Interleaved 31 P MRS imaging of human frontal and occipital lobes using dual RF coils in combination with single-channel transmitter-receiver and dynamic B0 shimming.

In vivo 31 P magnetic resonance spectroscopy (MRS) provides a unique tool for the non-invasive study of brain energy metabolism and mitochondrial function. The assessment of bioenergetic impairment in different brain regions is essential to understand the pathophysiology and progression of human brain diseases. This article presents a simple and effective approach which allows the interleaved measurement of 31 P spectra and imaging from two distinct human brain regions of interest with dynamic B0 shimming capability. A transistor-transistor logic controller was employed to actively switch the single-channel X-nuclear radiofrequency (RF) transmitter-receiver between two 31 P RF surface coils, enabling the interleaved acquisition of two 31 P free induction decays (FIDs) from human occipital and frontal lobes within the same repetition time. Linear gradients were incorporated into the RF pulse sequence to perform the first-order dynamic shimming to further improve spectral resolution. The overall results demonstrate that the approach provides a cost-effective and time-efficient solution for reliable 31 P MRS measurement of cerebral phosphate metabolites and adenosine triphosphate (ATP) metabolic fluxes from two human brain regions with high detection sensitivity and spectral quality at 7 T. The same design concept can be extended to acquire multiple spectra from more than two brain regions or can be employed for other magnetic resonance applications beyond the 31 P spin.

In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences.

NAD is an essential metabolite that exists in NAD(+) or NADH form in all living cells. Despite its critical roles in regulating mitochondrial energy production through the NAD(+)/NADH redox state and modulating cellular signaling processes through the activity of the NAD(+)-dependent enzymes, the method for quantifying intracellular NAD contents and redox state is limited to a few in vitro or ex vivo assays, which are not suitable for studying a living brain or organ. Here, we present a magnetic resonance (MR) -based in vivo NAD assay that uses the high-field MR scanner and is capable of noninvasively assessing NAD(+) and NADH contents and the NAD(+)/NADH redox state in intact human brain. The results of this study provide the first insight, to our knowledge, into the cellular NAD concentrations and redox state in the brains of healthy volunteers. Furthermore, an age-dependent increase of intracellular NADH and age-dependent reductions in NAD(+), total NAD contents, and NAD(+)/NADH redox potential of the healthy human brain were revealed in this study. The overall findings not only provide direct evidence of declined mitochondrial functions and altered NAD homeostasis that accompany the normal aging process but also, elucidate the merits and potentials of this new NAD assay for noninvasively studying the intracellular NAD metabolism and redox state in normal and diseased human brain or other organs in situ.

Deep Learning for Automated Liver Segmentation to Aid in the Study of Infectious Diseases in Nonhuman Primates.

With the advent of deep learning, convolutional neural networks (CNNs) have evolved as an effective method for the automated segmentation of different tissues in medical image analysis. In certain infectious diseases, the liver is one of the more highly affected organs, where an accurate liver segmentation method may play a significant role to improve the diagnosis, quantification, and follow-up. Although several segmentation algorithms have been proposed for liver or liver-tumor segmentation in computed tomography (CT) of human subjects, none of them have been investigated for nonhuman primates (NHPs), where the livers have a wide range in size and morphology. In addition, the unique characteristics of different infections or the heterogeneous immune responses of different NHPs to the infections appear with a diverse radiodensity distribution in the CT imaging. In this study, we investigated three state-of-the-art algorithms; VNet, UNet, and feature pyramid network (FPN) for automated liver segmentation in whole-body CT images of NHPs. The efficacy of the CNNs were evaluated on 82 scans of 37 animals, including pre and post-exposure to different viruses such as Ebola, Marburg, and Lassa. Using a 10-fold cross-validation, the best performance for the segmented liver was provided by the FPN; an average 94.77% Dice score, and 3.6% relative absolute volume difference. Our study demonstrated the efficacy of multiple CNNs, wherein the FPN outperforms VNet and UNet for liver segmentation in infectious disease imaging research.

