Characterization of hyperpolarization-activated cyclic nucleotide-gated channels in oligodendrocytes.

Mature oligodendrocytes (OLG) are the myelin-forming cells of the central nervous system. Recent work has shown a dynamic role for these cells in the plasticity of neural circuits, leading to a renewed interest in voltage-sensitive currents in OLG. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and their respective current (Ih) were recently identified in mature OLG and shown to play a role in regulating myelin length. Here we provide a biochemical and electrophysiological characterization of HCN channels in cells of the oligodendrocyte lineage. We observed that mice with a nonsense mutation in the Hcn2 gene (Hcn2ap/ap) have less white matter than their wild type counterparts with fewer OLG and fewer oligodendrocyte progenitor cells (OPCs). Hcn2ap/ap mice have severe motor impairments, although these deficits were not observed in mice with HCN2 conditionally eliminated only in oligodendrocytes (Cnpcre/+; Hcn2F/F). However, Cnpcre/+; Hcn2F/F mice develop motor impairments more rapidly in response to experimental autoimmune encephalomyelitis (EAE). We conclude that HCN2 channels in OLG may play a role in regulating metabolism.

In Vivo Assessment of Bone Quality Without X-rays.

PURPOSE OF REVIEW: This review summarizes recent advances in the assessment of bone quality using non-X-ray techniques. RECENT FINDINGS: Quantitative ultrasound (QUS) provides multiple measurements of bone characteristics based on the propagation of sound through bone, the attenuation of that sound, and different processing techniques. QUS parameters and model predictions based on backscattered signals can discriminate non-fracture from fracture cases with accuracy comparable to standard bone mineral density (BMD). With advances in magnetic resonance imaging (MRI), bound water and pore water, or a porosity index, can be quantified in several long bones in vivo. Since such imaging-derived measurements correlate with the fracture resistance of bone, they potentially provide new BMD-independent predictors of fracture risk. While numerous measurements of mineral, organic matrix, and bound water by Raman spectroscopy correlate with the strength and toughness of cortical bone, the clinical assessment of person's bone quality using spatially offset Raman spectroscopy (SORS) requires advanced spectral processing techniques that minimize contaminating signals from fat, skin, and blood. Limiting exposure of patients to ionizing radiation, QUS, MRI, and SORS has the potential to improve the assessment of fracture risk and track changes of new therapies that target bone matrix and micro-structure.

Insights and improvements in correspondence between axonal volume fraction measured with diffusion-weighted MRI and electron microscopy.

Biophysical diffusion-weighted imaging (DWI) models are increasingly used in neuroscience to estimate the axonal water fraction ( f AW ), which in turn is key for noninvasive estimation of the axonal volume fraction ( f A ). These models require thorough validation by comparison with a reference method, for example, electron microscopy (EM). While EM studies often neglect the unmyelinated axons and solely report the fraction of myelinated axons, in DWI both myelinated and unmyelinated axons contribute to the DWI signal. However, DWI models often include simplifications, for example, the neglect of differences in the compartmental relaxation times or fixed diffusivities, which in turn might affect the estimation of f AW . We investigate whether linear calibration parameters (scaling and offset) can improve the comparability between EM- and DWI-based metrics of f A . To this end, we (a) used six DWI models based on the so-called standard model of white matter (WM), including two models with fixed compartmental diffusivities (e.g., neurite orientation dispersion and density imaging, NODDI) and four models that fitted the compartmental diffusivities (e.g., white matter tract integrity, WMTI), and (b) used a multimodal data set including ex vivo diffusion DWI and EM data in mice with a broad dynamic range of fibre volume metrics. We demonstrated that the offset is associated with the volume fraction of unmyelinated axons and the scaling factor is associated with different compartmental T 2 and can substantially enhance the comparability between EM- and DWI-based metrics of f A . We found that DWI models that fitted compartmental diffusivities provided the most accurate estimates of the EM-based f A . Finally, we introduced a more efficient hybrid calibration approach, where only the offset is estimated but the scaling is fixed to a theoretically predicted value. Using this approach, a similar one-to-one correspondence to EM was achieved for WMTI. The method presented can pave the way for use of validated DWI-based models in clinical research and neuroscience.

Toward the use of MRI measurements of bound and pore water in fracture risk assessment.

