Publications by authors named "Danny J J Wang"

123 Publications

In-vivo imaging of targeting and modulation of depression-relevant circuitry by transcranial direct current stimulation: a randomized clinical trial.

Transl Psychiatry 2021 Feb 24;11(1):138. Epub 2021 Feb 24.

University of California, Los Angeles, CA, USA.

Recent clinical trials of transcranial direct current stimulation (tDCS) in depression have shown contrasting results. Consequently, we used in-vivo neuroimaging to confirm targeting and modulation of depression-relevant neural circuitry by tDCS. Depressed participants (N = 66, Baseline Hamilton Depression Rating Scale (HDRS) 17-item scores ≥14 and <24) were randomized into Active/Sham and High-definition (HD)/Conventional (Conv) tDCS groups using a double-blind, parallel design, and received tDCS individually targeted at the left dorsolateral prefrontal cortex (DLPFC). In accordance with Ampere's Law, tDCS currents were hypothesized to induce magnetic fields at the stimulation-target, measured in real-time using dual-echo echo-planar-imaging (DE-EPI) MRI. Additionally, the tDCS treatment trial (consisting of 12 daily 20-min sessions) was hypothesized to induce cerebral blood flow (CBF) changes post-treatment at the DLPFC target and in the reciprocally connected anterior cingulate cortex (ACC), measured using pseudo-continuous arterial spin labeling (pCASL) MRI. Significant tDCS current-induced magnetic fields were observed at the left DLPFC target for both active stimulation montages (Brodmann's area (BA) 46: p = 0.048, Cohen's d = 0.73; p = 0.018, d = 0.86; BA 9: p = 0.011, d = 0.92; p = 0.022, d = 0.83). Significant longitudinal CBF increases were observed (a) at the left DLPFC stimulation-target for both active montages (p = 3.5E-3, d = 0.98; p = 2.8E-3, d = 1.08), and (b) at ACC for the HD-montage only (p = 2.4E-3, d = 1.06; p = 0.075, d = 0.64). These results confirm that tDCS-treatment (a) engages the stimulation-target, and (b) modulates depression-relevant neural circuitry in depressed participants, with stronger network-modulations induced by the HD-montage. Although not primary outcomes, active HD-tDCS showed significant improvements of anhedonia relative to sham, though HDRS scores did not differ significantly between montages post-treatment.
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http://dx.doi.org/10.1038/s41398-021-01264-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904813PMC
February 2021

Evaluation of Cerebral Blood Flow Measured by 3D PCASL as Biomarker of Vascular Cognitive Impairment and Dementia (VCID) in a Cohort of Elderly Latinx Subjects at Risk of Small Vessel Disease.

Front Neurosci 2021 27;15:627627. Epub 2021 Jan 27.

Laboratory of FMRI Technology, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.

Cerebral small vessel disease (cSVD) affects arterioles, capillaries, and venules and can lead to cognitive impairments and clinical symptomatology of vascular cognitive impairment and dementia (VCID). VCID symptoms are similar to Alzheimer's disease (AD) but the neurophysiologic alterations are less well studied, resulting in no established biomarkers. The purpose of this study was to evaluate cerebral blood flow (CBF) measured by 3D pseudo-continuous arterial spin labeling (pCASL) as a potential biomarker of VCID in a cohort of elderly Latinx subjects at risk of cSVD. Forty-five elderly Latinx subjects (12 males, 69 ± 7 years) underwent repeated MRI scans ∼6 weeks apart. CBF was measured using 3D pCASL in the whole brain, white matter and 4 main vascular territories (leptomeningeal anterior, middle, and posterior cerebral artery (leptoACA, leptoMCA, leptoPCA), as well as MCA perforator). The test-retest repeatability of CBF was assessed by intra-class correlation coefficient (ICC) and within-subject coefficient of variation (wsCV). Absolute and relative CBF was correlated with gross cognitive measures and domain specific assessment of executive and memory function, vascular risks, and Fazekas scores and volumes of white matter hyperintensity (WMH). Neurocognitive evaluations were performed using Montreal Cognitive Assessment (MoCA) and neuropsychological test battery in the Uniform Data Set v3 (UDS3). Good to excellent test-retest repeatability was achieved (ICC = 0.77-0.85, wsCV 3-9%) for CBF measurements in the whole brain, white matter, and 4 vascular territories. Relative CBF normalized by global mean CBF in the leptoMCA territory was positively correlated with the executive function composite score, while relative CBF in the leptoMCA and MCA perforator territory was positively correlated with MoCA scores, controlling for age, gender, years of education, and testing language. Relative CBF in WM was negatively correlated with WMH volume and MoCA scores, while relative leptoMCA CBF was positively correlated with WMH volume. Reliable 3D pCASL CBF measurements were achieved in the cohort of elderly Latinx subjects. Relative CBF in the leptomeningeal and perforator MCA territories were the most likely candidate biomarker of VCID. These findings need to be replicated in larger cohorts with greater variability of stages of cSVD.
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http://dx.doi.org/10.3389/fnins.2021.627627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873482PMC
January 2021

Assessment of carotid stiffness by measuring carotid pulse wave velocity using a single-slice oblique-sagittal phase-contrast MRI.

Magn Reson Med 2021 Jul 5;86(1):442-455. Epub 2021 Feb 5.

USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

Purpose: Increased arterial stiffness has been shown to be one of the earliest markers of cerebrovascular dysfunction. As a surrogate marker of arterial stiffness, pulse wave velocity (PWV) quantifications are generally carried out on central and peripheral arteries. The purpose of this study was to develop and evaluate an MRI approach to assess carotid stiffness by measuring carotid PWV (cPWV) using a fast oblique-sagittal phase-contrast MRI sequence.

Methods: In 29 volunteers, a single-slice oblique-sagittal phase-contrast MRI sequence with retrospective cardiac gating was used to quantify blood velocity waveforms along a vessel segment covering the common carotid artery (CCA) and the internal carotid artery (ICA). The CCA-ICA segment length was measured from a region of interest selected on the magnitude image. Phase-contrast MRI-measured velocities were also used to quantify the ICA pulsatility index along with cPWV quantification.

Results: The mean value of cPWV calculated using the middle upslope area algorithm was 2.86 ± 0.71 and 3.97 ± 1.14 m/s in young and elderly subjects, respectively. Oblique-sagittal phase-contrast MRI-derived cPWV measurements showed excellent intrascan and interscan repeatability. cPWV and ICA pulsatility index were significantly greater in older subjects compared to those in the young subjects (P < .01 and P = .01, respectively). Also, increased cPWV values were associated with elevated systolic blood pressure (β = 0.05, P = .03).

Conclusion: This study demonstrated that oblique-sagittal phase-contrast MRI is a feasible technique for the quantification of both cPWV and ICA pulsatility index and showed their potential utility in evaluating cerebroarterial aging and age-related neurovascular disorders.
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http://dx.doi.org/10.1002/mrm.28677DOI Listing
July 2021

MarkVCID cerebral small vessel consortium: II. Neuroimaging protocols.

Alzheimers Dement 2021 Apr 21;17(4):716-725. Epub 2021 Jan 21.

Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

The MarkVCID consortium was formed under cooperative agreements with the National Institute of Neurologic Diseases and Stroke (NINDS) and National Institute on Aging (NIA) in 2016 with the goals of developing and validating biomarkers for the cerebral small vessel diseases associated with the vascular contributions to cognitive impairment and dementia (VCID). Rigorously validated biomarkers have consistently been identified as crucial for multicenter studies to identify effective strategies to prevent and treat VCID, specifically to detect increased VCID risk, diagnose the presence of small vessel disease and its subtypes, assess prognosis for disease progression or response to treatment, demonstrate target engagement or mechanism of action for candidate interventions, and monitor disease progression during treatment. The seven project sites and central coordinating center comprising MarkVCID, working with NINDS and NIA, identified a panel of 11 candidate fluid- and neuroimaging-based biomarker kits and established harmonized multicenter study protocols (see companion paper "MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols" for full details). Here we describe the MarkVCID neuroimaging protocols with specific focus on validating their application to future multicenter trials. MarkVCID procedures for participant enrollment; clinical and cognitive evaluation; and collection, handling, and instrumental validation of fluid samples are described in detail in a companion paper. Magnetic resonance imaging (MRI) has long served as the neuroimaging modality of choice for cerebral small vessel disease and VCID because of its sensitivity to a wide range of brain properties, including small structural lesions, connectivity, and cerebrovascular physiology. Despite MRI's widespread use in the VCID field, there have been relatively scant data validating the repeatability and reproducibility of MRI-based biomarkers across raters, scanner types, and time intervals (collectively defined as instrumental validity). The MRI protocols described here address the core MRI sequences for assessing cerebral small vessel disease in future research studies, specific sequence parameters for use across various research scanner types, and rigorous procedures for determining instrumental validity. Another candidate neuroimaging modality considered by MarkVCID is optical coherence tomography angiography (OCTA), a non-invasive technique for directly visualizing retinal capillaries as a marker of the cerebral capillaries. OCTA has theoretical promise as a unique opportunity to visualize small vessels derived from the cerebral circulation, but at a considerably earlier stage of development than MRI. The additional OCTA protocols described here address procedures for determining OCTA instrumental validity, evaluating sources of variability such as pupil dilation, and handling data to maintain participant privacy. MRI protocol and instrumental validation The core sequences selected for the MarkVCID MRI protocol are three-dimensional T1-weighted multi-echo magnetization-prepared rapid-acquisition-of-gradient-echo (ME-MPRAGE), three-dimensional T2-weighted fast spin echo fluid-attenuated-inversion-recovery (FLAIR), two-dimensional diffusion-weighted spin-echo echo-planar imaging (DWI), three-dimensional T2*-weighted multi-echo gradient echo (3D-GRE), three-dimensional T -weighted fast spin-echo imaging (T2w), and two-dimensional T2*-weighted gradient echo echo-planar blood-oxygenation-level-dependent imaging with brief periods of CO inhalation (BOLD-CVR). Harmonized parameters for each of these core sequences were developed for four 3 Tesla MRI scanner models in widespread use at academic medical centers. MarkVCID project sites are trained and certified for their instantiation of the consortium MRI protocols. Sites are required to perform image quality checks every 2 months using the Alzheimer's Disease Neuroimaging Initiative phantom. Instrumental validation for MarkVCID MRI-based biomarkers is operationally defined as inter-rater reliability, test-retest repeatability, and inter-scanner reproducibility. Assessments of these instrumental properties are performed on individuals representing a range of cerebral small vessel disease from mild to severe. Inter-rater reliability is determined by distribution of an independent dataset of MRI scans to each analysis site. Test-retest repeatability is determined by repeat MRI scans performed on individual participants on a single MRI scanner after a short (1- to 14-day) interval. Inter-scanner reproducibility is determined by repeat MRI scans performed on individuals performed across four MRI scanner models. OCTA protocol and instrumental validation The MarkVCID OCTA protocol uses a commercially available, Food and Drug Administration-approved OCTA apparatus. Imaging is performed on one dilated and one undilated eye to assess the need for dilation. Scans are performed in quadruplicate. MarkVCID project sites participating in OCTA validation are trained and certified by this biomarker's lead investigator. Inter-rater reliability for OCTA is assessed by distribution of OCTA datasets to each analysis site. Test-retest repeatability is assessed by repeat OCTA imaging on individuals on the same day as their baseline OCTA and a different-day repeat session after a short (1- to 14-day) interval. Methods were developed to allow the OCTA data to be de-identified by the sites before transmission to the central data management system. The MarkVCID neuroimaging protocols, like the other MarkVCID procedures, are designed to allow translation to multicenter trials and as a template for outside groups to generate directly comparable neuroimaging data. The MarkVCID neuroimaging protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the neuroimaging MarkVCID kits will undergo biological validation to determine its ability to measure important aspects of VCID such as cognitive function. The analytic methods for the neuroimaging-based kits and the results of these validation studies will be published separately. The results will ultimately determine the neuroimaging kits' potential usefulness for multicenter interventional trials in small vessel disease-related VCID.
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http://dx.doi.org/10.1002/alz.12216DOI Listing
April 2021

Optimization of adiabatic pulses for pulsed arterial spin labeling at 7 tesla: Comparison with pseudo-continuous arterial spin labeling.

Magn Reson Med 2021 Jun 11;85(6):3227-3240. Epub 2021 Jan 11.

Laboratory of FMRI Technology (LOFT), USC Mark & Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

Purpose: To optimize and evaluate adiabatic pulses for pulsed arterial spin labeling at ultrahigh field 7 tesla.

Methods: Four common adiabatic inversion pulses, including hyperbolic secant, wideband uniform rate smooth truncation, frequency offset corrected inversion, and time-resampled frequency offset corrected inversion pulses, were optimized based on a custom-defined loss function that included labeling efficiency and inversion band uniformity. The optimized pulses were implemented in flow-sensitive alternating inversion recovery sequences and tested on phantom and 11 healthy volunteers with 2 constraints: 1) specific absorption rate normalized; and 2) equal peak RF amplitude, respectively. A pseudo-continuous arterial spin labeling sequence was implemented for comparison. Quantitative metrics such as perfusion and relative labeling efficiency versus residual tissue signal were calculated.

Results: Among the 4 pulses, the wideband uniform rate smooth truncation pulse yielded the lowest loss in simulation and achieved a good balance between labeling efficiency and residual tissue signal from both phantom and in vivo experiments. Wideband uniform rate smooth truncation-pulsed arterial spin labeling showed significantly higher relative labeling efficiency compared to the other sequences (P < .01), whereas the perfusion signal was increased by 40% when the highest amplitude was used. The 4 pulsed arterial spin labeling sequences yielded comparable perfusion signals compared to pseudo-continuous arterial spin labeling but with less than half the specific absorption rate.

Conclusion: Optimized wideband uniform rate smooth truncation pulse with the highest amplitude allowed was recommended for 7 tesla pulsed arterial spin labeling.
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http://dx.doi.org/10.1002/mrm.28661DOI Listing
June 2021

Semiautomatic cerebrovascular territory mapping based on dynamic ASL MR angiography without vessel-encoded labeling.

