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Background and Purpose Methods Results Conclusions Ischemic strokes due to isolated posterior cerebral artery (PCA) occlusions represent 5% of all strokes but have significant impacts on patients’ quality of life, primarily due to visual deficits and thalamic involvement. Current guidelines for acute PCA occlusion management are sparse, and the prognostic value of perfusion imaging parameters remains underexplored.We conducted a retrospective analysis of 32 patients with isolated PCA occlusions treated at Johns Hopkins Medical Institutions between January 2017 and March 2023. Patients underwent pretreatment perfusion imaging, with perfusion parameters analyzed using RAPID software. The primary outcome was short‐term clinical outcome as measured by the National Institutes of Health Stroke Scale (NIHSS) at discharge.The median age of the cohort was 70 years, with 34% female and 66% male. Significant correlations were found between NIHSS at discharge and various perfusion parameters, including time‐to‐maximum (Tmax) >6 seconds (ρ = .55, p = .004), Tmax >8 seconds (ρ = .59, p = .002), Tmax >10 seconds (ρ = .6, p = .001), mismatch volume (ρ = .51, p = .008), and cerebral blood volume (CBV) < 34% (ρ = .59, p = .002).Tmax and CBV volumes significantly correlated with discharge NIHSS with marginal superiority of Tmax >10 seconds and CBV <42% volumes. These findings suggest that CT and MR perfusion imaging can play a crucial role in the acute management of PCA strokes, though larger, standardized studies are needed to validate these results and refine imaging thresholds specific to posterior circulation infarcts. [ABSTRACT FROM AUTHOR]

Purpose: The inflow‐based vascular‐space‐occupancy (iVASO) MRI was originally developed in a single‐slice mode to measure arterial cerebral blood volume (CBVa). When vascular crushers are applied in iVASO, the signals can be sensitized predominantly to small pial arteries and arterioles. The purpose of this study is to perform a systematic optimization and evaluation of a 3D iVASO sequence on both 3 T and 7 T for the quantification of CBVa values in the human brain. Methods: Three sets of experiments were performed in three separate cohorts. (1) 3D iVASO MRI protocols were compared to single‐slice iVASO, and the reproducibility of whole‐brain 3D iVASO MRI was evaluated. (2) The effects from different vascular crushers in iVASO were assessed. (3) 3D iVASO MRI results were evaluated in arterial and venous blood vessels identified using ultrasmall‐superparamagnetic‐iron‐oxides–enhanced MRI to validate its arterial origin. Results: 3D iVASO scans showed signal‐to‐noise ratio (SNR) and CBVa measures consistent with single‐slice iVASO with reasonable intrasubject reproducibility. Among the iVASO scans performed with different vascular crushers, the whole‐brain 3D iVASO scan with a motion‐sensitized‐driven‐equilibrium preparation with two binomial refocusing pulses and an effective TE of 50 ms showed the best suppression of macrovascular signals, with a relatively low specific absorption rate. When no vascular crusher was applied, the CBVa maps from 3D iVASO scans showed large CBVa values in arterial vessels but well‐suppressed signals in venous vessels. Conclusion: A whole‐brain 3D iVASO MRI scan was optimized for CBVa measurement in the human brain. When only microvascular signals are desired, a motion‐sensitized‐driven‐equilibrium–based vascular crusher with binomial refocusing pulses can be applied in 3D iVASO. [ABSTRACT FROM AUTHOR]

Background: Treatment-resistant glioblastoma (trGBM) is an aggressive brain tumor with a dismal prognosis, underscoring the need for better treatment options. Emerging data indicate that trGBM iron metabolism is an attractive therapeutic target. The novel iron mimetic, gallium maltolate (GaM), inhibits mitochondrial function via iron-dependent and -independent pathways. Methods: In vitro irradiated adult GBM U-87 MG cells were tested for cell viability and allowed to reach confluence prior to stereotactic implantation into the right striatum of male and female athymic rats. Advanced MRI at 9.4T was carried out weekly starting two weeks after implantation. Daily oral GaM (50mg/kg) or vehicle were provided on tumor confirmation. Longitudinal MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics Software (Imaging Biometrics LLC). Statistical analyses included Cox proportional hazards regression models, Kaplan-Meier survival plots, linear mixed model comparisons, and t-statistic for slopes comparison as indicator of tumor growth rate. Results: In this study we demonstrate non-invasively, using longitudinal MRI surveillance, the potent antineoplastic effects of GaM in a novel rat xenograft model of trGBM, as evidenced by extended suppression of tumor growth (23.56 mm3/week untreated, 5.76 mm3/week treated, P < 0.001), a blunting of tumor perfusion, and a significant survival benefit (median overall survival: 30 days untreated, 56 days treated; P < 0.001). The therapeutic effect was confirmed histologically by the presence of abundant cytotoxic cellular swelling, a significant reduction in proliferation markers (P < 0.01), and vessel normalization characterized by prominent vessel pruning, loss of branching, and uniformity of vessel lumina. Xenograft tumors in the treatment group were further characterized by an absence of an invasive edge and a significant reduction in both, MIB-1% and mitotic index (P < 0.01 each). Transferrin receptor and ferroportin expression in GaM-treated tumors illustrated cellular iron deprivation. Additionally, treatment with GaM decreased the expression of pro-angiogenic markers (von Willebrand Factor and VEGF) and increased the expression of anti-angiogenic markers, such as Angiopoietin-2. Conclusion: Monotherapy with the iron-mimetic GaM profoundly inhibits trGBM growth and significantly extends disease-specific survival in vivo. [ABSTRACT FROM AUTHOR]

