Rapid microstructural plasticity in the cortical semantic network following a short language learning session.

Despite the clear importance of language in our life, our vital ability to quickly and effectively learn new words and meanings is neurobiologically poorly understood. Conventional knowledge maintains that language learning-especially in adulthood-is slow and laborious. Furthermore, its structural basis remains unclear. Even though behavioural manifestations of learning are evident near instantly, previous neuroimaging work across a range of semantic categories has largely studied neural changes associated with months or years of practice. Here, we address rapid neuroanatomical plasticity accompanying new lexicon acquisition, specifically focussing on the learning of action-related language, which has been linked to the brain's motor systems. Our results show that it is possible to measure and to externally modulate (using transcranial magnetic stimulation (TMS) of motor cortex) cortical microanatomic reorganisation after mere minutes of new word learning. Learning-induced microstructural changes, as measured by diffusion kurtosis imaging (DKI) and machine learning-based analysis, were evident in prefrontal, temporal, and parietal neocortical sites, likely reflecting integrative lexico-semantic processing and formation of new memory circuits immediately during the learning tasks. These results suggest a structural basis for the rapid neocortical word encoding mechanism and reveal the causally interactive relationship of modal and associative brain regions in supporting learning and word acquisition.

Detection of recurrent high-grade glioma using microstructure characteristics of distinct metabolic compartments in a multimodal and integrative 18F-FET PET/fast-DKI approach.

OBJECTIVES: Differentiation between high-grade glioma (HGG) and post-treatment-related effects (PTRE) is challenging, but advanced imaging techniques were shown to provide benefit. We aim to investigate microstructure characteristics of metabolic compartments identified from amino acid PET and to evaluate the diagnostic potential of this multimodal and integrative O-(2-18F-fluoroethyl)-L-tyrosine-(FET)-PET and fast diffusion kurtosis imaging (DKI) approach for the detection of recurrence and IDH genotyping. METHODS: Fifty-nine participants with neuropathologically confirmed recurrent HGG (n = 39) or PTRE (n = 20) were investigated using static 18F-FET PET and a fast-DKI variant. PET and advanced diffusion metrics of metabolically defined (80-100% and 60-75% areas of 18F-FET uptake) compartments were assessed. Comparative analysis was performed using Mann-Whitney U tests with Holm-Sídák multiple-comparison test and Wilcoxon signed-rank test. Receiver operating characteristic (ROC) curves, regression, and Spearman's correlation analysis were used for statistical evaluations. RESULTS: Compared to PTRE, recurrent HGG presented increased 18F-FET uptake and diffusivity (MD60), but lower (relative) mean kurtosis tensor (rMKT60) and fractional anisotropy (FA60) (respectively p < .05). Diffusion metrics determined from the metabolic periphery showed improved diagnostic performance - most pronounced for FA60 (AUC = 0.86, p < .001), which presented similar benefit to 18F-FET PET (AUC = 0.86, p < .001) and was negatively correlated with amino acid uptake (rs = - 0.46, p < .001). When PET and DKI metrics were evaluated in a multimodal biparametric approach, TBRmax + FA60 showed highest diagnostic accuracy (AUC = 0.93, p < .001), which improved the detection of relapse compared to PET alone (difference in AUC = 0.069, p = .04). FA60 and MD60 distinguished the IDH genotype in the post-treatment setting. CONCLUSION: Detection of glioma recurrence benefits from a multimodal and integrative PET/DKI approach, which presented significant diagnostic advantage to the assessment based on PET alone. CLINICAL RELEVANCE STATEMENT: A multimodal and integrative 18F-FET PET/fast-DKI approach for the non-invasive microstructural characterization of metabolic compartments provided improved diagnostic capability for differentiation between recurrent glioma and post-treatment-related changes, suggesting a role for the diagnostic workup of patients in post-treatment settings. KEY POINTS: • Multimodal PET/MRI with integrative analysis of 18F-FET PET and fast-DKI presents clinical benefit for the assessment of CNS cancer, particularly for the detection of recurrent high-grade glioma. • Microstructure markers of the metabolic periphery yielded biologically pertinent estimates characterising the tumour microenvironment, and, thereby, presented improved diagnostic accuracy with similar accuracy to amino acid PET. • Combined 18F-FET PET/fast-DKI achieved the best diagnostic performance for detection of high-grade glioma relapse with significant benefit to the assessment based on PET alone.

