Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3.

OBJECTIVE: This study was undertaken to identify magnetic resonance (MR) metrics that are most sensitive to early changes in the brain in spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3) using an advanced multimodal MR imaging (MRI) protocol in the multisite trial setting. METHODS: SCA1 or SCA3 mutation carriers and controls (n = 107) underwent MR scanning in the US-European READISCA study to obtain structural, diffusion MRI, and MR spectroscopy data using an advanced protocol at 3T. Morphometric, microstructural, and neurochemical metrics were analyzed blinded to diagnosis and compared between preataxic SCA (n = 11 SCA1, n = 28 SCA3), ataxic SCA (n = 14 SCA1, n = 37 SCA3), and control (n = 17) groups using nonparametric testing accounting for multiple comparisons. MR metrics that were most sensitive to preataxic abnormalities were identified using receiver operating characteristic (ROC) analyses. RESULTS: Atrophy and microstructural damage in the brainstem and cerebellar peduncles and neurochemical abnormalities in the pons were prominent in both preataxic groups, when patients did not differ from controls clinically. MR metrics were strongly associated with ataxia symptoms, activities of daily living, and estimated ataxia duration. A neurochemical measure was the most sensitive metric to preataxic changes in SCA1 (ROC area under the curve [AUC] = 0.95), and a microstructural metric was the most sensitive metric to preataxic changes in SCA3 (AUC = 0.92). INTERPRETATION: Changes in cerebellar afferent and efferent pathways underlie the earliest symptoms of both SCAs. MR metrics collected with a harmonized advanced protocol in the multisite trial setting allow detection of disease effects in individuals before ataxia onset with potential clinical trial utility for subject stratification. ANN NEUROL 2022.

Deuterated water imaging of the rat brain following metabolism of [2 H7 ]glucose.

PURPOSE: To determine whether deuterated water (HDO) generated from the metabolism of [2 H7 ]glucose is a sensitive biomarker of cerebral glycolysis and oxidative flux. METHODS: A bolus of [2 H7 ]glucose was injected through the tail vein at 1.95 g/kg into Sprague-Dawley rats. A 2 H surface coil was placed on top of the head to record 2 H spectra of the brain every 1.3 minutes to measure glucose uptake and metabolism to HDO, lactate, and glutamate/glutamine. A two-point Dixon method based on a gradient-echo sequence was used to reconstruct deuterated glucose and water (HDO) images selectively. RESULTS: The background HDO signal could be detected and imaged before glucose injection. The 2 H NMR spectra showed arrival of [2 H7 ]glucose and its metabolism in a time-dependent manner. A ratio of the HDO to glutamate/glutamine resonances demonstrates a pseudo-steady state following injection, in which cerebral metabolism dominates wash-in of HDO generated by peripheral metabolism. Brain spectroscopy reveals that HDO generation is linear with lactate and glutamate/glutamine appearance in the appropriate pseudo-steady state window. Selective imaging of HDO and glucose is easily accomplished using a gradient-echo method. CONCLUSION: Metabolic imaging of HDO, as a marker of glucose, lactate, and glutamate/glutamine metabolism, has been shown here for the first time. Cerebral glucose metabolism can be assessed efficiently using a standard gradient-echo sequence that provides superior in-plane resolution compared with CSI-based techniques.

Across-vendor standardization of semi-LASER for single-voxel MRS at 3T.