Neurovascular coupling (NVC), or the adjustment of blood flow in response to local increases in neuronal activity is a hallmark of healthy brain function, and the physiological foundation for functional magnetic resonance imaging (fMRI). However, it remains only partly understood due to the high complexity of the structure and function of the cerebrovascular network. Here we set out to understand NVC at the network level, i.e. map cerebrovascular network reactivity to activation of neighbouring neurons within a 500×500×500 μm3 cortical volume (∼30 high-resolution 3-nL fMRI voxels). Using 3D two-photon fluorescence microscopy data, we quantified blood volume and flow changes in the brain vessels in response to spatially targeted optogenetic activation of cortical pyramidal neurons. We registered the vessels in a series of image stacks acquired before and after stimulations and applied a deep learning pipeline to segment the microvascular network from each time frame acquired. We then performed image analysis to extract the microvascular graphs, and graph analysis to identify the branch order of each vessel in the network, enabling the stratification of vessels by their branch order, designating branches 1–3 as precapillary arterioles and branches 4+ as capillaries. Forty-five percent of all vessels showed significant calibre changes; with 85 % of responses being dilations. The largest absolute CBV change was in the capillaries; the smallest, in the venules. Capillary CBV change was also the largest fraction of the total CBV change, but normalized to the baseline volume, arterioles and precapillary arterioles showed the biggest relative CBV change. From linescans along arteriole-venule microvascular paths, we measured red blood cell velocities and hematocrit, allowing for estimation of pressure and local resistance along these paths. While diameter changes following neuronal activation gradually declined along the paths; the pressure drops from arterioles to venules increased despite decreasing resistance: blood flow thus increased more than local resistance decreases would predict. By leveraging functional volumetric imaging and high throughput deep learning-based analysis, our study revealed distinct hemodynamic responses across the vessel types comprising the microvascular network. Our findings underscore the need for large, dense sampling of brain vessels for characterization of neurovascular coupling at the network level in health and disease.

BOLD fMRI signal has been used in conjunction with vasodilatory stimulation as a marker of cerebrovascular reactivity (CVR): the relative change in cerebral blood flow (CBF) arising from a unit change in the vasodilatory stimulus. Using numerical simulations, we demonstrate that the variability in the relative BOLD signal change induced by vasodilation is strongly influenced by the variability in deoxyhemoglobin-containing cerebral blood volume (CBV), as this source of variability is likely to be more prominent than that of CVR. It may, therefore, be more appropriate to describe the relative BOLD signal change induced by an isometabolic vasodilation as a proxy of deoxygenated CBV (CBVdHb) rather than CVR. With this in mind, a new method was implemented to map a marker of CBVdHb, termed BOLD-CBV, based on the normalization of voxel-wise BOLD signal variation by an estimate of the intravascular venous BOLD signal from voxels filled with venous blood. The intravascular venous BOLD signal variation, recorded during repeated breath-holding, was extracted from the superior sagittal sinus in a cohort of 27 healthy volunteers and used as a regressor across the whole brain, yielding maps of BOLD-CBV. In the same cohort, we demonstrated the potential use of BOLD-CBV for the normalization of stimulus-evoked BOLD fMRI by comparing group-level BOLD fMRI responses to a visuomotor learning task with and without the inclusion of voxel-wise vascular covariates of BOLD-CBV and the BOLD signal change per mmHg variation in end-tidal carbon dioxide (BOLD-CVR). The empirical measure of BOLD-CBV accounted for more between-subject variability in the motor task-induced BOLD responses than BOLD-CVR estimated from end-tidal carbon dioxide recordings. The new method can potentially increase the power of group fMRI studies by including a measure of vascular characteristics and has the strong practical advantage of not requiring experimental measurement of end-tidal carbon dioxide, unlike traditional methods to estimate BOLD-CVR. It also more closely represents a specific physiological characteristic of brain vasculature than BOLD-CVR, namely blood volume.

Purpose: Regorafenib is a multikinase inhibitor, approved as a preferred regimen for recurrent glioblastoma (rGB). Although its effects on prolonging survival could seem modest, it is still unclear whether a subset of patients, potentially identifiable by imaging biomarkers, might experience a more substantial positive effect. Our aim was to evaluate the potential value of magnetic resonance imaging-derived parameters as non-invasive biomarkers to predict response to regorafenib in patients with rGB. Methods: 20 patients with rGB underwent conventional and advanced MRI at diagnosis (before surgery), at recurrence and at first follow-up (3 months) during regorafenib. Maximum relative cerebral blood volume (rCBVmax) value, intra-tumoral susceptibility signals (ITSS), apparent diffusion coefficient (ADC) values, and contrast-enhancing tumor volumes were tested for correlation with response to treatment, progression-free survival (PFS), and overall survival (OS). Response at first follow-up was assessed according to Response Assessment in Neuro-Oncology (RANO) criteria. Results: 8/20 patients showed stable disease at first follow-up. rCBVmax values of the primary glioblastoma (before surgery) significantly correlated to treatment response; specifically, patients with stable disease displayed higher rCBVmax compared to progressive disease (p = 0.04, 2-group t test). Moreover, patients with stable disease showed longer PFS (p = 0.02, 2-group t test) and OS (p = 0.04, 2-group t test). ITSS, ADC values, and contrast-enhancing tumor volumes showed no correlation with treatment response, PFS nor OS. Conclusion: Our results suggest that rCBVmax of the glioblastoma at diagnosis could serve as a non-invasive biomarker of treatment response to regorafenib in patients with rGB. [ABSTRACT FROM AUTHOR]

Introduction: Progressive supranuclear palsy (PSP) is a four-repeat tauopathy characterized by multiple clinicopathologic subtypes. Advanced neuroimaging techniques have shown an early ability to distinguish PSP subtypes noninvasively for improved diagnosis. This study utilized tau PET imaging and MRI techniques at 7T to determine the neuroimaging profile of a participant with comorbid PSP and amyotrophic lateral sclerosis (ALS). Method: [18F]-flortaucipir PET imaging was performed on one participant with PSP-ALS, one participant with typical PSP (Richardson's syndrome; PSP-RS), and 15 healthy control volunteers. Standardized uptake value ratio (SUVR) in each brain region was compared between PSP participants and controls. Quantitative susceptibility mapping (QSM) and inflow-based vascular-space occupancy MRI at 7T were performed on the two PSP participants and on two age-matched healthy controls to evaluate for differences in regional brain iron content and arteriolar cerebral blood volume (CBVa), respectively. Results: In the participant with PSP-ALS, the precentral gyrus demonstrated the highest [18F]-flortaucipir uptake of all brain regions relative to controls (z-score 1.94). In the participant with PSP-RS, [18F]-flortaucipir uptake relative to controls was highest in subcortical regions, including the pallidum, thalamus, hippocampus, and brainstem (z-scores 1.08, 1.41, 1.49, 1.32, respectively). Susceptibility values as a measure of brain iron content were higher in the globus pallidus and substantia nigra than in the midbrain and pons in each participant, regardless of group. CBVa values tended to be higher in the subcortical gray matter in PSP participants than in controls, although large measurement variability was noted in controls across multiple regions. Conclusion: In vivo tau PET imaging of an individual with PSP-ALS overlap demonstrated increased tau burden in the motor cortex that was not observed in PSP-RS or control participants. Consistent with prior PET studies, tau burden in PSP-RS was mainly observed in subcortical regions, including the brainstem and basal ganglia. QSM data suggest that off-target binding to iron may account for some but not all of the increased [18F]-flortaucipir uptake in the basal ganglia in PSP-RS. These findings support existing evidence that tau PET imaging can distinguish among PSP subtypes by detecting distinct regional patterns of tau deposition in the brain. Larger studies are needed to determine whether CBVa is sensitive to changes in brain microvasculature in PSP. [ABSTRACT FROM AUTHOR]