Jawbone measurements of edentulous sites related to implant planning using magnetic resonance imaging compared to cone beam computed tomography: An ex vivo study.

AIM: To compare measurements on images obtained by magnetic resonance imaging (MRI) and cone beam CT (CBCT) for height, width, and area in alveolar bone sites in human jaw specimens. MATERIAL AND METHODS: Forty edentulous alveolar posterior sites in human cadaver specimens were imaged using CBCT scanners, and with zero-echo-time MRI (ZTE-MRI). Semi-automatic volume registration was performed to generate representative coronal sections of the sites related to implant planning. ZTE-MRI sections were also presented after grayscale inversion (INV MRI). Three observers measured bone height, bone width 5 mm from the alveolar crest, and bone area stretching from the width measurement to the top of the alveolar crest in the images. Interobserver agreement was assessed by intra-class correlation coefficients (ICC). The measurements were analyzed using two-way repeated measures ANOVA factoring observer and image type. RESULTS: ICC was >0.95 for bone height, width, and bone area. No significant differences among observers (p = 0.14) or image type (p = 0.60) were found for bone height. For bone width, observer (p = 0.14) was not a significant factor, while ZTE-MRI produced width estimates that were significantly different and systematically smaller than CBCT-based estimates (p ≤ 0.001). Observer (p = 0.06) was not a significant factor regarding the bone area measurements, contrary to the imaging type where ZTE-MRI led to significantly smaller area estimates than CBCT (p ≤ 0.001). CONCLUSION: Bone height measurements were essentially equivalent using CBCT and MRI. This was found regardless of grayscale choice for the MRI. However, ZTE-MRI resulted in smaller estimates of bone width and area.

Anesthesia-related brain microstructure modulations detected by diffusion magnetic resonance imaging.

Recent studies have shown significant changes to brain microstructure during sleep and anesthesia. In vivo optical microscopy and magnetic resonance imaging (MRI) studies have attributed these changes to anesthesia and sleep-related modulation of the brain's extracellular space (ECS). Isoflurane anesthesia is widely used in preclinical diffusion MRI (dMRI) and it is therefore important to investigate if the brain's microstructure is affected by anesthesia to an extent detectable with dMRI. Here, we employ diffusion kurtosis imaging (DKI) to assess brain microstructure in the awake and anesthetized mouse brain (n = 22). We find both mean diffusivity (MD) and mean kurtosis (MK) to be significantly decreased in the anesthetized mouse brain compared with the awake state (p < 0.001 for both). This effect is observed in both gray matter and white matter. To further investigate the time course of these changes we introduce a method for time-resolved fast DKI. With this, we show the time course of the microstructural alterations in mice (n = 5) as they transition between states in an awake-anesthesia-awake paradigm. We find that the decrease in MD and MK occurs rapidly after delivery of gas isoflurane anesthesia and that values normalize only slowly when the animals return to the awake state. Finally, time-resolved fast DKI is employed in an experimental mouse model of brain edema (n = 4), where cell swelling causes the ECS volume to decrease. Our results show that isoflurane affects DKI parameters and metrics of brain microstructure and point to isoflurane causing a reduction in the ECS volume. The demonstrated DKI methods are suitable for in-bore perturbation studies, for example, for investigating microstructural modulations related to sleep/wake-dependent functions of the glymphatic system. Importantly, our study shows an effect of isoflurane anesthesia on rodent brain microstructure that has broad relevance to preclinical dMRI.

Building a Data Bridge: Policies, Structures, and Governance Integrating Primary Care Into the Public Health Response to COVID-19.

PURPOSE: The effective integration of primary care into public health responses to the COVID-19 pandemic, particularly through data sharing, has received some attention in the literature. However, the specific policies and structures that facilitate this integration are understudied. This paper describes the experiences of clinicians and administrators in Alberta, Canada as they built a data bridge between primary care and public health to improve the province's community-based response to the pandemic. METHODS: Fifty-seven semistructured qualitative interviews were conducted with a range of primary care and public health stakeholders working inside the Calgary Health Zone. Interpretive description was used to analyze the interviews. RESULTS: SARS-CoV-2 test results produced by the local public laboratory were, initially, only available to central public health clinicians and not independent primary care physicians. This enabled centrally managed contact tracing but meant primary care physicians were unaware of their patients' COVID-19 status and unable to offer in-community follow-up care. Stakeholders from both central public health and independent primary care were able to leverage a policy commitment to the Patient Medical Home (PMH) care model, and a range of existing organizational structures, and governance arrangements to create a data bridge that would span the gap. CONCLUSIONS: Primary care systems looking to draw lessons from the data bridge's construction may consider ways to: leverage care model commitments to integration and adjust or create organization and governance structures which actively draw together primary care and non-primary care stakeholders to work on common projects. Such policies and structures develop trusting relationships, open the possibility for champions to emerge, and create the spaces in which integrative improvisation can take place.

