Altered oxidative neurometabolic response to methylene blue in bipolar disorder revealed by quantitative neuroimaging.

BACKGROUND: Cerebral mitochondrial and hemodynamic abnormalities have been implicated in Bipolar Disorder pathophysiology, likely contributing to neurometabolic vulnerability-leading to worsen clinical outcomes and mood instability. To investigate neurometabolic vulnerability in patients with BD, we combined multi-modal quantitative MRI assessment of cerebral oxygenation with acute administration of Methylene Blue, a neurometabolic/hemodynamic modulator acting on cerebral mitochondria. METHODS: Fifteen euthymic patients with chronic BD-type 1, and fifteen age/gender-matched healthy controls underwent two separate MRI sessions in a single-blinded randomized cross-over design, each after intravenous infusion of either MB (0.5 mg/kg) or placebo. MRI-based measures of Cerebral Blood Flow and Oxygen Extraction Fraction were integrated to compute Cerebral Metabolic Rate of Oxygen in Frontal Lobe, Anterior Cingulate, and Hippocampus-implicated in BD neurometabolic pathophysiology. Inter-daily variation in mood rating was used to assess mood instability. RESULTS: A decrease in global CBF and CMRO2 was observed after acutely administrating MB to all participants. Greater regional CMRO2 reductions were observed after MB, in patients compared to controls in FL (mean = -14.2 ± 19.5 % versus 2.3 ± 14.8 %), ACC (mean = -14.8 ± 23.7 % versus 2.4 ± 15.7 %). The effects on CMRO2 in those regions were primarily driven by patients with longer disease duration and higher mood instability. LIMITATIONS: Sample size; medications potentially impacting on response to MB. CONCLUSIONS: An altered neurometabolic response to MB, a mitochondrial/hemodynamic modulator, was observed in patients, supporting the hypothesis of vulnerability to neurometabolic stress in BD. Integrating quantitative imaging of cerebral oxygen metabolism with a mitochondrial-targeting pharmacological challenge could provide a novel biomarker of neurometabolic and cerebrovascular pathophysiology in BD.

Recommendations for quantitative cerebral perfusion MRI using multi-timepoint arterial spin labeling: Acquisition, quantification, and clinical applications.

Accurate assessment of cerebral perfusion is vital for understanding the hemodynamic processes involved in various neurological disorders and guiding clinical decision-making. This guidelines article provides a comprehensive overview of quantitative perfusion imaging of the brain using multi-timepoint arterial spin labeling (ASL), along with recommendations for its acquisition and quantification. A major benefit of acquiring ASL data with multiple label durations and/or post-labeling delays (PLDs) is being able to account for the effect of variable arterial transit time (ATT) on quantitative perfusion values and additionally visualize the spatial pattern of ATT itself, providing valuable clinical insights. Although multi-timepoint data can be acquired in the same scan time as single-PLD data with comparable perfusion measurement precision, its acquisition and postprocessing presents challenges beyond single-PLD ASL, impeding widespread adoption. Building upon the 2015 ASL consensus article, this work highlights the protocol distinctions specific to multi-timepoint ASL and provides robust recommendations for acquiring high-quality data. Additionally, we propose an extended quantification model based on the 2015 consensus model and discuss relevant postprocessing options to enhance the analysis of multi-timepoint ASL data. Furthermore, we review the potential clinical applications where multi-timepoint ASL is expected to offer significant benefits. This article is part of a series published by the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group, aiming to guide and inspire the advancement and utilization of ASL beyond the scope of the 2015 consensus article.

Bringing MRI to low- and middle-income countries: Directions, challenges and potential solutions.

The global disparity of magnetic resonance imaging (MRI) is a major challenge, with many low- and middle-income countries (LMICs) experiencing limited access to MRI. The reasons for limited access are technological, economic and social. With the advancement of MRI technology, we explore why these challenges still prevail, highlighting the importance of MRI as the epidemiology of disease changes in LMICs. In this paper, we establish a framework to develop MRI with these challenges in mind and discuss the different aspects of MRI development, including maximising image quality using cost-effective components, integrating local technology and infrastructure and implementing sustainable practices. We also highlight the current solutions-including teleradiology, artificial intelligence and doctor and patient education strategies-and how these might be further improved to achieve greater access to MRI.

