Functional Magnetic Resonance Imaging (fMRI) of the Visual Cortex with Wide-View Retinotopic Stimulation.

High-resolution retinotopic blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) with a wide-view presentation can be used to functionally map the peripheral and central visual cortex. This method for measuring functional changes of the visual brain allows for functional mapping of the occipital lobe, stimulating >100° (±50°) or more of the visual field, compared to standard fMRI visual presentation setups which usually cover <30° of the visual field. A simple wide-view stimulation system for BOLD fMRI can be set up using common MR-compatible projectors by placing a large mirror or screen close to the subject's face and using only the posterior half of a standard head coil to provide a wide-viewing angle without obstructing their vision. The wide-view retinotopic fMRI map can then be imaged using various retinotopic stimulation paradigms, and the data can be analyzed to determine the functional activity of visual cortical regions corresponding to central and peripheral vision. This method provides a practical, easy-to-implement visual presentation system that can be used to evaluate changes in the peripheral and central visual cortex due to eye diseases such as glaucoma and the vision loss that may accompany them.

Assessment of MRI to estimate metastatic dissemination risk and prometastatic effects of chemotherapy.

Metastatic dissemination in breast cancer is regulated by specialized intravasation sites called "tumor microenvironment of metastasis" (TMEM) doorways, composed of a tumor cell expressing the actin-regulatory protein Mena, a perivascular macrophage, and an endothelial cell, all in stable physical contact. High TMEM doorway number is associated with an increased risk of distant metastasis in human breast cancer and mouse models of breast carcinoma. Here, we developed a novel magnetic resonance imaging (MRI) methodology, called TMEM Activity-MRI, to detect TMEM-associated vascular openings that serve as the portal of entry for cancer cell intravasation and metastatic dissemination. We demonstrate that TMEM Activity-MRI correlates with primary tumor TMEM doorway counts in both breast cancer patients and mouse models, including MMTV-PyMT and patient-derived xenograft models. In addition, TMEM Activity-MRI is reduced in mouse models upon treatment with rebastinib, a specific and potent TMEM doorway inhibitor. TMEM Activity-MRI is an assay that specifically measures TMEM-associated vascular opening (TAVO) events in the tumor microenvironment, and as such, can be utilized in mechanistic studies investigating molecular pathways of cancer cell dissemination and metastasis. Finally, we demonstrate that TMEM Activity-MRI increases upon treatment with paclitaxel in mouse models, consistent with prior observations that chemotherapy enhances TMEM doorway assembly and activity in human breast cancer. Our findings suggest that TMEM Activity-MRI is a promising precision medicine tool for localized breast cancer that could be used as a non-invasive test to determine metastatic risk and serve as an intermediate pharmacodynamic biomarker to monitor therapeutic response to agents that block TMEM doorway-mediated dissemination.

Effects of chronic mild hyperoxia on retinal and choroidal blood flow and retinal function in the DBA/2J mouse model of glaucoma.

PURPOSE: To test the hypothesis that mild chronic hyperoxia treatment would improve retinal function despite a progressive decline in ocular blood flow in the DBA/2J mouse model of glaucoma. MATERIALS AND METHODS: DBA/2J mice were treated with chronic mild hyperoxia (30% O2) beginning at 4.5 months of age or were untreated by giving normal room air. Retinal and choroidal blood flow (RBF and ChBF, respectively) were measured at 4, 6, and 9 months of age by MRI. Blood flow was additionally measured under hypercapnia challenge (5% CO2 inhalation) to assess vascular reactivity. Intraocular pressure (IOP) was measured using a rebound tonometer at the same time points. Scotopic flash electroretinograms (ERGs) were recorded at 9 months of age. RESULTS: Both ChBF and RBF were reduced and significantly affected by age (p < 0.01), but neither were significantly affected by O2-treatment (p > 0.05). ChBF significantly increased in response to hypercapnia (p < 0.01), which was also unaffected by O2-treatment. Significant effects of age (p < 0.001) and of the interaction of age with treatment (p = 0.028) were found on IOP. IOP significantly decreased in O2-treated mice at 6 months compared to 4 months of age (p < 0.001), while IOP trended to increase with age in untreated mice. The amplitude of the b-wave from ERG was significantly increased in O2-treated DBA/2J compared to the untreated mice (p = 0.012), while the a-wave and oscillatory potentials were not significantly affected (p > 0.05). CONCLUSION: This study investigated the effects of chronic mild hyperoxia on retinal function and on retinal and choroidal blood flow in a mouse model of glaucoma. Retinal function was improved in the O2-treated mice at late stage, despite a progressive decline of RBF and ChBF with age that was comparable to untreated mice.

