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INTRODUCTION AND OBJECTIVE:Maintaining men on active surveillance (AS) for prostate cancer can be challenging. Although most men who eventually undergo treatment have experienced clinical progressi...

Rodent models of spinal cord injury (SCI) have been widely used in pre-clinical studies. Injuries may occur at different levels of the lumbar and thoracic cord, and the number of segments injured and their depths may vary along the spine. It is thereby challenging to build one universal RF coil that exhibits optimal performance for all spinal cord imaging applications, especially in an animal scanner with small in-bore space and limited hardware configurations. We developed an interchangeable RF coil system for a 9.4 T small animal MRI scanner, in which the users can select an optimal coil specialized for imaging specific parts of a rat spine. We also developed the associated animal management device for immobilization and positioning. The whole system allows ease of RF coil exchange, animal fixation, and positioning, and thus reduces the animal preparation time before the MRI scan significantly. Compared to a commercial general-purpose 2-cm-diameter coil that was used in our previous studies, the specialized coil optimized for Sprague-Dawley rat lumbar spinal cord imaging exhibits up to 2.4 times SNR improvement.

PURPOSE Cell size is a fundamental characteristic of all tissues, and changes in cell size in cancer reflect tumor status and response to treatments, such as apoptosis and cell-cycle arrest. Unfortunately, cell size can currently be obtained only by pathological evaluation of tumor tissue samples obtained invasively. Previous imaging approaches are limited to preclinical MRI scanners or require relatively long acquisition times that are impractical for clinical imaging. There is a need to develop cell-size imaging for clinical applications. METHODS We propose a clinically feasible IMPULSED (imaging microstructural parameters using limited spectrally edited diffusion) approach that can characterize mean cell sizes in solid tumors. We report the use of a combination of pulse sequences, using different gradient waveforms implemented on clinical MRI scanners and analytical equations based on these waveforms to analyze diffusion-weighted MRI signals and derive specific microstructural parameters such as cell size. We also describe comprehensive validations of this approach using computer simulations, cell experiments in vitro, and animal experiments in vivo and demonstrate applications in preoperative breast cancer patients. RESULTS With fast acquisitions (~7 minutes), IMPULSED can provide high-resolution (1.3 mm in-plane) mapping of mean cell size of human tumors in vivo on clinical 3T MRI scanners. All validations suggest that IMPULSED provides accurate and reliable measurements of mean cell size. CONCLUSION The proposed IMPULSED method can assess cell-size variations in tumors of breast cancer patients, which may have the potential to assess early response to neoadjuvant therapy.

Purpose A new approach to design parallel transmit (pTx) head arrays is proposed that integrates transmit radiofrequency pulse designs with electromagnetic modeling of array coil elements. Theory and methods An approach to design pTx head arrays is proposed that finds optimal groupings of a large number of coils into a small number of channels. An algorithm is proposed to extend array-compressed parallel transmit pulse design by adding the ability to optimally select and prune coil elements, in addition to optimizing compression weights. The performance of the method is demonstrated in simulations of dynamic multislice shimming of the human brain in axial, coronal, and sagittal directions, and of reduced field-of-view excitation targeting the human occipital lobe, with simulated electromagnetic field maps from a group of 5 human head models at 7T. Results For both dynamic multislice shimming and reduced field-of-view excitation, the method successfully designed pTx arrays that simultaneously achieved in general 15% lower mean excitation errors with 20% lower SDs, along with 20% lower mean global averaged specific absorption rate and 50% lower SD than previously reported pTx head array designs. Conclusion With the proposed optimal coil element selection algorithm, the array-compressed parallel transmit pulse design can be extended to design pTx transmit head arrays with joint consideration of the fields within the sample and the radiofrequency pulse. The pTx arrays from such an approach achieved higher transmit excitation accuracy, lower radiofrequency heating in subjects, and more robust performance across subjects compared with previously reported pTx head arrays with the same number of channels.

Resting-state functional MRI (rsfMRI) has recently revealed correlated signals in the spinal cord horns of monkeys and humans. However, the interpretation of these rsfMRI correlations as indicators of functional connectivity in the spinal cord remains unclear. Here, we recorded stimulus-evoked and spontaneous spiking activity and local field potentials (LFPs) from monkey spinal cord in order to validate fMRI measures. We found that both BOLD and electrophysiological signals elicited by tactile stimulation co-localized to the ipsilateral dorsal horn. Temporal profiles of stimulus-evoked BOLD signals covaried with LFP and multiunit spiking in a similar way to those observed in the brain. Functional connectivity of dorsal horns exhibited a U-shaped profile along the dorsal-intermediate-ventral axis. Overall, these results suggest that there is an intrinsic functional architecture within the gray matter of a single spinal segment, and that rsfMRI signals at high field directly reflect this underlying spontaneous neuronal activity., Resting-state fMRI shows networks of correlated activity in the spinal cord, similar to those in the brain, but whether fMRI is a valid measure of functional connectivity in spinal cord is unclear. Here, the authors show that fMRI corresponds well to electrophysiological measures of spinal cord activity.