Higher order diffusion imaging as a putative index of human sleep-related microstructural changes and glymphatic clearance.

The brain has a unique macroscopic waste clearance system, termed the glymphatic system which utilises perivascular tunnels surrounded by astroglia to promote cerebrospinal-interstitial fluid exchange. Rodent studies have demonstrated a marked increase in glymphatic clearance during sleep which has been linked to a sleep-induced expansion of the extracellular space and concomitant reduction in intracellular volume. However, despite being implicated in the pathophysiology of multiple human neurodegenerative disorders, non-invasive techniques for imaging glymphatic clearance in humans are currently limited. Here we acquired multi-shell diffusion weighted MRI (dwMRI) in twenty-one healthy young participants (6 female, 22.3 ± 3.2 years) each scanned twice, once during wakefulness and once during sleep induced by a combination of one night of sleep deprivation and 10 mg of the hypnotic zolpidem 30 min before scanning. To capture hypothesised sleep-associated changes in intra/extracellular space, dwMRI were analysed using higher order diffusion modelling with the prediction that sleep-associated increases in interstitial (extracellular) fluid volume would result in a decrease in diffusion kurtosis, particularly in areas associated with slow wave generation at the onset of sleep. In line with our hypothesis, we observed a global reduction in diffusion kurtosis (t15=2.82, p = 0.006) during sleep as well as regional reductions in brain areas associated with slow wave generation during early sleep and default mode network areas that are highly metabolically active during wakefulness. Analysis with a higher-order representation of diffusion (MAP-MRI) further indicated that changes within the intra/extracellular domain rather than membrane permeability likely underpin the observed sleep-associated decrease in kurtosis. These findings identify higher-order modelling of dwMRI as a potential new non-invasive method for imaging glymphatic clearance and extend rodent findings to suggest that sleep is also associated with an increase in interstitial fluid volume in humans.

Arterial spin labeling signal in the CSF: Implications for partial volume correction and blood-CSF barrier characterization.

For better quantification of perfusion with arterial spin labeling (ASL), partial volume correction (PVC) is used to disentangle the signals from gray matter (GM) and white matter within any voxel. Based on physiological considerations, PVC algorithms typically assume zero signal in the cerebrospinal fluid (CSF). Recent measurements, however, have shown that CSF-ASL signal can exceed 10% of GM signal, even when using recommended ASL labeling parameters. CSF signal is expected to particularly affect PVC results in the choroid plexus. This study aims to measure the impact of CSF signal on PVC perfusion measurements, and to investigate the potential use of PVC to retrieve pure CSF-ASL signal for blood-CSF barrier characterization. In vivo imaging included six pCASL sequences with variable label duration and post-labeling delay (PLD), and an eight-echo 3D-GRASE readout. A dataset was simulated to estimate the effect of CSF-PVC with known ground-truth parameters. Differences between the results of CSF-PVC and non-CSF-PVC were estimated for regions of interest (ROIs) based on GM probability, and a separate ROI isolating the choroid plexus. In vivo, the suitability of PVC-CSF signal as an estimate of pure CSF was investigated by comparing its time course with the long-TE CSF signal. Results from both simulation and in vivo data indicated that including the CSF signal in PVC improves quantification of GM CBF by approximately 10%. In simulated data, this improvement was greater for multi-PLD (model fitting) quantification than for single PLD (~1-5% difference). In the choroid plexus, the difference between CSF-PVC and non-CSF-PVC was much larger, averaging around 30%. Long-TE (pure) CSF signal could not be estimated from PVC CSF signal as it followed a different time course, indicating the presence of residual macrovascular signal in the PVC. The inclusion of CSF adds value to PVC for more accurate measurements of GM perfusion, and especially for quantification of perfusion in the choroid plexus and study of the glymphatic system.

A framework for advancing sustainable magnetic resonance imaging access in Africa.