Background: Relative cerebral blood volume (rCBV) obtained from dynamic susceptibility contrast (DSC) MRI is widely used to distinguish high grade glioma recurrence from post treatment radiation effects (PTRE). Application of rCBV thresholds yield maps to distinguish between regional tumor burden and PTRE, a biomarker termed the fractional tumor burden (FTB). FTB is generally measured using conventional double-dose, single-echo DSC-MRI protocols; recently, a single-dose, dual-echo DSC-MRI protocol was clinically validated by direct comparison to the conventional double-dose, single-echo protocol. As the single-dose, dual-echo acquisition enables reduction in the contrast agent dose and provides greater pulse sequence parameter flexibility, there is a compelling need to establish dual-echo DSC-MRI based FTB mapping. In this study, we determine the optimum standardized rCBV threshold for the single-dose, dual-echo protocol to generate FTB maps that best match those derived from the reference standard, double-dose, single-echo protocol. Methods: The study consisted of 23 high grade glioma patients undergoing perfusion scans to confirm suspected tumor recurrence. We sequentially acquired single dose, dual-echo and double dose, single-echo DSC-MRI data. For both protocols, we generated leakage-corrected standardized rCBV maps. Standardized rCBV (sRCBV) thresholds of 1.0 and 1.75 were used to compute single-echo FTB maps as the reference for delineating PTRE (sRCBV < 1.0), tumor with moderate angiogenesis (1.0 < sRCBV < 1.75), and tumor with high angiogenesis (sRCBV > 1.75) regions. To assess the sRCBV agreement between acquisition protocols, the concordance correlation coefficient (CCC) was computed between the mean tumor sRCBV values across the patients. A receiver operating characteristics (ROC) analysis was performed to determine the optimum dual-echo sRCBV threshold. The sensitivity, specificity, and accuracy were compared between the obtained optimized threshold (1.64) and the standard reference threshold (1.75) for the dual-echo sRCBV threshold. Results: The mean tumor sRCBV values across the patients showed a strong correlation (CCC = 0.96) between the two protocols. The ROC analysis showed maximum accuracy at thresholds of 1.0 (delineate PTRE from tumor) and 1.64 (differentiate aggressive tumors). The reference threshold (1.75) and the obtained optimized threshold (1.64) yielded similar accuracy, with slight differences in sensitivity and specificity which were not statistically significant (1.75 threshold: Sensitivity = 81.94%; Specificity: 87.23%; Accuracy: 84.58% and 1.64 threshold: Sensitivity = 84.48%; Specificity: 84.97%; Accuracy: 84.73%). Conclusions: The optimal sRCBV threshold for single-dose, dual-echo protocol was found to be 1.0 and 1.64 for distinguishing tumor recurrence from PTRE; however, minimal differences were observed when using the standard threshold (1.75) as the upper threshold, suggesting that the standard threshold could be used for both protocols. While the prior study validated the agreement of the mean sRCBV values between the protocols, this study confirmed that their voxel-wise agreement is suitable for reliable FTB mapping. Dual-echo DSC-MRI acquisitions enable robust single-dose sRCBV and FTB mapping, provide pulse sequence parameter flexibility and should improve reproducibility by mitigating variations in preload dose and incubation time. [ABSTRACT FROM AUTHOR]

BackgroundRelative cerebral blood volume (rCBV) obtained from dynamic susceptibility contrast (DSC) MRI is widely used to distinguish high grade glioma recurrence from post treatment radiation effects (PTRE). Application of rCBV thresholds yield maps to distinguish between regional tumor burden and PTRE, a biomarker termed the fractional tumor burden (FTB). FTB is generally measured using conventional double-dose, single-echo DSC-MRI protocols; recently, a single-dose, dual-echo DSC-MRI protocol was clinically validated by direct comparison to the conventional double-dose, single-echo protocol. As the single-dose, dual-echo acquisition enables reduction in the contrast agent dose and provides greater pulse sequence parameter flexibility, there is a compelling need to establish dual-echo DSC-MRI based FTB mapping. In this study, we determine the optimum standardized rCBV threshold for the single-dose, dual-echo protocol to generate FTB maps that best match those derived from the reference standard, double-dose, single-echo protocol.MethodsThe study consisted of 23 high grade glioma patients undergoing perfusion scans to confirm suspected tumor recurrence. We sequentially acquired single dose, dual-echo and double dose, single-echo DSC-MRI data. For both protocols, we generated leakage-corrected standardized rCBV maps. Standardized rCBV (sRCBV) thresholds of 1.0 and 1.75 were used to compute single-echo FTB maps as the reference for delineating PTRE (sRCBV < 1.0), tumor with moderate angiogenesis (1.0 < sRCBV < 1.75), and tumor with high angiogenesis (sRCBV > 1.75) regions. To assess the sRCBV agreement between acquisition protocols, the concordance correlation coefficient (CCC) was computed between the mean tumor sRCBV values across the patients. A receiver operating characteristics (ROC) analysis was performed to determine the optimum dual-echo sRCBV threshold. The sensitivity, specificity, and accuracy were compared between the obtained optimized threshold (1.64) and the standard reference threshold (1.75) for the dual-echo sRCBV threshold.ResultsThe mean tumor sRCBV values across the patients showed a strong correlation (CCC = 0.96) between the two protocols. The ROC analysis showed maximum accuracy at thresholds of 1.0 (delineate PTRE from tumor) and 1.64 (differentiate aggressive tumors). The reference threshold (1.75) and the obtained optimized threshold (1.64) yielded similar accuracy, with slight differences in sensitivity and specificity which were not statistically significant (1.75 threshold: Sensitivity = 81.94%; Specificity: 87.23%; Accuracy: 84.58% and 1.64 threshold: Sensitivity = 84.48%; Specificity: 84.97%; Accuracy: 84.73%).ConclusionsThe optimal sRCBV threshold for single-dose, dual-echo protocol was found to be 1.0 and 1.64 for distinguishing tumor recurrence from PTRE; however, minimal differences were observed when using the standard threshold (1.75) as the upper threshold, suggesting that the standard threshold could be used for both protocols. While the prior study validated the agreement of the mean sRCBV values between the protocols, this study confirmed that their voxel-wise agreement is suitable for reliable FTB mapping. Dual-echo DSC-MRI acquisitions enable robust single-dose sRCBV and FTB mapping, provide pulse sequence parameter flexibility and should improve reproducibility by mitigating variations in preload dose and incubation time.