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.

Resting-State Functional Magnetic Resonance Imaging of Interhemispheric Functional Connectivity in Experimental Traumatic Brain Injury.

Although resting-state functional magnetic resonance imaging (rsfMRI) has the potential to offer insights into changes in functional connectivity networks after traumatic brain injury (TBI), there are few studies that examine the effects of moderate TBI for monitoring functional recovery in experimental TBI, and thus the neural correlates of brain recovery from moderate TBI remain incompletely understood. Non-invasive rsfMRI was used to longitudinally investigate changes in interhemispheric functional connectivity (IFC) after a moderate TBI to the unilateral sensorimotor cortex in rats (n = 9) up to 14 days. Independent component analysis of the rsfMRI data was performed. Correlations of rsfMRI sensorimotor networks were made with changes in behavioral scores, lesion volume, and T2- and diffusion-weighted images across time. TBI animals showed less localized rsfMRI patterns in the sensorimotor network compared to sham (n = 6) and normal (n = 5) animals. rsfMRI clusters in the sensorimotor network showed less bilateral symmetry compared to sham and normal animals, indicative of IFC disruption. With time after injury, many of the rsfMRI patterns in the sensorimotor network showed more bilateral symmetry, indicative of IFC recovery. The disrupted IFC in the sensorimotor and subsequent partial recovery showed a positive correlation with changes in behavioral scores. Overall, rsfMRI detected widespread disruption and subsequent recovery of IFC within the sensorimotor networks post-TBI, which correlated with behavioral changes. Therefore, rsfMRI offers the means to probe functional brain reorganization and thus has the potential to serve as an imaging marker to longitudinally stage TBI and monitor for novel treatments.

Diabetic mice have retinal and choroidal blood flow deficits and electroretinogram deficits with impaired responses to hypercapnia.

PURPOSE: The purpose of this study was to investigate neuronal and vascular functional deficits in the retina and their association in a diabetic mouse model. We measured electroretinography (ERG) responses and choroidal and retinal blood flow (ChBF, RBF) with magnetic resonance imaging (MRI) in healthy and diabetic mice under basal conditions and under hypercapnic challenge. METHODS: Ins2Akita diabetic (Diab, n = 8) and age-matched, wild-type C57BL/6J mice (Ctrl, n = 8) were studied under room air and moderate hypercapnia (5% CO2). Dark-adapted ERG a-wave, b-wave, and oscillatory potentials (OPs) were measured for a series of flashes. Regional ChBF and RBF under air and hypercapnia were measured using MRI in the same mice. RESULTS: Under room air, Diab mice had compromised ERG b-wave and OPs (e.g., b-wave amplitude was 422.2±10.7 µV in Diab vs. 600.1±13.9 µV in Ctrl, p < 0.001). Under hypercapnia, OPs and b-wave amplitudes were significantly reduced in Diab (OPs by 30.3±3.0% in Diab vs. -3.0±3.6% in Ctrl, b-wave by 17.9±1.4% in Diab vs. 1.3±0.5% in Ctrl). Both ChBF and RBF had significant differences in regional blood flow, with Diab mice having substantially lower blood flow in the nasal region (ChBF was 5.4±1.0 ml/g/min in Diab vs. 8.6±1.0 ml/g/min in Ctrl, RBF was 0.91±0.10 ml/g/min in Diab vs. 1.52±0.24 ml/g/min in Ctrl). Under hypercapnia, ChBF increased in both Ctrl and Diab without significant group difference (31±7% in Diab vs. 17±7% in Ctrl, p > 0.05), but an increase in RBF was not detected for either group. CONCLUSIONS: Inner retinal neuronal function and both retinal and choroidal blood flow were impaired in Diab mice. Hypercapnia further compromised inner retinal neuronal function in diabetes, while the blood flow response was not affected, suggesting that the diabetic retina has difficulty adapting to metabolic challenges due to factors other than impaired blood flow regulation.