Magn Reson Med 2021 May 21;85(5):2735-2746. Epub 2020 Dec 21.

USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Purpose: Characterizing vessel territories can provide crucial information for evaluation of cerebrovascular disorders. In this study, we present a novel postprocessing pipeline for vascular territorial imaging of cerebral arteries based on a noncontrast enhanced time-resolved 4D magnetic resonance angiography (MRA).

Methods: Eight healthy participants, 1 Moyamoya patient, and 1 arteriovenous malformations patient were recruited. Territorial segmentation and relative blood flow rate calculations of cerebral arteries including left and right middle cerebral arteries and left and right posterior cerebral arteries were carried out based on the 4D MRA-derived arterial arrival time maps of intracranial vessels.

Results: Among healthy young subjects, the average relative blood flow rate values corresponding to left and right middle cerebral arteries and left and right posterior cerebral arteries were 35.9 ± 5.9%, 32.9 ± 7.5%, 15.4 ± 3.8%, and 15.9 ± 2.5%, respectively. Excellent agreement was observed between relative blood flow rate values obtained from the proposed 4D MRA-based method and reference 2D phase contrast MRI. Abnormal cerebral circulations were visualized and quantified on both patients using the developed technique.

Conclusion: The vascular territorial imaging technique developed in this study allowed for the generation of territorial maps with user-defined level of details within a clinically feasible scan time, and as such may provide useful information to assess cerebral circulation balance in different pathologies.
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http://dx.doi.org/10.1002/mrm.28623DOI Listing
May 2021

Comparison Between Blood-Brain Barrier Water Exchange Rate and Permeability to Gadolinium-Based Contrast Agent in an Elderly Cohort.

Front Neurosci 2020 30;14:571480. Epub 2020 Nov 30.

Laboratory of FMRI Technology (LOFT), USC Mark & Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.

Dynamic contrast-enhanced (DCE) MRI using intravenous injection of gadolinium-based contrast agents (GBCAs) is commonly used for imaging blood-brain barrier (BBB) permeability. Water is an alternative endogenous tracer with limited exchange rate across the BBB. A direct comparison between BBB water exchange rate and BBB permeability to GBCA is missing. The purpose of this study was to directly compare BBB permeability to GBCA (Ktrans and k = Ktrans/Vp) and water exchange rate (kw) in a cohort of elderly subjects at risk of cerebral small vessel disease (cSVD). Ktrans/k and kw were measured by DCE-MRI and diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL), respectively, at 3 Tesla in 16 elderly subjects (3 male, age = 67.9 ± 3.0 yrs) at risk of cSVD. The test-retest reproducibility of kw measurements was evaluated with repeated scans ~6 weeks apart. Mixed effects linear regression was performed in the whole brain, gray matter (GM), white matter (WM), and 6 subcortical brain regions to investigate associations between Ktrans/k and test-retest kw. In addition, kw and Ktrans/k were compared in normal appearing white matter (NAWM), white matter hyperintensity (WMH) lesions and penumbra. Significant correlation was found between kw and Ktrans only in WM (β = 6.7 × 10, = 0.036), caudate (β = 8.6 × 10, = 0.029), and middle cerebral artery (MCA) perforator territory (β = 6.9 × 10, = 0.009), but not in the whole brain, GM or rest 5 brain regions. Significant correlation was found between kw and k in MCA perforator territory (β = 1.5 × 10, = 0.049), medial-temporal lobe (β = 3.5 × 10, = 0.032), and hippocampus (β = 3.4 × 10, = 0.038), but not in the rest brain regions. Good reproducibility of kw measurements (ICC=0.75) was achieved. Ktrans was significantly lower inside WMH than WMH penumbra (16.2%, = 0.026), and k was significantly lower in NAWM than in the WMH penumbra (20.8%, < 0.001). kw provides a measure of water exchange rate across the BBB with good test-retest reproducibility. The BBB mechanism underlying kw and Ktrans/k is likely to be different, as manifested by correlations in only three brain regions for each pair of comparison between kw and Ktrans or k.
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http://dx.doi.org/10.3389/fnins.2020.571480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733970PMC
November 2020

High-Resolution Neurovascular Imaging at 7T: Arterial Spin Labeling Perfusion, 4-Dimensional MR Angiography, and Black Blood MR Imaging.

Magn Reson Imaging Clin N Am 2021 Feb 2;29(1):53-65. Epub 2020 Nov 2.

Laboratory of FMRI Technology (LOFT), USC Mark & Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, 2025 Zonal Avenue, Los Angeles, CA 90033, USA; Department of Neurology, Keck School of Medicine, University of Southern California, 2025 Zonal Avenue, Los Angeles, CA 90033, USA. Electronic address:

Ultrahigh field offers increased resolution and contrast for neurovascular imaging. Arterial spin labeling methods benefit from an increased intrinsic signal-to-noise ratio of MR imaging signal and a prolonged tracer half-life at ultrahigh field, allowing the visualization of layer-dependent microvascular perfusion. Arterial spin labeling-based time-resolved 4-dimensional MR angiography at 7T provides a detailed depiction of the vascular architecture and dynamic blood flow pattern with high spatial and temporal resolutions. High-resolution black blood MR imaging at 7T allows detailed characterization of small perforating arteries such as lenticulostriate arteries. All techniques benefit from advances in parallel radiofrequency transmission technologies at ultrahigh field.
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http://dx.doi.org/10.1016/j.mric.2020.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694883PMC
February 2021

Brain arteriolosclerosis.

Acta Neuropathol 2021 01 24;141(1):1-24. Epub 2020 Oct 24.

Sanders-Brown Center on Aging, Department of Pathology, University of Kentucky, Lexington, KY, 40536, USA.

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here, we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer's disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g., hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that factored in comorbid diseases, B-ASC was independently associated with impairments of global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability.
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http://dx.doi.org/10.1007/s00401-020-02235-6DOI Listing
January 2021

Lower retinal capillary density in minimal cognitive impairment among older Latinx adults.

Alzheimers Dement (Amst) 2020 25;12(1):e12071. Epub 2020 Aug 25.

Department of Ophthalmology, USC Roski Eye Institute Keck School of Medicine of the University of Southern California Los Angeles California USA.

Introduction: We investigated the hypothesis that retinal capillary perfusion is a biomarker of early cognitive decline and cerebrovascular perfusion associated with small vessel disease in a pilot data set of Latinx adults at high risk for vascular cognitive impairment and dementia.

Methods: High-resolution optical coherence tomography angiography (OCTA) images were acquired from dilated eyes of Latinx subjects using a 3 × 3 mm scan pattern from a commercially available device. A previously validated method was used to quantify the density of perfused retinal capillaries as the retinal vessel skeleton density (VSD). The association of VSD with Clinical Dementia Rating Sum of Boxes, total Montreal Cognitive Assessment (MoCA) score, and individual MoCA test elements were analyzed using multivariate statistics that adjusted for confounders. VSD was also compared with magnetic resonance imaging (MRI) measures of cerebrovascular reactivity (CVR) and perfusion in the middle cerebral artery perforator (MCA-Perf) territory.