Quantitative Assessment of Occipital Metabolic and Energetic Changes in Parkinson's Patients, Using In Vivo 31P MRS-Based Metabolic Imaging at 7T.

Abnormal energy metabolism associated with mitochondrial dysfunction is thought to be a major contributor to the progression of neurodegenerative diseases such as Parkinson's disease (PD). Recent advancements in the field of magnetic resonance (MR) based metabolic imaging provide state-of-the-art technologies for non-invasively probing cerebral energy metabolism under various brain conditions. In this proof-of-principle clinical study, we employed quantitative 31P MR spectroscopy (MRS) imaging techniques to determine a constellation of metabolic and bioenergetic parameters, including cerebral adenosine triphosphate (ATP) and other phosphorous metabolite concentrations, intracellular pH and nicotinamide adenine dinucleotide (NAD) redox ratio, and ATP production rates in the occipital lobe of cognitive-normal PD patients, and then we compared them with age-sex matched healthy controls. Small but statistically significant differences in intracellular pH, NAD and ATP contents and ATPase enzyme activity between the two groups were detected, suggesting that subtle defects in energy metabolism and mitochondrial function are quantifiable before regional neurological deficits or pathogenesis begin to occur in these patients. Pilot data aiming to evaluate the bioenergetic effect of mitochondrial-protective bile acid, ursodeoxycholic acid (UDCA) were also obtained. These results collectively demonstrated that in vivo 31P MRS-based neuroimaging can non-invasively and quantitatively assess key metabolic-energetic metrics in the human brain. This provides an exciting opportunity to better understand neurodegenerative diseases, their progression and response to treatment.

Evaluation of a 16-channel transceiver loop + dipole antenna array for human head imaging at 10.5 tesla.

We evaluated a 16-channel loop + dipole (LD) transceiver antenna array with improved specific absorption rate (SAR) efficiency for 10.5 Tesla (T) human head imaging apsplications. Three different array designs with equal inner dimensions were considered: an 8-channel dipole antenna, an 8-channel loop, and a 16-channel LD antenna arrays. Signal-to-noise ratio (SNR) and B1 + efficiency (in units of µT per √W) were simulated and measured in 10.5 T magnetic resonance imaging (MRI) experiments. For the safety validation, 10 g SAR and SAR efficiency (defined as the B1 + over √ (peak 10 g SAR)) were calculated through simulation. Finally, high resolution porcine brain images were acquired with the 16-channel LD antenna array, including a fast turbo-spin echo (TSE) sequence incorporating B1 shimming techniques. Both the simulation and experiments demonstrated that the combined 16-channel LD antenna array showed similar B1 + efficiency compared to the 8-channel dipole antenna and the 8-channel loop arrays in a circular polarized (CP) mode. In a central 2 mm × 2 mm region of the phantom, however, the 16-channel LD antenna array showed an improvement in peak 10 g SAR of 27.5 % and 32.5 % over the 8-channel dipole antenna and the 8-channel loop arrays, respectively. We conclude that the proposed 16-channel head LD antenna array design is capable of achieving ~7% higher SAR efficiency at 10.5 T compared to either the 8-channel loop-only or the 8-channel dipole-only antenna arrays of the same dimensions.

Tunable Ultrahigh Dielectric Constant (tuHDC) Ceramic Technique to Largely Improve RF Coil Efficiency and MR Imaging Performance.

