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Cerebrovascular reactivity (CVR) deficits may index vulnerability to vascular brain injury and cognitive impairment, but findings on age-related changes in CVR have been mixed, and no studies to date have directly compared age-related changes in CVR to hypercapnia versus hypocapnia. The present study compared CVR in 31 cognitively unimpaired older adults (ages 55-87) and 30 healthy younger adults (ages 18-28). Breath control tasks induced CVR to hypocapnia (0.1 Hz paced breathing) and hypercapnia (15s breath holds) during pseudo-continuous arterial spin labeling MRI. Relative to younger adults, cognitively unimpaired older adults displayed lower levels of global CVR under both hypocapnia and hypercapnia. In region-of-interest analyses, older adults exhibited attenuated CVR to hypocapnia in select frontal and temporal regions, and lower CVR to hypercapnia in all cortical, limbic, and subcortical regions examined, relative to younger adults. Results indicate age-related deficits in CVR are detectible even in cognitively unimpaired older adults and are disproportionately related to vasodilatory (hypercapnia) responses relative to vasoconstrictive (hypocapnia) responses. Findings may offer means for early detection of cerebrovascular dysfunction.

Noncontrast magnetic resonance imaging techniques for measuring brain perfusion include arterial spin labeling (ASL) and intravoxel incoherent motion (IVIM). These techniques provide noninvasive and repeatable assessment of cerebral blood flow or cerebral blood volume without the need for intravenous contrast. This article discusses the technical aspects of ASL and IVIM with a focus on normal physiologic variations, technical parameters, and artifacts. Multiple pediatric clinical applications are presented, including tumors, stroke, vasculopathy, vascular malformations, epilepsy, migraine, trauma, and inflammation.

ObjectiveTo test the hypothesis that cerebral blood flow (CBF) assessed with arterial spin labelling (ASL) MRI is increased and standardised neurological examination is altered in infants with neonatal opioid withdrawal syndrome (NOWS) compared with those without.DesignProspective cohort study.SettingLevel IV neonatal intensive care unit and outpatient primary care centre.ParticipantsInfants with NOWS receiving pharmacological treatment and unexposed controls matched for gestational age at birth and post-menstrual age at MRI.Main outcomesCBF assessed by ASL on non-sedated 3-Tesla MRI and standardised Hammersmith Neonatal Neurological Examination (HNNE) within 14 days of birth.ResultsThirty infants with NOWS and 31 control infants were enrolled and included in the final analysis. Global CBF across the brain was higher in the NOWS group compared with controls (14.2 mL/100 g/min±5.5 vs 10.7 mL/100 g/min±4.3, mean±SD, Cohen’s d=0.72). HNNE total optimality score was lower in the NOWS group compared with controls (25.9±3.6 vs 28.4±2.4, mean±SD, Cohen’s d=0.81). A penalised logistic regression model including both CBF and HNNE items discriminated best between the two groups.ConclusionsIncreased cerebral perfusion and neurological examination abnormalities characterise infants with NOWS compared with those without intrauterine drug exposure and suggest prenatal substance exposure affects fetal brain development. Identifying neurological and neuroimaging characteristics of infants with NOWS can contribute to understanding mechanisms underlying later outcomes and to designing potential new treatments.

Brain damage caused by small vessel disease (SVD) differs between males and females. We aimed to examine the pure sex-specific neuroanatomical mechanisms of SVD adjusted for voxel-based expected effects of age and sex on healthy brain volume. Thirty-one female and 32 male genetic SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL) patients and 55 sex- and age-matched healthy controls (HCs) underwent 7-Tesla MRI examinations. Voxel-based W-score maps were calculated from volumes and deformations of brain tissues, controlling for the expected effects of age and sex in HCs. Significant cognitive declines in working memory and executive function were identified in male CADASIL patients compared to female patients. Greater gray matter (GM) atrophy was found in the bilateral orbitofrontal cortex (OFC), left anterior cingulate cortex (ACC), left entorhinal cortex (EC), and right temporooccipital cortex in male CADASIL patients than in females. Working memory was associated with volumes in the right OFC specific to female CADASIL patients, whereas visuospatial ability was associated with the right hOcl (primary visual area, BA 17) volume specific to males. The current findings indicate that sex affects the pathogenesis of CADASIL, ranging from differences in neuroanatomy to those in behavioral performance, which may facilitate the development of more effective sex-specific therapeutic strategies for CADASIL and SVD.