While MRI contrast agents such as those based on Gadolinium are needed for high-resolution mapping of brain metabolism, these contrast agents require intravenous administration, and there are rising concerns over their safety and invasiveness. Furthermore, non-contrast MRI scans are more commonly performed than those with contrast agents and are readily available for analysis in public databases such as the Alzheimer's Disease Neuroimaging Initiative (ADNI). In this article, we hypothesize that a deep learning model, trained using quantitative steady-state contrast-enhanced structural MRI datasets, in mice and humans, can generate contrast-equivalent information from a single non-contrast MRI scan. The model was first trained, optimized, and validated in mice, and was then transferred and adapted to humans. We observe that the model can substitute for Gadolinium-based contrast agents in approximating cerebral blood volume, a quantitative representation of brain activity, at sub-millimeter granularity. Furthermore, we validate the use of our deep-learned prediction maps to identify functional abnormalities in the aging brain using locally obtained MRI scans, and in the brain of patients with Alzheimer's disease using publicly available MRI scans from ADNI. Since it is derived from a commonly-acquired MRI protocol, this framework has the potential for broad clinical utility and can also be applied retrospectively to research scans across a host of neurological/functional diseases. [ABSTRACT FROM AUTHOR]

Background: Cerebral hyperperfusion syndrome (CHS) is a relatively rare but critical perioperative complication after CEA and CAS. We herein report a case with a preoperative increase in CBV, not OEF, in a patient who suffered from CHS both after CEA and after CAS for the same lesion. Case description: An 82-year-old female with a history of transient right hemiparesis was admitted to our hospital. 3DCTA demonstrated severe stenosis of the left neck ICA with severe calcification. 15O-PET indicated an increase of CBV was observed, but an increase of OEF was not observed in the left MCA territory. She underwent left CEA and suffered from CHS. After four months of left CEA, she suffered from right hemiparesis and was admitted to our hospital. MRI DWI revealed a spotty high signal lesion in the left frontal subcortex due to re-stenosis of the left neck ICA following CEA. She underwent CAS and suffered from CHS again. Finally, she was discharged home with mRS1. Conclusion: To our knowledge, no previous reports have described CHS after CEA and CAS for the same lesion, as occurred in our case. This case could suggest that regardless of CEA and CAS procedures, an increase of CBV was related to CHS rather than the longstanding chronic ischemia, which might increase OEF.

Bevacizumab is a therapeutic drug used in treatment of recurrent glioblastoma to inhibit angiogenesis. Treatment response is often monitored through the use of perfusion MRI measures of cerebral blood volume, flow, and other pharmacokinetic parameters; however, most methods for deriving these perfusion parameters can produce errors depending on bolus kinetics. Recently, a number of new methods have been developed to overcome these challenges. In the current study we examine cerebral blood volume and blood flow characteristics in 45 recurrent glioblastoma patients before and after treatment with bevacizumab. Perfusion MRI data was processed using a standard single value decomposition (SVD) technique, two block-circulant SVD techniques, and a Bayesian estimation technique. A proportional hazards model showed that patients with a large decrease in relative blood volume (RBV) after treatment had extended overall survival (P = 0.0048). Patients with large pre-treatment relative blood flow (RBF) showed extended progression-free survival (P = 0.0216) and overall survival (P = 0.0112), and patients with a large decrease in RBF following treatment showed extended overall survival (P = 0.0049). These results provide evidence that blood volume and blood flow measurements can be used as biomarkers in patients treated with bevacizumab.

Superparamagnetic iron-oxide nanoparticles are robust contrast agents for magnetic resonance imaging (MRI) used for sensitive structural and functional mapping of the cerebral blood volume (CBV) when administered intravenously. To date, many CBV-MRI studies are conducted with Feraheme, manufactured for the clinical treatment of iron-deficiency. Unfortunately, Feraheme is currently not available outside the United States due to commercial and regulatory constraints, making CBV-MRI methods either inaccessible or very costly to achieve. To address this barrier, we developed a simple, one-pot recipe to synthesize Carboxymethyl-dextran coated Iron Oxide Nanoparticles, namely, “CION”, suitable for preclinical CBV-MRI applications. Here we disseminate a step-by-step instruction of our one-pot synthesis protocol, which allows CION to be produced in laboratories with minimal cost. We also characterized different CION-conjugations by manipulating polymer to metal stoichiometric ratio in terms of their size, surface chemistry, and chemical composition, and shifts in MR relaxivity and pharmacokinetics. We performed several proof-of-concept experiments in vivo, demonstrating the utility of CION for functional and structural MRI applications, including hypercapnic CO2 challenge, visual stimulation, targeted optogenetic stimulation, and microangiography. We also present evidence that CION can serve as a cross-modality research platform by showing concurrent in vivo optical and MRI measurement of CBV using fluorescent-labeled CION. The simplicity and cost-effectiveness of our one-pot synthesis method should allow researchers to reproduce CION and tailor the relaxivity and pharmacokinetics according to their imaging needs. It is our hope that this work makes CBV-MRI more openly available and affordable for a variety of research applications.