Magnetic resonance imaging (MRI) technology has profoundly transformed current healthcare systems globally, owing to advances in hardware and software research innovations. Despite these advances, MRI remains largely inaccessible to clinicians, patients, and researchers in low-resource areas, such as Africa. The rapidly growing burden of noncommunicable diseases in Africa underscores the importance of improving access to MRI equipment as well as training and research opportunities on the continent. The Consortium for Advancement of MRI Education and Research in Africa (CAMERA) is a network of African biomedical imaging experts and global partners, implementing novel strategies to advance MRI access and research in Africa. Upon its inception in 2019, CAMERA sets out to identify challenges to MRI usage and provide a framework for addressing MRI needs in the region. To this end, CAMERA conducted a needs assessment survey (NAS) and a series of symposia at international MRI society meetings over a 2-year period. The 68-question NAS was distributed to MRI users in Africa and was completed by 157 clinicians and scientists from across Sub-Saharan Africa (SSA). On average, the number of MRI scanners per million people remained at less than one, of which 39% were obsolete low-field systems but still in use to meet daily clinical needs. The feasibility of coupling stable energy supplies from various sources has contributed to the growing number of higher-field (1.5 T) MRI scanners in the region. However, these systems are underutilized, with only 8% of facilities reporting clinical scans of 15 or more patients per day, per scanner. The most frequently reported MRI scans were neurological and musculoskeletal. The CAMERA NAS combined with the World Health Organization and International Atomic Energy Agency data provides the most up-to-date data on MRI density in Africa and offers a unique insight into Africa's MRI needs. Reported gaps in training, maintenance, and research capacity indicate ongoing challenges in providing sustainable high-value MRI access in SSA. Findings from the NAS and focused discussions at international MRI society meetings provided the basis for the framework presented here for advancing MRI capacity in SSA. While these findings pertain to SSA, the framework provides a model for advancing imaging needs in other low-resource settings.

Diffusion-weighted MR spectroscopy (DW-MRS) is sensitive to LPS-induced changes in human glial morphometry: A preliminary study.

BACKGROUND: Low-dose lipopolysaccharide (LPS) is a well-established experimental method for inducing systemic inflammation and shown by microscopy to activate microglia in rodents. Currently, techniques for in-vivo imaging of glia in humans are limited to TSPO (Translocator protein) PET, which is expensive, methodologically challenging, and has poor cellular specificity. Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) sensitizes MR spectra to diffusion of intracellular metabolites, potentially providing cell-specific information about cellular morphology. In this preliminary study, we applied DW-MRS to measure changes in the apparent diffusion coefficients (ADC) of glial and neuronal metabolites to healthy participants who underwent an LPS administration protocol. We hypothesized that the ADC of glial metabolites will be selectively modulated by LPS-induced glial activation. METHODS: Seven healthy male volunteers, (mean 25.3 ± 5.9 years) were each tested in two separate sessions once after LPS (1 ng/Kg intravenously) and once after placebo (saline). Physiological responses were monitored during each session and serial blood samples and Profile of Mood States (POMS) completed to quantify white blood cell (WBC), cytokine and mood responses. DW-MRS data were acquired 5-5½ hours after injection from two brain regions: grey matter in the left thalamus, and frontal white matter. RESULTS: Body temperature, heart rate, WBC and inflammatory cytokines were significantly higher in the LPS compared to the placebo condition (p < 0.001). The ADC of the glial metabolite choline (tCho) was also significantly increased after LPS administration compared to placebo (p = 0.008) in the thalamus which scaled with LPS-induced changes in POMS total and negative mood (Adj R2 = 0.83; p = 0.004). CONCLUSIONS: DW-MRS may be a powerful new tool sensitive to glial cytomorphological changes in grey matter induced by systemic inflammation.

Partial volume correction in arterial spin labeling perfusion MRI: A method to disentangle anatomy from physiology or an analysis step too far?