The semi-adiabatic localization by adiabatic selective refocusing (sLASER) sequence provides single-shot full intensity signal with clean localization and minimal chemical shift displacement error and was recommended by the international MRS Consensus Group as the preferred localization sequence at high- and ultra-high fields. Across-vendor standardization of the sLASER sequence at 3 tesla has been challenging due to the B1 requirements of the adiabatic inversion pulses and maximum B1 limitations on some platforms. The aims of this study were to design a short-echo sLASER sequence that can be executed within a B1 limit of 15 µT by taking advantage of gradient-modulated RF pulses, to implement it on three major platforms and to evaluate the between-vendor reproducibility of its perfomance with phantoms and in vivo. In addition, voxel-based first and second order B0 shimming and voxel-based B1 adjustments of RF pulses were implemented on all platforms. Amongst the gradient-modulated pulses considered (GOIA, FOCI and BASSI), GOIA-WURST was identified as the optimal refocusing pulse that provides good voxel selection within a maximum B1 of 15 µT based on localization efficiency, contamination error and ripple artifacts of the inversion profile. An sLASER sequence (30 ms echo time) that incorporates VAPOR water suppression and 3D outer volume suppression was implemented with identical parameters (RF pulse type and duration, spoiler gradients and inter-pulse delays) on GE, Philips and Siemens and generated identical spectra on the GE 'Braino' phantom between vendors. High-quality spectra were consistently obtained in multiple regions (cerebellar white matter, hippocampus, pons, posterior cingulate cortex and putamen) in the human brain across vendors (5 subjects scanned per vendor per region; mean signal-to-noise ratio > 33; mean water linewidth between 6.5 Hz to 11.4 Hz). The harmonized sLASER protocol is expected to produce high reproducibility of MRS across sites thereby allowing large multi-site studies with clinical cohorts.

Longitudinal evaluation of tumor microenvironment in rat focal brainstem glioma using diffusion and perfusion MRI.

BACKGROUND: Brainstem gliomas are aggressive and difficult to treat. Growth of these tumors may be characterized with MRI methods. PURPOSE: To visualize longitudinal changes in tumor volume, vascular leakiness, and tissue microstructure in an animal model of brainstem glioma. STUDY TYPE: Prospective animal model. ANIMAL MODEL: Male Sprague-Dawley rats (n = 9) were imaged with 9L gliosarcoma cells infused into the pontine reticular formation of the brainstem. The MRI tumor microenvironment was studied at 3 and 10 days postimplantation of tumor cells. FIELD STRENGTH/SEQUENCE: Diffusion tensor imaging (DTI) and dynamic contrast-enhanced (DCE)-MRI were performed at 4.7T using spin-echo multislice echo planar imaging and gradient echo multislice imaging, respectively. ASSESSMENT: Tumor leakiness was assessed by the forward volumetric transfer constant, Ktrans , estimated from DCE-MRI data. Tumor structure was evaluated with fractional anisotropy (FA) obtained from DTI. Tumor volumes, delineated by a T1 map, T2 -weighted image, FA, and DCE signal enhancement were compared. STATISTICAL TESTS: Changes in the assessed parameters within and across the groups (ie, rats 3 and 10 days post tumor cell implantation) were evaluated with Wilcoxon rank-sum tests. RESULTS: Day 3 tumors were visible mainly on contrast-enhanced images, while day 10 tumors were visible in both contrast-enhanced and diffusion-weighted images. Mean Ktrans at day 10 was 41% lower than at day 3 (P = 0.23). In day 10 tumors, FA was regionally lower in the tumor compared to normal tissue (P = 0.0004), and tumor volume, segmented based on FA map, was significantly smaller (P ≤ 0.05) than that obtained from other contrasts. DATA CONCLUSION: Contrast-enhanced MRI was found to be more sensitive in detecting early-stage tumor boundaries than other contrasts. Areas of the tumor outlined by DCE-MRI and DTI were significantly different. Over the observed period of tumor growth, average vessel leakiness decreased with tumor progression. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:1322-1332.

Detection of axonal degeneration in a mouse model of Huntington's disease: comparison between diffusion tensor imaging and anomalous diffusion metrics.

OBJECTIVE: The goal of this work is to study the changes in white matter integrity in R6/2, a well-established animal model of Huntington's disease (HD) that are captured by ex vivo diffusion imaging (DTI) using a high field MRI (17.6 T). MATERIALS AND METHODS: DTI and continuous time random walk (CTRW) models were used to fit changes in the diffusion-weighted signal intensity in the corpus callosum of controls and in R6/2 mice. RESULTS: A significant 13% decrease in fractional anisotropy, a 7% increase in axial diffusion, and a 33% increase in radial diffusion were observed between R6/2 and control mice. No change was observed in the CTRW beta parameter, but a significant decrease in the alpha parameter (- 21%) was measured. Histological analysis of the corpus callosum showed a decrease in axonal organization, myelin alterations, and astrogliosis. Electron microscopy studies demonstrated ultrastructural changes in degenerating axons, such as an increase in tortuosity in the R6/2 mice. CONCLUSIONS: DTI and CTRW diffusion models display quantitative changes associated with the microstructural alterations observed in the corpus callosum of the R6/2 mice. The observed increase in the diffusivity and decrease in the alpha CTRW parameter providing support for the use of these diffusion models for non-invasive detection of white matter alterations in HD.