• We acquired in situ 3D two-photon fluorescence microscopy data in an optogenetic mouse model and applied our deep learning-based vascular segmentation and image analysis pipeline to map geometric changes across the cerebrovascular network following neuronal activation. • Following neuronal stimulation, 45 % of all vessels showed caliber changes and only 15 % of the responses were constrictions. The absolute CBV change was the largest in the capillaries and smallest in the venules. • We presented first hitherto experimentally-based profiles of resistance and pressure along brain arteriovenous paths, demonstrating U-shaped resistance and sigmoidal pressure gradients. • The flow increases were greater than local resistance decreases would predict, supporting luxurious perfusion of the activated brain region. Neurovascular coupling (NVC), or the adjustment of blood flow in response to local increases in neuronal activity is a hallmark of healthy brain function, and the physiological foundation for functional magnetic resonance imaging (fMRI). However, it remains only partly understood due to the high complexity of the structure and function of the cerebrovascular network. Here we set out to understand NVC at the network level, i.e. map cerebrovascular network reactivity to activation of neighbouring neurons within a 500×500×500 μm3 cortical volume (∼30 high-resolution 3-nL fMRI voxels). Using 3D two-photon fluorescence microscopy data, we quantified blood volume and flow changes in the brain vessels in response to spatially targeted optogenetic activation of cortical pyramidal neurons. We registered the vessels in a series of image stacks acquired before and after stimulations and applied a deep learning pipeline to segment the microvascular network from each time frame acquired. We then performed image analysis to extract the microvascular graphs, and graph analysis to identify the branch order of each vessel in the network, enabling the stratification of vessels by their branch order, designating branches 1–3 as precapillary arterioles and branches 4+ as capillaries. Forty-five percent of all vessels showed significant calibre changes; with 85 % of responses being dilations. The largest absolute CBV change was in the capillaries; the smallest, in the venules. Capillary CBV change was also the largest fraction of the total CBV change, but normalized to the baseline volume, arterioles and precapillary arterioles showed the biggest relative CBV change. From linescans along arteriole-venule microvascular paths, we measured red blood cell velocities and hematocrit, allowing for estimation of pressure and local resistance along these paths. While diameter changes following neuronal activation gradually declined along the paths; the pressure drops from arterioles to venules increased despite decreasing resistance: blood flow thus increased more than local resistance decreases would predict. By leveraging functional volumetric imaging and high throughput deep learning-based analysis, our study revealed distinct hemodynamic responses across the vessel types comprising the microvascular network. Our findings underscore the need for large, dense sampling of brain vessels for characterization of neurovascular coupling at the network level in health and disease. [ABSTRACT FROM AUTHOR]

The lecture is devoted to the peculiarities of changes in tissue and cell perfusion of the brain with a rare pathology – venous ischemic stroke. Venous stroke, being a “relatively unknown cerebrovascular disease”, occurs up to 5 % of all cases of stroke. The terms “venous ischemia” and “venous stroke” have long been used in the literature and the definition of the venous nature of stroke should lead to a change in therapeutic tactics. Neuroimaging should ensure the verification of stroke and cerebral venous sinus thrombosis, which are the main cause of such a stroke. A certain “alertness” to the venous nature of the stroke with the expansion of the volume of radiologic methods of investigation and the performance of angiographic and perfusion CT and MR techniques, diffusion MRI allowed to increase the number of diagnosed and verified venous strokes from 0.4 % of the total number of stroke patients to 2.4 %. A distinctive feature of venous ischemic stroke from the arterial is moderate hyperemia in the central part in cases where necrosis does not develop and perifocal hyperperfusion in the development of necrosis. Moderate plethora, defined by perfusion parameters (up to 30 % CBF, CBV, MTT) of CT, MRI and SPECT techniques, and not oligemia is the primary damaging factor of the pathogenesis of venous stroke in contrast to the arterial and hyperemia patterns should be the reference points in emergency diagnosis venous stroke along with tomoangiographic symptoms of cerebral venous sinustrombosis.

Background: Temporal lobe epilepsy (TLE) is the most common form of focal seizures. To localize the epileptic site for surgery, different neuroimaging tools are used. Perfusion magnetic resonance imaging (MRI) is one of the modalities used to evaluate the cerebral hemodynamics and localize intracranial neoplasia and cerebrovascular events. Two contrast-based perfusion imaging sequences are described, including dynamic susceptibility contrast-enhanced MRI (DSC-MRI) and dynamic contrast-enhanced MRI (DCE-MRI). The most commonly measured parameters include the relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), and mean transit time (MTT). Objectives: This study aimed to evaluate the blood perfusion parameters, such as rCBVand rCBF, in patients diagnosed with mesial temporal lobe epilepsy (MTLE), using DSC-perfusion MRI to determine whether there is a change in these parameters and if this modality can be used to diagnose and localize the epileptic side. Methods: Twenty-two patients, who were diagnosed with TLE clinically and electrophysiologically by a neurologist, were investigated in this study. The patients were examined for the presence of any other lesions, such as tumors or cerebrovascular disease as the exclusion criteria. Perfusion images were processed by the Siemens perfusion software, and the rCBVand rCBF maps were generated based on the gamma variate fit. For qualitative analysis, coronal reconstruction of rCBVand rCBF maps was performed. For quantitative analysis, a single neuroradiologist placed the region of interest (ROI) on the hippocampus and the parahippocampal gyrus on T1W images at the same level of DSC images. After determining the CBVand CBF values relative to the ROI of each side, the asymmetry index (AI) was calculated. Results: In patients with unilateral epilepsy, the blood perfusion parameters in the ipsilateral side of the brain were significantly lower than the contralateral side (P < 0.0001); the mean values of both parameters were significantly lower in the affected side as compared to the opposite side. Conclusions: In patients with TLE, significantly lower blood perfusion parameters in the affected side of the brain can help radiologists and neurologists to lateralize the MTLE side. [ABSTRACT FROM AUTHOR]

Functional MRI responses are localized to the synaptic sites of evoked inhibitory neurons, but it is unknown whether, or by what mechanisms, these neurons initiate functional hyperemia. Here, the neuronal origins of these hemodynamic responses were investigated by fMRI or local field potential and blood flow measurements during topical application of pharmacological agents when GABAergic granule cells in the rat olfactory bulb were synaptically targeted. First, to examine if postsynaptic activation of these inhibitory neurons was required for neurovascular coupling, we applied an NMDA receptor antagonist during cerebral blood volume-weighted fMRI acquisition and found that responses below the drug application site (up to ~1.5 mm) significantly decreased within ~30 min. Similarly, large decreases in granule cell postsynaptic activities and blood flow responses were observed when AMPA or NMDA receptor antagonists were applied. Second, inhibition of nitric oxide synthase preferentially decreased the initial, fast component of the blood flow response, while inhibitors of astrocyte-specific glutamate transporters and vasoactive intestinal peptide receptors did not decrease blood flow responses. Third, inhibition of GABA release with a presynaptic GABAB receptor agonist caused less reduction of neuronal and blood flow responses compared to the postsynaptic glutamate receptor antagonists. In conclusion, local hyperemia by synaptically-evoked inhibitory neurons was primarily driven by their postsynaptic activities, possibly through NMDA receptor-dependent calcium signaling that was not wholly dependent on nitric oxide.

