Three-Dimensional Printed Anatomic Models Derived From Magnetic Resonance Imaging Data: Current State and Image Acquisition Recommendations for Appropriate Clinical Scenarios.

Three-dimensional (3D) printing technologies have been increasingly utilized in medicine over the past several years and can greatly facilitate surgical planning thereby improving patient outcomes. Although still much less utilized compared to computed tomography (CT), magnetic resonance imaging (MRI) is gaining traction in medical 3D printing. The purpose of this study was two-fold: 1) to determine the prevalence in the existing literature of using MRI to create 3D printed anatomic models for surgical planning and 2) to provide image acquisition recommendations for appropriate clinical scenarios where MRI is the most suitable imaging modality. The workflow for creating 3D printed anatomic models from medical imaging data is complex and involves image segmentation of the regions of interest and conversion of that data into 3D surface meshes, which are compatible with printing technologies. CT is most commonly used to create 3D printed anatomic models due to the high image quality and relative ease of performing image segmentation from CT data. As compared to CT datasets, 3D printing using MRI data offers advantages since it provides exquisite soft tissue contrast needed for accurate organ segmentation and it does not expose patients to unnecessary ionizing radiation. MRI, however, often requires complicated imaging techniques and time-consuming postprocessing procedures to generate high-resolution 3D anatomic models needed for 3D printing. Despite these challenges, 3D modeling and printing from MRI data holds great clinical promises thanks to emerging innovations in both advanced MRI imaging and postprocessing techniques. EVIDENCE LEVEL: 2 TECHNICAL EFFICATCY: 5.

Neural correlates of working memory function in pediatric cancer survivors treated with chemotherapy: an fMRI study.

The goal of this study is to investigate the neural correlates of working memory function associated with chemotherapy in pediatric cancer survivors using event-related functional MRI (fMRI) analysis. Fifteen pediatric cancer survivors treated with chemotherapy and 15 healthy controls were studied. Blood oxygenation level dependent (BOLD) fMRI was acquired. A visual n-back task was used to test working memory function during the fMRI scan. Responses were recorded via an MRI compatible button box for analysis. fMRI scans were analyzed using statistical parametric mapping software. All statistics were corrected for multiple comparisons by false discovery rate, with p < 0.05 as significance. Patients however gave more incorrect responses (p < 0.05), more no responses (p < 0.05), and longer response times (p < 0.05) compared with healthy controls. Correct responses generated significantly lower BOLD responses in the posterior cingulate for pediatric cancer survivors compared with controls (p < 0.05). Incorrect responses generated significantly greater BOLD responses in the angular gyrus in survivors (p < 0.05), and no response trials generated greater BOLD responses within the superior parietal lobule (p < 0.05) compared with controls. Working memory impairment appears to be due to an inability to manipulate information and to retrieve information from memory. The ability to delineate the affected neural circuits associated with chemotherapy-induced cognitive impairment could inform treatment strategies, identify patients at high risk of developing cognitive deficits, and pre-emptively tailor behavioral enrichment to overcome specific cognitive deficits.

Repolarized macrophages, induced by intermediate stereotactic dose radiotherapy and immune checkpoint blockade, contribute to long-term survival in glioma-bearing mice.

INTRODUCTION: Glioblastoma multiforme (GBM) is a deadly brain tumor with a short expected median survival, despite current standard-of-care treatment. We explored the combination of intermediate stereotactic dose radiation therapy and immune checkpoint inhibitor therapy as a novel treatment strategy for GBM. METHODS: Glioma xenograft-bearing mice were exposed to high dose brain-directed radiation (10 Gy single exposure) as well as mouse anti-PD-1 antibody. The tumor-bearing animals were randomized to four groups: no treatment, radiation alone, anti-PD-1 alone, and radiation + anti-PD-1. Survival was followed, and tumor growth was monitored using MRI. Immunohistochemistry, gene expression arrays, and flow cytometry were used to characterize the treatment-induced effects. Pharmacologic inhibitors of T-lymphocytes, bone marrow derived macrophages, and microglia were used to assess the respective roles of different immune populations in observed treatment effects. RESULTS: We found the combined treatment with high dose radiation and immunotherapy to be highly effective with a 75% complete pathologic response and dramatically improved survival outcomes. We found both CD8+ T-cells and macrophages to be necessary for the full effect of combined therapy, with T lymphocytes appearing to play a role early on and macrophages mediating a later phase of the combined treatment effect. Radiation treatment appeared to trigger macrophage repolarization, increasing M1/M2 ratio. CONCLUSIONS: These findings point to a novel immunologic mechanism underlying the interaction between radiotherapy and immunotherapy. They also provide the basis for clinical investigation of immunogenic dose radiation in combination with immune checkpoint blockade as a potential treatment approach for newly diagnosed high grade gliomas.