This work introduces an innovative magnetic resonance (MR) imaging technology that incorporates radiofrequency (RF) coil(s) with permittivity-tunable ultrahigh dielectric constant (tuHDC) ceramics to significantly improve RF coil transmission and reception efficiencies, MR imaging sensitivity and signal-to-noise ratio (SNR). The tuHDC ceramics made of composite barium strontium titanate (BST) compounds (Ba0.6 Sr0.4 TiO3) have low dielectric loss and very high permittivity tunability from 2,000 to 15000 by varying the ceramic temperature between 0°C and 40°C to achieve an optimal permittivity for MR imaging application. We demonstrated for the first time the proof of concept using the BST-based tuHDC-RF-coil technology to improve MR spectroscopic imaging performance of 17O nuclide at 10.5 Tesla (T) at a low ceramic temperature and 23Na nuclide at 7T at room temperature. We discovered a large and spatially independent noise reduction under an optimal ceramic temperature, which synergistically resulted in an unprecedented SNR improvement. Large improvements were also demonstrated for 1H MRI on a 1.5T clinical scanner using the same ceramics. The tuHDC-RF-coil technology is robust, flexible and cost-effective; it presents a technical breakthrough to significantly improve imaging sensitivity and resolution for broad MR imaging applications; which is critical for advancing biomedical and neuroscience research, and improving diagnostic imaging.

Pharmacokinetics, Safety, and Tolerability of Orally Administered Ursodeoxycholic Acid in Patients With Parkinson's Disease-A Pilot Study.

Mitochondrial dysfunction is implicated in the pathogenesis of Parkinson's disease. Preliminary data have shown lower brain adenosine triphosphate (ATP) levels in Parkinson's disease versus age-matched healthy controls. Ursodeoxycholic acid (UDCA) may improve impaired mitochondrial function. Our objective was to evaluate UDCA tolerability, pharmacokinetics, and its effect on brain bioenergetics in individuals with Parkinson's disease. An open-label, prospective, multiple-ascending-dose study of oral UDCA in 5 individuals with Parkinson's disease was completed. A blood safety panel, plasma concentrations of UDCA and UDCA conjugates, and brain ATP levels were measured before and after therapy (week 1: 15 mg/kg/day; week 2: 30 mg/kg/day; and weeks 3-6: 50 mg/kg/day). UDCA and conjugates were measured using liquid chromatography-mass spectrometry. ATP levels and ATPase activity were measured using 7-Tesla 31 P magnetic resonance spectroscopy. Secondary measures included the Unified Parkinson's Disease Rating Scale and Montreal Cognitive Assessment. UDCA was generally well tolerated. The most frequent adverse event was gastrointestinal discomfort, rated by subjects as mild to moderate. Noncompartmental pharmacokinetic analysis resulted in (mean ± standard deviation) a maximum concentration of 8749 ± 2840 ng/mL and half-life of 2.1 ± 0.71 hr. Magnetic resonance spectroscopy data were obtained in 3 individuals with Parkinson's disease and showed modest increases in ATP and decreases in ATPase activity. Changes in Unified Parkinson's Disease Rating Scale (parts I-IV) and Montreal Cognitive Assessment scores (mean ± standard deviation) were -4.6 ± 6.4 and 2 ± 1.7, respectively. This is the first report of UDCA use in individuals with Parkinson's disease. Its pharmacokinetics are variable, and at high doses it appears reasonably well tolerated. Our findings warrant additional studies of its effect on brain bioenergetics.

Quantitative analysis of spatial averaging effect on chemical shift imaging SNR and noise coherence with k-space sampling schemes.

Spatial averaging of multiple voxels from high-resolution chemical shift imaging (hrCSI) is a common strategy for in vivo metabolic studies to achieve a better signal-to-noise ratio (SNR) for a region-of-interest. However, the mechanism about how the spatial averaging approach influences the respective spectral signal and noise and its relevance to the k-space sampling schemes remains unclear. Using three-dimension 17O CSI technique with the weighted k-space sampling method of Fourier series window, we performed quantitative SNR comparisons between a single low-resolution CSI (lrCSI) voxel (being 27 times larger than the hrCSI voxel size) and the spatially averaged hrCSI voxels with matched sampling volume and location. We demonstrated that the averaged hrCSI voxel spectrum had a large SNR loss (> 4 times) compared to the lrCSI voxel, which was resulted from unmatched increases in signal (~1.9 fold) and noise (~9.3 fold). The signal increase was caused by the spatial overlapping between the adjacent hrCSI voxels. The substantial noise increase was mainly attributed to the strong noise coherence among hrCSI voxels acquired with the weighted k-space sampling. This study presents a quantitative relation between the k-space sampling schemes to an apparent SNR penalty of the spatial averaging approach. The information could be useful for designing CSI acquisition method and determination of optimal spatial resolution for in vivo metabolic imaging studies.