PurposeTo compare "standardization," "Gaussian normalization," and "Z-score normalization" intensity transformation techniques in dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) estimates of cerebral blood volume (CBV) in human gliomas. DSC-MRI is a well-established biomarker for CBV in brain tumors; however, DSC-MRI estimates of CBV are semiquantitative. The use of image intensity transformation algorithms provides a mechanism for obtaining quantitatively similar CBV maps with the same intensity scaling.Materials and methodsThe coefficient of variance (CV) in normal-appearing white matter and relative contrast between tumor regions and normal tissue was compared between the three CBV transformations across five different MR scanners in 96 patients with gliomas.ResultsThe results suggest all normalization techniques improved variability and relative tumor contrast of CBV measurements compared with nonnormalized CBV maps. The results suggest Gaussian normalization of CBV maps provided slightly lower CV in normal white matter and provided slightly higher tumor contrast for glioblastomas (WHO grade IV) compared with other techniques.ConclusionThe results suggest Gaussian normalization of leakage-corrected CBV maps may be the best choice for image intensity correction for use in large-scale, multicenter clinical trials where MR scanners and protocols vary widely due to ease of implementation, lowest variability, and highest tumor to normal tissue contrast.

This dataset is based on multimodal MRI and FAP-specific PET/CT Imaging applied to 13 patients with histologically proven glioblastomas. Imaging Data was processed using Medical Imaging Interaction Toolkit (MITK) software. MRI images (contrast enhanced T1w, T2w/FLAIR, ADC, rCBV) were co-registrated with FAP-specific PET images. T2w/FLAIR hyperintensities and contrast enhancing lesions were segmented manually. Necrotic areas were segmented manually and subtracted from T2w/FLAIR hyperintensities and contrast enhancing lesions. Voxelwise ADC/rCBV and PET signal intensities in projection on T2w/FLAIR hyperintensities and contrast enhancing lesions were extracted using the pixel dumper function of the MITK software and stored as excel-files. The data presented in this article has been analysed and described in the article FAP-specific “PET signaling shows a moderately positive correlation with relative CBV and no correlation with ADC in 13 IDH wildtype Glioblastomas” published in the European Journal of Radiology.

Purpose: Leptomeningeal collaterals can slow down infarction growth; however, despite good collaterals in the DAWN and DEFUSE 3 trials, outcomes were devastating if reperfusion was not attempted. The aim of this study was to compare the influence of collaterals on morphological and functional outcome in patients with acute middle cerebral artery (MCA) stroke undergoing intravenous thrombolysis (IVT) vs. supportive care (non-IVT). Methods: Out of 1639 consecutive patients examined with multiparametric computed tomography (CT) for suspected ischemic stroke, all patients with confirmed MCA stroke who did not undergo endovascular thrombectomy were selected. Propensity score matching (PSM) was used to match IVT and non-IVT treated patients for potential confounders including age, sex, National Institutes of Health Stroke Scale (NIHSS) score on admission, Alberta Stroke Program Early CT Score (ASPECTS), and occlusion site. Regression analysis after PSM was performed to identify independent associations. Results: After PSM, 90 IVT patients were matched with 90 non-IVT patients. In multivariable regression analysis, a high regional leptomeningeal collateral (rLMC) score was independently associated with lower final infarction volume (FIV) in the IVT group (b = −0.472, p < 0.001) but not in the non-IVT group (b = −0.116, p = 0.327). The trichotomized rLMC scores predicted functional outcome in IVT treated patients (adjusted odds ratio, aOR = 4.57, 95% confidence interval, CI, 1.03–20.32, p = 0.046) but showed no independent association with outcome in the non-IVT group (aOR = 0.69, 95% CI 0.07–6.80, p = 0.753). Conclusion: Good collaterals favored smaller FIV and good functional outcome in IVT treated patients but not in non-IVT treated patients. Good collateral flow may have limited prognostic value if IVT is not administered to attempt reperfusion [ABSTRACT FROM AUTHOR]

• Patients with TNEs showed a significantly higher CBV increase ratio than those without in MMD. • Postoperative CBV increase correlated with the CHBs. • We hypothesize that the pathophysiology of the CHBs are vasogenic edemas in MMD. Transient neurological events (TNEs) are observed after direct bypass surgery in patients with moyamoya disease (MMD). Although a correlation between cortical hyperintensity belt signs (CHBs) and TNEs has been reported, the pathophysiology of CHBs is still unknown. The purpose of this study was to reveal the pathophysiology of CHBs by using dynamic susceptibility contrast-magnetic resonance imaging. Thirty patients with MMD were included in this study. We provided scores (0–2) for the existence of CHBs on postoperative FLAIR images. We placed the ROI for the presented area of CHBs in the images of cerebral blood flow, CBV, and MTT. We calculated the change of the hemodynamic parameters (increase ratio, IR) and analyzed the relationship between IRs, CHB scores, and TNEs. TNEs were observed in 15 cases (50%) and CHBs were detected in 28 cases (93%). TNEs showed significantly higher CHB scores than those without (p < 0.05). The group of CHB score 2 showed a significantly higher CBV IR than the group with of score 0 (p < 0.05). Patients with TNEs showed a significantly higher CBV IR than those without (p < 0.05). As for the cut-off level to predict an appearance of TNEs, the CBV IR was 1.36 by the Receiver Operating Characteristic analysis, and the sensitivity and specificity were 80% respectively. We hypothesize that the pathophysiology of the CHBs are vasogenic edemas because the postoperative CBV increase correlated with the CHBs. [ABSTRACT FROM AUTHOR]