Susceptibility tensor imaging (STI) of the brain.

Susceptibility tensor imaging (STI) is a recently developed MRI technique that allows quantitative determination of orientation-independent magnetic susceptibility parameters from the dependence of gradient echo signal phase on the orientation of biological tissues with respect to the main magnetic field. By modeling the magnetic susceptibility of each voxel as a symmetric rank-2 tensor, individual magnetic susceptibility tensor elements as well as the mean magnetic susceptibility and magnetic susceptibility anisotropy can be determined for brain tissues that would still show orientation dependence after conventional scalar-based quantitative susceptibility mapping to remove such dependence. Similar to diffusion tensor imaging, STI allows mapping of brain white matter fiber orientations and reconstruction of 3D white matter pathways using the principal eigenvectors of the susceptibility tensor. In contrast to diffusion anisotropy, the main determinant factor of the susceptibility anisotropy in brain white matter is myelin. Another unique feature of the susceptibility anisotropy of white matter is its sensitivity to gadolinium-based contrast agents. Mechanistically, MRI-observed susceptibility anisotropy is mainly attributed to the highly ordered lipid molecules in the myelin sheath. STI provides a consistent interpretation of the dependence of phase and susceptibility on orientation at multiple scales. This article reviews the key experimental findings and physical theories that led to the development of STI, its practical implementations, and its applications for brain research. Copyright © 2016 John Wiley & Sons, Ltd.

MRI of brain tissue oxygen tension under hyperbaric conditions.

The brain depends on a continuous supply of oxygen to maintain its structural and functional integrity. This study measured T1 from MRI under normobaric air, normobaric oxygen, hyperbaric air, and hyperbaric oxygen (HBO) conditions as a marker of tissue pO2 since dissolved molecular oxygen acts as an endogenous contrast agent. Brain tissue T1 decreased corresponding to increased pO2 with increasing inhaled oxygen concentrations, and tissue oxygenation was estimated from the T1 changes between different inhaled oxygen levels. Tissue pO2 difference maps between different oxygen conditions showed heterogeneous pO2 changes in the brain. MRI-derived tissue pO2 was markedly lower than the arterial pO2 but was slightly higher than venous pO2. Additionally, for comparison with published extracellular tissue pO2 data obtained using oxygen electrodes and other invasive techniques, a model was used to estimate extracellular and intracellular pO2 from the MRI-derived mean tissue pO2. This required multiple assumptions, and so the effects of the assumptions and parameters used in modeling brain pO2 were evaluated. MRI-derived pO2 values were strongly dependent on assumptions about the extra- and intracellular compartments but were relatively less sensitive to variations in the relaxivity constant of oxygen and contribution from oxygen in the cerebral blood compartment. This approach may prove useful in evaluating tissue oxygenation in disease states such as stroke.

Intrinsic Resting-State Functional Connectivity in the Human Spinal Cord at 3.0 T.

PURPOSE: To apply resting-state functional magnetic resonance (MR) imaging to map functional connectivity of the human spinal cord. MATERIALS AND METHODS: Studies were performed in nine self-declared healthy volunteers with informed consent and institutional review board approval. Resting-state functional MR imaging was performed to map functional connectivity of the human cervical spinal cord from C1 to C4 at 1 × 1 × 3-mm resolution with a 3.0-T clinical MR imaging unit. Independent component analysis (ICA) was performed to derive resting-state functional MR imaging z-score maps rendered on two-dimensional and three-dimensional images. Seed-based analysis was performed for cross validation with ICA networks by using Pearson correlation. RESULTS: Reproducibility analysis of resting-state functional MR imaging maps from four repeated trials in a single participant yielded a mean z score of 6 ± 1 (P < .0001). The centroid coordinates across the four trials deviated by 2 in-plane voxels ± 2 mm (standard deviation) and up to one adjacent image section ± 3 mm. ICA of group resting-state functional MR imaging data revealed prominent functional connectivity patterns within the spinal cord gray matter. There were statistically significant (z score > 3, P < .001) bilateral, unilateral, and intersegmental correlations in the ventral horns, dorsal horns, and central spinal cord gray matter. Three-dimensional surface rendering provided visualization of these components along the length of the spinal cord. Seed-based analysis showed that many ICA components exhibited strong and significant (P < .05) correlations, corroborating the ICA results. Resting-state functional MR imaging connectivity networks are qualitatively consistent with known neuroanatomic and functional structures in the spinal cord. CONCLUSION: Resting-state functional MR imaging of the human cervical spinal cord with a 3.0-T clinical MR imaging unit and standard MR imaging protocols and hardware reveals prominent functional connectivity patterns within the spinal cord gray matter, consistent with known functional and anatomic layouts of the spinal cord.

Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain.

Purpose To investigate the sustained-attention and memory-enhancing neural correlates of the oral administration of methylene blue in the healthy human brain. Materials and Methods The institutional review board approved this prospective, HIPAA-compliant, randomized, double-blinded, placebo-controlled clinical trial, and all patients provided informed consent. Twenty-six subjects (age range, 22-62 years) were enrolled. Functional magnetic resonance (MR) imaging was performed with a psychomotor vigilance task (sustained attention) and delayed match-to-sample tasks (short-term memory) before and 1 hour after administration of low-dose methylene blue or a placebo. Cerebrovascular reactivity effects were also measured with the carbon dioxide challenge, in which a 2 × 2 repeated-measures analysis of variance was performed with a drug (methylene blue vs placebo) and time (before vs after administration of the drug) as factors to assess drug × time between group interactions. Multiple comparison correction was applied, with cluster-corrected P < .05 indicating a significant difference. Results Administration of methylene blue increased response in the bilateral insular cortex during a psychomotor vigilance task (Z = 2.9-3.4, P = .01-.008) and functional MR imaging response during a short-term memory task involving the prefrontal, parietal, and occipital cortex (Z = 2.9-4.2, P = .03-.0003). Methylene blue was also associated with a 7% increase in correct responses during memory retrieval (P = .01). Conclusion Low-dose methylene blue can increase functional MR imaging activity during sustained attention and short-term memory tasks and enhance memory retrieval. © RSNA, 2016 Online supplemental material is available for this article.

MRI of cerebral blood flow under hyperbaric conditions in rats.

Hyperbaric oxygen (HBO) therapy has a number of clinical applications. However, the effects of acute HBO on basal cerebral blood flow (CBF) and neurovascular coupling are not well understood. This study explored the use of arterial spin labeling MRI to evaluate changes in baseline and forepaw stimulus-evoked CBF responses in rats (n = 8) during normobaric air (NB), normobaric oxygen (NBO) (100% O2 ), 3 atm absolute (ATA) hyperbaric air (HB) and 3 ATA HBO conditions. T1 was also measured, and the effects of changes in T1 caused by increasing oxygen on the CBF calculation were investigated. The major findings were as follows: (i) increased inhaled oxygen concentrations led to a reduced respiration rate; (ii) increased dissolved paramagnetic oxygen had significant effects on blood and tissue T1 , which affected the CBF calculation using the arterial spin labeling method; (iii) the differences in blood T1 had a larger effect than the differences in tissue T1 on CBF calculation; (iv) if oxygen-induced changes in blood and tissue T1 were not taken into account, CBF was underestimated by 33% at 3 ATA HBO, 10% at NBO and <5% at HB; (v) with correction, CBF values under HBO, HB and NBO were similar (p > 0.05) and all were higher than CBF under NB by ~40% (p < 0.05), indicating that hypercapnia from the reduced respiration rate masks oxygen-induced vasoconstriction, although blood gas was not measured; and (vi) substantial stimulus-evoked CBF increases were detected under HBO, similar to NB, supporting the notion that activation-induced CBF regulation in the brain does not operate through an oxygen-sensing mechanism. CBF MRI provides valuable insights into the effects of oxygen on basal CBF and neurovascular coupling under hyperbaric conditions. Copyright © 2016 John Wiley & Sons, Ltd.

Spatiotemporal changes in diffusion, T2 and susceptibility of white matter following mild traumatic brain injury.