Aerosol containment device design considerations and performance evaluation metrics.

BACKGROUND: Spurred by the Coronavirus infectious disease 2019 pandemic, aerosol containment devices (ACDs) were developed to capture infectious respiratory aerosols generated by patients at their source. Prior reviews indicated that such devices had low evidence of effectiveness, but did not address how ACDs should be evaluated, how well they should perform, nor have clearly defined performance standards. Towards developing design criteria for ACDs, two questions were posed: 1) What characteristics have guided the design of ACDs? 2) How have these characteristics been evaluated? METHODS: A scoping review was performed consistent with PRISMA guidelines. Data were extracted with respect to general study information, intended use of the device, device design characteristics and evaluation. RESULTS: Fifty-four articles were included. Evaluation was most commonly performed with respect to device aerosol containment (n = 31, 61%), with only 5 (9%), 3 (6%) and 8 (15%) formally assessing providing experience, patient experience and procedure impact, respectively. Nearly all of the studies that explored provider experience and procedure impact studied intubation. Few studies provided a priori performance criteria for any evaluation metric, or referenced any external guidelines by which to bench mark performance. CONCLUSION: With respect to aerosol containment, ACDs should reduce exposure among HCP with the device compared with the absence of the device, and provide ≥90% reduction in respirable aerosols, equivalent in performance to N95 filtering facepiece respirators, if the goal is to reduce reliance on personal protective equipment. The ACD should not increase awkward or uncomfortable postures, or adversely impact biomechanics of the procedure itself as this could have implications for procedure outcomes. A variety of standardized instruments exist to assess the experience of patients and healthcare personnel. Integration of ACDs into routine clinical practice requires rigorous studies of aerosol containment and the user experience.

Alveolar bone measurements in magnetic resonance imaging compared with cone beam computed tomography: a pilot, ex-vivo study.

OBJECTIVES: To compare alveolar bone height and width measurements from zero-echo-time MRI (ZTE-MRI) and cone beam CT (CBCT), in human specimens. MATERIAL AND METHODS: Twenty posterior edentulous sites in human cadaver specimens were imaged with CBCT and ZTE-MRI. Bone height and width at 1, 3, 5, 7 and 9 mm from the top of the alveolar ridge was measured by two trained observers in cross-sections of a site where an implant was to be planned. Twenty percent of the sample was measured in duplicate to assess method error and intra-observer reproducibility (ICC). The differences between CBCT and ZTE-MRI measurements were compared (t-test). RESULTS: Inter- and intra-observer reproducibility was >0.90. The method error (average between observers) for bone height was 0.45 mm and 0.39 mm, and for bone width (average) was 0.52 mm and 0.80 mm (CBCT and ZTE-MRI, respectively). The majority of the bone measurement differences were statistically insignificant, except bone width measurements at 5 mm (p ≤ .05 for both observers). Mean measurement differences were not larger than the method error. CONCLUSION: ZTE-MRI is not significantly different from CBCT when comparing measurements of alveolar bone height and width.

Fibroblast-Specific Proteotranscriptomes Reveal Distinct Fibrotic Signatures of Human Sinoatrial Node in Nonfailing and Failing Hearts.