Results: The mean (± SD) age of the subjects was 68 (± 6) years. For every 0.01-unit lower VSD, the risk of having a CDR-SOB >0 was 20% higher (95%CI = 5%-90%;  = .031). Similarly, a lower VSD was associated with lower total MoCA score (r = 0.3; = .038). The Visuospatial/Executive domain of the MoCA assessment showed the strongest association with VSD ( = 0.02;  = .022). Lower retinal VSD was associated with worse MRI measure of CVR (r = 0.7,  = .04) and less perfusion in the MCA-Perf territory (r = 0.45,  = .02).

Discussion: Impaired retinal capillary perfusion is associated with cognitive impairment and abnormalities in cerebrovascular perfusion and function. OCTA-based retinal capillary assessment holds promise for identifying and quantifying retinal correlates of neurovascular abnormalities associated with vascular cognitive impairment.
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http://dx.doi.org/10.1002/dad2.12071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447879PMC
August 2020

Low Dose CT Perfusion With K-Space Weighted Image Average (KWIA).

IEEE Trans Med Imaging 2020 12 30;39(12):3879-3890. Epub 2020 Nov 30.

CTP (Computed Tomography Perfusion) is widely used in clinical practice for the evaluation of cerebrovascular disorders. However, CTP involves high radiation dose (≥~200mGy) as the X-ray source remains continuously on during the passage of contrast media. The purpose of this study is to present a low dose CTP technique termed K-space Weighted Image Average (KWIA) using a novel projection view-shared averaging algorithm with reduced tube current. KWIA takes advantage of k-space signal property that the image contrast is primarily determined by the k-space center with low spatial frequencies and oversampled projections. KWIA divides each 2D Fourier transform (FT) or k-space CTP data into multiple rings. The outer rings are averaged with neighboring time frames to achieve adequate signal-to-noise ratio (SNR), while the center region of k-space remains unchanged to preserve high temporal resolution. Reduced dose sinogram data were simulated by adding Poisson distributed noise with zero mean on digital phantom and clinical CTP scans. A physical CTP phantom study was also performed with different X-ray tube currents. The sinogram data with simulated and real low doses were then reconstructed with KWIA, and compared with those reconstructed by standard filtered back projection (FBP) and simultaneous algebraic reconstruction with regularization of total variation (SART-TV). Evaluation of image quality and perfusion metrics using parameters including SNR, CNR (contrast-to-noise ratio), AUC (area-under-the-curve), and CBF (cerebral blood flow) demonstrated that KWIA is able to preserve the image quality, spatial and temporal resolution, as well as the accuracy of perfusion quantification of CTP scans with considerable (50-75%) dose-savings.
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http://dx.doi.org/10.1109/TMI.2020.3006461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704693PMC
December 2020

Reperfusion Into Severely Damaged Brain Tissue Is Associated With Occurrence of Parenchymal Hemorrhage for Acute Ischemic Stroke.

Front Neurol 2020 26;11:586. Epub 2020 Jun 26.

Department of Neurology, USC Stevens Neuroimaging and Informatics Institute, USC, Los Angeles, CA, United States.

This study aims to quantify the reperfusion status within severely damaged brain tissue and to evaluate its relationship with high grade of hemorrhagic transformation (HT). Pseudo-continuous ASL was performed along with DWI in 102 patients within 24 h post-treatments. The infarction core was identified using ADC values <550 × 10 mm/s. CBF within the infarction core and its contralateral counterpart were acquired. CBF at the 25th, median, and 75th percentiles of the contralateral counterpart were used as thresholds and the ASL reperfusion volume above the threshold was labeled as vol-25, -50, and -75, respectively. Recanalization was defined according to Thrombolysis in Myocardial Infarction (TIMI) criteria. Quantified reperfusion within the infarction core differed significantly in patients with complete and incomplete recanalization. In the ROC analysis for the prediction of parenchymal hematoma (PH), ASL reperfusion vol-25 had the highest area under the curve (AUC) when compared with ASL vol-50 and ASL vol-75. ASL reperfusion vol-25 had significantly higher AUC compared with ADC threshold volume in the prediction of PH (0.783 vs. 0.685, = 0.0036) and PH-2 (0.844 vs. 0.754, = 0.0035). In stepwise multivariate logistic regression analysis, only ASL reperfusion vol-25 emerged as an independent predictor of PH (OR = 3.51, 95% CI: 1.65-7.45, < 0.001) and PH-2 (OR = 2.32, 95% CI: 1.13-4.76, = 0.022). Increased reperfusion volume within severely damaged brain tissue is associated with the occurrence of higher grade of HT.
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http://dx.doi.org/10.3389/fneur.2020.00586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332705PMC
June 2020

Concurrent Imaging of Markers of Current Flow and Neurophysiological Changes During tDCS.

Front Neurosci 2020 21;14:374. Epub 2020 Apr 21.

Laboratory of FMRI Technology, Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, United States.

Despite being a popular neuromodulation technique, clinical translation of transcranial direct current stimulation (tDCS) is hampered by variable responses observed within treatment cohorts. Addressing this challenge has been difficult due to the lack of an effective means of mapping the neuromodulatory electromagnetic fields together with the brain's response. In this study, we present a novel imaging technique that provides the capability of concurrently mapping markers of tDCS currents, as well as the brain's response to tDCS. A dual-echo echo-planar imaging (DE-EPI) sequence is used, wherein the phase of the acquired MRI-signal encodes the tDCS current induced magnetic field, while the magnitude encodes the blood oxygenation level dependent (BOLD) contrast. The proposed technique was first validated in a custom designed phantom. Subsequent test-retest experiments in human participants showed that tDCS-induced magnetic fields can be detected reliably . The concurrently acquired BOLD data revealed large-scale networks characteristic of a brain in resting-state as well as a 'cathodal' and an 'anodal' resting-state component under each electrode. Moreover, 'cathodal's BOLD-signal was observed to significantly decrease with the applied current at the group level in all datasets. With its ability to image markers of electromagnetic cause as well as neurophysiological changes, the proposed technique may provide an effective means to visualize neural engagement in tDCS at the group level. Our technique also contributes to addressing confounding factors in applying BOLD fMRI concurrently with tDCS.
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http://dx.doi.org/10.3389/fnins.2020.00374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186453PMC
April 2020

Editorial: Advances in Multi-Scale Analysis of Brain Complexity.

Front Neurosci 2020 15;14:337. Epub 2020 Apr 15.

Laboratory of Functional MRI Technology, Keck School of Medicine, Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, United States.

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http://dx.doi.org/10.3389/fnins.2020.00337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175804PMC
April 2020

Robust functional mapping of layer-selective responses in human lateral geniculate nucleus with high-resolution 7T fMRI.

Proc Biol Sci 2020 04 15;287(1925):20200245. Epub 2020 Apr 15.

State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, People's Republic of China.