Impaired white matter integrity in traumatic brain injury (TBI) can lead to deficits in various neurological functions. The differentiation of the underlying pathological processes, e.g. edema, demyelination, axonal damage, to name a few, is of key clinical interest for the assessment of white matter injury. In this study, a combination of T2 , diffusion and susceptibility MRI was used to study the spatiotemporal changes in white matter at 1 h, 3 h, and 1, 2, 7 and 14 days following TBI, using a rat controlled cortical impact (CCI) model. Based on radial diffusivity (RD), the rats were divided into two groups: group 1 showed widespread increases in RD along the corpus callosum of the ipsilesional hemisphere at day 2, and group 2 showed normal RD. Based on this group separation, group 1 also showed similar widespread changes in fractional anisotropy (FA) and T2 at day 2, and group 2 showed normal FA and T2 . The widespread changes in RD and T2 in group 1 on day 2 were apparently dominated by edema, which obscured possible myelin and axonal damage. In contrast, the susceptibility of group 1 showed more localized increases near the impact site on day 2, and otherwise similar contrast to the contralesional hemisphere. The localized susceptibility increase is probably a result of demyelination and axonal injury. The extent of brain damage between the two groups revealed by MRI was consistent with behavioral results, with the first group showing significantly increased forelimb asymmetry and increased forelimb foot fault deficits. Our results suggest that the combination of T2 , diffusion and susceptibility MRI may provide an opportunity for the differential assessment of edema and axonal damage in TBI. Copyright © 2016 John Wiley & Sons, Ltd.

Cerebral angiography, blood flow and vascular reactivity in progressive hypertension.

Chronic hypertension alters cerebral vascular morphology, cerebral blood flow (CBF), cerebrovascular reactivity, and increses susceptibility to neurological disorders. This study evaluated: i) the lumen diameters of major cerebral and downstream arteries using magnetic resonance angiography, ii) basal CBF, and iii) cerebrovascular reactivity to hypercapnia of multiple brain regions using arterial-spin-labeling technique in spontaneously hypertensive rats (SHR) at different stages. Comparisons were made with age-matched normotensive Wistar Kyoto (WKY) rats. In 10-week SHR, lumen diameter started to reduce, basal CBF, and hypercapnic CBF response were higher from elevated arterial blood pressure, but there was no evidence of stenosis, compared to age-matched WKY. In 20-week SHR, lumen diameter remained reduced, CBF returned toward normal from vasoconstriction, hypercapnic CBF response reversed and became smaller, but without apparent stenosis. In 40-week SHR, lumen diameter remained reduced and basal CBF further decreased, resulting in larger differences compared to WKY. There was significant stenosis in main supplying cerebral vessels. Hypercapnic CBF response further decreased, with some animals showing negative hypercapnic CBF responses in some brain regions, indicative of compromised cerebrovascular reserve. The territory with negative hypercapnia CBF responses corresponded with the severity of stenosis in arteries that supplied those territories. We also found enlargement of downstream vessels and formation of collateral vessels as compensatory responses to stenosis of upstream vessels. The middle cerebral and azygos arteries were amongst the most susceptible to hypertension-induced changes. Multimodal MRI provides clinically relevant data that might be useful to characterize disease pathogenesis, stage disease progression, and monitor treatment effects in hypertension.

Functional MRI during hyperbaric oxygen: Effects of oxygen on neurovascular coupling and BOLD fMRI signals.

Hyperbaric oxygen (HBO) therapy is used to treat a number of ailments. Improved understanding of how HBO affects neuronal activity, cerebral blood flow (CBF) and blood-oxygenation-level dependent (BOLD) changes could shed light on the role of oxygen in neurovascular coupling and help guide HBO treatments. The goal of this study was to test two hypotheses: i) activation-induced CBF fMRI response is not dependent on hemoglobin deoxygenation, and ii) activation-induced BOLD fMRI is markedly attenuated under HBO. CBF and BOLD fMRI of forepaw stimulation in anesthetized rats under HBO at 3 atmospheres absolute (ATA) were compared with normobaric air. Robust BOLD and CBF fMRI were detected under HBO. Inflow effects and spin-density changes did not contribute significantly to the BOLD fMRI signal under HBO. Analysis of the T2(⁎)-weighted signal at normobaric air and 1, 2 and 3ATA oxygen in the tissue and the superior sagittal sinus showed a strong dependence on increasing inhaled [O2]. Spontaneous electrophysiological activity and evoked local-field potentials were reduced under HBO. The differences between normobaric air and HBO in basal and evoked electrical activity could not fully account for the strong BOLD responses under HBO. We concluded that activation-induced CBF regulation in the brain does not operate through an oxygen-sensing mechanism and that stimulus-evoked BOLD responses and the venous T2(⁎)-weighted signals still have room to increase under 3ATA HBO. To our knowledge, this is the first fMRI study under HBO, providing insights into the effects of HBO on neural activity, neurovascular coupling, tissue oxygenation, and the BOLD signal.