The current clinical assessment of fracture risk lacks information about the inherent quality of a person's bone tissue. Working toward an imaging-based approach to quantify both a bone tissue quality marker (tissue hydration as water bound to the matrix) and a bone microstructure marker (porosity as water in pores), we hypothesized that the concentrations of bound water (Cbw) are lower and concentrations of pore water (Cpw) are higher in patients with osteoporosis (OP) than in age- and sex-matched adults without the disease. Using recent developments in ultrashort echo time (UTE) magnetic resonance imaging (MRI), maps of Cbw and Cpw were acquired from the uninjured distal third radius (Study 1) of 20 patients who experienced a fragility fracture of the distal radius (Fx) and 20 healthy controls (Non-Fx) and from the tibia mid-diaphysis (Study 2) of 30 women with clinical OP (low T-scores) and 15 women without OP (normal T-scores). In Study 1, Cbw was significantly lower (p = 0.0018) and Cpw was higher (p = 0.0022) in the Fx than in the Non-Fx group. In forward stepwise, logistic regression models using Bayesian Information Criterion for selecting the best set of predictors (from imaging parameters, age, BMI, and DXA scanner type), the area-under-the-receiver operator characteristics-curve (AUC with 95 % confidence intervals) was 0.73 (0.56, 0.86) for hip aBMD (best predictors without MRI) and 0.86 (0.70, 0.95) for the combination of Cbw and Cpw (best predictors overall). In Study 2, Cbw was significantly lower (p = 0.0005) in women with OP (23.8 ± 4.3 1H mol/L) than in women without OP (29.9 ± 6.4 1H mol/L); Cpw was significantly higher by estimate of 2.9 1H mol/L (p = 0.0298) with clinical OP, but only when accounting for the type of UTE-MRI scan with 3D providing higher values than 2D (p < 0.0001). Lastly, Cbw, but not Cpw, was sensitive to bone forming osteoporosis medications over 12-months. UTE-MRI-derived measurements of bound and pore water concentrations are potential, aBMD-independent predictors of fracture risk.

Experimental demonstration of diffusion limitations on resolution and SNR in MR microscopy.

PURPOSE: MR microscopy is in principle capable of producing images at cellular resolution (<10 µm), but various factors limit the quality achieved in practice. A recognized limit on the signal to noise ratio and spatial resolution is the dephasing of transverse magnetization caused by diffusion of spins in strong gradients. Such effects may be reduced by using phase encoding instead of frequency encoding read-out gradients. However, experimental demonstration of the quantitative benefits of phase encoding are lacking, and the exact conditions in which it is preferred are not clearly established. We quantify the conditions where phase encoding outperforms a readout gradient with emphasis on the detrimental effects of diffusion on SNR and resolution. METHODS: A 15.2 T Bruker MRI scanner, with 1 T/m gradients, and micro solenoid RF coils < 1 mm in diameter, were used to quantify diffusion effects on resolution and the signal to noise ratio of frequency and phase encoded acquisitions. Frequency and phase encoding's spatial resolution and SNR per square root time were calculated and measured for images at the diffusion limited resolution. The point spread function was calculated and measured for phase and frequency encoding using additional constant time phase gradients with voxels 3-15 µm in dimension. RESULTS: The effect of diffusion during the readout gradient on SNR was experimentally demonstrated. The achieved resolutions of frequency and phase encoded acquisitions were measured via the point-spread-function and shown to be lower than the nominal resolution. SNR per square root time and actual resolution were calculated for a wide range of maximum gradient amplitudes, diffusion coefficients, and relaxation properties. The results provide a practical guide on how to choose between phase encoding and a conventional readout. Images of excised rat spinal cord at 10 µm × 10 µm in-plane resolution demonstrate phase encoding's benefits in the form of higher measured resolution and higher SNR than the same image acquired with a conventional readout. CONCLUSION: We provide guidelines to determine the extent to which phase encoding outperforms frequency encoding in SNR and resolution given a wide range of voxel sizes, sample, and hardware properties.

Implantable, Bioresorbable Radio Frequency Resonant Circuits for Magnetic Resonance Imaging.

Magnetic resonance imaging (MRI) is widely used in clinical care and medical research. The signal-to-noise ratio (SNR) in the measurement affects parameters that determine the diagnostic value of the image, such as the spatial resolution, contrast, and scan time. Surgically implanted radiofrequency coils can increase SNR of subsequent MRI studies of adjacent tissues. The resulting benefits in SNR are, however, balanced by significant risks associated with surgically removing these coils or with leaving them in place permanently. As an alternative, here the authors report classes of implantable inductor-capacitor circuits made entirely of bioresorbable organic and inorganic materials. Engineering choices for the designs of an inductor and a capacitor provide the ability to select the resonant frequency of the devices to meet MRI specifications (e.g., 200 MHz at 4.7 T MRI). Such devices enhance the SNR and improve the associated imaging capabilities. These simple, small bioelectronic systems function over clinically relevant time frames (up to 1 month) at physiological conditions and then disappear completely by natural mechanisms of bioresorption, thereby eliminating the need for surgical extraction. Imaging demonstrations in a nerve phantom and a human cadaver suggest that this technology has broad potential for post-surgical monitoring/evaluation of recovery processes.