The mismatch in the spatial resolution of Arterial Spin Labeling (ASL) MRI perfusion images and the anatomy of functionally distinct tissues in the brain leads to a partial volume effect (PVE), which in turn confounds the estimation of perfusion into a specific tissue of interest such as gray or white matter. This confound occurs because the image voxels contain a mixture of tissues with disparate perfusion properties, leading to estimated perfusion values that reflect primarily the volume proportions of tissues in the voxel rather than the perfusion of any particular tissue of interest within that volume. It is already recognized that PVE influences studies of brain perfusion, and that its effect might be even more evident in studies where changes in perfusion are co-incident with alterations in brain structure, such as studies involving a comparison between an atrophic patient population vs control subjects, or studies comparing subjects over a wide range of ages. However, the application of PVE correction (PVEc) is currently limited and the employed methodologies remain inconsistent. In this article, we outline the influence of PVE in ASL measurements of perfusion, explain the main principles of PVEc, and provide a critique of the current state of the art for the use of such methods. Furthermore, we examine the current use of PVEc in perfusion studies and whether there is evidence to support its wider adoption. We conclude that there is sound theoretical motivation for the use of PVEc alongside conventional, 'uncorrected', images, and encourage such combined reporting. Methods for PVEc are now available within standard neuroimaging toolboxes, which makes our recommendation straightforward to implement. However, there is still more work to be done to establish the value of PVEc as well as the efficacy and robustness of existing PVEc methods.

ExploreASL: An image processing pipeline for multi-center ASL perfusion MRI studies.

Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners. The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. To facilitate collaboration and data-exchange, the toolbox follows several standards and recommendations for data structure, provenance, and best analysis practice. ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a variety of clinical populations, resulting in four processing modules: Import, Structural, ASL, and Population that perform tasks, respectively, for data curation, structural and ASL image processing and quality control, and finally preparing the results for statistical analyses on both single-subject and group level. We illustrate ExploreASL processing results from three cohorts: perinatally HIV-infected children, healthy adults, and elderly at risk for neurodegenerative disease. We show the reproducibility for each cohort when processed at different centers with different operating systems and MATLAB versions, and its effects on the quantification of gray matter cerebral blood flow. ExploreASL facilitates the standardization of image processing and quality control, allowing the pooling of cohorts which may increase statistical power and discover between-group perfusion differences. Ultimately, this workflow may advance ASL for wider adoption in clinical studies, trials, and practice.

Cognitive Impairment Correlates Linearly with Mean Flow Velocity by Transcranial Doppler below a Definable Threshold.

INTRODUCTION: Low cerebral blood flow can affect cognition in patients with high-grade asymptomatic internal carotid artery stenosis. Current clinical algorithms use stroke risk to determine which patients should undergo revascularization without considering cognitive decline. Although correlations between low-flow and cognitive impairment have been reported, it is not known whether a threshold exists below which such a correlation expresses itself. Such information would be critical in treatment decisions about whether to intervene in patients with high-grade carotid artery stenosis who are at risk for cognitive decline. OBJECTIVE: To determine how reduced blood flow correlates with lower cognitive scores. METHODS: Patients with ≥80% unilateral internal carotid artery stenosis with no history of stroke were recruited from inpatient and outpatient practices at a single, large, comprehensive stroke center. Patients underwent bilateral insonation of middle cerebral arteries with standard 2-Hz probes over the temporal windows with transcranial Doppler. Cognitive assessments were performed by an experienced neuropsychologist using a cognitive battery comprising 14 standardized tests with normative samples grouped by age. Z-scores were generated for each test and averaged to obtain a composite Z-score for each patient. Multivariable linear regression examined associations between mean flow velocity (MFV) and composite Z-score, adjusting for age, education, and depression. The Davies test was used to determine if there was a breakpoint for a non-zero difference in slope of a segmented relationship over the range of composite Z-score values. RESULTS: Forty-two patients with unilateral high-grade internal carotid artery stenosis without stroke were enrolled (26 males, age = 74 ± 9 years, education = 16 ± 3 years). Average composite Z-score was -0.31 SD below the age-specific normative mean (range -2.8 to +1.2 SD). In linear regression adjusted for age, education, and depression, MFV correlated with cognitive Z-score (ß = 0.308, p = 0.043). A single breakpoint in the range of composite Z-scores was identified at 45 cm/s. For MFV <45 cm/s, Z-score decreased 0.05 SD per cm/s MFV (95% CI: 0.01-0.10). For MFV >45 cm/s, Z-score change was nonsignificant (95% CI: -0.07 to 0.05). CONCLUSIONS: In high-grade, asymptomatic carotid artery stenosis, cognitive impairment correlated linearly with lower flow in the hemisphere fed by the occluded internal carotid artery, but only below a threshold of MFV = 45 cm/s. Identifying a hemodynamic threshold for cognitive decline using a simple, noninvasive method may influence revascularization decision-making in otherwise "asymptomatic" carotid disease.