BACKGROUND: Up to 50% of the adult human sinoatrial node (SAN) is composed of dense connective tissue. Cardiac diseases including heart failure (HF) may increase fibrosis within the SAN pacemaker complex, leading to impaired automaticity and conduction of electric activity to the atria. Unlike the role of cardiac fibroblasts in pathologic fibrotic remodeling and tissue repair, nothing is known about fibroblasts that maintain the inherently fibrotic SAN environment. METHODS: Intact SAN pacemaker complex was dissected from cardioplegically arrested explanted nonfailing hearts (non-HF; n=22; 48.7±3.1 years of age) and human failing hearts (n=16; 54.9±2.6 years of age). Connective tissue content was quantified from Masson trichrome-stained head-center and center-tail SAN sections. Expression of extracellular matrix proteins, including collagens 1 and 3A1, CILP1 (cartilage intermediate layer protein 1), and POSTN (periostin), and fibroblast and myofibroblast numbers were quantified by in situ and in vitro immunolabeling. Fibroblasts from the central intramural SAN pacemaker compartment (≈10×5×2 mm3) and right atria were isolated, cultured, passaged once, and treated ± transforming growth factor ß1 and subjected to comprehensive high-throughput next-generation sequencing of whole transcriptome, microRNA, and proteomic analyses. RESULTS: Intranodal fibrotic content was significantly higher in SAN pacemaker complex from HF versus non-HF hearts (57.7±2.6% versus 44.0±1.2%; P<0.0001). Proliferating phosphorylated histone 3+/vimentin+/CD31- (cluster of differentiation 31) fibroblasts were higher in HF SAN. Vimentin+/α-smooth muscle actin+/CD31- myofibroblasts along with increased interstitial POSTN expression were found only in HF SAN. RNA sequencing and proteomic analyses identified unique differences in mRNA, long noncoding RNA, microRNA, and proteomic profiles between non-HF and HF SAN and right atria fibroblasts and transforming growth factor ß1-induced myofibroblasts. Specifically, proteins and signaling pathways associated with extracellular matrix flexibility, stiffness, focal adhesion, and metabolism were altered in HF SAN fibroblasts compared with non-HF SAN. CONCLUSIONS: This study revealed increased SAN-specific fibrosis with presence of myofibroblasts, CILP1, and POSTN-positive interstitial fibrosis only in HF versus non-HF human hearts. Comprehensive proteotranscriptomic profiles of SAN fibroblasts identified upregulation of genes and proteins promoting stiffer SAN extracellular matrix in HF hearts. Fibroblast-specific profiles generated by our proteotranscriptomic analyses of the human SAN provide a comprehensive framework for future studies to investigate the role of SAN-specific fibrosis in cardiac rhythm regulation and arrhythmias.

The primary care COVID-19 integrated pathway: a quantitative study of rapid response to health and social impacts of COVID-19.

Context: The first wave of COVID-19 in Calgary, Alberta health zone accelerated Primary Care (PC) integration. Specifically, it connected Family Physicians (FPs) with their counterparts in the broader health system to deliver wraparound patient care through a COVID-19 Integrated Pathway (CIP). A key element of the CIP included a data sharing platform that facilitated the provision of test results directly to the FP identified by patients. Public Health provided test results for all patients to the primary care system so they could be followed up by primary care to improve their outcomes. Objectives: To evaluate the CIP by describing its function and capacity to facilitate FP follow-up with COVID positive patients; and to inform refinement of the CIP for future use. Study Design: This abstract reports on the quantitative arm of a mixed methods study. Setting/Dataset: The Calgary Health Zone. Primary data were drawn from the Calgary COVID-19 Care Clinic (C4), a designated hub clinic for COVID-19 patients. Secondary data were drawn from provincially maintained records of hospitalization, emergency department visits, and FP claims. Participants: FPs and COVID-19 patients. Intervention: The data platform and PC attachment elements of the CIP. Outcome Measures: The characteristics of patients cared for via the CIP (age, sex, ethnicity, and risk-level); the proportion of patients without a FP who were attached to an FP; the number of patients followed by their FP in the community, and the number of specialist consultations made by FPs to support care, time from diagnosis to follow-up with PC/FP; ED and acute care utilization. Results: Between Apr. 16 and Sep. 27, 2020, 7706 patients were referred by the Public Health team to the C4 clinic. Of those, 51.4% were male, the median age was 36 y., and 86 deaths were reported. The majority of patients were referred to local PC networks where follow-up was conducted using the CIP: 3223 (43%) already had their own FP, 2448 (32%) were successfully attached to an FP, and 1899 (25%) of these patients were monitored by C4 physicians - these patients either did not have FP or their FP was not available to follow the patient. 8.6% of these patients visited ED and 3.1% were hospitalized. More than 80% of these patients had at least of 5 visits with their FP. Conclusion: Data suggest that the CIP facilitated primary care based management of patients with COVID-19.

Comprehensive evaluation of electrophysiological and 3D structural features of human atrial myocardium with insights on atrial fibrillation maintenance mechanisms.