• Deoxyhemoglobin sensitive blood volume (CBV) is derived from breath-hold BOLD fMRI. • This BOLD-CBV marker is compared to typical BOLD cerebrovascular reactivity (CVR). • BOLD-CBV and BOLD-CVR are compared as vascular covariates in task-evoked BOLD fMRI. BOLD fMRI signal has been used in conjunction with vasodilatory stimulation as a marker of cerebrovascular reactivity (CVR): the relative change in cerebral blood flow (CBF) arising from a unit change in the vasodilatory stimulus. Using numerical simulations, we demonstrate that the variability in the relative BOLD signal change induced by vasodilation is strongly influenced by the variability in deoxyhemoglobin-containing cerebral blood volume (CBV), as this source of variability is likely to be more prominent than that of CVR. It may, therefore, be more appropriate to describe the relative BOLD signal change induced by an isometabolic vasodilation as a proxy of deoxygenated CBV (CBV dHb) rather than CVR. With this in mind, a new method was implemented to map a marker of CBV dHb , termed BOLD-CBV, based on the normalization of voxel-wise BOLD signal variation by an estimate of the intravascular venous BOLD signal from voxels filled with venous blood. The intravascular venous BOLD signal variation, recorded during repeated breath-holding, was extracted from the superior sagittal sinus in a cohort of 27 healthy volunteers and used as a regressor across the whole brain, yielding maps of BOLD-CBV. In the same cohort, we demonstrated the potential use of BOLD-CBV for the normalization of stimulus-evoked BOLD fMRI by comparing group-level BOLD fMRI responses to a visuomotor learning task with and without the inclusion of voxel-wise vascular covariates of BOLD-CBV and the BOLD signal change per mmHg variation in end-tidal carbon dioxide (BOLD-CVR). The empirical measure of BOLD-CBV accounted for more between-subject variability in the motor task-induced BOLD responses than BOLD-CVR estimated from end-tidal carbon dioxide recordings. The new method can potentially increase the power of group fMRI studies by including a measure of vascular characteristics and has the strong practical advantage of not requiring experimental measurement of end-tidal carbon dioxide, unlike traditional methods to estimate BOLD-CVR. It also more closely represents a specific physiological characteristic of brain vasculature than BOLD-CVR, namely blood volume. [ABSTRACT FROM AUTHOR]

The magnitude and shape of blood oxygen level-dependent (BOLD) responses in functional MRI (fMRI) studies vary across brain regions, subjects, and populations. This variability may be secondary to neural activity or vasculature differences, thus complicating interpretations of BOLD signal changes in fMRI experiments. We compare the BOLD responses to neural activity and a vascular challenge and test a method to dissociate these influences in 26 younger subjects (ages 18-36) and 24 older subjects (ages 51-78). Each subject performed a visuornotor saccade task (a vascular response to neural activity) and a breathholding task (vascular dilation induced by hypercapnia) during separate runs in the same scanning session. For the saccade task, signal magnitude showed a significant decrease with aging in FEF, SEF, and V1, and a delayed time-to-peak with aging in V1. The signal magnitudes from the saccade and hypercapnia tasks showed significant linear regressions within subjects and across individuals and populations. These two tasks had weaker, but sometimes significant linear regressions for time-to-peak and coherence phase measures. The significant magnitude decrease with aging in V1 remained after dividing the saccade task magnitude by the hypercapnia task magnitude, implying that the signal decrease is neural in origin. These findings may lead to a method to identify vascular reactivity-induced differences in the BOLD response across populations and the development of methods to account for the influence of these vasculature differences in a simple, noninvasive manner. (c) 2006 Wiley-Liss, Inc.

Este estudo objetivou avaliar a qualidade organizacional e gerencial do Curso de Certificaçãode Equipe de Arbitragem Superliga de Voleibol 2012/2013, oferecido na modalidade de ensinoa distância, promovido pela Universidade Corporativa do Voleibol (UCV), regida pela ConfederaçãoBrasileira de Voleibol (CBV) em parceria com o Centro de Educação a Distância daUniversidade Estadual de Montes Claros (CEAD/Unimontes) na percepção de árbitros e apontadores.A amostra foi constituída por 256 árbitros e apontadores. Um questionário on-line foiaplicado, contendo 26 questões acerca da organização do curso, com vistas à avaliação de suaqualidade para o aprimoramento de futuras ofertas. Para análise dos dados, utilizou-se o testede proporção binominal através do SPSS – versão 20.0 com nível de significância p ≤ 0,05. Resultadossignificativos foram observados nas variáveis ambiente virtual de aprendizagem, tutoria,professor, material didático, desempenho pessoal, conteúdo e suporte técnico com asserçõesde satisfatório e plenamente satisfatório. O alunado percebeu a carga horária do curso comosatisfatória. Quanto aos objetivos pessoais, se dividiram entre incrementar a formação profissionale integrar o quadro oficial de árbitros. Concluiu-se que o curso posicionou-se como umprograma de qualidade nos aspectos gerenciais, organizacionais e estruturais para o preparodos árbitros para atuarem em campeonatos, revelando condições favoráveis para novas ofertas.

Isocitrate dehydrogenase (IDH) mutant and wildtype glioblastoma multiforme (GBM) often show overlapping features on magnetic resonance imaging (MRI), representing a diagnostic challenge. Deep learning showed promising results for IDH identification in mixed low/high grade glioma populations; however, a GBM-specific model is still lacking in the literature. Our aim was to develop a GBM-tailored deep-learning model for IDH prediction by applying convoluted neural networks (CNN) on multiparametric MRI. We selected 100 adult patients with pathologically demonstrated WHO grade IV gliomas and IDH testing. MRI sequences included: MPRAGE, T1, T2, FLAIR, rCBV and ADC. The model consisted of a 4-block 2D CNN, applied to each MRI sequence. Probability of IDH mutation was obtained from the last dense layer of a softmax activation function. Model performance was evaluated in the test cohort considering categorical cross-entropy loss (CCEL) and accuracy. Calculated performance was: rCBV (accuracy 83%, CCEL 0.64), T1 (accuracy 77%, CCEL 1.4), FLAIR (accuracy 77%, CCEL 1.98), T2 (accuracy 67%, CCEL 2.41), MPRAGE (accuracy 66%, CCEL 2.55). Lower performance was achieved on ADC maps. We present a GBM-specific deep-learning model for IDH mutation prediction, with a maximal accuracy of 83% on rCBV maps. Highest predictivity achieved on perfusion images possibly reflects the known link between IDH and neoangiogenesis through the hypoxia inducible factor.