Introduction We tested if water exchange across the blood-brain barrier (BBB), estimated with a noninvasive magnetic resonance imaging (MRI) technique, is associated with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and neuropsychological function. Methods Forty cognitively normal older adults (67-86 years old) were scanned with diffusion-prepared, arterial spin labeling (DP-ASL), which estimates water exchange rate across the BBB (kw ). Participants also underwent CSF draw and neuropsychological testing. Multiple linear regression models were run with kw as a predictor of CSF concentrations and neuropsychological scores. Results In multiple brain regions, BBB kw was positively associated with CSF amyloid beta (Aβ)42 concentration levels. BBB kw was only moderately associated with neuropsychological performance. Discussion Our results suggest that low water exchange rate across the BBB is associated with low CSF Aβ42 concentration. These findings suggest that kw may be a promising noninvasive indicator of BBB Aβ clearance functions, a possibility which should be further tested in future research.

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.

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 pHD = 0.048, Cohen’s dHD = 0.73; pConv = 0.018, dConv = 0.86; BA 9: pHD = 0.011, dHD = 0.92; pConv = 0.022, dConv = 0.83). Significant longitudinal CBF increases were observed (a) at the left DLPFC stimulation-target for both active montages (pHD = 3.5E−3, dHD = 0.98; pConv = 2.8E−3, dConv = 1.08), and (b) at ACC for the HD-montage only (pHD = 2.4E−3, dHD = 1.06; pConv = 0.075, dConv = 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.

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.

Due to the use of improvised explosive devices, blast exposure and mild traumatic brain injury (mTBI) have become hallmark injuries of the Iraq and Afghanistan wars. Although the mechanisms of the effects of blast on human neurobiology remain active areas of investigation, research suggests that the cerebrovasculature may be particularly vulnerable to blast via molecular processes that impact cerebral blood flow. Given that recent work suggests that blast exposure, even without a subsequent TBI, may have negative consequences on brain structure and function, the current study sought to further understand the effects of blast exposure on perfusion. One hundred and eighty military personnel underwent pseudo-continuous arterial spin labeling (pCASL) imaging and completed diagnostic and clinical interviews. Whole-brain analyses revealed that with an increasing number of total blast exposures, there was significantly increased perfusion in the right middle/superior frontal gyri, supramarginal gyrus, lateral occipital cortex, and posterior cingulate cortex as well as bilateral anterior cingulate cortex, insulae, middle/superior temporal gyri and occipital poles. Examination of other neurotrauma and clinical variables such as close-range blast exposures, mTBI, and PTSD yielded no significant effects. These results raise the possibility that perfusion may be an important neural marker of brain health in blast exposure.

IntroductionTo evaluate the clinical validity of free water (FW), a diffusion tensor imaging-based biomarker kit proposed by the MarkVCID consortium, by investigating the association between mean FW (mFW) and executive function.MethodsBaseline mFW was related to a baseline composite measure of executive function (EFC), adjusting for relevant covariates, in three MarkVCID sub-cohorts, and replicated in five, large, independent legacy cohorts. In addition, we tested whether baseline mFW predicted accelerated EFC score decline (mean follow-up time: 1.29 years).ResultsHigher mFW was found to be associated with lower EFC scores in MarkVCID legacy and sub-cohorts (p-values&nbsp