Cortical thickness and functional connectivity changes in Chinese chess experts.

BACKGROUND: Repeated practice to acquire expertise could result in the structural and functional changes in relevant brain circuits as a result of long-term potentiation, neurogenesis, glial genesis, and remodeling. PURPOSE: The goal of this study is to use surface-based morphology (SBM) to study cortical thickness differences in Chinese chess experts and novices, and to use regions of cortical thickness differences as seeds to guide a resting state connectivity analysis of the same population. METHODS: A raw public dataset from Huaxi MR Research Center consisting of 29 Chinese chess experts and 29 novices was used in this study, with both T1-weighted and resting state functional MRI. Surface based morphometry was performed on the T1 images with the Freesurfur pipeline, with a vertex significance threshold of p<0.05 and a cluster false discovery rate of α < 0.05. Regions with significant differences were used in a seed-based comparison of resting state functional connectivity carried out with Statistical Parameter Mapping (SPM) and the Connectivity Toolbox (CONN). Regions of connectivity differences within groups were computed with a voxel significance threshold of p<0.05 and a cluster false discovery rate of α < 0.01. RESULTS: Ten regions of the cortex of Chinese chess experts were found to be thinner than chess novices, including regions involved in visual processing, attention, working and episodic memory, and mental imagery, as well as several regions in the prefrontal cortex. There were no regions where experts' cortices were thicker than novices. Three of the thinner regions exhibited increased functional connectivity to distant brain regions in chess experts. CONCLUSIONS: Brain regions that are structurally affected by chess training are associated with processes that would likely have a high utility in chess expertise. Using a hierarchical control model, we hypothesize that the functional changes linked with some of these structural changes are related to the professionally trained chess players' ability to perceive and use contextual information, visuospatial perception, and outcome prediction in the domain of chess, all contributing to their exceptional performance.

Anatomical brain MRI study of pediatric cancer survivors treated with chemotherapy: Correlation with behavioral measures.

The negative impacts of chemotherapy on pediatric patients treated with chemotherapy during the formative years of brain development are understudied compared to adult chemotherapy cancer patients. This work investigated the morphometry, cortical thickness, and subcortical volumes using MRI and their correlations with behavioral measures in pediatric oncology survivors treated with chemotherapy. Chemotherapy-treated childhood cancer survivors (N = 15, 15.12 ± 5.98 years old) diagnosed with a non-central nervous system malignancy and healthy age-matched controls (N = 15, 15.13 ± 4.21 years old) were studied. MRI was acquired at 3 Tesla. Behavioral Rating Inventory of Executive Functioning (BRIEF) Parental Rating, Purdue Pegboard manual dexterity and n-back working memory measures were administered. Structural MRI scans at 3 Tesla were acquired. Voxel-based morphometry, cortical thickness and subcortical volumes were analyzed and correlated with behavioral scores. Parametric statistics with a p < .05 and adjusted for multiple comparison corrections were performed. Patients exhibited significantly smaller gray-matter volumes in the left globus pallidum, bilateral thalami, left caudate and left nucleus accumbens (p < .05) and thinner cortex in the right parahippocampal gyrus (p < .05) compared to controls. BRIEF scores were similar to normative values. Purdue Pegboard revealed manual dexterity deficits compared to normative values, and the n-back task showed working-memory deficits in patients compared to controls. Left thalamus volume positively correlated with dexterity performance (p = .029). The number of correct answers positively correlated and the number of incorrect answers negatively correlated with total-brain and white-matter volume (p < .05), but not gray-matter volume (p > .05). Our results support the hypothesis that the neurotoxicity of systemic chemotherapy has widespread negative effects on brain development in pediatric oncology patients with relatively mild cognitive deficits. MRI identified neuroanatomical changes have the potential to provide neural correlates of the sequelae associated with pediatric chemotherapy.