Atrial fibrillation (AF) occurrence and maintenance is associated with progressive remodeling of electrophysiological (repolarization and conduction) and 3D structural (fibrosis, fiber orientations, and wall thickness) features of the human atria. Significant diversity in AF etiology leads to heterogeneous arrhythmogenic electrophysiological and structural substrates within the 3D structure of the human atria. Since current clinical methods have yet to fully resolve the patient-specific arrhythmogenic substrates, mechanism-based AF treatments remain underdeveloped. Here, we review current knowledge from in-vivo, ex-vivo, and in-vitro human heart studies, and discuss how these studies may provide new insights on the synergy of atrial electrophysiological and 3D structural features in AF maintenance. In-vitro studies on surgically acquired human atrial samples provide a great opportunity to study a wide spectrum of AF pathology, including functional changes in single-cell action potentials, ion channels, and gene/protein expression. However, limited size of the samples prevents evaluation of heterogeneous AF substrates and reentrant mechanisms. In contrast, coronary-perfused ex-vivo human hearts can be studied with state-of-the-art functional and structural technologies, such as high-resolution near-infrared optical mapping and contrast-enhanced MRI. These imaging modalities can resolve atrial arrhythmogenic substrates and their role in reentrant mechanisms maintaining AF and validate clinical approaches. Nonetheless, longitudinal studies are not feasible in explanted human hearts. As no approach is perfect, we suggest that combining the strengths of direct human atrial studies with high fidelity approaches available in the laboratory and in realistic patient-specific computer models would elucidate deeper knowledge of AF mechanisms. We propose that a comprehensive translational pipeline from ex-vivo human heart studies to longitudinal clinically relevant AF animal studies and finally to clinical trials is necessary to identify patient-specific arrhythmogenic substrates and develop novel AF treatments.

Microstructural changes in the brain after long-term post-concussion symptoms: A randomized trial.

A recent randomized controlled trial in young patients with long-term post-concussion symptoms showed that a novel behavioral intervention "Get going After concussIoN" is superior to enhanced usual care in terms of symptom reduction. It is unknown whether these interventional effects are associated with microstructural brain changes. The aim of this study was to examine whether diffusion-weighted MRI indices, which are sensitive to the interactions between cellular structures and water molecules' Brownian motion, respond differently to the interventions of the above-mentioned trial and whether such differences correlate with the improvement of post-concussion symptoms. Twenty-three patients from the intervention group (mean age 22.8, 18 females) and 19 patients from the control group (enhanced usual care) (mean age 23.9, 14 females) were enrolled. The primary outcome measure was the mean kurtosis tensor, which is sensitive to the microscopic complexity of brain tissue. The mean kurtosis tensor was significantly increased in the intervention group (p = 0.003) in the corpus callosum but not in the thalamus (p = 0.78) and the hippocampus (p = 0.34). An increase in mean kurtosis tensor in the corpus callosum tended to be associated with a reduction in symptoms, but this association did not reach significance (p = 0.059). Changes in diffusion tensor imaging metrics did not differ between intervention groups and were not associated with symptoms. The current study found different diffusion-weighted MRI responses from the microscopic cellular structures of the corpus callosum between patients receiving a novel behavioral intervention and patients receiving enhanced usual care. Correlations with improvement of post-concussion symptoms were not evident.

Visualization of live, mammalian neurons during Kainate-infusion using magnetic resonance microscopy.

Since its first description and development in the late 20th century, diffusion magnetic resonance imaging (dMRI) has proven useful in describing the microstructural details of biological tissues. Signal generated from the protons of water molecules undergoing Brownian motion produces contrast based on the varied diffusivity of tissue types. Images employing diffusion contrast were first used to describe the diffusion characteristics of tissues, later used to describe the fiber orientations of white matter through tractography, and most recently proposed as a functional contrast method capable of delineating neuronal firing in the active brain. Thanks to the molecular origins of its signal source, diffusion contrast is inherently useful at describing features of the microenvironment; however, limitations in achievable resolution in magnetic resonance imaging (MRI) scans precluded direct visualization of tissue microstructure for decades following MRI's inception as an imaging modality. Even after advancements in MRI hardware had permitted the visualization of mammalian cells, these specialized systems could only accommodate fixed specimens that prohibited the observation and characterization of physiological processes. The goal of the current study was to visualize cellular structure and investigate the subcellular origins of the functional diffusion contrast mechanism (DfMRI) in living, mammalian tissue explants. Using a combination of ultra-high field spectrometers, micro radio frequency (RF) coils, and an MRI-compatible superfusion device, we are able to report the first live, mammalian cells-α-motor neurons-visualized with magnetic resonance microscopy (MRM). We are also able to report changes in the apparent diffusion of the stratum oriens within the hippocampus-a layer comprised primarily of pyramidal cell axons and basal dendrites-and the spinal cord's ventral horn following exposure to kainate.