Laminar fMRI based on BOLD and CBV contrast at ultrahigh magnetic fields has been applied for studying the dynamics of mesoscopic brain networks. However, the quantitative interpretations of BOLD/CBV fMRI results are confounded by different baseline physiology across cortical layers. Here we introduce a novel 3D zoomed pseudo-continuous arterial spin labeling technique at 7T that offers the unique capability for quantitative measurements of laminar cerebral blood flow (CBF) both at rest and during task activation with high spatial specificity and sensitivity. We found arterial transit time in superficial layers is ∼100 msec shorter than in middle/deep layers revealing the dynamics of labeled blood flowing from pial arteries to downstream microvasculature. Resting state CBF peaked in the middle layers which is highly consistent with microvascular density measured from human cortex specimens. Finger tapping induced a robust two-peak laminar profile of CBF increases in the superficial (somatosensory and premotor input) and deep (spinal output) layers of M1, while finger brushing task induced a weaker CBF increase in superficial layers (somatosensory input). We further demonstrated that top-down attention induced a predominant CBF increase in deep layers and a smaller CBF increase on top of the lower baseline CBF in superficial layers of V1 (feedback cortical input), while bottom-up stimulus driven activity peaked in the middle layers (feedforward thalamic input). These quantitative laminar profiles of perfusion activity suggest an important role of M1 superficial layers for the computation of finger movements, and that visual attention may amplify deep layer output to the subcortex.Significance StatementCBF or microvascular perfusion measured by arterial spin labeling (ASL) is a key parameter for in vivo assessment of neurovascular function. Compared to BOLD or VASO fMRI, ASL perfusion contrast offers the unique capability for quantitative CBF measurements both at baseline and during task activation, which is critical for quantitative estimation of metabolic activities tightly related to neuronal activation. We proposed a zoomed 3D ASL technique at 7T for laminar perfusion imaging with high spatial specificity and sensitivity. This technique is able to differentiate and quantify the input/output and feedforward/feedback activities of human motor and visual cortex, thereby providing an important tool for quantitative assessment of neurovascular function and metabolic activities of neural circuits across cortical layers.

OBJECTIVE: We present an easy-to-implement technique for accurate electrode placement over repeated transcranial electrical stimulation (tES) sessions across participants and time. tES is an emerging, non-invasive neuromodulation technique that delivers electrical stimulation using scalp electrodes. APPROACH: The tES electrode placement technique was developed during an exploratory clinical trial aimed at targeting a specific MNI-atlas cortical coordinate in N=59 depressed participants (32F, mean age: 31.1 ± 8.3 SD). Each participant completed 12 sessions of active or sham stimulation, administered using high-definition (HD) or conventional sized electrode montages placed according to the proposed technique. Neuronavigation data measuring the distances between the identified and the intended stimulation site, simulations, and cerebral blood flow (CBF) data at baseline and post-treatment were acquired to evaluate the targeting characteristics of the proposed technique. MAIN RESULTS: Neuronavigation measurements indicate accurate electrode placement to within 1cm of the stimulation target on average across repeated sessions. Simulations predict that these placement characteristics result in minimal electric field differences at the stimulation target ( >0.90 correlation, and

Purpose: To achieve high spatial resolution (isotropic-2 mm) perfusion imaging using 2D simultaneous multi-slice (SMS) pseudo-continuous arterial spin labeling (pCASL) and slice dithered enhanced resolution (SLIDER) technique for super-resolution reconstruction.Methods: The SLIDER-SMS pCASL with a multiband factor of 4 was implemented at 3T with three numbers of slice shift (2/3/4) for the slice thickness of 4/6/8 mm, respectively. Super-resolution reconstruction was performed with singular value decomposition and different levels of Tikhonov regularizations. Temporal and spatial signal-to-noise ratio (SNR) as well as spatial blurring effects of super-resolution ASL images were measured in five healthy subjects and compared with those of reference high-resolution ASL images.Results: Compared to conventional 2D SMS ASL, super-resolution ASL images with isotropic-2-mm resolution yielded 42, 61, and 88% higher spatial SNR, and 18, 55, and 105% higher temporal SNR with slice shift number of 2/3/4, respectively. Spatial blurring effect increased for SLIDER reconstruction from two to four slice shifts.Conclusion: The proposed SLIDER-SMS pCASL technique can achieve whole-brain high-resolution perfusion images with ∼15-min scan time and improved SNR compared to standard 2D SMS pCASL. Caution needs to be exercised on quantifying and controlling blurring effects of SLIDER reconstruction.