Functional, anatomical and diffusion tensor MRI study of radiology expertise.

BACKGROUND: Repeated practice to acquire expertise could result in the structural and functional changes in relevant brain circuits as a result of long-term potentiation, neurogenesis, glial genesis, and remodeling. PURPOSE: The goal of this study is to use task fMRI to study the brain of expert radiologists performing a diagnosis task where a series of medical images were presented during fMRI acquisition for 12s and participants were asked to choose a diagnosis. Structural and diffusion-tensor MRI were also acquired. METHODS: Radiologists (N = 12, 11M, 38.2±10.3 years old) and non-radiologists (N = 17, 15M, 30.6±5.5 years old) were recruited with informed consent. Medical images were presented for 12 s and three multiple choices were displayed and the participants were asked to choose a diagnosis. fMRI, structural and diffusion-tensor MRI were acquired. fMRI analysis used FSL to determine differences in fMRI responses between groups. Voxel-wise analysis was performed to determine if subcortical volume, cortical thickness and fractional anisotropy differed between groups. Correction for multiple comparisons used false discovery rate. RESULTS: Radiologists showed overall lower task-related brain activation than non-radiologists. Radiologists showed significantly lower activation in the left lateral occipital cortex, left superior parietal lobule, occipital pole, right superior frontal and precentral gyri, lingual gyrus, and the left intraparietal sulcus (p<0.05). There were no significant differences between groups in cortical thickness, subcortical volume and fractional anisotropy (p>0.05). CONCLUSIONS: Radiologists and non-radiologists had no significant difference in structural metrics. However, in diagnosis tasks, radiologists showed markedly lower task-related brain activations overall as well as a number of high-order visual and non-visual brain regions than non-radiologists. Some brain circuits appear to be uniquely associated with differential-diagnosis paradigm expertise that are not involved in simpler object-recognition cases. Improved understanding of the brain circuitry involved in acquisition of expertise might be used to design optimal training paradigms.

Retinal Vascular and Anatomical Features in the Spontaneously Hypertensive Rat.

Purpose: To evaluate whether invivo optical imaging methods and histology can detect comparable vascular and neuronal damage in the retina due to the effects of progressive chronic hypertension on the retinal vasculature and neurons using the spontaneously hypertensive rat (SHR) model at young and old ages. Methods: Male SHR and normotensive Wistar Kyoto (WKY) rats were studied at 10 and 40 weeks of age (n = 6 each group). Arterial blood pressure was measured with a tail-cuff. Under anesthesia, fundus photography was used to measure retinal arterial diameters and optical coherence tomography was used to measure retinal layer thicknesses. Histology was then used to measure microvascular and cell density in different retinal layers. Results: Blood pressure was significantly higher in SHR than WKY in both age groups (p < .05). Fundus images showed no gross abnormalities, hemorrhage, or stenosis in all groups. Retinal vessels, however, appeared more tortuous in SHR compared to WKY at both ages. Retinal vessel diameters in SHR were significantly narrower than in WKY at both age groups (p < .05). Microvascular densities at 10 weeks were not significantly different (p > .05) but were markedly reduced in SHR at 40 weeks compared to WKY (p < .05). The outer nuclear layer thickness of SHR was significantly thinner than that of WKY at both ages (p < .05), consistent with histological cell density measurements (p < .05). The ganglion cell layer and inner nuclear layer thicknesses were not significantly different between SHR and WKY (p > .05), consistent with the corresponding histological cell density measurements (p > .05). Conclusion: In vivo optical imaging showed that systemic hypertension progressively reduces retinal arterial diameter and thicknesses of the outer retina in spontaneously hypertensive rats, with consistent vascular and neuronal findings from histology.