Accurate estimates of the BOLD hemodynamic response function (HRF) are crucial for the interpretation and analysis of event-related functional MRI data. To date, however, there have been no comprehensive measurements of the HRF in white matter (WM) despite increasing evidence that BOLD signals in WM change after a stimulus. We performed an event-related cognitive task (Stroop color-word interference) to measure the HRF in selected human WM pathways. The task was chosen in order to produce robust, distributed centers of activity throughout the cortex. To measure the HRF in WM, fiber tracts were reconstructed between each pair of activated cortical areas. We observed clear task-specific HRFs with reduced magnitudes, delayed onsets and prolonged initial dips in WM tracts compared with activated grey matter, thus calling for significant changes to current standard models for accurately characterizing the HRFs in WM and for modifications of standard methods of analysis of functional imaging data., The hemodynamic response function (HRF) describes how changes in brain activity manifest as a transient signal (BOLD) that is detected by fMRI imaging. Here, the authors show that the HRF in white matter shows reduced magnitudes, delayed onsets, and prolonged initial dips compared to the grey matter HRF.

Blood oxygenation level-dependent (BOLD) signals in white matter (WM) have usually been ignored or undetected, consistent with the lower vascular density and metabolic demands in WM than in gray matter (GM). Despite converging evidence demonstrating the reliable detection of BOLD signals in WM evoked by neural stimulation and in a resting state, few studies have examined the relationship between BOLD functional signals and tissue metabolism in WM. By analyzing simultaneous recordings of MRI and PET data, we found that the correlations between low frequency resting state BOLD signals in WM are spatially correlated with local glucose uptake, which also covaried with the amplitude of spontaneous low frequency fluctuations in BOLD signals. These results provide further evidence that BOLD signals in WM reflect variations in metabolic demand associated with neural activity, and suggest they should be incorporated into more complete models of brain function.

Measurements of the variations of spin-locking relaxation rates (R

Previous studies have demonstrated that BOLD signals in gray matter in resting-state functional MRI (RSfMRI) have variable time lags. We investigated the corresponding variations of signal latencies in white matter within 1393 subjects (both sexes included) from the Brain Genomics Superstruct Project. We divided the dataset into ten equal groups to study both the patterns and reproducibility of latency estimates within white matter. We constructed time delay matrices by computing cross-correlation functions between voxel pairs. Projections of voxel latencies were highly correlated (average Pearson correlation coefficient = 0.89) across the subgroups, confirming the reproducibility and structure of signal lags in white matter. We also applied a clustering analysis to identify functional networks within white matter. Analysis of latencies within and between networks revealed a similar pattern of inter- and intra-network communication to that reported for gray matter. Moreover, a unidirectional path, from inferior to superior regions, of BOLD signal propagation was revealed by higher resolution clustering. The variations of lag structure within white matter are associated with different sensory states (eyes open vs eyes closed, and eyes open with fixation vs. eyes closed). These findings provide additional insight into the character and roles of white matter BOLD signals in brain functions. Significance Statement Functional MRI (fMRI) has had major impacts on clinical and basic neuroscience, and it has been used extensively to study the functional role and spatiotemporal organization of gray matter in different states. However, functional MRI signals from white matter have usually been ignored or even identified as artifacts. We used fMRI data from 1393 subjects to demonstrate (1) fMRI BOLD signals in white matter are robustly detectable in a resting state and exhibit a reproducible, spatiotemporal organization, similar to gray matter; (2) functional networks within white matter can be obtained by applying clustering analysis on the white matter connectivity matrix; (3) the pattern of signal latencies within and between networks resembles the results for gray matter. Further studies on the Beijing EOEC dataset II also revealed that the variations of latencies within white matter alter with different sensory (visual) states. Our findings demonstrate the that resting-state BOLD signals within white matter should be incorporated into comprehensive models of brain function.