The lateral geniculate nucleus (LGN) of the thalamus is the major subcortical relay of retinal input to the visual cortex. It plays important roles in visual perception and cognition and is closely related with several eye diseases and brain disorders. Primate LGNs mainly consist of six layers of monocular neurons with distinct cell types and functions. The non-invasive measure of layer-selective activities of the human LGN would have broad scientific and clinical implications. Using high-resolution functional magnetic resonance imaging (fMRI) at 7 Tesla (T) and carefully designed visual stimuli, we achieved robust functional mapping of eye-specific and also magnocellular/parvocellular-specific laminar patterns of the human LGN. These laminar patterns were highly reproducible with different pulse sequences scanned on separate days, between different subjects, and were in remarkable consistency with the simulation from high-resolution histology of the human LGNs. These findings clearly demonstrate that 7T fMRI can robustly resolve layer-specific responses of the human LGN. This paves the way for future investigation of the critical roles of the LGN in human visual perception and cognition, as well as the neural mechanisms of many developmental and neurodegenerative diseases.
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http://dx.doi.org/10.1098/rspb.2020.0245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211434PMC
April 2020

Single and repeated ketamine treatment induces perfusion changes in sensory and limbic networks in major depressive disorder.

Eur Neuropsychopharmacol 2020 04 12;33:89-100. Epub 2020 Feb 12.

Department of Neurology, Ahamason-Lovelace Brain Mapping Center, United States; Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, 635 Charles E Young Drive South Suite, Los Angeles, CA 90095-7334, United States. Electronic address:

Ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depressive disorder (MDD). Yet, how single and repeated ketamine treatment induces brain systems-level neuroplasticity underlying symptom improvement is unknown. Advanced multiband imaging (MB) pseudo-continuous arterial spin labeling (pCASL) perfusion MRI data was acquired from patients with treatment resistant depression (TRD) (N = 22, mean age=35.2 ± 9.95 SD, 27% female) at baseline, and 24 h after receiving single, and four subanesthetic (0.5 mg/kg) intravenous ketamine infusions. Changes in global and regional CBF were compared across time points, and relationships with overall mood, anhedonia and apathy were examined. Comparisons between patients at baseline and controls (N = 18, mean age=36.11 ± 14.5 SD, 57% female) established normalization of treatment effects. Results showed increased regional CBF in the cingulate and primary and higher-order visual association regions after first ketamine treatment. Baseline CBF in the fusiform, and acute changes in CBF in visual areas were related to symptom improvement after single and repeated ketamine treatment, respectively. In contrast, after serial infusion therapy, decreases in regional CBF were observed in the bilateral hippocampus and right insula with ketamine treatment. Findings demonstrate that neurophysiological changes occurring with single and repeated ketamine treatment follow both a regional and temporal pattern including sensory and limbic regions. Initial changes are observed in the posterior cingulate and precuneus and primary and higher-order visual areas, which relate to clinical responses. However, repeated exposure to ketamine, though not relating to clinical outcome, appears to engage deeper limbic structures and insula. ClinicalTrials.gov: Biomarkers of Fast Acting Therapies in Major Depression, https://clinicaltrials.gov/ct2/show/NCT02165449, NCT02165449.
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http://dx.doi.org/10.1016/j.euroneuro.2020.01.017DOI Listing
April 2020

A review of transcranial direct current stimulation (tDCS) for the individualized treatment of depressive symptoms.

Pers Med Psychiatry 2019 Nov-Dec;17-18:17-22. Epub 2019 May 7.

Ahmanson-Lovelace Brain Mapping Center, University of California Los Angeles, Los Angeles, California.

Transcranial direct current stimulation (tDCS) is a low intensity neuromodulation technique shown to elicit therapeutic effects in a number of neuropsychological conditions. Independent randomized sham-controlled trials and meta- and mega-analyses demonstrate that tDCS targeted to the left dorsolateral prefrontal cortex can produce a clinically meaningful response in patients with major depressive disorder (MDD), but effects are small to moderate in size. However, the heterogeneous presentation, and the neurobiology underlying particular features of depression suggest clinical outcomes might benefit from empirically informed patient selection. In this review, we summarize the status of tDCS research in MDD with focus on the clinical, biological, and intrinsic and extrinsic factors shown to enhance or predict antidepressant response. We also discuss research strategies for optimizing tDCS to improve patient-specific clinical outcomes. TDCS appears suited for both bipolar and unipolar depression, but is less effective in treatment resistant depression. TDCS may also better target core aspects of depressed mood over vegetative symptoms, while pretreatment patient characteristics might inform subsequent response. Peripheral blood markers of gene and immune system function have not yet proven useful as predictors or correlates of tDCS response. Though further research is needed, several lines of evidence suggest that tDCS administered in combination with pharmacological and cognitive behavioral interventions can improve outcomes. Tailoring stimulation to the functional and structural anatomy and/or connectivity of individual patients can maximize physiological response in targeted networks, which in turn could translate to therapeutic benefits.
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http://dx.doi.org/10.1016/j.pmip.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959848PMC
May 2019

Deep Learning Detection of Penumbral Tissue on Arterial Spin Labeling in Stroke.

Stroke 2020 02 30;51(2):489-497. Epub 2019 Dec 30.

From the Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles (K.W., Q.S., S.J.M., H.K., D.J.J.W.).

Background and Purpose- Selection of patients with acute ischemic stroke for endovascular treatment generally relies on dynamic susceptibility contrast magnetic resonance imaging or computed tomography perfusion. Dynamic susceptibility contrast magnetic resonance imaging requires injection of contrast, whereas computed tomography perfusion requires high doses of ionizing radiation. The purpose of this work was to develop and evaluate a deep learning (DL)-based algorithm for assisting the selection of suitable patients with acute ischemic stroke for endovascular treatment based on 3-dimensional pseudo-continuous arterial spin labeling (pCASL). Methods- A total of 167 image sets of 3-dimensional pCASL data from 137 patients with acute ischemic stroke scanned on 1.5T and 3.0T Siemens MR systems were included for neural network training. The concurrently acquired dynamic susceptibility contrast magnetic resonance imaging was used to produce labels of hypoperfused brain regions, analyzed using commercial software. The DL and 6 machine learning (ML) algorithms were trained with 10-fold cross-validation. The eligibility for endovascular treatment was determined retrospectively based on the criteria of perfusion/diffusion mismatch in the DEFUSE 3 trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke). The trained DL algorithm was further applied on twelve 3-dimensional pCASL data sets acquired on 1.5T and 3T General Electric MR systems, without fine-tuning of parameters. Results- The DL algorithm can predict the dynamic susceptibility contrast-defined hypoperfusion region in pCASL with a voxel-wise area under the curve of 0.958, while the 6 ML algorithms ranged from 0.897 to 0.933. For retrospective determination for subject-level endovascular treatment eligibility, the DL algorithm achieved an accuracy of 92%, with a sensitivity of 0.89 and specificity of 0.95. When applied to the GE pCASL data, the DL algorithm achieved a voxel-wise area under the curve of 0.94 and a subject-level accuracy of 92% for endovascular treatment eligibility. Conclusions- pCASL perfusion magnetic resonance imaging in conjunction with the DL algorithm provides a promising approach for assisting decision-making for endovascular treatment in patients with acute ischemic stroke.
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http://dx.doi.org/10.1161/STROKEAHA.119.027457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224203PMC
February 2020

Consensus-based technical recommendations for clinical translation of renal ASL MRI.