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.

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.

Convolutional Neural Network Detection of Axillary Lymph Node Metastasis Using Standard Clinical Breast MRI.

BACKGROUND: Axillary lymph node status is important for breast cancer staging and treatment planning as the majority of breast cancer metastasis spreads through the axillary lymph nodes. There is currently no reliable noninvasive imaging method to detect nodal metastasis associated with breast cancer. MATERIALS AND METHODS: Magnetic resonance imaging (MRI) data were those from the peak contrast dynamic image from 1.5 Tesla MRI scanners at the pre-neoadjuvant chemotherapy stage. Data consisted of 66 abnormal nodes from 38 patients and 193 normal nodes from 61 patients. Abnormal nodes were those determined by expert radiologist based on 18Fluorodeoxyglucose positron emission tomography images. Normal nodes were those with negative diagnosis of breast cancer. The convolutional neural network consisted of 5 convolutional layers with filters from 16 to 128. Receiver operating characteristic analysis was performed to evaluate prediction performance. For comparison, an expert radiologist also scored the same nodes as normal or abnormal. RESULTS: The convolutional neural network model yielded a specificity of 79.3% ± 5.1%, sensitivity of 92.1% ± 2.9%, positive predictive value of 76.9% ± 4.0%, negative predictive value of 93.3% ± 1.9%, accuracy of 84.8% ± 2.4%, and receiver operating characteristic area under the curve of 0.91 ± 0.02 for the validation data set. These results compared favorably with scoring by radiologists (accuracy of 78%). CONCLUSION: The results are encouraging and suggest that this approach may prove useful for classifying lymph node status on MRI in clinical settings in patients with breast cancer, although additional studies are needed before routine clinical use can be realized. This approach has the potential to ultimately be a noninvasive alternative to lymph node biopsy.

Functional MRI of the mouse olfactory system.

Although olfactory dysfunction is an early warning sign of Alzheimer's and Parkinson's diseases, and is commonly present in a range of other neurodegenerative disorders, the mechanisms for its pathogenesis are not yet clear. Since fMRI allows the mapping of spatial and temporal patterns of activity in multiple brain regions simultaneously, it serves as a powerful tool to study olfactory dysfunction in animal models of neurodegenerative diseases. Nonetheless, there have been no reports to date of mapping odor-induced activation patterns beyond the olfactory bulb to the extended networks of olfactory and limbic archicortex, likely due to the small size of the mouse brain. Therefore, using an 11.7 T magnet and a blood volume-weighted fMRI technique, we mapped the functional neuroanatomy of the mouse olfactory system. Consistent with reports on imaging of the much larger human brain, we mapped activity in regions of the olfactory bulb, as well as olfactory and limbic archicortex. By using two distinct odorants, we further demonstrated odorant-specific activation patterns. Our work thus provides a methodological framework for fMRI studies of olfactory dysfunction in mouse models of neurodegeneration.

Resting-state functional connectivity networks associated with fatigue in multiple sclerosis with early age onset.