A method for estimating and removing streaking artifacts in quantitative susceptibility mapping.

Quantitative susceptibility mapping (QSM) is a novel MRI method for quantifying tissue magnetic property. In the brain, it reflects the molecular composition and microstructure of the local tissue. However, susceptibility maps reconstructed from single-orientation data still suffer from streaking artifacts which obscure structural details and small lesions. We propose and have developed a general method for estimating streaking artifacts and subtracting them from susceptibility maps. Specifically, this method uses a sparse linear equation and least-squares (LSQR)-algorithm-based method to derive an initial estimation of magnetic susceptibility, a fast quantitative susceptibility mapping method to estimate the susceptibility boundaries, and an iterative approach to estimate the susceptibility artifact from ill-conditioned k-space regions only. With a fixed set of parameters for the initial susceptibility estimation and subsequent streaking artifact estimation and removal, the method provides an unbiased estimate of tissue susceptibility with negligible streaking artifacts, as compared to multi-orientation QSM reconstruction. This method allows for improved delineation of white matter lesions in patients with multiple sclerosis and small structures of the human brain with excellent anatomical details. The proposed methodology can be extended to other existing QSM algorithms.

Brain high-energy phosphates and creatine kinase synthesis rate under graded isoflurane anesthesia: An in vivo (31) P magnetization transfer study at 11.7 tesla.

PURPOSE: The creatine kinase rate of metabolic adenosine triphosphate (ATP) synthesis is an important metabolic parameter but is challenging to measure in vivo due to limited signal-to-noise ratio and long measurement time. THEORY AND METHODS: This study reports the implementation of an accelerated (31) P Four Angle Saturation Transfer (FAST) method to measure the forward creatine kinase (CK) rate of ATP synthesis. Along with a high-field scanner (11.7 Tesla) and a small sensitive surface coil, the forward CK rate in the rat brain was measured in ∼5 min. RESULTS: Under 1.2% isoflurane, the forward CK rate constant and metabolic flux were, respectively, kf , CK =0.26 ± 0.02 s(-1) and Ff,CK =70.8 ± 4.6 µmol/g/min. As a demonstration of utility and sensitivity, measurements were made under graded isoflurane. Under 2.0% isoflurane, kf , CK =0.16 ± 0.02 s(-1) and Ff,CK =410.0 ± 4.2 µmol/g/min, corresponding to a 38% and 42% reduction, respectively, relative to 1.2% isoflurane. By contrast, the ATP and phosphocreatine concentrations were unaltered. CONCLUSION: This study demonstrated the (31) P FAST measurement of creatine kinase rate of ATP synthesis in rat brain with reasonable temporal resolution. Different isoflurane levels commonly used in animal models significantly alter the CK reaction rate but not ATP and phosphocreatine concentrations.

White matter lesion load is associated with resting state functional MRI activity and amyloid PET but not FDG in mild cognitive impairment and early Alzheimer's disease patients.

PURPOSE: To quantify and investigate the interactions between multimodal MRI/positron emission tomography (PET) imaging metrics in elderly patients with early Alzheimer's disease (AD), mild cognitive impairment (MCI) and healthy controls. MATERIALS AND METHODS: Thirteen early AD, 17 MCI patients, and 14 age-matched healthy aging controls from the Alzheimer's Disease Neuroimaging Initiative database were selected based on availability of data. Default mode network (DMN) functional connectivity and fractional amplitude of low frequency fluctuation (fALFF) were obtained for resting state functional MRI (RS-fMRI). White matter lesion load (WMLL) was quantified from MRI T2-weighted FLAIR images. Amyloid deposition with PET [(18)F]-Florbetapir tracer and metabolism of glucose by means of [(18)F]-fluoro-2-deoxyglucose (FDG) images were quantified using ratio of standard uptake values (rSUV). RESULTS: Whole-brain WMLL and amyloid deposition were significantly higher (P < 0.005) in MCI and AD patients compared with controls. RS-fMRI results showed significantly reduced (corrected P < 0.05) DMN connectivity and altered fALFF activity in both MCI and AD groups. FDG uptake results showed hypometabolism in AD and MCI patients compared with controls. Correlations (P < 0.05) were found between WMLL and amyloid load, FDG uptake and amyloid load, as well as between amyloid load (rSUV) and fALFF. CONCLUSION: Our quantitative results of four MRI and PET imaging metrics (fALFF/DMN, WMLL, amyloid, and FDG rSUV values) agree with published values. Significant correlations between MRI metrics, including WMLL/functional activity and PET amyloid load suggest the potential of MRI and PET-based biomarkers for early detection of AD.