Diffusion Kurtosis Imaging maps neural damage in the EAE model of multiple sclerosis.

Diffusion kurtosis imaging (DKI) is an imaging modality that yields novel disease biomarkers and in combination with nervous tissue modeling, provides access to microstructural parameters. Recently, DKI and subsequent estimation of microstructural model parameters has been used for assessment of tissue changes in neurodegenerative diseases and associated animal models. In this study, mouse spinal cords from the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS) were investigated for the first time using DKI in combination with biophysical modeling to study the relationship between microstructural metrics and degree of animal dysfunction. Thirteen spinal cords were extracted from animals with varied grades of disability and scanned in a high-field MRI scanner along with five control specimen. Diffusion weighted data were acquired together with high resolution T2* images. Diffusion data were fit to estimate diffusion and kurtosis tensors and white matter modeling parameters, which were all used for subsequent statistical analysis using a linear mixed effects model. T2* images were used to delineate focal demyelination/inflammation. Our results reveal a strong relationship between disability and measured microstructural parameters in normal appearing white matter and gray matter. Relationships between disability and mean of the kurtosis tensor, radial kurtosis, radial diffusivity were similar to what has been found in other hypomyelinating MS models, and in patients. However, the changes in biophysical modeling parameters and in particular in extra-axonal axial diffusivity were clearly different from previous studies employing other animal models of MS. In conclusion, our data suggest that DKI and microstructural modeling can provide a unique contrast capable of detecting EAE-specific changes correlating with clinical disability.

Rapid solution of the Bloch-Torrey equation in anisotropic tissue: Application to dynamic susceptibility contrast MRI of cerebral white matter.

Blood vessel related magnetic resonance imaging (MRI) contrast provides a window into the brain's metabolism and function. Here, we show that the spin echo dynamic susceptibility contrast (DSC) MRI signal of the brain's white matter (WM) strongly depends on the angle between WM tracts and the main magnetic field. The apparent cerebral blood flow and volume are 20% larger in fibres perpendicular to the main magnetic field compared to parallel fibres. We present a rapid numerical framework for the solution of the Bloch-Torrey equation that allows us to explore the isotropic and anisotropic components of the vascular tree. By fitting the simulated spin echo DSC signal to the measured data, we show that half of the WM vascular volume is comprised of vessels running in parallel with WM fibre tracts. The WM blood volume corresponding to the best fit to the experimental data was 2.82%, which is close to the PET gold standard of 2.6%.

Diffusion time dependence of microstructural parameters in fixed spinal cord.

Biophysical modelling of diffusion MRI is necessary to provide specific microstructural tissue properties. However, estimating model parameters from data with limited diffusion gradient strength, such as clinical scanners, has proven unreliable due to a shallow optimization landscape. On the other hand, estimation of diffusion kurtosis (DKI) parameters is more robust, and its parameters may be connected to microstructural parameters, given an appropriate biophysical model. However, it was previously shown that this procedure still does not provide sufficient information to uniquely determine all model parameters. In particular, a parameter degeneracy related to the relative magnitude of intra-axonal and extra-axonal diffusivities remains. Here we develop a model of diffusion in white matter including axonal dispersion and demonstrate stable estimation of all model parameters from DKI in fixed pig spinal cord. By employing the recently developed fast axisymmetric DKI, we use stimulated echo acquisition mode to collect data over a two orders of magnitude diffusion time range with very narrow diffusion gradient pulses, enabling finely resolved measurements of diffusion time dependence of both net diffusion and kurtosis metrics, as well as model intra- and extra-axonal diffusivities, and axonal dispersion. Our results demonstrate substantial time dependence of all parameters except volume fractions, and the additional time dimension provides support for intra-axonal diffusivity to be larger than extra-axonal diffusivity in spinal cord white matter, although not unambiguously. We compare our findings for the time-dependent compartmental diffusivities to predictions from effective medium theory with reasonable agreement.

Diffusion MRI and MR spectroscopy reveal microstructural and metabolic brain alterations in chronic mild stress exposed rats: A CMS recovery study.