Metal Transporter Zip14 (Slc39a14) Deletion in Mice Increases Manganese Deposition and Produces Neurotoxic Signatures and Diminished Motor Activity.

Mutations in human ZIP14 have been linked to symptoms of the early onset of Parkinsonism and Dystonia. This phenotype is likely related to excess manganese accumulation in the CNS. The metal transporter ZIP14 (SLC39A14) is viewed primarily as a zinc transporter that is inducible via proinflammatory stimuli. In vitro evidence shows that ZIP14 can also transport manganese. To examine a role for ZIP14 in manganese homeostasis, we used Zip14 knock-out (KO) male and female mice to conduct comparative metabolic, imaging, and functional studies. Manganese accumulation was fourfold to fivefold higher in brains of Zip14 KO mice compared with young adult wild-type mice. There was less accumulation of subcutaneously administered 54Mn in the liver, gallbladder, and gastrointestinal tract of the KO mice, suggesting that manganese elimination is impaired with Zip14 ablation. Impaired elimination creates the opportunity for atypical manganese accumulation in tissues, including the brain. The intensity of MR images from brains of the Zip14 KO mice is indicative of major manganese accumulation. In agreement with excessive manganese accumulation was the impaired motor function observed in the Zip14 KO mice. These results also demonstrate that ZIP14 is not essential for manganese uptake by the brain. Nevertheless, the upregulation of signatures of brain injury observed in the Zip14 KO mice demonstrates that normal ZIP14 function is an essential factor required to prevent manganese-linked neurodegeneration.SIGNIFICANCE STATEMENT Manganese is an essential micronutrient. When acquired in excess, manganese accumulates in tissues of the CNS and is associated with neurodegenerative disease, particularly Parkinson-like syndrome and dystonia. Some members of the ZIP metal transporter family transport manganese. Using mutant mice deficient in the ZIP14 metal transporter, we have discovered that ZIP14 is essential for manganese elimination via the gastrointestinal tract, and a lack of ZIP14 results in manganese accumulation in critical tissues such as the brain, as measured by MRI, and produces signatures of brain injury and impaired motor function. Humans with altered ZIP14 function would lack this gatekeeper function of ZIP14 and therefore would be prone to manganese-related neurological diseases.

Temporal lobe epilepsy affects spatial organization of entorhinal cortex connectivity.

Evidence for structural connectivity patterns within the medial temporal lobe derives primarily from postmortem histological studies. In humans and nonhuman primates, the parahippocampal gyrus (PHg) is subdivided into parahippocampal (PHc) and perirhinal (PRc) cortices, which receive input from distinct cortical networks. Likewise, their efferent projections to the entorhinal cortex (ERc) are distinct. The PHc projects primarily to the medial ERc (M-ERc). The PRc projects primarily to the lateral portion of the ERc (L-ERc). Both M-ERc and L-ERc, via the perforant pathway, project to the dentate gyrus and hippocampal (HC) subfields. Until recently, these neural circuits could not be visualized in vivo. Diffusion tensor imaging algorithms have been developed to segment gray matter structures based on probabilistic connectivity patterns. However, these algorithms have not yet been applied to investigate connectivity in the temporal lobe or changes in connectivity architecture related to disease processes. In this study, this segmentation procedure was used to classify ERc gray matter based on PRc, ERc, and HC connectivity patterns in 7 patients with temporal lobe epilepsy (TLE) without hippocampal sclerosis (mean age, 14.86 ±â€¯3.34 years) and 7 healthy controls (mean age, 23.86 ±â€¯2.97 years). Within samples paired t-tests allowed for comparison of ERc connectivity between epileptogenic and contralateral hemispheres. In healthy controls, there were no significant within-group differences in surface area, volume, or cluster number of ERc connectivity-defined regions (CDR). Likewise, in line with histology results, ERc CDR in the control group were well-organized, uniform, and segregated via PRc/PHc afferent and HC efferent connections. Conversely, in TLE, there were significantly more PRc and HC CDR clusters in the epileptogenic than the contralateral hemisphere. The surface area of the PRc CDR was greater, and that of the HC CDRs was smaller, in the epileptogenic hemisphere as well. Further, there was no clear delineation between M-ERc and L-ERc connectivity with PRc, PHc or HC in TLE. These results suggest a breakdown of the spatial organization of PHg-ERc-HC connectivity in TLE. Whether this breakdown is the cause or result of epileptic activity remains an exciting research question.