MAGMA 2020 Feb 12;33(1):141-161. Epub 2019 Dec 12.

Department of Radiology, Clínica Universidad de Navarra, Pamplona, Spain.

Objectives: This study aimed at developing technical recommendations for the acquisition, processing and analysis of renal ASL data in the human kidney at 1.5 T and 3 T field strengths that can promote standardization of renal perfusion measurements and facilitate the comparability of results across scanners and in multi-centre clinical studies.

Methods: An international panel of 23 renal ASL experts followed a modified Delphi process, including on-line surveys and two in-person meetings, to formulate a series of consensus statements regarding patient preparation, hardware, acquisition protocol, analysis steps and data reporting.

Results: Fifty-nine statements achieved consensus, while agreement could not be reached on two statements related to patient preparation. As a default protocol, the panel recommends pseudo-continuous (PCASL) or flow-sensitive alternating inversion recovery (FAIR) labelling with a single-slice spin-echo EPI readout with background suppression and a simple but robust quantification model.

Discussion: This approach is considered robust and reproducible and can provide renal perfusion images of adequate quality and SNR for most applications. If extended kidney coverage is desirable, a 2D multislice readout is recommended. These recommendations are based on current available evidence and expert opinion. Nonetheless they are expected to be updated as more data become available, since the renal ASL literature is rapidly expanding.
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http://dx.doi.org/10.1007/s10334-019-00800-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021752PMC
February 2020

Differences in high-definition transcranial direct current stimulation over the motor hotspot versus the premotor cortex on motor network excitability.

Sci Rep 2019 11 26;9(1):17605. Epub 2019 Nov 26.

Neural Plasticity and Neurorehabilitation Laboratory, Chan Division of Occupational Science and Occupational Therapy, University of Southern California, Los Angeles, CA, United States.

The effectiveness of transcranial direct current stimulation (tDCS) placed over the motor hotspot (thought to represent the primary motor cortex (M1)) to modulate motor network excitability is highly variable. The premotor cortex-particularly the dorsal premotor cortex (PMd)-may be a promising alternative target to reliably modulate motor excitability, as it influences motor control across multiple pathways, one independent of M1 and one with direct connections to M1. This double-blind, placebo-controlled preliminary study aimed to differentially excite motor and premotor regions using high-definition tDCS (HD-tDCS) with concurrent functional magnetic resonance imaging (fMRI). HD-tDCS applied over either the motor hotspot or the premotor cortex demonstrated high inter-individual variability in changes on cortical motor excitability. However, HD-tDCS over the premotor cortex led to a higher number of responders and greater changes in local fMRI-based complexity than HD-tDCS over the motor hotspot. Furthermore, an analysis of individual motor hotspot anatomical locations revealed that, in more than half of the participants, the motor hotspot is not located over anatomical M1 boundaries, despite using a canonical definition of the motor hotspot. This heterogeneity in stimulation site may contribute to the variability of tDCS results. Altogether, these preliminary findings provide new considerations to enhance tDCS reliability.
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http://dx.doi.org/10.1038/s41598-019-53985-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879500PMC
November 2019

Human Placenta Blood Flow During Early Gestation With Pseudocontinuous Arterial Spin Labeling MRI.

J Magn Reson Imaging 2020 04 4;51(4):1247-1257. Epub 2019 Nov 4.

Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

Background: Noninvasive measurement of placental blood flow is the major technical challenge for predicting ischemic placenta (IPD). Pseudocontinuous arterial spin labeling (pCASL) MRI was recently shown to be promising, but the potential value in predicting the subsequence development of IPD is not known.

Purpose: To derive global and regional placental blood flow parameters from longitudinal measurements of pCASL MRI and to assess the associations between perfusion-related parameters and IPD.

Study Type: Prospective.

Population: Eighty-four women completed two pCASL MRI scans (first; 14-18 weeks and second; 19-24 weeks) from prospectively recruited 118 subjects. A total of 69 subjects were included for the analysis, of which 15 subjects developed IPD.

Field Strength/sequence: 3T/T -weighted half-Fourier single-shot turbo spin-echo (HASTE) and pCASL.

Assessment: Four perfusion-related parameters in the placenta were derived: placenta volume, placental blood flow (PBF), high PBF (hPBF), and relative hPBF. The longitudinal changes of the parameters and their association with IPD were tested after being normalizing to the 16th and 20th weeks of gestation.

Statistical Tests: Comparisons between two gestational ages within subjects were performed using the paired Wilcoxon tests, and comparisons between normal and IPD groups were performed using the unpaired Wilcoxon tests.

Results: The difference between the first and second MRI scans was statistically significant for volume (156.6 cm vs. 269.7 cm , P < 0.001) and PBF (104.9 ml/100g/min vs. 111.3 ml/100g/min, P = 0.02) for normal subjects, indicating an increase in pregnancy with advancing gestation. Of the parameters tested, the difference between the normal and IPD subjects was most pronounced in hPBF (278.1 ml/100g/min vs. 180.7 ml/100g/min, P < 0.001) and relative hPBF (259.1% vs. 183.2%, P < 0.001) at 16 weeks.

Data Conclusion: The high perfusion-related image parameters for IPD were significantly decreased from normal pregnancy at 14-18 weeks of gestation.

Level Of Evidence: 2 TECHNICAL EFFICACY STAGE: 1 J. Magn. Reson. Imaging 2020;51:1247-1257.
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http://dx.doi.org/10.1002/jmri.26944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654100PMC
April 2020

An Automatic Estimation of Arterial Input Function Based on Multi-Stream 3D CNN.

Front Neuroinform 2019 5;13:49. Epub 2019 Jul 5.

Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing, China.

Arterial input function (AIF) is estimated from perfusion images as a basic curve for the following deconvolution process to calculate hemodynamic variables to evaluate vascular status of tissues. However, estimation of AIF is currently based on manual annotations with prior knowledge. We propose an automatic estimation of AIF in perfusion images based on a multi-stream 3D CNN, which combined spatial and temporal features together to estimate the AIF ROI. The model is trained by manual annotations. The proposed method was trained and tested with 100 cases of perfusion-weighted imaging. The result was evaluated by dice similarity coefficient, which reached 0.79. The trained model had a better performance than the traditional method. After segmentation of the AIF ROI, the AIF was calculated by the average of all voxels in the ROI. We compared the AIF result with the manual and traditional methods, and the parameters of further processing of AIF, such as time to the maximum of the tissue residue function (Tmax), relative cerebral blood flow, and mismatch volume, which are calculated in the Section Results. The result had a better performance, the average mismatch volume reached 93.32% of the manual method, while the other methods reached 85.04 and 83.04%. We have applied the method on the cloud platform, Estroke, and the local version of its software, NeuBrainCare, which can evaluate the volume of the ischemic penumbra, the volume of the infarct core, and the ratio of mismatch between perfusion and diffusion images to help make treatment decisions, when the mismatch ratio is abnormal.
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http://dx.doi.org/10.3389/fninf.2019.00049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624480PMC
July 2019

Characterization of lenticulostriate arteries with high resolution black-blood T1-weighted turbo spin echo with variable flip angles at 3 and 7 Tesla.