Magnetic resonance imaging of the retina: from mice to men.

This mini-review provides an overview of magnetic resonance imaging (MRI) applications to study rodent, cat, non-human primate, and human retinas. These techniques include T(1) - and T(2) -weighted anatomical, diffusion, blood flow, blood volume, blood-oxygenation level dependent, manganese-enhanced, physiological, and functional MRI. Applications to study the retinas in diabetic retinopathy, glaucoma, and retinal degeneration are also reviewed. MRI offers some unique advantages compared with existing imaging techniques and has the potential to further our understanding of physiology and function in healthy and diseased retinas.

MRI under hyperbaric air and oxygen: effects on local magnetic field and relaxation times.

PURPOSE: Hyperbaric oxygen therapy has shown efficacies in the treatment of a number of diseases. The goal of this study was to develop a rodent hyperbaric chamber for MRI studies and to investigate the effects of hyperbaric air and hyperbaric oxygen on local magnetic field (B0 ) and MRI relaxation parameters in the rat brain. METHODS: A hyperbaric chamber, constructed to fit inside an animal MRI scanner, was pressurized with air to four atmospheres, while oxygen was delivered locally via nose cone. B0 , T2 , T2 *, and T1 maps in the rat brain were evaluated under normobaric air, hyperbaric air, and hyperbaric oxygen at 7T. RESULTS: Under hyperbaric oxygen, images exhibited artifacts and temporal instability, attributable to fluctuating oxygen concentration from air and oxygen mixing near the imaging region. Physically shielding the imaging region from fluctuating oxygen concentration resolved the problems. With increasing oxygen at hyperbaric pressure, B0 was shifted downfield with increased inhomogeneity near the ear canals and nose. Brain T2 and T2 * were lengthened, and T1 was shortened. CONCLUSION: This study establishes the means to perform MRI on rodents under hyperbaric conditions. Hyperbaric air and hyperbaric oxygen have significant effects on B0 and tissue relaxation parameters compared with normobaric air.

Comparison of retinal and cerebral blood flow between continuous arterial spin labeling MRI and fluorescent microsphere techniques.

PURPOSE: To compare basal retinal and cerebral blood flow (BF) values using continuous arterial spin labeling (CASL) MRI and fluorescent microspheres. MATERIALS AND METHODS: A total of 41 animals were used. BF was measured using an established microsphere technique (a mixture of 2.5 million 8 µm green and 0.5 million 10 µm blue fluorescent microspheres) and CASL MRI blood flow measurement in the rat retina and brain at 7 Tesla (T) and 11.7T, respectively. RESULTS: Retinal BF by MRI was 1.18 ± 0.57 mL/g/min and choroidal BF was 8.14 ± 1.8 mL/g/min (n = 6). Microsphere retinal BF was 9.12 ± 2.8 µL/min per tissue and choroidal BF was 73.38 ± 44 µL/min per tissue (n = 18), corresponding to a retinal BF value of 1.22 ± 0.36 mL/g/min by means of a wet weight conversion. The wet-weight of the choroid could not be determined. To corroborate our findings, cerebral BF (CBF) by MRI was also analyzed. In the cerebral cortices, CBF was 0.91 ± 0.29 mL/g/min (n = 14) by CASL MRI and 1.09 ± 0.37 mL/g/min (n = 6) by microspheres. There were no significant differences found between MRI and microsphere blood flow in the retina and brain. CONCLUSION: BF values in the rat retina and cerebral cortex by MRI are in agreement with those obtained by the microsphere technique.

Improved MRI methods to quantify retinal and choroidal blood flow applied to a model of glaucoma.