Methods to Compare Predicted and Observed Phosphene Experience in tACS Subjects.

Background: Phosphene generation is an objective physical measure of potential transcranial alternating current stimulation (tACS) biological side effects. Interpretations from phosphene analysis can serve as a first step in understanding underlying mechanisms of tACS in healthy human subjects and assist validation of computational models. Objective/Hypothesis: This preliminary study introduces and tests methods to analyze predicted phosphene occurrence using computational head models constructed from tACS recipients against verbal testimonies of phosphene sensations. Predicted current densities in the eyes and the occipital lobe were also verified against previously published threshold values for phosphenes. Methods: Six healthy subjects underwent 10 Hz tACS while being imaged in an MRI scanner. Two different electrode montages, T7-T8 and Fpz-Oz, were used. Subject ratings of phosphene experience were collected during tACS and compared against current density distributions predicted in eye and occipital lobe regions of interest (ROIs) determined for each subject. Calculated median current densities in each ROI were compared to minimum thresholds for phosphene generation. Main Results: All subjects reported phosphenes, and predicted median current densities in ROIs exceeded minimum thresholds for phosphenes found in the literature. Higher current densities in the eyes were consistently associated with decreased phosphene generation for the Fpz-Oz montage. There was an overall positive association between phosphene perceptions and current densities in the occipital lobe. Conclusions: These methods may have promise for predicting phosphene generation using data collected during in-scanner tACS sessions and may enable better understanding of phosphene origin. Additional empirical data in a larger cohort is required to fully test the robustness of the proposed methods. Future studies should include additional montages that could dissociate retinal and occipital stimulation.

The hippocampus: detailed assessment of normative two-dimensional measurements, signal intensity, and subfield conspicuity on routine 3T T2-weighted sequences.

PURPOSE: The hippocampus has a critical role in many common disease processes. Currently, routine 3 Tesla structural MRI is a mainstay of clinical diagnosis. The goal of our study is to evaluate the normal variability in size and/or conspicuity of the hippocampal subcomponents in routine clinical 3 Tesla high-resolution T2-weighted images to provide a basis for better defining pathological derangements. Additionally, we utilize diffusion data acquired from a 17.6 Tesla MRI of the hippocampus as a benchmark to better illustrate these subcomponents. METHODS: The hippocampus was retrospectively assessed on 104 clinically normal patients undergoing coronal T2-weighted imaging. The conspicuity of the majority of hippocampal subcomponents was assessed in each portion of the hippocampus. Additionally, easily applicable cross-sectional measurements and signal intensities were obtained to evaluate the range of normal, as well as inter- and intra-subject variability. RESULTS: The normal range of cross-sectional measurements of the hippocampal subcomponents was calculated. There was minimal side-to-side variability in cross-sectional measurements of hippocampal subcomponents (< 5%) with the exception of the subiculum (R>L by 8.3%) and the CA4/DG (R>L by 5.8%). The internal architecture showed high variability in visibility of subcomponents between different segments of the hippocampus. CONCLUSIONS: Confident clinical assessment of the hippocampus requires a thorough knowledge of hippocampal size and signal, but also the internal architecture expected to be seen. The data provided in this study will provide the reader with vital information necessary for distinguishing a normal from abnormal exam.

Toward 20 T magnetic resonance for human brain studies: opportunities for discovery and neuroscience rationale.

An initiative to design and build magnetic resonance imaging (MRI) and spectroscopy (MRS) instruments at 14 T and beyond to 20 T has been underway since 2012. This initiative has been supported by 22 interested participants from the USA and Europe, of which 15 are authors of this review. Advances in high temperature superconductor materials, advances in cryocooling engineering, prospects for non-persistent mode stable magnets, and experiences gained from large-bore, high-field magnet engineering for the nuclear fusion endeavors support the feasibility of a human brain MRI and MRS system with 1 ppm homogeneity over at least a 16-cm diameter volume and a bore size of 68 cm. Twelve neuroscience opportunities are presented as well as an analysis of the biophysical and physiological effects to be investigated before exposing human subjects to the high fields of 14 T and beyond.