Finite element analysis of bone mechanical properties using MRI-derived bound and pore water concentration maps.

Ultrashort echo time (UTE) MRI techniques can be used to image the concentration of water in bones. Particularly, quantitative MRI imaging of collagen-bound water concentration (Cbw) and pore water concentration (Cpw) in cortical bone have been shown as potential biomarkers for bone fracture risk. To investigate the effect of Cbw and Cpw on the evaluation of bone mechanical properties, MRI-based finite element models of cadaver radii were generated with tissue material properties derived from 3 D maps of Cbw and Cpw measurements. Three-point bending tests were simulated by means of the finite element method to predict bending properties of the bone and the results were compared with those from direct mechanical testing. The study results demonstrate that these MRI-derived measures of Cbw and Cpw improve the prediction of bone mechanical properties in cadaver radii and have the potential to be useful in assessing patient-specific bone fragility risk.

Fast bound and pore water mapping of cortical bone with arbitrary slice oriented two-dimensional ultra-short echo time.

PURPOSE: Extend fast, two-dimensional (2D) methods of bound and pore water mapping in bone to arbitrary slice orientation. METHODS: To correct for slice profile artifacts caused by gradient errors of half pulse 2D ultra-short echo time (UTE), we developed a library of predistorted gradient waveforms that can be used to interpolate optimized gradient waveforms for 2D UTE slice selection. We also developed a method to estimate and correct for a bulk phase difference between the two half pulse excitations used for 2D UTE signal excitation. Bound water images were acquired in three healthy subjects with adiabatic inversion recovery prepared 2D UTE, while pore water images were acquired after short-T2 signals were suppressed with double adiabatic inversion recovery preparation. The repeatability of bound and pore water imaging with 2D UTE was tested by repeating acquisitions after repositioning. RESULTS: The library-based interpolation of optimized slice select gradient waveforms combined with the method to estimate bulk phase between two excitations provided compact slice profiles for half pulse excited 2D UTE. Quantitative bound and pore water values were highly repeatable-the pooled SD of bound water across all three subjects was 0.38 mol 1 $$ {}^1 $$ H/L, while pooled SD of pore water was 0.30 mol 1 $$ {}^1 $$ H/L. CONCLUSION: Fast, quantitative, 2D UTE-based bound and pore water images can be acquired at arbitrary oblique orientations after correcting for errors in the slice select gradient waveform and bulk phase shift between the two half acquisitions.

T1 relaxation of bound and pore water in cortical bone.

MRI measures of bound and/or pore water concentration in cortical bone offer potential diagnostics of bone fracture risk. The transverse relaxation characteristics of both bound and pore water are relatively well understood and have been used to design clinical MRI pulse sequences to image each water pool quantitatively. However, these methods are also sensitive to longitudinal relaxation characteristics, which have been less well studied. Here, spectroscopic relaxometry measurements of 31 human cortical bone specimens provided a more detailed picture of T 1 of both bound and pore water. The results included mean, standard deviation, and range of T 1 spectra from both bound and pore water, as well as novel presentations of the 2D T 1 - T 2 distribution of pore water. Importantly, for each sample the pore water T 1 spectrum was found to span more than one order of magnitude and varied substantially across the 31 sample studies. Because many existing methods assume pore water T 1 to be mono-exponential and constant across individuals, the results were used to compute the potential effect neglecting this intra- and intersample T 1 variation on accurate MRI measurement of both bound and pore water concentrations. The greatest effect was found for adiabatic inversion recovery (AIR) based measurements of bound water concentration, which showed an average of 8.8% and as much as 37% error when using a common mono-exponential assumption of pore water T 1 . Despite these errors, the simulated AIR measurements were still moderately well correlated with the bound water concentrations derived from the spectroscopic data.

Behavioral and brain anatomical analysis of Foxg1 heterozygous mice.