BACKGROUND: Fatigue is one of the most commonly experienced symptoms in multiple sclerosis (MS). The neural correlates of fatigue in MS, in general and specifically in early onset, remain poorly understood. This study employed resting-state fMRI (rsfMRI) to investigate the functional connectivity of fatigue in MS patients with early age onset. METHODS: Twenty-seven relapsing-remitting MS patients (20 ± 7yo at the age of diagnosis and 26.0 ±â€¯5.5yo at the time of study) were recruited and 22 patients were studied. Structural and rsfMRI sequences were performed on a 3-Tesla Seimens MRI scanner. Seed-based analysis was performed using CONN Functional Connectivity Toolbox for Statistic Parametric Mapping. The Fatigue Severity Scale (FSS) and the Modified Fatigue Impact scale (MFIS) as well as EDSS, Beck Depression Inventory, and symptomatology were measured. Non-fatigued (N = 12) and fatigued patients (N = 10) were separated based on FSS scores, with a score of 5 or greater being classified as fatigued. Group differences in rsfMRI between non-fatigued and fatigued patients were analyzed. Correlations between these functional connectivity differences and behavioral fatigue scores were also analyzed. RESULTS: Ages, disease duration, lesion load, lesion volume, and neurologic disability were not significantly different between non-fatigued and fatigued patients (p > 0.05). Fatigued patients showed significantly stronger connectivity between the right thalamus and right precentral gyrus (T = 4.58, p = 0.015), and a trending increase in connectivity between the left hippocampus and left precentral gyrus (T = 7.55, p = 0.051). Patients with fatigue showed significantly reduced connectivity between the right thalamus and left parietal operculum (T= -4.28, p = 0.0002), left thalamus and right superior frontal gyrus (T=-5.54, p = 0.046), and between the left insula and posterior cingulate (T=-9.4, p = 0.003). The connectivity between the left insula and posterior cingulate was significantly correlated with the cognitive score of MFIS (R2 = -0.471, p = 0.027) and FSS (R2 = -0.719, p = 0.0001). The connectivity between the right thalamus and left parietal operculum was significantly correlated with MFIS cognitive scores (R2 = -0.431, p = 0.045) and with FSS scores (R2 = 0.402, p = 0.006). Correlations remained significant after accounting for depression scores. CONCLUSIONS: rsfMRI identified Alterations in two distinct connections (the connectivity between insula and posterior cingulate gyrus and between the right thalamus and right precentral gyrus) that differed between fatigued and non-fatigued patients, as well as correlated with cognitive fatigue severity. These findings suggest that disruption of sensorimotor, high-order motor, and non-motor executive function likely contributes to the neural mechanism of fatigue in MS. Knowledge of the neural mechanisms of underlying MS fatigue could inform more effective treatment strategies.

Chronic oral methylene blue treatment in a rat model of focal cerebral ischemia/reperfusion.

A single acute low-dose methylene blue (MB), an FDA-grandfathered drug, has been shown to ameliorate behavioral deficits and reduces MRI-defined infarct volume in experimental ischemic stroke when administered intravenously or intraperitoneally. The efficacy of chronic MB treatment in ischemic stroke remains unknown. In a randomized, double-blinded and vehicle-controlled design, we investigated the efficacy of chronic oral MB administration in ischemic stroke longitudinally up to 60 days post injury using MRI and behavioral tests, with end-point histology. The major findings were chronic oral MB treatment, compared to vehicle, i) improves functional behavioral outcomes starting on day 7 and up to 60 days, ii) reduces MRI-defined total lesion volumes from day 14 and up to 60 days where some initial abnormal MRI-defined core and perfusion-diffusion mismatch were salvaged, iii) reduces white-matter damage, iv) gray matter and white matter damages are consistent with Nissl stains and Black Gold stain histology. These findings provide further evidence that long-term oral administration of low-dose MB is safe and has positive therapeutic effects in chronic ischemic stroke.

Intraarterial transplantation of human umbilical cord blood mononuclear cells in hyperacute stroke improves vascular function.