Voxelized Model of Brain Infusion That Accounts for Small Feature Fissures: Comparison With Magnetic Resonance Tracer Studies.

Convection enhanced delivery (CED) is a promising novel technology to treat neural diseases, as it can transport macromolecular therapeutic agents greater distances through tissue by direct infusion. To minimize off-target delivery, our group has developed 3D computational transport models to predict infusion flow fields and tracer distributions based on magnetic resonance (MR) diffusion tensor imaging data sets. To improve the accuracy of our voxelized models, generalized anisotropy (GA), a scalar measure of a higher order diffusion tensor obtained from high angular resolution diffusion imaging (HARDI) was used to improve tissue segmentation within complex tissue regions of the hippocampus by capturing small feature fissures. Simulations were conducted to reveal the effect of these fissures and cerebrospinal fluid (CSF) boundaries on CED tracer diversion and mistargeting. Sensitivity analysis was also conducted to determine the effect of dorsal and ventral hippocampal infusion sites and tissue transport properties on drug delivery. Predicted CED tissue concentrations from this model are then compared with experimentally measured MR concentration profiles. This allowed for more quantitative comparison between model predictions and MR measurement. Simulations were able to capture infusate diversion into fissures and other CSF spaces which is a major source of CED mistargeting. Such knowledge is important for proper surgical planning.

On random walks and entropy in diffusion-weighted magnetic resonance imaging studies of neural tissue.

PURPOSE: In diffusion-weighted MRI studies of neural tissue, the classical model assumes the statistical mechanics of Brownian motion and predicts a monoexponential signal decay. However, there have been numerous reports of signal decays that are not monoexponential, particularly in the white matter. THEORY: We modeled diffusion in neural tissue from the perspective of the continuous time random walk. The characteristic diffusion decay is represented by the Mittag-Leffler function, which relaxes a priori assumptions about the governing statistics. We then used entropy as a measure of the anomalous features for the characteristic function. METHODS: Diffusion-weighted MRI experiments were performed on a fixed rat brain using an imaging spectrometer at 17.6 T with b-values arrayed up to 25,000 s/mm(2). Additionally, we examined the impact of varying either the gradient strength, q, or mixing time, Δ, on the observed diffusion dynamics. RESULTS: In white and gray matter regions, the Mittag-Leffler and entropy parameters demonstrated new information regarding subdiffusion and produced different image contrast from that of the classical diffusion coefficient. The choice of weighting on q and Δ produced different image contrast within the regions of interest. CONCLUSION: We propose these parameters have the potential as biomarkers for morphology in neural tissue.

Absolute magnetic susceptibility of rat brain tissue.

PURPOSE: This study was performed to test the commonly held hypothesis that the absolute magnetic susceptibility of brain tissue is close to that of water since water accounts for over 50% of the tissue composition. In addition, the absolute value of susceptibility of brain tissue is needed for the development of materials that are implanted into or in close proximity to tissue. METHODS: The absolute magnetic susceptibilities of different sections of rat brain, which were exsanguinated and perfusion-fixed, have been measured in a commercial superconducting quantum interference device magnetometer operating in fields up to 7T. RESULTS: The average measured values ranged from -(9.51 ± 0.01) × 10(-6) for the cerebellum to -(8.99 ± 0.01) × 10(-6) for a mixture of hippocampus, corpus callosum, and striatum. The time evolution of the samples was also studied, and deviations of <1% were observed after 4 weeks, although this trend was sample-specific. CONCLUSION: The measured susceptibilities are close to the value measured for high-performance liquid chromatography H2 O and depend on the amount of gray and white matter regions present in the samples.

Phase shift in the 24-hour rhythm of hippocampal EEG spiking activity in a rat model of temporal lobe epilepsy.