Cytological features such as cell size and intracellular morphology provide fundamental information on cell status and hence may provide specific information on changes that arise within biological tissues. Such information is usually obtained by invasive biopsy in current clinical practice, which suffers several well-known disadvantages. Recently, novel MRI methods such as IMPULSED (imaging microstructural parameters using limited spectrally edited diffusion) have been developed for direct measurements of mean cell size non-invasively. The IMPULSED protocol is based on using temporal diffusion spectroscopy (TDS) to combine measurements of water diffusion over a wide range of diffusion times to probe cellular microstructure over varying length scales. IMPULSED has been shown to provide rapid, robust, and reliable mapping of mean cell size and is suitable for clinical imaging. More recently, cell size distributions have also been derived by appropriate analyses of data acquired with IMPULSED or similar sequences, which thus provides MRI-cytometry. This review summarizes the basic principles, practical implementations, validations, and example applications of MR cell size imaging based on TDS and demonstrates how cytometric information can be used in various applications. In addition, the limitations and potential future directions of MR cytometry are identified including the diagnosis of nonalcoholic steatohepatitis of the liver and the assessment of treatment response of cancers.

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.

Recent studies have demonstrated that the mathematical model used for analyzing and interpreting fMRI data in gray matter (GM) is inappropriate for detecting or describing blood-oxygenation-level-dependent (BOLD) signals in white matter (WM). In particular the hemodynamic response function (HRF) which serves as the regressor in general linear models is different in WM compared to GM. We recently reported measurements of the frequency contents of resting-state time courses in WM that showed distinct power spectra which depended on local structural-vascular-functional associations. In addition, multiple studies of GM have revealed how functional connectivity between regions, as measured by the correlation between BOLD time series, varies dynamically over time. We therefore investigated whether and how BOLD signals from WM in a resting state varied over time. We measured voxel-wise spectrograms, which reflect the time-varying spectral patterns of WM time courses. The results suggest that the spectral patterns are non-stationary but could be categorized into five modes that recurred over time. These modes showed distinct spatial distributions of their occurrences and durations, and the distributions were highly consistent across individuals. In addition, one of the modes exhibited a strong coupling of its occurrence between GM and WM across individuals, and two communities of WM voxels were identified according to the hierarchical structures of transitions among modes. Moreover, the total number of transitions in each community predicts specific human behaviors. Last, these modes are coupled to the shape of instantaneous HRFs. Our findings extend previous studies and reveal the non-stationary nature of spectral patterns of BOLD signals over time, providing a spatial-temporal-frequency characterization of resting-state signals in WM.

Objectives: Identifying new strategies to improve response to poly ADP-ribose polymerase inhibitors (PARPi) in women with homologous recombination (HR)-proficient ovarian cancer is a key clinical challenge. The nuclear orphan receptor NR4A1 has pro-tumor effects in ovarian cancer cells through transcriptional regulation of key genes promoting growth, survival and HR DNA repair. NR4A1 is also expressed in immune cells in the tumor microenvironment and may play a role in inhibiting re-polarization of pro-tumor M2-like tumor-associated macrophages (TAMs) to a more effective anti-tumor M1-like TAM phenotype. Our group has shown that the NF-kappaB (NF-ĸB) pathway is a key regulator of TAM phenotype, with upregulated NF-ĸB signaling promoting M1-like functions. Our goal therefore was to determine whether inhibition of NR4A1 can improve responses to PARPi both by increased tumor DNA damage and apoptosis, and by promoting an anti-tumor M1 phenotype in TAMs by modulating NF-ĸB activity. Methods: Cultured HR-proficient ID8 mouse ovarian cancer cells, mouse ovarian TAMs and mouse bone marrow-derived macrophages were treated with the established NR4A1 antagonist C-DIM-pPHOH (C-DIM) and/or the PARPi olaparib (OLA) for 24-72 hours. C57BL/6 mice with established intra-peritoneal ID8 tumors were treated with vehicle, C-DIM, OLA or combined C-DIM/OLA for 3 weeks. Standard techniques were used to determine cell growth (Sulforhodamine B assay), HR efficiency (BRCA1 and RAD51 foci formation), NF-ĸB activity (nuclear p65, luciferase reporter activity), and expression of markers of DNA damage (pH2AX), apoptosis (cleaved PARP), proliferation (PCNA), and macrophage M1 (CCL3, iNOS) and M2 (CD206, arginase-1) polarization. Statistical significance (p Download : Download high-res image (260KB) Download : Download full-size image Results: In ID8 cells, co-treatment with C-DIM and OLA significantly reduced cell growth and HR efficiency, and increased DNA-damage-induced apoptosis, compared to OLA treatment alone. NR4A1 was highly expressed in macrophages, and C-DIM increased NF-ĸB activity and induced M1 polarization alone and when combined with olaparib. Similar effects of combined treatment were observed in vivo. Compared to mice treated with OLA alone, there was significantly reduced ascites volume and omental tumor mass in C-DIM/OLA mice at the time of sacrifice. Combined treatment also reduced proliferation and increased DNA damage and apoptosis in harvested tumors, and increased M1 polarization of TAMs in ascites fluid, compared to OLA mice. Conclusions: NR4A1 inhibition sensitizes ovarian tumors to PARPi though direct effects on tumors by targeting the HR pathway, and by modulating TAM function towards an anti-tumor phenotype. These findings have important implications for expanding the use of PARPi in women with HR-proficient ovarian tumors, which would benefit a substantial number of women with this devastating disease.