FOXG1 Syndrome (FS) is a devastating neurodevelopmental disorder that is caused by a heterozygous loss-of-function (LOF) mutation of the FOXG1 gene, which encodes a transcriptional regulator important for telencephalic brain development. People with FS have marked developmental delays, impaired ambulation, movement disorders, seizures, and behavior abnormalities including autistic features. Current therapeutic approaches are entirely symptomatic, however the ability to rescue phenotypes in mouse models of other genetic neurodevelopmental disorders such as Rett syndrome, Angelman syndrome, and Phelan-McDermid syndrome by postnatal expression of gene products has led to hope that similar approaches could help modify the disease course in other neurodevelopmental disorders such as FS. While FoxG1 protein function plays a critical role in embryonic brain development, the ongoing adult expression of FoxG1 and behavioral phenotypes that present when FoxG1 function is removed postnatally provides support for opportunity for improvement with postnatal treatment. Here we generated a new mouse allele of Foxg1 that disrupts protein expression and characterized the behavioral and structural brain phenotypes in heterozygous mutant animals. These mutant animals display changes in locomotor behavior, gait, anxiety, social interaction, aggression, and learning and memory compared to littermate controls. Additionally, they have structural brain abnormalities reminiscent of people with FS. This information provides a framework for future studies to evaluate the potential for post-natal expression of FoxG1 to modify the disease course in this severe neurodevelopmental disorder.

Improving Transcranial Acoustic Targeting: The Limits of CT-Based Velocity Estimates and the Role of MR.

Transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) enables the noninvasive treatment of the deep brain. This capacity relies on the ability to focus acoustic energy through the in-tact skull, a feat that requires accurate estimates of the acoustic velocity in individual patient skulls. In current practice, these estimates are generated using a pretreatment computed tomography (CT) scan and then registered to a magnetic resonance (MR) dataset on the day of the treatment. Treatment safety and efficacy can be improved by eliminating the need to register the CT data to the MR images and by improving the accuracy of acoustic velocity measurements. In this study, we examine the capacity of MR to supplement or replace CT as a means of estimating velocity in the skull. We find that MR can predict velocity with less but comparable accuracy to CT. We then use micro-CT imaging to better understand the limitations of Hounsfield unit (HU)-based estimates of velocity, demonstrating that the macrostructure of pores in the skull contributes to the acoustic velocity of the bone. We find evidence that detailed T2 measurements provide information about pore macrostructure similar to the information obtained with micro-CT, offering a potential clinical mechanism for improving patient-specific estimates of acoustic velocity in the human skull.

Mapping pH using stimulated echoes formed via chemical exchange.

PURPOSE: RACETE (refocused acquisition of chemical exchange transferred excitations) is a recently developed approach to imaging solute exchange with water. However, it lacks biophysical specificity, as it is sensitive to exchange rates, relaxation rates, solute concentration, and macromolecular content. We modified this sequence and developed a protocol and corresponding metric with specific sensitivity to the solute exchange rate and hence a means for mapping pH. THEORY AND METHODS: RACETE splits the two gradients traditionally used in a stimulated-echo sequence into one applied after exciting solutes and one applied after exciting water, hence requiring exchange for echo formation. In this work, we leverage the dependence of the stimulated-echo signal on the exchange process. By preserving the total irradiation power and using a ratio metric, the other signal dependencies cancel, leaving a specific measure of exchange rate. Additionally, artifacts due to off-resonance excitation of water are addressed using a phase cancelling approach; and a gradient-echo imaging sequence with a variable flip angle excitation is tailored for a fast read-out of RECETE prepared signals. This method is validated using numerical simulations and salicylic acid phantom experiments at 9.4 T. RESULTS: Numerical simulations and phantom experiments demonstrate that the ratio-metric is a single-variable function of exchange rate with extremely low dependence on confounding factors. Additionally, artifacts due to direct water excitation are removed and robustness to B0 and B1 inhomogeneities is demonstrated. CONCLUSION: The proposed method can be used for fast pH mapping with robustness against the confounding effects that widely exist in other methods.

HR-pQCT parameters of the distal radius correlate with the bending strength of the radial diaphysis.