Purpose: Blood flow (BF) of the retinal and choroidal vasculatures can be quantitatively imaged using MRI. This study sought to improve methods of data acquisition and analysis for MRI of layer-specific retinal and choroidal BF and then applied this approach to detect reduced ocular BF in a well-established mouse model of glaucoma from both eyes. Methods: Quantitative BF magnetic resonance imaging (MRI) was performed on glaucomatous DBA/2J and normal C57BL/6J mice. Arterial spin labeling MRI was applied to image retinal and choroidal BF using custom-made dual eye coils that could image both eyes during the same scan. Statistics using data from a single eye or two eyes were compared. BF values were calculated using two approaches. The BF rate per quantity of tissue was calculated as commonly done, and the peak BF values of the retinal and choroidal vasculatures were taken. Additionally, the BF rate per retinal surface area was calculated using a new analysis approach to attempt to reduce partial volume and variability by integrating BF over the retinal and choroidal depths. Results: Ocular BF of both eyes could be imaged using the dual coil setup without effecting scan time. Intraocular pressure was significantly elevated in DBA/2J mice compared to C57BL/6J mice (P<0.01). Both retinal and choroidal BF were significantly decreased in DBA/2J mice in comparison to the age-matched normal C57BL/6J mice across all measurements (P < 0.01). From simulations, the values from the integrated BF analysis method had less partial volume effect, and from in vivo scans, this analysis approach also improved power. Conclusion: The dual eye coil setup allows bilateral eye data acquisition, increasing the amount of data acquired without increasing acquisition times in vivo. The reduced ocular BF found using the improved acquisition and analysis approaches replicated the results of previous studies on DBA/2J mice. The ocular hypertensive stress-induced BF reduction found within these mice may represent changes associated with glaucomatous progression.

Methylene blue potentiates stimulus-evoked fMRI responses and cerebral oxygen consumption during normoxia and hypoxia.

Methylene blue USP (MB) at low doses has metabolic-enhancing and antioxidant properties and exhibits experimental neurotherapeutic benefits, but little is known about its in vivo effects on cerebral blood flow (CBF), functional evoked responses, and the associated changes in cerebral metabolic rate of oxygen (CMRO2). This study used magnetic resonance imaging (MRI) to evaluate the in vivo effects of a single intravenous MB therapeutic dose (0.5mg/kg) on basal CBF, blood oxygenation level-dependent (BOLD) and CBF responses to hypercapnic (5% CO2 in air) inhalation, as well as changes in BOLD, CBF, and CMRO2 during forepaw stimulation in the rat brain. MB did not have significant effects on arterial oxygen saturation, heart rate and fMRI responses to hypercapnia. However, MB significantly potentiated forepaw-evoked BOLD and CBF changes under normoxia. To further evaluate in vivo effects of MB under metabolic stress conditions, MRI measurements were also made under mild hypoxia (15% O2). Hypoxia per se increased evoked functional MRI responses. MB under hypoxia further potentiated forepaw-evoked BOLD, CBF and oxygen consumption responses relative to normoxia. These findings provide insights into MB's effects on cerebral hemodynamics in vivo and could help to optimize treatments in neurological diseases with mitochondrial dysfunction and oxidative stress.

Ultra high-resolution fMRI and electrophysiology of the rat primary somatosensory cortex.

High-resolution functional-magnetic-resonance-imaging (fMRI) has been used to study brain functions at increasingly finer scale, but whether fMRI can accurately reflect layer-specific neuronal activities is less well understood. The present study investigated layer-specific cerebral-blood-volume (CBV) fMRI and electrophysiological responses in the rat cortex. CBV fMRI at 40×40 µm in-plane resolution was performed on an 11.7-T scanner. Electrophysiology used a 32-channel electrode array that spanned the entire cortical depth. Graded electrical stimulation was used to study activations in different cortical layers, exploiting the notion that most of the sensory-specific neurons are in layers II-V and most of the nociceptive-specific neurons are in layers V-VI. CBV response was strongest in layer IV of all stimulus amplitudes. Current source density analysis showed strong sink currents at cortical layers IV and VI. Multi-unit activities mainly appeared at layers IV-VI and peaked at layer V. Although our measures showed scaled activation profiles during modulation of stimulus amplitude and failed to detect specific recruitment at layers V and VI during noxious electrical stimuli, there appears to be discordance between CBV fMRI and electrophysiological peak responses, suggesting neurovascular uncoupling at laminar resolution. The technique implemented in the present study offers a means to investigate intracortical neurovascular function in the normal and diseased animal models at laminar resolution.