PURPOSE To optimize pseudo-continuous arterial spin labeling (pCASL) for 7 T, and to further improve the labeling efficiency with parallel RF transmission transmit B1 ( B1+ ) shimming. METHODS pCASL parameters were optimized based on B1+/B0 field distributions at 7 T with simulation. To increase labeling efficiency, the B1+ amplitude at inflowing arteries was increased with parallel RF transmission B1+ shimming. The "indv-shim" with shimming weights calculated for each individual subject, and the "univ-shim" with universal weights calculated on a group of 12 subjects, were compared with circular polarized (CP) shim. The optimized pCASL sequences with three B1+ shimming modes (indv-shim, univ-shim, and CP-shim) were evaluated in 6 subjects who underwent two repeated scans 24 hours apart, along with a pulsed ASL sequence. Quantitative metrics including mean B1+ amplitude, perfusion, and intraclass correlation coefficient were calculated. The optimized 7T pCASL was compared with standard 3T pCASL on 5 subjects, using spatial SNR and temporal SNR. RESULTS The optimal pCASL parameter set (RF duration/gap = 300/250 us, Gave=0.6mT/m,gRatio=10 ) achieved robust perfusion measurement in the presence of B1+/B0 inhomogeneities. Both indv-shim and univ-shim significantly increased B1+ amplitude compared with CP-shim in simulation and in vivo experiment (P < .01). Compared with CP-shim, perfusion signal was increased by 9.5% with indv-shim (P < .05) and by 5.3% with univ-shim (P = .35). All three pCASL sequences achieved fair to good repeatability (intraclass correlation coefficient ≥ 0.5). Compared with 3T pCASL, the optimized 7T pCASL achieved 78.3% higher spatial SNR and 200% higher temporal SNR. CONCLUSION The optimized pCASL achieved robust perfusion imaging at 7 T, while both indv-shim and univ-shim further increased labeling efficiency.

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.

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.

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.

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.

Recently, the first 7-T MR system was approved for clinical use in the United States. Unfortunately, relatively few metallic implants have undergone testing to determine if they are acceptable or pose hazards to research subjects and patients at this ultra-high-field strength. Therefore, in lieu of not performing a research or clinical MRI exam at 7-T, the supervising physician may make a decision to scan the individual with an untested metallic implant based on an analysis of the risks vs. the benefits. We present a case report of a research subject with bilateral, total knee replacement implants that safely underwent MRI of the brain at 7-T and provide guidelines for healthcare professionals to follow in order to ensure safety in research subjects or patients with metallic implants referred for 7-T scans.

Photoacoustic computed tomography (PACT) has been extensively explored in animal brains but never in the human brain due to its limited field of view (FOV), imaging speed, penetration depth, and sensitivity. Here, we present the first application of PACT in functional human brain imaging. Motor and language functional tasks were employed and performed by post-hemicraniectomy patients. The brain activities were recorded at a 10-cm–diameter FOV, 350-μm/2-s spatiotemporal resolution, and ~2-cm penetration depth using a newly developed massively parallel three-dimensional PACT system. Quantitative validation of the PACT results against 7 Tesla MRI revealed comparable angiographic structures and functional activation in the same FOV. The obtained results represent a critical step toward broader-scope human brain imaging applications using PACT technology.

Blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging of the human brain requires bulky equipment for the generation of magnetic fields. Photoacoustic computed tomography obviates the need for magnetic fields by using light and sound to measure deoxyhaemoglobin and oxyhaemoglobin concentrations to then quantify oxygen saturation and blood volumes. Yet, the available imaging speeds, fields of view (FOV), sensitivities and penetration depths have been insufficient for functional imaging of the human brain. Here, we show that massively parallel ultrasonic transducers arranged hemispherically around the human head can produce tomographic images of the brain with a 10-cm-diameter FOV and spatial and temporal resolutions of 350 µm and 2 s, respectively. In patients who had a hemicraniectomy, a comparison of functional photoacoustic computed tomography and 7 T BOLD functional magnetic resonance imaging showed a strong spatial correspondence in the same FOV and a high temporal correlation between BOLD signals and photoacoustic signals, with the latter enabling faster detection of functional activation. Our findings establish the use of photoacoustic computed tomography for human brain imaging. Massively parallel ultrasonic transducers arranged hemispherically around the human head enable functional photoacoustic computed tomography of the human brain with a 10-cm-diameter field of view and resolutions of 350 µm and 2 s.