For over a century epileptic seizures have been known to cluster at specific times of the day. Recent studies have suggested that the circadian regulatory system may become permanently altered in epilepsy, but little is known about how this affects neural activity and the daily pattern of seizures. To investigate, we tracked long-term changes in the rate of spontaneous hippocampal EEG spikes (SPKs) in a rat model of temporal lobe epilepsy. In healthy animals, SPKs oscillated with near 24-h period; however, after injury by status epilepticus, a persistent phase shift of ∼12 h emerged in animals that later went on to develop chronic spontaneous seizures. Additional measurements showed that global 24-h rhythms, including core body temperature and theta state transitions, did not phase shift. Instead, we hypothesized that locally impaired circadian input to the hippocampus might be responsible for the SPK phase shift. This was investigated with a biophysical computer model in which we showed that subtle changes in the relative strengths of circadian input could produce a phase shift in hippocampal neural activity. MRI provided evidence that the medial septum, a putative circadian relay center for the hippocampus, exhibits signs of damage and therefore could contribute to local circadian impairment. Our results suggest that balanced circadian input is critical to maintaining natural circadian phase in the hippocampus and that damage to circadian relay centers, such as the medial septum, may disrupt this balance. We conclude by discussing how abnormal circadian regulation may contribute to the daily rhythms of epileptic seizures and related cognitive dysfunction.

Characterization of Anomalous Diffusion in Porous Biological Tissues Using Fractional Order Derivatives and Entropy.

In this high-resolution magnetic resonance imaging (MRI) study at 17.6 Tesla of a fixed rat brain, we used the continuous time random walk theory (CTRW) for Brownian motion to characterize anomalous diffusion. The complex mesoporus structure of biological tissues (membranes, organelles, and cells) perturbs the motion of the random walker (water molecules in proton MRI) introducing halts between steps (waiting times) and restrictions on step sizes (jump lengths). When such waiting times and jump lengths are scaled with probability distributions that follow simple inverse power laws (t-(1+α), |x|-(1+ß)) non-Gaussian motion gives rise to sub- and super- diffusion. In the CTRW approach, the Fourier transform yields a solution to the generalized diffusion equation that can be expressed by the Mittag-Leffler function (MLF), Eα (- Dα, ß|q|ßΔα). We interrogated both white and gray matter regions in a 1 mm slice of a fixed rat brain (190 µm in plane resolution) with diffusion weighted MRI experiments using b-values up to 25,000 s/mm2, by independently varying q and Δ. When fitting these data to our model, the fractional order parameters, α and ß, and the entropy measure, [Formula: see text], were found to provide excellent contrast between white and gray matter and to give results that were sensitive to the type of diffusion experiment performed.

Perivascular network segmentations derived from high-field MRI and their implications for perivascular and parenchymal mass transport in the rat brain.

A custom segmentation workflow was applied to ex vivo high-field MR images of rat brains acquired following in vivo intraventricular contrast agent infusion to generate maps of the perivascular spaces (PVS). The resulting perivascular network segmentations enabled analysis of perivascular connections to the ventricles, parenchymal solute clearance, and dispersive solute transport within PVS. Numerous perivascular connections between the brain surface and the ventricles suggest the ventricles integrate into a PVS-mediated clearance system and raise the possibility of cerebrospinal fluid (CSF) return from the subarachnoid space to the ventricles via PVS. Assuming rapid solute exchange between the PVS and CSF spaces primarily by advection, the extensive perivascular network decreased the mean clearance distance from parenchyma to the nearest CSF compartment resulting in an over 21-fold reduction in the estimated diffusive clearance time scale, irrespective of solute diffusivity. This corresponds to an estimated diffusive clearance time scale under 10 min for amyloid-beta which suggests that the widespread distribution of PVS may render diffusion an effective parenchymal clearance mechanism. Additional analysis of oscillatory solute dispersion within PVS indicates that advection rather than dispersion is likely the primary transport mechanism for dissolved compounds greater than 66 kDa in the long (> 2 mm) perivascular segments identified here, although dispersion may be significant for smaller compounds in shorter perivascular segments.

Role of convection and diffusion on DCE-MRI parameters in low leakiness KHT sarcomas.