Spatial coefficient of variation of arterial spin labeling MRI as a cerebrovascular correlate of carotid occlusive disease.

Clinical interpretation of arterial spin labeling (ASL) perfusion MRI in cerebrovascular disease remains challenging mainly because of the method's sensitivity to concomitant contributions from both intravascular and tissue compartments. While acquisition of multi-delay images can differentiate between the two contributions, the prolonged acquisition is prone to artifacts and not practical for clinical applications. Here, the utility of the spatial coefficient of variation (sCoV) of a single-delay ASL image as a marker of the intravascular contribution was evaluated by testing the hypothesis that sCoV can detect the effects of differences in label arrival times between ipsi- and contra-lateral hemispheres even in the absence of a hemispheric difference in CBF. Hemispheric lateralization values for sCoV and CBF were computed from ASL images acquired on 28 patients (age 73.9 ± 10.2 years, 8 women) with asymptomatic unilateral carotid occlusion. The results showed that sCoV lateralization predicted the occluded side with 96.4% sensitivity, missing only 1 patient. In contrast, the sensitivity of the CBF lateralization was 71.4%, with 8 patients showing no difference in CBF between hemispheres. The findings demonstrate the potential clinical utility of sCoV as a cerebrovascular correlate of large vessel disease. Using sCoV in tandem with CBF, vascular information can be obtained in image processing without the need for additional scan-time.

Late-life brain perfusion after prenatal famine exposure.

Early nutritional deprivation may cause irreversible damage to the brain and seems to affect cognitive function in older age. We investigated whether prenatal undernutrition was associated with brain perfusion differences in older age. We acquired Arterial spin labeling scans in 118 Dutch famine birth cohort members. Using linear regression analyses, cerebral blood flow was compared between exposed and unexposed groups in gray matter (GM) and white matter (WM), perfusion territories, the neurodegeneration-related regions anterior and posterior cingulate cortex and precuneus. Furthermore, we compared the GM/WM ratio and the spatial coefficient of variation as a proxy of overall cerebrovascular health. The WM arterial spin labeling signal and the GM/WM ratio were significantly lower and higher, respectively, among exposed participants (-2.5 mL/100 g/min [95% CI: -4.3 to -0.8; p = 0.01] and 0.48 [0.19 to 0.76; p = 0.002], respectively). Exposed men had lower cerebral blood flow in anterior and posterior cingulate cortices (-8.0 mL/100 g/min [-15.1 to -0.9; p = 0.03]; -11.4 mL/100 g/min [-19.6 to -3.2; p = 0.02]) and higher spatial coefficient of variation (0.05 [0.00 to 0.09; p = 0.05]). The latter seemed largely mediated by higher 2h-glucose levels at age 50. Our findings suggest that prenatal undernutrition affects brain perfusion parameters providing further evidence for life-long effects of undernutrition during early brain development.

Effects of systematic partial volume errors on the estimation of gray matter cerebral blood flow with arterial spin labeling MRI.

OBJECTIVE: Partial volume (PV) correction is an important step in arterial spin labeling (ASL) MRI that is used to separate perfusion from structural effects when computing the mean gray matter (GM) perfusion. There are three main methods for performing this correction: (1) GM-threshold, which includes only voxels with GM volume above a preset threshold; (2) GM-weighted, which uses voxel-wise GM contribution combined with thresholding; and (3) PVC, which applies a spatial linear regression algorithm to estimate the flow contribution of each tissue at a given voxel. In all cases, GM volume is obtained using PV maps extracted from the segmentation of the T1-weighted (T1w) image. As such, PV maps contain errors due to the difference in readout type and spatial resolution between ASL and T1w images. Here, we estimated these errors and evaluated their effect on the performance of each PV correction method in computing GM cerebral blood flow (CBF). MATERIALS AND METHODS: Twenty-two volunteers underwent scanning using 2D echo planar imaging (EPI) and 3D spiral ASL. For each PV correction method, GM CBF was computed using PV maps simulated to contain estimated errors due to spatial resolution mismatch and geometric distortions which are caused by the mismatch in readout between ASL and T1w images. Results were analyzed to assess the effect of each error on the estimation of GM CBF from ASL data. RESULTS: Geometric distortion had the largest effect on the 2D EPI data, whereas the 3D spiral was most affected by the resolution mismatch. The PVC method outperformed the GM-threshold even in the presence of combined errors from resolution mismatch and geometric distortions. The quantitative advantage of PVC was 16% without and 10% with the combined errors for both 2D and 3D ASL. Consistent with theoretical expectations, for error-free PV maps, the PVC method extracted the true GM CBF. In contrast, GM-weighted overestimated GM CBF by 5%, while GM-threshold underestimated it by 16%. The presence of PV map errors decreased the calculated GM CBF for all methods. CONCLUSION: The quality of PV maps presents no argument for the preferential use of the GM-threshold method over PVC in the clinical application of ASL.