High-resolution imaging of distinct human corpus callosum microstructure and topography of structural connectivity to cortices at high field.

Characterization of the microstructural properties and topography of the human corpus callosum (CC) is key to understanding interhemispheric neural communication and brain function. In this work, we tested the hypothesis that high-resolution T1 relaxometry at high field has adequate sensitivity and specificity for characterizing microstructural properties of the human CC, and elucidating the structural connectivity of the callosal fibers to the cortices of origin. The high-resolution parametric T1 images acquired from healthy subjects (N = 16) at 7 T clearly showed a consistent T1 distribution among individuals with substantial variation along the human CC axis, which is highly similar to the spatial patterns of myelin density and myelinated axon size based on the histology study. Compared to the anterior part of the CC, the posterior midbody and splenium had significantly higher T1 values. In conjunction with T1-based classification method, the splenial T1 values were decoded more reliably compared to a conventional partitioning method, showing a much higher T1 value in the inferior splenium than in the middle/superior splenium. Moreover, the T1 profile of the callosal subdivision represented the topology of the fiber connectivity to the projected cortical regions: the fibers in the posterior midbody and inferior splenium with a higher T1 (inferring a larger axon size) were mainly connected to motor-sensory and visual cortical areas, respectively; in contrast, the fibers in the anterior/posterior CC with a lower T1 (inferring a smaller axon size) were primarily connected to the frontal/parietal-temporal areas. These findings indicate that high-resolution T1 relaxometry imaging could provide a complementary and robust neuroimaging tool, useful for exploring the complex tissue properties and topographic organization of the human corpus callosum.

Functional energetic responses and individual variance of the human brain revealed by quantitative imaging of adenosine triphosphate production rates.

Cellular ATP energy metabolism and regulation are essential for brain function and health. Given the high ATP expenditure at resting-state, it is not yet clear how the human brain at working-state can effectively regulate ATP production to meet higher energy requirement. Through quantitative measurement of regional cerebral ATP production rates and associated neurophysiological parameters in human visual cortex at rest and during visual stimulation, we found significant stimulus-induced and highly correlated neuroenergetic changes, indicating distinctive and complementary roles of the ATP synthesis reactions in supporting evoked neuronal activity and maintaining ATP homeostasis. We also uncovered large individual variances in the neuroenergetic responses and significant reductions in intracellular [H+] and free [Mg2+] during the stimulation. These results provide new insights into the mechanism underlying the brain ATP energy regulation and present a sensitive and much-needed neuroimaging tool for quantitatively assessing neuroenergetic state in healthy and diseased human brain.

Involvement of the central somatosensory system in restless legs syndrome: A neuroimaging study.

OBJECTIVE: To investigate morphologic changes in the somatosensory cortex and the thickness of the corpus callosum subdivisions that provide interhemispheric connections between the 2 somatosensory cortical areas. METHODS: Twenty-eight patients with severe restless legs syndrome (RLS) symptoms and 51 age-matched healthy controls were examined with high-resolution MRI at 3.0 tesla. The vertex-wise analysis in conjunction with a novel cortical surface classification method was performed to assess the cortical thickness across the whole-brain structures. In addition, the thickness of the midbody of the corpus callosum that links postcentral gyri in the 2 hemispheres was measured. RESULTS: We demonstrated that a morphologic change occurred in the brain somatosensory system in patients with RLS compared to controls. Patients with RLS exhibited a 7.5% decrease in average cortical thickness in the bilateral postcentral gyrus (p < 0.0001). Accordingly, there was a substantial decrease in the corpus callosum posterior midbody (p < 0.008) wherein the callosal fibers are connected to the postcentral gyrus, suggesting altered white matter properties in the somatosensory pathway. CONCLUSION: Our results provide in vivo evidence of morphologic changes in the primary somatosensory system, which could be responsible for the sensory functional symptoms of RLS. These results provide a better understanding of the pathophysiology underlying the RLS sensory symptoms and could lead to a potential imaging marker for RLS.