Chronic mild stress (CMS) induced depression elicits several debilitating symptoms and causes a significant economic burden on society. High variability in the symptomatology of depression poses substantial impediment to accurate diagnosis and therapy outcome. CMS exposure induces significant metabolic and microstructural alterations in the hippocampus (HP), prefrontal cortex (PFC), caudate-putamen (CP) and amygdala (AM), however, recovery from these maladaptive changes are limited and this may provide negative effects on the therapeutic treatment and management of depression. The present study utilized anhedonic rats from the unpredictable CMS model of depression to study metabolic recovery in the ventral hippocampus (vHP) and microstructural recovery in the HP, AM, CP, and PFC. The study employed 1H MR spectroscopy (1H MRS) and in-vivo diffusion MRI (d-MRI) at the age of week 18 (week 1 post CMS exposure) week 20 (week 3 post CMS) and week 25 (week 8 post CMS exposure) in the anhedonic group, and at the age of week 18 and week 22 in the control group. The d-MRI data have provided an array of diffusion tensor metrics (FA, MD, AD, and RD), and fast kurtosis metrics (MKT, WL and WT). CMS exposure induced a significant metabolic alteration in vHP, and significant microstructural alterations were observed in the HP, AM, and PFC in comparison to the age match control and within the anhedonic group. A significantly high level of N-acetylaspartate (NAA) was observed in vHP at the age of week 18 in comparison to age match control and week 20 and week 25 of the anhedonic group. HP and AM showed significant microstructural alterations up to the age of week 22 in the anhedonic group. PFC showed significant microstructural alterations only at the age of week 18, however, most of the metrics showed significantly higher value at the age of week 20 in the anhedonic group. The significantly increased NAA concentration may indicate impaired catabolism due to astrogliosis or oxidative stress. The significantly increased WL in the AM and HP may indicate hypertrophy of AM and reduced volume of HP. Such metabolic and microstructural alterations could be useful in disease diagnosis and follow-up treatment intervention in depression and similar disorders.

Diffusion MRI findings in patients with extensive and minimal post-concussion symptoms after mTBI and healthy controls: a cross sectional study.

PRIMARY OBJECTIVES: We hypothesized that the microstructure of the corpus callosum, thalamus and hippocampus, as measured with diffusion and Mean of the Kurtosis Tensor (MKT) MRI, differs between healthy subjects and patients with extensive and minimal post-concussion symptoms (PCS) and that MKT measures correlate with PCS severity and self-reported cognitive symptoms. RESEARCH DESIGN: A cross-sectional study comparing patients with extensive PCS and patients with minimal PCS 2-5 months after mild traumatic brain injury (mTBI) with each other and with an external healthy control group. METHODS AND PROCEDURES: Diffusion MRI was obtained in 25 patients with extensive PCS and in 25 patients with minimal PCS as measured by the Rivermead Post-concussion Symptoms Questionnaire. The patients were matched on age, sex and time since accident. Data from an external healthy control group (n = 27) was included. MAIN OUTCOME AND RESULTS: There was no difference in MKT between the two groups with mTBI and no correlation between MKT and PCS. There was no difference between the three groups in other diffusion measures. CONCLUSIONS: Our results did not point to microstructural changes in the corpus callosum, thalamus and hippocampus in relation to PCS after mTBI.

Adenosine-Induced Atrial Fibrillation: Localized Reentrant Drivers in Lateral Right Atria due to Heterogeneous Expression of Adenosine A1 Receptors and GIRK4 Subunits in the Human Heart.