Abstract The protracted accumulation of amyloid-β (Aβ) is a major pathologic hallmark of Alzheimer's disease and may trigger secondary pathological processes that include neurovascular damage. This study was aimed at investigating long-term effects of Aβ burden on cerebral blood volume of arterioles and pial arteries (CBVa), possibly present before manifestation of dementia. Aβ burden was assessed by 11C Pittsburgh compound-B positron emission tomography in 22 controls and 18 persons with mild cognitive impairment (MCI), [ages: 75(±6) years]. After 2 years, inflow-based vascular space occupancy at ultra-high field strength of 7-Tesla was administered for measuring CBVa, and neuropsychological testing for cognitive decline. Crushing gradients were incorporated during MR-imaging to suppress signals from fast-flowing blood in large arteries, and thereby sensitize inflow-based vascular space occupancy to CBVa in pial arteries and arterioles. CBVa was significantly elevated in MCI compared to cognitively normal controls and regional CBVa related to local Aβ deposition. For both MCI and controls, Aβ burden and follow-up CBVa in several brain regions synergistically predicted cognitive decline over 2 years. Orbitofrontal CBVa was positively associated with apolipoprotein E e4 carrier status. Increased CBVa may reflect long-term effects of region-specific pathology associated with Aβ deposition. Additional studies are needed to clarify the role of the arteriolar system and the potential of CBVa as a biomarker for Aβ-related vascular downstream pathology. Highlights • 11C-PiB-PET for Aβ and 7 Tesla iVASO MRI for CBVa in non-demented old aged adults. • Increased CBVa is a correlate of cognitive decline associated with Aβ-burden. • Local Aβ-deposits indicate brain regions with increased CBVa after 2 years. • High orbitofrontal CBVa is associated with APOE4 carrier status. • CBVa may represent a downstream marker of metabolic change associated with Aβ. [ABSTRACT FROM AUTHOR]

Background and Purpose: The role of Alberta Stroke Program Early CT score (ASPECTS) in predicting which patients are likely to benefit from endovascular therapy (EVT) is not well defined. An automated software (e-ASPECTS) has been created to solve its poor interrater reliability. We aim to evaluate correlation between radiologist (Rx) and e-ASPECTS scoring with cerebral blood volume (CBV) infarct core and with final infarct volume; as well as with long-term functional outcome.Methods: We included patients with acute ischemic stroke and large vessel occlusion who underwent EVT. We measured baseline radiologist (Rx) ASPECTS and e-ASPECTS, and baseline CBV infarct core on CT perfusion. Final infarct volume was measured on 24-hour control CT.Results: We included 184 patients, in which 82.1% of patients achieved complete recanalization. Median Rx-ASPECTS/e-ASPECTS was 9 (IQR 8-10 vs. IQR 7.75-10) and mean CBV lesion was 29.51 (±47.41) mL. Correlation (rs ) between ASPECTS and e-ASPECTS was .44 (P < .01). Both ASPECTS scores correlated with CBV after 180 minutes of symptom onset (rs = -.41 vs. -.54, P < .01) and with final infarct volume in patients with complete recanalization (rs = -.40 vs. -.43, P < .01). In a logistic regression, either Rx-ASPECTS, e-ASPECTS, and CBV (OR 1.60 vs. 1.87 vs. .96; P < .05) predicted a low infarct volume. Rx-ASPECTS and e-ASPECTS also predicted functional independence (mRS 0-2) at 3 months (1.52 vs. 1.37; P < .05).Conclusion: ASPECTS and e-ASPECTS showed a mild correlation with CBV. Rx-ASPECTS, e-ASPECTS, and CBV predicted a low infarct volume after thrombectomy in recanalized patients but only Rx-ASPECTS and e-ASPECTS predicted functional independence at 3 months. [ABSTRACT FROM AUTHOR]

Abstract The measurement of cerebral blood volume (CBV) has been the topic of numerous neuroimaging studies. To date, however, most in vivo imaging approaches can only measure CBV summed over all types of blood vessels, including arterial, capillary and venous vessels in the microvasculature (i.e. total CBV or CBVtot). As different types of blood vessels have intrinsically different anatomy, function and physiology, the ability to quantify CBV in different segments of the microvascular tree may furnish information that is not obtainable from CBVtot, and may provide a more sensitive and specific measure for the underlying physiology. This review attempts to summarize major efforts in the development of MRI techniques to measure arterial (CBVa) and venous CBV (CBVv) separately. Advantages and disadvantages of each type of method are discussed. Applications of some of the methods in the investigation of flow-volume coupling in healthy brains, and in the detection of pathophysiological abnormalities in brain diseases such as arterial steno-occlusive disease, brain tumors, schizophrenia, Huntington's disease, Alzheimer's disease, and hypertension are demonstrated. We believe that the continual development of MRI approaches for the measurement of compartment-specific CBV will likely provide essential imaging tools for the advancement and refinement of our knowledge on the exquisite details of the microvasculature in healthy and diseased brains. Highlights • To date, most CBV MRI methods measure total CBV. • Arterial and venous blood vessels are intrinsically different. • Here, MRI methods for CBVa and CBVv measurement are reviewed. • Compartment specific flow-volume coupling is investigated using the methods. • Applications of the methods in brain diseases are demonstrated. [ABSTRACT FROM AUTHOR]

Brain imaging has revealed that the CA1 subregion of the hippocampus is hyperactive in prodromal and diagnosed patients with schizophrenia (SCZ), and that glutamate is a driver of this hyperactivity. Strikingly, mice deficient in the glutamate synthetic enzyme glutaminase have CA1 hypoactivity and a SCZ-resilience profile, implicating glutamate-metabolizing enzymes. To address this further, we examined mice with a brain-wide deficit in the glutamate-metabolizing enzyme glutamate dehydrogenase (GDH), encoded by Glud1, which should lead to glutamate excess due to reduced glutamate metabolism in astrocytes. We found that Glud1 -deficient mice have behavioral abnormalities in the 3 SCZ symptom domains, with increased baseline and amphetamine-induced hyperlocomotion as a positive symptom proxy, nest building and social preference as a negative symptom proxy, and reversal/extradimensional set shifting in the water T-maze and contextual fear conditioning as a cognitive symptom proxy. Neuroimaging of cerebral blood volume revealed hippocampal hyperactivity in CA1, which was associated with volume reduction. Parameters of hippocampal synaptic function revealed excess glutamate release and an elevated excitatory/inhibitory balance in CA1. Finally, in a direct clinical correlation using imaging-guided microarray, we found a significant SCZ-associated postmortem reduction in GLUD1 expression in CA1. These findings advance GLUD1 deficiency as a driver of excess hippocampal excitatory transmission and SCZ symptoms, and identify GDH as a target for glutamate modulation pharmacotherapy for SCZ. More broadly, these findings point to the likely involvement of alterations in glutamate metabolism in the pathophysiology of SCZ. [ABSTRACT FROM AUTHOR]

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