Large improvement of RF transmission efficiency and reception sensitivity for human in vivo31P MRS imaging using ultrahigh dielectric constant materials at 7T.

In vivo31P MRS provides a unique and important imaging tool for studying high-energy phosphate metabolism and bioenergetics noninvasively. However, compared to 1H MRS, 31P MRS with a relatively low gyromagnetic ratio (γ) has a lower and limited sensitivity even at ultrahigh field. The proof of concept has been recently demonstrated that the use of high dielectric constant (HDC) materials between RF coil and object sample could increase MRI signal and reduce required RF transmission power for reaching the same RF pulse flip angle in the region of interest. For low-γ MRS applications operated at relatively lower frequency, however, it demands the dielectric materials with a much higher permittivity for achieving optimal performance. We conducted a 31P MRS imaging study using ultra-HDC (uHDC; with a relative permittivity of ~1200) material blocks incorporated with an RF volume coil at ultrahigh field of 7.0T. The experimental results from phantom and human calf muscle demonstrate that the uHDC technique significantly enhanced RF magnetic transmit field (B1+) and reception field (B1-) and the gain could reach up to two folds in the tissue near the uHDC blocks. The overall results indicate that the incorporation of the uHDC materials having an appropriate permittivity value with a RF coil can significantly increase detection sensitivity and reduces RF transmission power for X-nuclei MRS applications at ultrahigh field. The uHDC technology could provide an efficient, cost-effective engineering solution for achieving high detection sensitivity and concurrently minimizing tissue heating concern for human MRS and MRI applications.

Postmortem and imaging based analyses reveal CNS decreased myelination in restless legs syndrome.

BACKGROUND: Restless legs syndrome (RLS) is a neurological disorder characterized by a strong urge to move the legs and has been shown in many studies with abnormally low brain iron. Iron deficiency is associated with hypomyelination in brains of animals. Therefore we hypothesized that a myelin deficit should be present in the brains of patients with RLS. METHODS: We performed Western blot analysis on myelin isolated from RLS (n=11) and control (n=11) brain tissue obtained at autopsy for the expression of the integral myelin proteins, myelin basic protein (MBP), and proteolipid protein (PLP) and the oligodendrocyte specific enzyme 3'5'-cyclic nucleotide phosphohydrolase (CNPase). To expand the postmortem findings to in vivo, we analyzed the brains of RLS patients (n=23) and controls (n=23) using voxel-based morphometry (VBM). RESULTS: The expression of MBP, PLP and CNPase in the myelin from RLS was decreased by approximately 25% (p<0.05) compared to controls. The amounts of transferrin (Tf) and H-ferritin (H-Frt) in the myelin fraction were also significantly decreased in RLS compared to controls. The imaging analysis revealed significant small decreases in white matter volume in RLS patients compared to controls in the corpus callosum, anterior cingulum and precentral gyrus. CONCLUSION: A decrease in myelin similar to that reported in animal models of iron deficiency was found in the brains of individuals with RLS. The evidence for less myelin and loss of myelin integrity in RLS brains, coupled with decreased ferritin and transferrin in the myelin fractions, is a compelling argument for brain iron insufficiency in RLS. These data also indicate the need to look beyond the sensorimotor symptoms that typically define the syndrome and its assumed relation to the dopaminergic system. Understanding the full range of RLS pathology may help us better understand the complex, intermittent nature and diversity of the clinical features of RLS and expand our consideration of treatment options for RLS.