Resting state cerebral blood flow with arterial spin labeling MRI in developing human brains.

The development of brain circuits is coupled with changes in neurovascular coupling, which refers to the close relationship between neural activity and cerebral blood flow (CBF). Studying the characteristics of CBF during resting state in developing brain can be a complementary way to understand the functional connectivity of the developing brain. Arterial spin labeling (ASL), as a noninvasive MR technique, is particularly attractive for studying cerebral perfusion in children and even newborns. We have collected pulsed ASL data in resting state for 47 healthy subjects from young children to adolescence (aged from 6 to 20 years old). In addition to studying the developmental change of static CBF maps during resting state, we also analyzed the CBF time series to reveal the dynamic characteristics of CBF in differing age groups. We used the seed-based correlation analysis to examine the temporal relationship of CBF time series between the selected ROIs and other brain regions. We have shown the developmental patterns in both static CBF maps and dynamic characteristics of CBF. While higher CBF of default mode network (DMN) in all age groups supports that DMN is the prominent active network during the resting state, the CBF connectivity patterns of some typical resting state networks show distinct patterns of metabolic activity during the resting state in the developing brains.

Photon vs. proton radiochemotherapy: Effects on brain tissue volume and perfusion.

BACKGROUND AND PURPOSE: To compare the structural and hemodynamic changes of healthy brain tissue in the cerebral hemisphere contralateral to the tumor following photon and proton radiochemotherapy. MATERIALS AND METHODS: Sixty-seven patients (54.9 ±14.0 years) diagnosed with glioblastoma undergoing adjuvant photon (n = 47) or proton (n = 19) radiochemotherapy with temozolomide after tumor resection underwent T1-weighted and arterial spin labeling MRI. Changes in volume and perfusion before and 3 to 6 months after were compared between therapies. RESULTS: A decrease in gray matter (GM) (-2.2%, P<0.001) and white matter (WM) (-1.2%, P<0.001) volume was observed in photon-therapy patients compared to the pre-radiotherapy baseline. In contrast, for the proton-therapy group, no significant differences in GM (0.3%, P = 0.64) or WM (-0.4%, P = 0.58) volume were observed. GM volume decreased with 0.9% per 10 Gy dose increase (P<0.001) and differed between the radiation modalities (P<0.001). Perfusion decreased in photon-therapy patients (-10.1%, P = 0.002), whereas the decrease in proton-therapy patients, while comparable in magnitude, did not reach statistical significance (-9.1%, P = 0.12). There was no correlation between perfusion decrease and either dose (P = 0.64) or radiation modality (P = 0.94). CONCLUSIONS: Our results show that the tissue volume decrease depends on radiation dose delivered to the healthy hemisphere and differs between treatment modalities. In contrast, the decrease in perfusion was comparable for both irradiation modalities. We conclude that proton therapy may reduce brain-volume loss when compared to photon therapy.

Altered cerebral hemodyamics and cortical thinning in asymptomatic carotid artery stenosis.