Complex molecular cell dynamics in acute kidney injury and its heterogeneous etiologies in patient populations in clinical settings have revealed the potential advantages and disadvantages of emerging novel damage biomarkers. Imaging techniques have been developed over the past decade to further our understanding about diseased organs, including the kidneys. Understanding the compositional, structural, and functional changes in damaged kidneys via several imaging modalities would enable a more comprehensive analysis of acute kidney injury, including its risks, diagnosis, and prognosis. This review summarizes recent imaging studies for acute kidney injury and discusses their potential utility in clinical settings.

Graphical abstract, Highlights • Compare sensitivity and specificity of CEST and NOE measures from 6-pool fitting. • Differentiate regional molecular signatures at and around spinal cord injury. • Provide parameters that improve the diagnostic accuracy of molecular alteration. • Down-sampled data acquisition can capture the characteristic molecular profile. • High translational potential for clinical assessment of spinal cord injury., Purpose The sensitivity and accuracy of chemical exchange saturation transfer (CEST) and nuclear Overhauser enhancement (NOE) effects for assessing injury-associated changes in cervical spinal cords were evaluated in squirrel monkeys. Multiple interacting pools of protons, including one identified by an NOE at −1.6 ppm relative to water (NOE(-1.6)), were derived and quantified from fitting proton Z-spectra. The effects of down-sampled data acquisitions and corrections for non-specific factors including T1, semi-solid magnetization transfer, and direct saturation of free water (DS), were investigated. The overall goal is to develop a protocol for rapid data acquisition for assessing the molecular signatures of the injured spinal cord and its surrounding regions. Methods MRI scans were recorded of anesthetized squirrel monkeys at 9.4 T, before and after a unilateral dorsal column sectioning of the cervical spinal cord. Z-spectral images at 51 different RF offsets were acquired. The amplitudes of CEST and NOE effects from multiple proton pools were quantified using a six-pool Lorenzian fitting of each Z-spectrum (MTRmfit). In addition, down-sampled data using reduced selections of RF offsets were analyzed and compared. An apparent exchange-dependent relaxation (AREXmfit) method was also used to correct for non-specific factors in quantifying regional spectra around lesion sites. Results The parametric maps from multi-pool fitting using the complete sampling data (P51e) detected unilateral changes at and around the injury. The maps derived from selected twofold down-sampled data with appropriate interpolation (P26sI51) revealed quite similar spatial distributions of different pools as those obtained using P51e at each resonance shift. Across 10 subjects, both data acquisition schemes detected significant decreases in NOE(-3.5) and NOE(-1.6) and increases in DS(0.0) and CEST(3.5) at the lesion site relative to measures of the normal tissues before injury. AREXmfit of cysts and other abnormal tissues at and around the lesion site also exhibited significant changes, especially at 3.5, −1.6 and −3.5 ppm RF offsets. Conclusion These results confirm that a reduced set of RF offsets and down sampling are adequate for CEST imaging of injured spinal cord and allow shorter imaging times and/or permit additional signal averaging. AREXmfit correction improved the accuracy of CEST and NOE measures. The results provide a rapid (~13 mins), sensitive, and accurate protocol for deriving multiple NOE and CEST effects simultaneously in spinal cord imaging at high field.