Neuroimage 2019 10 31;199:184-193. Epub 2019 May 31.

USC Stevens Neuroimaging and Informatics Institute, Department of Neurology, University of Southern California, Los Angeles, CA, USA. Electronic address:

Objectives: The lenticulostriate arteries (LSAs) with small diameters of a few hundred microns take origin directly from the high flow middle cerebral artery (MCA), making them especially susceptible to damage (e.g. by hypertension). This study aims to present high resolution (isotropic ∼0.5 mm), black blood MRI for the visualization and characterization of LSAs at both 3 T and 7 T.

Materials And Methods: T1-weighted 3D turbo spin-echo with variable flip angles (T1w TSE-VFA) sequences were optimized for the visualization of LSAs by performing extended phase graph (EPG) simulations. Twenty healthy volunteers (15 under 35 years old, 5 over 60 years old) were imaged with the T1w TSE-VFA sequences at both 3 T and 7 T. Contrast-to-noise ratio (CNR) was quantified, and LSAs were manually segmented using ITK-SNAP. Automated Reeb graph shape analysis was performed to extract features including vessel length and tortuosity. All quantitative metrics were compared between the two field strengths and two age groups using ANOVA.

Results: LSAs can be clearly delineated using optimized 3D T1w TSE-VFA at 3 T and 7 T, and a greater number of LSA branches can be detected compared to those by time-of-flight MR angiography (TOF MRA) at 7 T. The CNR of LSAs was comparable between 7 T and 3 T. T1w TSE-VFA showed significantly higher CNR than TOF MRA at the stem portion of the LSAs branching off the medial middle cerebral artery. The mean vessel length and tortuosity were greater on TOF MRA compared to TSE-VFA. The number of detected LSAs by both TSE-VFA and TOF MRA was significantly reduced in aged subjects, while the mean vessel length measured on 7 T TSE-VFA showed significant difference between the two age groups.

Conclusion: The high-resolution black-blood 3D T1w TSE-VFA sequence offers a new method for the visualization and quantification of LSAs at both 3 T and 7 T, which may be applied for a number of pathological conditions related to the damage of LSAs.
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http://dx.doi.org/10.1016/j.neuroimage.2019.05.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688958PMC
October 2019

Recent Advances in Pediatric Brain, Spine, and Neuromuscular Magnetic Resonance Imaging Techniques.

Pediatr Neurol 2019 07 12;96:7-23. Epub 2019 Mar 12.

Radiology, Nationwide Children's Hospital, Columbus, Ohio. Electronic address:

Magnetic resonance imaging (MRI) is a powerful radiologic tool with the ability to generate a variety of proton-based signal contrast from tissues. Owing to this immense flexibility in signal generation, new MRI techniques are constantly being developed, tested, and optimized for clinical utility. In addition, the safe and nonionizing nature of MRI makes it a suitable modality for imaging in children. In this review article, we summarize a few of the most popular advances in MRI techniques in recent years. In particular, we highlight how these new developments have affected brain, spine, and neuromuscular imaging and focus on their applications in pediatric patients. In the first part of the review, we discuss new approaches such as multiphase and multidelay arterial spin labeling for quantitative perfusion and angiography of the brain, amide proton transfer MRI of the brain, MRI of brachial plexus and lumbar plexus nerves (i.e., neurography), and T2 mapping and fat characterization in neuromuscular diseases. In the second part of the review, we focus on describing new data acquisition strategies in accelerated MRI aimed collectively at reducing the scan time, including simultaneous multislice imaging, compressed sensing, synthetic MRI, and magnetic resonance fingerprinting. In discussing the aforementioned, the review also summarizes the advantages and disadvantages of each method and their current state of commercial availability from MRI vendors.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.03.001DOI Listing
July 2019

Vascular dysfunction-The disregarded partner of Alzheimer's disease.

Alzheimers Dement 2019 01;15(1):158-167

Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA. Electronic address:

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.
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http://dx.doi.org/10.1016/j.jalz.2018.07.222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338083PMC
January 2019

Mapping water exchange across the blood-brain barrier using 3D diffusion-prepared arterial spin labeled perfusion MRI.

Magn Reson Med 2019 05 18;81(5):3065-3079. Epub 2018 Dec 18.

Laboratory of FMRI Technology (LOFT), Mark & Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, California.

Purpose: To present a novel MR pulse sequence and modeling algorithm to quantify the water exchange rate (k ) across the blood-brain barrier (BBB) without contrast, and to evaluate its clinical utility in a cohort of elderly subjects at risk of cerebral small vessel disease (SVD).

Methods: A diffusion preparation module with spoiling of non-Carr-Purcell-Meiboom-Gill signals was integrated with pseudo-continuous arterial spin labeling (pCASL) and 3D gradient and spin echo (GRASE) readout. The tissue/capillary fraction of the arterial spin labeling (ASL) signal was separated by appropriate diffusion weighting (b = 50 s/mm ). k was quantified using a single-pass approximation (SPA) model with total generalized variation (TGV) regularization. Nineteen elderly subjects were recruited and underwent 2 MRIs to evaluate the reproducibility of the proposed technique. Correlation analysis was performed between k and vascular risk factors, Clinical Dementia Rating (CDR) scale, neurocognitive assessments, and white matter hyperintensity (WMH).

Results: The capillary/tissue fraction of ASL signal can be reliably differentiated with the diffusion weighting of b = 50 s/mm , given ~100-fold difference between the (pseudo-)diffusion coefficients of the 2 compartments. Good reproducibility of k measurements (intraclass correlation coefficient = 0.75) was achieved. Average k was 105.0 ± 20.6, 109.6 ± 18.9, and 94.1 ± 19.6 min for whole brain, gray and white matter. k was increased by 28.2%/19.5% in subjects with diabetes/hypercholesterolemia. Significant correlations between k and vascular risk factors, CDR, executive/memory function, and the Fazekas scale of WMH were observed.

Conclusion: A diffusion prepared 3D GRASE pCASL sequence with TGV regularized SPA modeling was proposed to measure BBB water permeability noninvasively with good reproducibility. k may serve as an imaging marker of cerebral SVD and associated cognitive impairment.
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http://dx.doi.org/10.1002/mrm.27632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414249PMC
May 2019

Multidelay multiparametric arterial spin labeling perfusion MRI and mild cognitive impairment in early stage Parkinson's disease.

Hum Brain Mapp 2019 03 7;40(4):1317-1327. Epub 2018 Dec 7.

Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.