Cortical thinning is a potentially important biomarker, but the pathophysiology in cerebrovascular disease is unknown. We investigated the association between regional cortical blood flow and regional cortical thickness in patients with asymptomatic unilateral high-grade internal carotid artery disease without stroke. Twenty-nine patients underwent high resolution anatomical and single-delay, pseudocontinuous arterial spin labeling magnetic resonance imaging with partial volume correction to assess gray matter baseline flow. Cortical thickness was estimated using Freesurfer software, followed by co-registration onto each patient's cerebral blood flow image space. Paired t-tests assessed regional cerebral blood flow in motor cortex (supplied by the carotid artery) and visual cortex (indirectly supplied by the carotid) on the occluded and unoccluded side. Pearson correlations were calculated between cortical thickness and regional cerebral blood flow, along with age, hypertension, diabetes and white matter hyperintensity volume. Multiple regression and generalized estimating equation were used to predict cortical thickness bilaterally and in each hemisphere separately. Cortical blood flow correlated with thickness in motor cortex bilaterally (p = 0.0002), and in the occluded and unoccluded sides individually; age (p = 0.002) was also a predictor of cortical thickness in the motor cortex. None of the variables predicted cortical thickness in visual cortex. Blood flow was significantly lower on the occluded versus unoccluded side in the motor cortex (p<0.0001) and in the visual cortex (p = 0.018). On average, cortex was thinner on the side of occlusion in motor but not in visual cortex. The association between cortical blood flow and cortical thickness in carotid arterial territory with greater thinning on the side of the carotid occlusion suggests that altered cerebral hemodynamics is a factor in cortical thinning.

Decreased cerebral perfusion in Duchenne muscular dystrophy patients.

Duchenne muscular dystrophy is caused by dystrophin gene mutations which lead to the absence of the protein dystrophin. A significant proportion of patients suffer from learning and behavioural disabilities, in addition to muscle weakness. We have previously shown that these patients have a smaller total brain and grey matter volume, and altered white matter microstructure compared to healthy controls. Patients with more distal gene mutations, predicted to affect dystrophin isoforms Dp140 and Dp427, showed greater grey matter reduction. Now, we studied if cerebral blood flow in Duchenne muscular dystrophy patients is altered, since cerebral expression of dystrophin also occurs in vascular endothelial cells and astrocytes associated with cerebral vasculature. T1-weighted anatomical and pseudo-continuous arterial spin labeling cerebral blood flow images were obtained from 26 patients and 19 age-matched controls (ages 8-18 years) on a 3 tesla MRI scanner. Group comparisons of cerebral blood flow were made with and without correcting for grey matter volume using partial volume correction. Results showed that patients had a lower cerebral blood flow than controls (40.0 ± 6.4 and 47.8 ± 6.3 mL/100 g/min respectively, p = 0.0002). This reduction was independent of grey matter volume, suggesting that they are two different aspects of the pathophysiology. Cerebral blood flow was lowest in patients lacking Dp140. There was no difference in CBF between ambulant and non-ambulant patients. Only three patients showed a reduced left ventricular ejection fraction. No correlation between cerebral blood flow and age was found. Our results indicate that cerebral perfusion is reduced in Duchenne muscular dystrophy patients independent of the reduced grey matter volume.

Measurement of cortical thickness asymmetry in carotid occlusive disease.

Despite being considered an important anatomical parameter directly related to neuronal density, cortical thickness is not routinely assessed in studies of the human brain in vivo. This paucity has been largely due to the size and convoluted shape of the human cortex, which has made it difficult to develop automated algorithms that can measure cortical thickness efficiently and reliably. Since the development of such an algorithm by Fischl and Dale in 2000, the number of studies investigating the relationship between cortical thickness and other physiological parameters in the brain has been on the rise. There have been no studies however that have validated cortical asymmetry against known vascular anatomy. To this aim, using high-resolution MRI, we measured cortical thickness and volume in the primary motor (M1) and primary visual (V1) cortex in patients with unilateral, high-grade carotid occlusive disease (n = 29, age = 74 ± 10 years). These regions were selected based on the hypothesis that there will be thinning of the cortical thickness of M1 in the territory supplied by the occluded carotid artery, whereas V1 will show no asymmetry since its blood supply is provided by unaffected posterior arteries. To test for an effect of handedness, cortical thickness and volume were also measured in healthy volunteers (n = 8, age = 37 ± 13 years). In patients, we found thinner cortex in M1 on the occluded side (mean = 2.07 ± 0.19 mm vs 2.15 ± 0.20 mm, p = 0.0008) but no hemispheric difference in V1 (1.80 ± 0.17 mm in occluded vs 1.78 ± 0.16 mm in unoccluded, p = 0.31). Although the mean cortical volume of M1 in the occluded hemisphere was also lower, the difference did not reach statistical significance (p = 0.09). Similarly, in healthy controls, the results showed no hemispheric asymmetry in either cortical thickness or volume in either region (p > 0.1). To test for an orientation bias in the method, the analysis was repeated with images flipped from neurological to radiological orientation. While the algorithm did not yield identical results for the two orientations, the effect did not alter the findings of the study. These results provide a method for within-subject validation of a pathophysiological effect of carotid occlusive disease on the human cortex and warrant further investigation for underlying mechanisms.