High resolution, peripheral quantitative computed tomography (HR-pQCT) scanners can now characterize an individual's trabecular architecture, cortical structure, and volumetric bone mineral density at a nominal resolution of 61 µm. While predictions of failure load of the distal radius and tibial diaphysis in compression by finite element analysis (FEA) of HR-pQCT scans have been validated against mechanical tests of cadaveric bones in compression, namely for images with nominal resolutions of 82 µm and 165 µm, the HR-pQCT parameters that best predict bending strength of cortical bone remain unknown. Therefore, we scanned cadaveric forearms from 31 elderly donors (Female: 72.8 ± 8.8 years and Male: 72.1 ± 6.3 years), and then loaded the radial diaphysis to failure in three-point bending after denuding each bone (38 in total). The cortical parameters had stronger correlations with ultimate moment than the trabecular parameters such that cortical area and estimated failure load of the distal radius had the highest Spearman correlation coefficients (r = 0.89 and r = 0.81, respectively, p < 0.0001). Despite being a known determinant of bone strength, cortical porosity of the distal radius did not correlate with ultimate moment (p = 0.8537). In multivariate linear regressions with section modulus (SM) of the radial diaphysis as one of two predictors of bending strength, cortical area and cortical thickness were each significant contributors to the prediction of ultimate moment. Their contribution was one-half and one-third, respectively, of the contribution from SM. None of the HR-pQCT parameters were strongly correlated with post-yield displacement, an indicator of bone brittleness. In support of HR-pQCT imaging of the distal radius to identify individuals with osteoporosis, the present study found that parameters of the cortex and failure load predictions by linear FEA are strongly related to the bending strength of cortical bone.

A hybrid numeric-analytic solution for pulsed CEST.

Chemical exchange saturation transfer (CEST) methods measure the effect of magnetization exchange between solutes and water. While CEST methods are often implemented using a train of off-resonant shaped RF pulses, they are typically analyzed as if the irradiation were continuous. This approximation does not account for exchange of rotated magnetization, unique to pulsed irradiation and exploited by chemical exchange rotation transfer methods. In this work, we derive and test an analytic solution for the steady-state water signal under pulsed irradiation by extending a previous work to include the effects of pulse shape. The solution is largely accurate at all offsets, but this accuracy diminishes at higher exchange rates and when applying pulse shapes with large root-mean-squared to mean ratios (such as multi-lobe sinc pulses).

Noninvasive diffusion MRI to determine the severity of peripheral nerve injury.

OBJECTIVE: Primary repair of peripheral nerves is recommended following transection; however, patient management following repair is challenged by a lack of biomarkers to nerve regeneration. Previous studies have demonstrated that diffusion magnetic resonance imaging (MRI) may provide viable biomarkers of nerve regeneration in injury models; though, these methods have not been systematically evaluated in graded partial transections and repairs. METHODS: Ex vivo diffusion MRI was performed in fixed rat sciatic nerve samples 4 or 12 weeks following partial nerve transection and repair (25% cut = 12, 50% cut = 12 and 75% cut = 11), crush injuries (n = 12), and sham surgeries (n = 9). Behavioral testing and histologic evaluation were performed in the same animals and nerve samples for comparison. RESULTS: Diffusion tractography provided visual characterizations of nerve damage and recovery consistent with the expected degree of injury within each cohort. In addition, quantitative indices from diffusion MRI correlated with both histological and behavioral evaluations, the latter of indicated full recovery for sham and crush nerves and limited recovery in all partially transected/repaired nerves. Nerve recovery between 4 and 12 weeks was statistically significant in partial transections 50% and 75% depth cuts (p = 0.043 and p = 0.022) but not for 25% transections. INTERPRETATION: Our findings suggest that DTI can i) distinguish different degrees of partial nerve transection following surgical repair and ii) map spatially heterogeneous nerve recovery (e.g., due to collateral sprouting) from 4 to 12 weeks in partially transected nerves.

Efficient gradient waveform measurements with variable-prephasing.

Accurate measurement of gradient waveform errors can often improve image quality in sequences with time varying readout and excitation waveforms. Self-encoding or offset-slice sequences are commonly used to measure gradient waveforms. However, the self-encoding method requires a long scan time, while the offset-slice method is often low precision, requiring the thickness of the excited slice to be small compared to the maximal k-space encoded by the test waveform. This work introduces a hybrid these methods, called variable-prephasing. Using a straightforward algebraic model, we demonstrate that variable-prephasing improves the precision of the waveform measurement by allowing acquisition of larger slice thicknesses. Experiments in a phantom were used to validate the theoretical predictions, showing that the precision of variable-prephasing gradient waveform measurements improves with increasing slice thickness.

A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes.