BACKGROUND: Human umbilical cord blood (hUCB) cell therapy is a promising treatment for ischemic stroke. The effects of hyperacute stem cell transplantation on cerebrovascular function in ischemic stroke are, however, not well understood. This study evaluated the effects of hyperacute intraarterial transplantation of hUCB mononuclear cells (MNCs) on cerebrovascular function in stroke rats using serial magnetic resonance imaging (MRI). METHODS: HUCB MNCs or vehicle were administered to stroke rats via the internal carotid artery immediately after reperfusion at 60 min following ischemia onset. Lesion volumes were longitudinally evaluated by MRI on days 0, 2, 14, and 28 after stroke, accompanied by behavioral tests. Cerebral blood flow (CBF) and cerebrovascular reactivity were measured by perfusion MRI and CO2 functional MRI (fMRI) at 28 days post-stroke; corresponding vascular morphological changes were also detected by immunohistology in the same animals. RESULTS: We found that CBF to the stroke-affected region at 28 days was improved (normalized CBF value: 1.41 ± 0.30 versus 0.49 ± 0.07) by intraarterial transplantation of hUCB MNCs in the hyperacute stroke phase, compared to vehicle control. Cerebrovascular reactivity within the stroke-affected area, measured by CBF fMRI, was also increased (35.2 ± 3.5% versus 12.8 ± 4.3%), as well as the corresponding cerebrovascular density. Some engrafted cells appeared with microvascular-like morphology and stained positive for von Willebrand Factor (an endothelial cell marker), suggesting they differentiated into endothelial cells. Some engrafted cells also connected to host endothelial cells, suggesting they interacted with the host vasculature. Compared to the vehicle group, infarct volume at 28 days in the stem cell treated group was significantly smaller (160.9 ± 15.7 versus 231.2 ± 16.0 mm3); behavioral deficits were also markedly reduced by stem cell treatment at day 28 (19.5 ± 1.0% versus 30.7 ± 4.7% on the foot fault test; 68.2 ± 4.6% versus 86.6 ± 5.8% on the cylinder test). More tissue within initial perfusion-diffusion mismatch was rescued in the treatment group. CONCLUSIONS: Intraarterial hUCB MNC transplantation during the hyperacute phase of ischemic stroke improved cerebrovascular function and reduced behavioral deficits and infarct volume.

Retinotopic fMRI Reveals Visual Dysfunction and Functional Reorganization in the Visual Cortex of Mild to Moderate Glaucoma Patients.

PURPOSE: To investigate retinotopic functional representation in the visual cortex of mild to moderate primary open-angle glaucoma (POAG) participants and age-matched normal volunteers using high-resolution retinotopic blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI). METHODS: fMRI was performed on 9 POAG participants (61±11 y old) and 9 age-matched controls (58±5 y old) were studied. A wide-view visual presentation (±55 degrees) was used to evaluate central and peripheral vision. Cortical magnification factors and BOLD% changes as a function of eccentricity. Correlation analysis between BOLD% changes and visual field scores, and between BOLD% changes and retinal nerve fiber layer thicknesses was performed. Comparison of BOLD% changes for individual visual field quadrants between POAG subgroups and normal group was performed. RESULTS: BOLD% changes of POAG participants in peripheral visual regions were reduced compared to normals but similar in central visual regions, consistent with the notion of peripheral vision being affected first and more compared to central vision. fMRI retinotopic mapping revealed enlarged representation of the parafovea in the visual cortex of POAG participants compared to normals. Cortical magnification of the central, but not peripheral, visual representation in the visual cortex was larger in POAG participants, suggesting functional remapping. BOLD% changes of individual visual field quadrants were significantly correlated with visual field scores and with retinal nerve fiber layer thickness in the corresponding quadrants. CONCLUSIONS: These results support the hypothesis that there are functional alteration and remapping in the topographic representation of the visual cortex in POAG participants, and these changes are correlated with disease severity.

Methylene blue modulates functional connectivity in the human brain.

Methylene blue USP (MB) is a FDA-grandfathered drug used in clinics to treat methemoglobinemia, carbon monoxide poisoning and cyanide poisoning that has been shown to increase fMRI evoked blood oxygenation level dependent (BOLD) response in rodents. Low dose MB also has memory enhancing effect in rodents and humans. However, the neural correlates of the effects of MB in the human brain are unknown. We tested the hypothesis that a single low oral dose of MB modulates the functional connectivity of neural networks in healthy adults. Task-based and task-free fMRI were performed before and one hour after MB or placebo administration utilizing a randomized, double-blinded, placebo-controlled design. MB administration was associated with a reduction in cerebral blood flow in a task-related network during a visuomotor task, and with stronger resting-state functional connectivity in multiple regions linking perception and memory functions. These findings demonstrate for the first time that low-dose MB can modulate task-related and resting-state neural networks in the human brain. These neuroimaging findings support further investigations in healthy and disease populations.

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.