Mild cognitive impairment (MCI), a well-defined nonmotor manifestation of Parkinson's disease (PD), greatly impairs functioning and quality of life. However, the contribution of cerebral perfusion, quantified by arterial spin labeling (ASL), to MCI in PD remains poorly understood. The selection of an optimal delay time is difficult for single-delay ASL, a problem which is avoided by multidelay ASL. This study uses a multidelay multiparametric ASL to investigate cerebral perfusion including cerebral blood flow (CBF) and arterial transit time (ATT) in early stage PD patients exhibiting MCI using a voxel-based brain analysis. Magnetic resonance imaging data were acquired on a 3.0 T system at rest in 39 early stage PD patients either with MCI (PD-MCI, N = 22) or with normal cognition (PD-N, N = 17), and 36 age- and gender-matched healthy controls (HCs). CBF and ATT were compared among the three groups with SPM using analysis of variance followed by post hoc analyses to define regional differences and examine their relationship to clinical data. PD-MCI showed prolonged ATT in right thalamus compared to both PD-N and HC, and in right supramarginal gyrus compared to HC. PD-N showed shorter ATT in left superior frontal cortex compared to HC. Prolonged ATT in right thalamus was negatively correlated with the category fluency test (p = .027, r = -0.495) in the PD-MCI group. This study shows that ATT may be a more sensitive marker than CBF for the MCI, and highlights the potential role of thalamus and inferior parietal region for MCI in early stage PD.
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http://dx.doi.org/10.1002/hbm.24451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865659PMC
March 2019

Imbalance of Functional Connectivity and Temporal Entropy in Resting-State Networks in Autism Spectrum Disorder: A Machine Learning Approach.

Front Neurosci 2018 27;12:869. Epub 2018 Nov 27.

Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, United States.

Two approaches to understanding the etiology of neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) involve network level functional connectivity (FC) and the dynamics of neuronal signaling. The former approach has revealed both increased and decreased FC in individuals with ASD. The latter approach has found high frequency EEG oscillations and higher levels of epilepsy in children with ASD. Together, these findings have led to the hypothesis that atypical excitatory-inhibitory neural signaling may lead to imbalanced association pathways. However, simultaneously reconciling local temporal dynamics with network scale spatial connectivity remains a difficult task and thus empirical support for this hypothesis is lacking. We seek to fill this gap by combining two powerful resting-state functional MRI (rs-fMRI) methods-functional connectivity (FC) and wavelet-based regularity analysis. Wavelet-based regularity analysis is an entropy measure of the local rs-fMRI time series signal. We examined the relationship between the RSN entropy and integrity in individuals with ASD and controls from the Autism Brain Imaging Data Exchange (ABIDE) cohort using a putative set of 264 functional brain regions-of-interest (ROI). We observed that an imbalance in intra- and inter-network FC across 11 RSNs in ASD individuals ( = 0.002) corresponds to a weakened relationship with RSN temporal entropy ( = 0.02). Further, we observed that an estimated RSN entropy model significantly distinguished ASD from controls ( = 0.01) and was associated with level of ASD symptom severity ( = 0.003). Imbalanced brain connectivity and dynamics at the network level coincides with their decoupling in ASD. The association with ASD symptom severity presents entropy as a potential biomarker.
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http://dx.doi.org/10.3389/fnins.2018.00869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277800PMC
November 2018

Multi-phase 3D arterial spin labeling brain MRI in assessing cerebral blood perfusion and arterial transit times in children at 3T.

Clin Imaging 2019 Jan - Feb;53:210-220. Epub 2018 Nov 6.

Laboratory of FMRI Technology (LOFT), Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, USA.

Background: 3D pseudocontinuous arterial spin labeling (pCASL) with a single post-labeling delay time is commonly used to measure cerebral blood flow (CBF). Multi-phase pCASL has been developed to simultaneously estimate CBF and arterial transit time (ATT).

Purpose: To evaluate the clinical feasibility of multi-phase 3D pCASL in pediatric patients, and to compare the estimation of ATT and CBF via linear weighted-delay and traditional non-linear iterative curve-fitting routines.

Material & Methods: Forty patients (average age: 8.6 y, 5 d-22.4 y) referred for routine brain MRI underwent additional 5-7 min of pCASL scans at 3T using 5 PLDs between 300 and 2300 ms. Data were post-processed by two algorithms for estimating CBF and ATT. Average CBF and ATT values were computed for vascular territories including the anterior, middle and posterior cerebral arteries as well as regions based on the Alberta Stroke Program Early CT Score template. Pearson correlation coefficients and linear regression were used for statistical analysis. The clinical value of multi-phase CASL was evaluated by a neuroradiologist based on asymmetric CBF and ATT maps in patients.

Results: All pCASL scans were successfully completed, generating diagnostic results. CBF computed from weighted-delay and curve-fitting methods agreed strongly, with Pearson correlation coefficients ranging from 0.97-0.99 across the measured regions (p < 0.05). Correlation coefficients for ATT ranged from 0.87-0.96 (p < 0.05). CBF and ATT maps were found to add valuable information to clinical diagnosis in 17 of 40 pediatric patients.

Conclusion: Our preliminary results demonstrate the feasibility and potential clinical utility of multi-phase pCASL for simultaneous CBF and ATT quantification in pediatric patients.
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http://dx.doi.org/10.1016/j.clinimag.2018.11.001DOI Listing
March 2019

Default Mode Network Complexity and Cognitive Decline in Mild Alzheimer's Disease.

Front Neurosci 2018 23;12:770. Epub 2018 Oct 23.

USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, United States.

The human resting-state is characterized by spatially coherent brain activity at a low temporal frequency. The default mode network (DMN), one of so-called resting-state networks, has been associated with cognitive processes that are directed toward the self, such as introspection and autobiographic memory. The DMN's integrity appears to be crucial for mental health. For example, patients with Alzheimer's disease or other psychiatric conditions show disruptions of functional connectivity within the brain regions of the DMN. However, in prodromal or early stages of Alzheimer's disease, physiological alterations are sometimes elusive, despite manifested cognitive impairment. While functional connectivity assesses the signal correlation between brain areas, multi-scale entropy (MSE) measures the complexity of the blood-oxygen level dependent signal within an area and thus might show local changes before connectivity is affected. Hence, we investigated alterations of functional connectivity and MSE within the DMN in fifteen mild Alzheimer's disease patients as compared to fourteen controls. Potential associations of MSE with functional connectivity and cognitive abilities [i.e., mini-mental state examination (MMSE)] were assessed. A moderate decrease of DMN functional connectivity between posterior cingulate cortex and right hippocampus in Alzheimer's disease was found, whereas no differences were evident for whole-network functional connectivity. In contrast, the Alzheimer's disease group yielded lower global DMN-MSE than the control group. The most pronounced regional effects were localized in left and right hippocampi, and this was true for most scales. Moreover, MSE significantly correlated with functional connectivity, and DMN-MSE correlated positively with the MMSE in Alzheimer's disease. Most interestingly, the right hippocampal MSE was positively associated with semantic memory performance. Thus, our results suggested that cognitive decline in Alzheimer's disease is reflected by decreased signal complexity in DMN nodes, which might further lead to disrupted DMN functional connectivity. Additionally, altered entropy in Alzheimer's disease found in the majority of the scales indicated a disturbance of both local information processing and information transfer between distal areas. Conclusively, a loss of nodal signal complexity potentially impairs synchronization across nodes and thus preempts functional connectivity changes. MSE presents a putative functional marker for cognitive decline that might be more sensitive than functional connectivity alone.
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http://dx.doi.org/10.3389/fnins.2018.00770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206840PMC
October 2018