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 T2 -weighted fast spin-echo imaging (T2w), and two-dimensional T2*-weighted gradient echo echo-planar blood-oxygenation-level-dependent imaging with brief periods of CO2 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.

Head motion during MRI acquisition presents significant challenges for neuroimaging analyses. In this work, we present a retrospective motion correction framework built on a Fourier domain motion simulation model combined with established 3D convolutional neural network (CNN) architectures. Quantitative evaluation metrics were used to validate the method on three separate multi-site datasets. The 3D CNN was trained using motion-free images that were corrupted using simulated artifacts. CNN based correction successfully diminished the severity of artifacts on real motion affected data on a separate test dataset as measured by significant improvements in image quality metrics compared to a minimal motion reference image. On the test set of 13 image pairs, the mean peak signal-to-noise-ratio was improved from 31.7 to 33.3 dB. Furthermore, improvements in cortical surface reconstruction quality were demonstrated using a blinded manual quality assessment on the Parkinson's Progression Markers Initiative (PPMI) dataset. Upon applying the correction algorithm, out of a total of 617 images, the number of quality control failures was reduced from 61 to 38. On this same dataset, we investigated whether motion correction resulted in a more statistically significant relationship between cortical thickness and Parkinson's disease. Before correction, significant cortical thinning was found to be restricted to limited regions within the temporal and frontal lobes. After correction, there was found to be more widespread and significant cortical thinning bilaterally across the temporal lobes and frontal cortex. Our results highlight the utility of image domain motion correction for use in studies with a high prevalence of motion artifacts, such as studies of movement disorders as well as infant and pediatric subjects.

Arterial spin labeled (ASL) perfusion MRI is an appealing neuroimaging technology to study brain development due to its entirely noninvasive nature and several physiological properties of a child brain. In this chapter, we discussed 1. How physiological parameter variations (blood T1, arterial transit time and blood flow velocity) of the pediatric population affect the accuracy of perfusion quantification; 2. Current research on perfusion across typical brain development and neurodevelopmental disorders; and 3. New technical developments to improve spatial resolution, quantification accuracy and robustness to motion for pediatric ASL studies.

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.

Introduction: Single ventricle heart disease (SVHD) adolescents with a single right ventricle (RV) have worse cognition and mood function compared to single left ventricle (LV) which may result from variability in ventricular function or structure related sequela after Fontan completion. However, it is unclear whether RV SVHD has worse cerebral blood flow (CBF) in cognitive and mood regulatory areas over LV SVHD compared to healthy controls. Methods: Cross-sectional, comparative design, 14 adolescents with RV SVHD (age 16.1±1.5 years; 7 male), 6 LV SVHD (age, 16.3±1.0 years; 4 male), and 25 healthy controls (age, 15.9±1.4 years; 13 male) were studied. SVHD participants were recruited who have undergone surgical palliation with Fontan completion from local pediatric cardiology clinics. Self-reported healthy controls were recruited from the community. Brain MRI studies were performed using a 3.0-Tesla MRI scanner and 3D pseudo-continuous arterial spin labelling data were collected. We calculated whole-brain CBF maps, normalized to a common space, and assessed brain changes between RV and LV SVHD and controls [ANCOVA; covariates, age and sex; p Results: Regional brain CBF was reduced in single RV over LV SVHD. Multiple brain sites showed more widespread reduced CBF values in RV over LV SVHD compared to controls (Figure 1, p Conclusion: Single RV adolescents show more widespread reduced CBF than single LV in cognitive and mood regulatory sites, which may result from variable function or structure related sequela between ventricle types. The findings indicate that the therapeutic approach should recognize the differences in CBF based on ventricle type and investigate interventions to optimize CBF in single RV SVHD.

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 B1+ 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 B1+ amplitude allowed was recommended for 7 tesla pulsed arterial spin labeling.

Background and Purpose: 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).Methods: Pseudo-continuous ASL was performed along with DWI in 102 patients within 24 h post-treatments. The infarction core was identified using ADC values

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 in vivo. 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.

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.