT were assessed with 2-sample t tests. Functional significance was explored through correlations between VT and scores on the Positive and Negative Syndrome Scale and a computerized neurocognitive battery (PennCNB). RESULTS: No group differences in [18F]-VAT VT were observed. However, within the SCZ group, psychosis symptom severity was positively associated with VT in multiple regions of interest, with the strongest effects in the hippocampus, thalamus, midbrain, cerebellum, and cortex. In addition, in the SCZ group, working memory performance was negatively associated with VT in the substantia innominata and several cortical regions of interest including the dorsolateral prefrontal cortex. CONCLUSIONS: In this initial study, the severity of 2 important features of SCZ-psychosis and working memory deficit-was strongly associated with [18F]-VAT VT in several cortical and subcortical regions. These correlations provide preliminary evidence of cholinergic activity involvement in SCZ and, if replicated in larger samples, could lead to a more complete mechanistic understanding of psychosis and cognitive deficits in SCZ and the development of therapeutic targets.

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

Importance: The link between psychosis and dopaminergic dysfunction is established, but no generalizable biomarkers with clear potential for clinical adoption exist. Objective: To 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 Participants: This 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 Measures: NM-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. Results: Of 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 Relevance: This 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.

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.

Altered hierarchical gradients of intrinsic neural timescales in mild cognitive impairment and Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects millions of older adults in the US and worldwide. Resting-state functional magnetic resonance imaging (rs-fMRI) has become a widely used neuroimaging tool 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 intrinsic neural signals using rs-fMRI, is thought to quantify the duration that neural information is stored in a local cortical circuit. The heterogeneity of the timescales is considered to be a basis of the functional hierarchy in the brain. In addition, INT captures an aspect of circuit dynamics relevant to excitation/inhibition (E/I) balance, which is thought to be broadly relevant for cognitive functions. Here we examined its relevance to AD. We used rs-fMRI data of 904 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The subjects were divided into 4 groups based on their baseline and end-visit clinical status, which were cognitively normal (CN), stable MCI, Converter, and AD groups. Linear mixed effect model and pairwise comparison were implemented to investigate the large-scale hierarchical organization and local differences. We observed high similarities between AD and Converter groups. Specifically, among the eight identified ROIs with distinct INT alterations in AD, three ROIs (inferior temporal, caudate, pallidum areas) exhibit stable and significant alteration in AD converter. In addition, distinct INT related pathological changes in stable MCI and AD/Converter were found. For AD and Converter groups, neural information is stored for a longer time in lower hierarchical order areas, while higher levels of hierarchy seem to be preferentially impaired in stable MCI leading to a less pronounced hierarchical gradient effect. These results inform that the INT holds great potential as an additional measure for AD prediction, a stable biomarker for clinical diagnosis and an important therapeutic target in AD.

Gradient boosting decision-tree-based algorithm with neuroimaging for personalized treatment in depression.

Introduction: Pretreatment positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and magnetic resonance spectroscopy (MRS) may identify biomarkers for predicting remission (absence of depression). Yet, no such image-based biomarkers have achieved clinical validity. The purpose of this study was to identify biomarkers of remission using machine learning (ML) with pretreatment FDG-PET/MRS neuroimaging, to reduce patient suffering and economic burden from ineffective trials. Methods: This study used simultaneous PET/MRS neuroimaging from a double-blind, placebo-controlled, randomized antidepressant trial on 60 participants with major depressive disorder (MDD) before initiating treatment. After eight weeks of treatment, those with ≤ 7 on 17-item Hamilton Depression Rating Scale were designated a priori as remitters (free of depression, 37%). Metabolic rate of glucose uptake (metabolism) from 22 brain regions were acquired from PET. Concentrations (mM) of glutamine and glutamate and gamma-aminobutyric acid (GABA) in anterior cingulate cortex were quantified from MRS. The data were randomly split into 67% train and cross-validation (n = 40), and 33% test (n = 20) sets. The imaging features, along with age, sex, handedness, and treatment assignment (selective serotonin reuptake inhibitor or SSRI vs. placebo) were entered into the eXtreme Gradient Boosting (XGBoost) classifier for training. Results: In test data, the model showed 62% sensitivity, 92% specificity, and 77% weighted accuracy. Pretreatment metabolism of left hippocampus from PET was the most predictive of remission. Conclusions: The pretreatment neuroimaging takes around 60 minutes but has potential to prevent weeks of failed treatment trials. This study effectively addresses common issues for neuroimaging analysis, such as small sample size, high dimensionality, and class imbalance.

Deep rTMS of the insula and prefrontal cortex in smokers with schizophrenia: Proof-of-concept study.

Patients with schizophrenia have a high prevalence of cigarette smoking and respond poorly to conventional treatments, highlighting the need for new therapies. We conducted a mechanistic, proof-of-concept study using bilateral deep repetitive transcranial magnetic stimulation (dTMS) of insular and prefrontal cortices at high frequency, using the specialized H4 coil. Feasibility of dTMS was tested for disruption of tobacco self-administration, insula target engagement, and insula circuit modulation, all of which were a priori outcomes of interest. Twenty patients completed the study, consisting of weekday dTMS sessions (randomization to active dTMS or sham; double-blind; 10 patients per group), a laboratory tobacco self-administration paradigm (pre/post assessments), and multimodal imaging (three MRI total sessions). Results showed that participants assigned to active dTMS were slower to initiate smoking their first cigarette compared with sham, consistent with smoking disruption. The imaging analyses did not reveal significant Time × Group interactions, but effects were in the anticipated directions. In arterial spin labeling analyses testing for target engagement, an overall decrease in insula blood flow, measured during a post-treatment MRI versus baseline, was numerically more pronounced in the active dTMS group than sham. In fMRI analyses, resting-state connectivity between the insula and default mode network showed a numerically greater change from baseline in the active dTMS group than sham, consistent with a functional change to insula circuits. Exploratory analyses further suggested a therapeutic effect of dTMS on symptoms of psychosis. These initial observations pave the way for future confirmatory studies of dTMS in smoking patients with schizophrenia.