The solid tumor is an abnormal environment that is resistant to systemically delivered drugs. Increased plasma leakiness and extracellular matrix density along with poor lymphatic function can result in interstitial flow that attenuates the effectiveness of therapeutics. This study expands upon a previously presented magnetic resonance (MR) imaging-based porous media model by investigating low permeability tumors, where interstitial flow may have increased effect on systemically delivered solutes. The solute transport of the porous media model is compared to that of experiment and the two-compartment model. Small non-necrotic tumors (n=3) were MR-imaged, serially, for 90 min after a bolus injection of Gd-based contrast agent (CA). These data provided for the calculation of experimental CA concentration over 90 min, while only early time points (15 min) were used to create vascular permeability, K(trans), maps for the porous media model. A K(trans) scale factor (range=1.3-2.5) in the porous media model was found to account for the reduction of permeability (measured by two-compartment model) due to interstitial flow. The optimized porous media simulations showed: 1) better dynamic CA behavior agreement with the experimental data than the two-compartment model (>33% reduction of RMS error); 2) similar spatial CA distribution trends across tumor with increased uptake at the tumor boundary.

Restoration of breathing after opioid overdose and spinal cord injury using temporal interference stimulation.

Respiratory insufficiency is a leading cause of death due to drug overdose or neuromuscular disease. We hypothesized that a stimulation paradigm using temporal interference (TI) could restore breathing in such conditions. Following opioid overdose in rats, two high frequency (5000 Hz and 5001 Hz), low amplitude waveforms delivered via intramuscular wires in the neck immediately activated the diaphragm and restored ventilation in phase with waveform offset (1 Hz or 60 breaths/min). Following cervical spinal cord injury (SCI), TI stimulation via dorsally placed epidural electrodes uni- or bilaterally activated the diaphragm depending on current and electrode position. In silico modeling indicated that an interferential signal in the ventral spinal cord predicted the evoked response (left versus right diaphragm) and current-ratio-based steering. We conclude that TI stimulation can activate spinal motor neurons after SCI and prevent fatal apnea during drug overdose by restoring ventilation with minimally invasive electrodes.

Evaluation of early microstructural changes in the R6/1 mouse model of Huntington's disease by ultra-high field diffusion MR imaging.

Diffusion MRI (dMRI) has been able to detect early structural changes related to neurological symptoms present in Huntington's disease (HD). However, there is still a knowledge gap to interpret the biological significance at early neuropathological stages. The purpose of this study is two-fold: (i) establish if the combination of Ultra-High Field Diffusion MRI (UHFD-MRI) techniques can add a more comprehensive analysis of the early microstructural changes observed in HD, and (ii) evaluate if early changes in dMRI microstructural parameters can be linked to cellular biomarkers of neuroinflammation. Ultra-high field magnet (16.7T), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) techniques were applied to fixed ex-vivo brains of a preclinical model of HD (R6/1 mice). Fractional anisotropy (FA) was decreased in deep and superficial grey matter (GM) as well as white matter (WM) brain regions with well-known early HD microstructure and connectivity pathology. NODDI parameters associated with the intracellular and extracellular compartment, such as intracellular ventricular fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fractions (IsoVF) were altered in R6/1 mice GM. Further, histological studies in these areas showed that glia cell markers associated with neuroinflammation (GFAP & Iba1) were consistent with the dMRI findings. dMRI can be used to extract non-invasive information of neuropathological events present in the early stages of HD. The combination of multiple imaging techniques represents a better approach to understand the neuropathological process allowing the early diagnosis and neuromonitoring of patients affected by HD.

Development of an inductively coupled MR coil system for imaging and spectroscopic analysis of an implantable bioartificial construct at 11.1 T.

Developing a method to noninvasively monitor tissue-engineered constructs is critical for the optimization of construct design and for assessing therapeutic efficacy. For this purpose, NMR is a powerful technique that can be used to obtain both images and spectroscopic data. But the inherent sensitivity of NMR limits the observation of a bioartificial construct with current NMR surface coil technology. In this study, we address this limitation through the development of an inductively coupled, implantable coil system, demonstrate its use at high field (11.1 T), and investigate the use of this coil system for monitoring a bioartificial construct in vitro and in vivo. The results establish that large gains in signal to noise can be obtained with this coil system over that obtainable with a surface coil. This coil system provides a means to quantitatively analyze the structure and function of implanted bioartificial organs.