The metabotropic glutamate receptor 7 (mGlu7) is a G protein-coupled receptor that has been recently linked to neurodevelopmental disorders. This association is supported by the identification of GRM7 variants in patients with autism spectrum disorder, attention deficit hyperactivity disorder, and severe developmental delay. One GRM7 mutation previously reported in 2 patients results in a single amino acid change, I154T, within the mGlu7 ligand-binding domain. Here, we report 2 new patients with this mutation who present with severe developmental delay and epilepsy. Functional studies of the mGlu7-I154T mutant reveal that this substitution resulted in significant loss of mGlu7 protein expression in HEK293A cells and in mice. We show that this occurred posttranscriptionally at the level of protein expression and trafficking. Similar to mGlu7-global KO mice, mGlu7-I154T animals exhibited reduced motor coordination, deficits in contextual fear learning, and seizures. This provides functional evidence that a disease-associated mutation affecting the mGlu7 receptor was sufficient to cause neurological dysfunction in mice and further validates GRM7 as a disease-causing gene in the human population.

Initial findings in traumatic peripheral nerve injury and repair with diffusion tensor imaging.

OBJECTIVE: Management of peripheral nerve injuries requires physicians to rely on qualitative measures from patient history, electromyography, and physical exam. Determining a successful nerve repair can take months to years for proximal injuries, and the resulting delays in clinical decision-making can lead to a negative impact on patient outcomes. Early identification of a failed nerve repair could prevent permanent muscle atrophy and loss of function. This study aims to test the feasibility of performing diffusion tensor imaging (DTI) to evaluate injury and recovery following repair of wrist trauma. We hypothesize that DTI provides a noninvasive and reliable assessment of regeneration, which may improve clinical decision-making and alter the clinical course of surgical interventions. METHODS: Clinical and MRI measurements from subjects with traumatic peripheral nerve injury, carpal tunnel syndrome, and healthy control subjects were compared to evaluate the relationship between DTI metrics and injury severity. RESULTS: Fractional anisotropy from DTI was sensitive to differences between damaged and healthy nerves, damaged and compressed nerves, and injured and healthy contralateral nerves. Longitudinal measurements in two injury subjects also related to clinical outcomes. Implications of other diffusion measures are also discussed. INTERPRETATION: DTI is a sensitive tool for wrist nerve injuries and can be utilized for monitoring nerve recovery. Across three subjects with nerve injuries, this study has shown how DTI can detect abnormalities between injured and healthy nerves, measure recovery, and determine if re-operation was successful. Additional comparisons to carpal tunnel syndrome and healthy nerves show that DTI is sensitive to the degree of impairment.

Chemical exchange rotation transfer imaging of phosphocreatine in muscle.

In chemical exchange saturation transfer (CEST) imaging, the signal at 2.6 ppm from the water resonance in muscle has been assigned to phosphocreatine (PCr). However, this signal has limited specificity for PCr since the signal is also sensitive to exchange with protein and macromolecular protons when using some conventional quantification methods, and will vary with changes in the water longitudinal relaxation rate. Correcting for these effects while maintaining reasonable acquisition times is challenging. As an alternative approach to overcome these problems, here we evaluate chemical exchange rotation transfer (CERT) imaging of PCr in muscle at 9.4 T. Specifically, the CERT metric, AREXdouble,cpw at 2.6 ppm, was measured in solutions containing the main muscle metabolites, in tissue homogenates with controlled PCr content, and in vivo in rat leg muscles. PCr dominates CERT metrics around 2.6 ppm (although with nontrivial confounding baseline contributions), indicating that CERT is well-suited to PCr specific imaging, and has the added benefit of requiring a relatively small number of acquisitions.

A simple estimate of axon size with diffusion MRI.

Noninvasive estimation of mean axon diameter presents a new opportunity to explore white matter plasticity, development, and pathology. Several diffusion-weighted MRI (DW-MRI) methods have been proposed to measure the average axon diameter in white matter, but they typically require many diffusion encoding measurements and complicated mathematical models to fit the signal to multiple tissue compartments, including intra- and extra-axonal spaces. Here, Monte Carlo simulations uncovered a straightforward DW-MRI metric of axon diameter: the change in radial apparent diffusion coefficient estimated at different effective diffusion times, ΔD⊥. Simulations indicated that this metric increases monotonically within a relevant range of effective mean axon diameter while being insensitive to changes in extra-axonal volume fraction, axon diameter distribution, g-ratio, and influence of myelin water. Also, a monotonic relationship was found to exist for signals coming from both intra- and extra-axonal compartments. The slope in ΔD⊥ with effective axon diameter increased with the difference in diffusion time of both oscillating and pulsed gradient diffusion sequences.