BACKGROUND: Adenosine provokes atrial fibrillation (AF) with a higher activation frequency in right atria (RA) versus left atria (LA) in patients, but the underlying molecular and functional substrates are unclear. We tested the hypothesis that adenosine-induced AF is driven by localized reentry in RA areas with highest expression of adenosine A1 receptor and its downstream GIRK (G protein-coupled inwardly rectifying potassium channels) channels (IK,Ado). METHODS: We applied biatrial optical mapping and immunoblot mapping of various atrial regions to reveal the mechanism of adenosine-induced AF in explanted failing and nonfailing human hearts (n=37). RESULTS: Optical mapping of coronary-perfused atria (n=24) revealed that adenosine perfusion (10-100 µmol/L) produced more significant shortening of action potential durations in RA (from 290±45 to 239±41 ms, 17.3±10.4%; P<0.01) than LA (from 307±24 to 286±23 ms, 6.7±6.6%; P<0.01). In 10 hearts, adenosine induced AF (317±116 s) that, when sustained (≥2 minutes), was primarily maintained by 1 to 2 localized reentrant drivers in lateral RA. Tertiapin (10-100 nmol/L), a selective GIRK channel blocker, counteracted adenosine-induced action potential duration shortening and prevented AF induction. Immunoblotting showed that the superior/middle lateral RA had significantly higher adenosine A1 receptor (2.7±1.7-fold; P<0.01) and GIRK4 (1.7±0.8-fold; P<0.05) protein expression than lateral/posterior LA. CONCLUSIONS: This study revealed a 3-fold RA-to-LA adenosine A1 receptor protein expression gradient in the human heart, leading to significantly greater RA versus LA repolarization sensitivity in response to adenosine. Sustained adenosine-induced AF is maintained by reentrant drivers localized in lateral RA regions with the highest adenosine A1 receptor/GIRK4 expression. Selective atrial GIRK channel blockade may effectively treat AF during conditions with increased endogenous adenosine.

Precision and accuracy of diffusion kurtosis estimation and the influence of b-value selection.

Diffusion kurtosis imaging (DKI) is an extension of diffusion tensor imaging that accounts for leading non-Gaussian diffusion effects. In DKI studies, a wide range of different gradient strengths (b-values) is used, which is known to affect the estimated diffusivity and kurtosis parameters. Hence there is a need to assess the accuracy and precision of the estimated parameters as a function of b-value. This work examines the error in the estimation of mean of the kurtosis tensor (MKT) with respect to the ground truth, using simulations based on a biophysical model for both gray (GM) and white (WM) matter. Model parameters are derived from densely sampled experimental data acquired in ex vivo rat brain and in vivo human brain. Additionally, the variability of MKT is studied using the experimental data. Prevalent fitting protocols are implemented and investigated. The results show strong dependence on the maximum b-value of both net relative error and standard deviation of error for all of the employed fitting protocols. The choice of b-values with minimum MKT estimation error and standard deviation of error was found to depend on the protocol type and the tissue. Protocols that utilize two terms of the cumulant expansion (DKI) were found to achieve minimum error in GM at b-values less than 1 ms/µm2 , whereas maximal b-values of about 2.5 ms/µm2 were found to be optimal in WM. Protocols including additional higher order terms of the cumulant expansion were found to provide higher accuracy for the more commonly used b-value regime in GM, but were associated with higher error in WM. Averaged over multiple voxels, a net average error of around 15% for both WM and GM was observed for the optimal b-value choice. These results suggest caution when using DKI generated metrics for microstructural modeling and when comparing results obtained using different fitting techniques and b-values.

White matter biomarkers from fast protocols using axially symmetric diffusion kurtosis imaging.

White matter tract integrity (WMTI) can characterize brain microstructure in areas with highly aligned fiber bundles. Several WMTI biomarkers have now been validated against microscopy and provided promising results in studies of brain development and aging, as well as in a number of brain disorders. Currently, WMTI is mostly used in dedicated animal studies and clinical studies of slowly progressing diseases, and has not yet emerged as a routine clinical tool. To this end, a less data intensive experimental method would be beneficial by enabling high resolution validation studies, and ease clinical applications by speeding up data acquisition compared with typical diffusion kurtosis imaging (DKI) protocols utilized as part of WMTI imaging. Here, we evaluate WMTI based on recently introduced axially symmetric DKI, which has lower data demand than conventional DKI. We compare WMTI parameters derived from conventional DKI with those calculated analytically from axially symmetric DKI. We employ numerical simulations, as well as data from fixed rat spinal cord (one sample) and in vivo human (three subjects) and rat brain (four animals). Our analysis shows that analytical WMTI based on axially symmetric DKI with sparse data sets (19 images) produces WMTI metrics that correlate strongly with estimates based on traditional DKI data sets (60 images or more). We demonstrate the preclinical potential of the proposed WMTI technique in in vivo rat brain (300 µm isotropic resolution with whole brain coverage in a 1 h acquisition). WMTI parameter estimates are subject to a duality leading to two solution branches dependent on a sign choice, which is currently debated. Results from both of these branches are presented and discussed throughout our analysis. The proposed fast WMTI approach may be useful for preclinical research and e.g. clinical evaluation of patients with traumatic white matter injuries or symptoms of neurovascular or neuroinflammatory disorders.