Dissociation among hemodynamic measures in asymptomatic high grade carotid artery stenosis.

BACKGROUND: Cerebral blood flow (CBF) regulation is a critical element in cerebrovascular pathophysiology, particularly in large vessel disease, but the best method to use for hemodynamic assessment is not clear. We examined 4 different blood-flow related measures in patients with unilateral high-grade carotid artery disease, assessing asymmetry between the occluded vs non-occluded side, and the correlations among the measures. METHODS: Thirty-three patients (age 50-93, 19 M) with unilateral 80-100% ICA occlusion but no stroke underwent: 1) mean flow velocity (MFV) in both middle cerebral arteries by transcranial Doppler (TCD), 2) quantitative resting CBF using pseudo-continuous arterial spin labeling (pCASL) MRI, 3) vasomotor reactivity (VMR) in response to 5% CO2 inhalation, and 4) dynamic cerebral autoregulation (DCA) assessing the counter-regulation of blood flow to spontaneous changes in blood pressure using TCD monitoring and finger photoplethysmography. Paired t-tests and Pearson correlations assessed side-to-side differences within each measure, and correlations between measures. RESULTS: CBF (p=0.001), MFV (p<0.001), VMR (p=0.008), and DCA (p=0.047) all showed significantly lower values on the occluded side. The 4 measures were independent of each other on correlation analysis, even when controlling for age and anterior circle of Willis collateral (all partial correlations <0.233 and p-values >0.468). CONCLUSIONS: These 4 measures showed high sensitivity to the occluded carotid artery, but their dissociation suggests that any given measure only partially characterizes the hemodynamic state. Additional research is needed to explore the multifaceted biology of cerebral blood flow regulation.

Improved partial volume correction method for detecting brain activation in disease using Arterial Spin Labeling (ASL) fMRI.

The insight provided by fMRI, particularly BOLD fMRI, has been critical to the understanding of human brain function. Unfortunately, the application of fMRI techniques in clinical research has been held back by several factors. In order for the clinical field to successfully apply fMRI, two main challenges posed by aging and diseased brains need to be overcome: (1) difficulties in signal measurement and interpretation, and (2) partial voluming effects (PVE). Recent work has addressed the first challenge by developing fMRI methods that, in contrast to BOLD, provide a direct measurement of a physiological correlate of function. One such method is Arterial Spin Labeling (ASL) fMRI, which provides images of cerebral blood flow (CBF) in physiologically meaningful units. Although the problems caused by PVE can be mitigated to some degree through the acquisition of high spatial resolution fMRI data, both hardware and experimental design considerations limit this solution. Our team has developed a PVE correction (PVEc) algorithm that produces CBF images that are theoretically independent of tissue content and the associated PVE. The main drawback of the current PVEc method is that it introduces an inherent smoothing of the functional data. This smoothing effect can reduce the sensitivity of the method, complicating the detection of local changes in CBF, such as those due to stroke or activation. Here, we present results from an improved PVEc algorithm (ssPVEc), which uses high-resolution structural space information to correct for the tissue-driven heterogeneity in the ASL signal. We tested the ssPVEc method on ASL images obtained on patients with asymptomatic carotid occlusive disease during rest and motor activation. Our results showed that the sensitivity of the ssPVEc method (defined as the average T-value in the activated region) was at least 1.5 times greater than that of the original, functional space, fsPVEc, for all patients.