Spontaneous fluctuations in MRI signals from gray matter (GM) in the brain are interpreted as originating from variations in neural activity, and their inter-regional correlations may be analyzed to reveal functional connectivity. However, most studies of intrinsic neuronal activity have ignored the spontaneous fluctuations that also arise in white matter (WM). In this work, we explore spontaneous fluctuations in resting state MRI signals in WM based on spatial independent component analyses (ICA), a data-driven approach that separates signals into independent sources without making specific modeling assumptions. ICA has become widely accepted as a valuable approach for identifying functional connectivity within cortex but has been rarely applied to derive equivalent structures within WM. Here, BOLD signal changes in WM of a group of subjects performing motor tasks were first detected using ICA, and a spatial component whose time course was consistent with the task was found, demonstrating the analysis is sensitive to evoked BOLD signals in WM. Secondly, multiple spatial components were derived by applying ICA to identify those voxels in WM whose MRI signals showed similar temporal behaviors in a resting state. These functionally-related structures are grossly symmetric and coincide with corresponding tracts identified from diffusion MRI. Finally, functional connectivity was quantified by calculating correlations between pairs of structures to explore the synchronicity of resting state BOLD signals across WM regions, and the experimental results revealed that there exist two distinct groupings of functional correlations in WM tracts at rest. Our study provides further insights into the nature of activation patterns, functional responses and connectivity in WM, and support previous suggestions that BOLD signals in WM show similarities with cortical activations and are characterized by distinct underlying structures in tasks and at rest.

This study aims to evaluate how parameters derived from diffusion tensor imaging reflect axonal disruption and demyelination in specific white matter tracts within the spinal cord of squirrel monkeys following traumatic injuries, and their relationships to function and behavior. After a unilateral section of the dorsal white matter tract of the cervical spinal cord, we found that both lesioned dorsal and intact lateral tracts on the lesion side exhibited prominent disruptions in fiber orientation, integrity and myelination. The degrees of pathological changes were significantly more severe in segments below the lesion than above. The lateral tract on the opposite (non-injured) side was minimally affected by the injury. Over time, RD, FA, and AD values of the dorsal and lateral tracts on the injured side closely tracked measurements of the behavioral recovery. This unilateral section of the dorsal spinal tract provides a realistic model in which axonal disruption and demyelination occur together in the cord. Our data show that specific tract and segmental FA and RD values are sensitive to the effects of injury and reflect specific behavioral changes, indicating their potential as relevant indicators of recovery or for assessing treatment outcomes. These observations have translational value for guiding future studies of human subjects with spinal cord injuries.

We evaluated the use of quantitative MRI relaxometry, including the dispersion of spin-lock relaxation with different locking fields, for detecting and assessing tubular dilation and fibrosis in a mouse model of unilateral ureter obstruction (UUO). C57BL/6 J and BALB/c mice that exhibit different levels of tubular dilation and renal fibrosis after UUO were subjected to MR imaging at 7 T. Mice were imaged before UUO surgery, and at 5, 10 and 15 days after surgery. We acquired maps of relaxation rates and fit the dispersion of spin-lock relaxation rates R1ρ at different locking fields (frequencies) to a model of exchanging water pools, and assessed the sensitivity of the derived quantities for detecting tubular dilation and fibrosis in kidney. Histological scores for tubular dilation and fibrosis, based on luminal space and positive fibrotic areas in sections, were obtained for comparison. Histology detected extensive tubular dilation and mild to moderate fibrosis in the UUO kidneys, in which enlargement of luminal space, deposition of collagen, and reductions in capillary density were observed in the cortex and outer stripe of the outer medulla. Relaxation rates R1 , R2 and R1ρ clearly decreased in these regions of UUO kidneys longitudinally. While R1 showed the highest detectability to tubular dilation and overall changes in UUO kidneys, Sρ , a parameter derived from R1ρ dispersion data, showed the highest correlation with renal fibrosis in UUO. While relaxation parameters are sensitive to tubular dilation in UUO kidneys, Sρ depends primarily on the average exchange rate between water and other chemically shifted resonances such as hydroxyls and amides, and provides additional specific information for evaluating fibrosis in kidney disease.

Blood-oxygenation-level-dependent (BOLD) signals in magnetic resonance imaging indirectly reflect neural activity in cortex, but they are also detectable in white matter (WM). BOLD signals in WM exhibit strong correlations with those in gray matter (GM) in a resting state, but their interpretation and relationship to GM activity in a task are unclear. We performed a parametric visual object recognition task designed to modulate the BOLD signal response in GM regions engaged in higher order visual processing, and measured corresponding changes in specific WM tracts. Human faces embedded in different levels of random noise have previously been shown to produce graded changes in BOLD activation in for example, the fusiform gyrus, as well as in electrophysiological (N170) evoked potentials. The magnitudes of BOLD responses in both GM regions and selected WM tracts varied monotonically with the stimulus strength (noise level). In addition, the magnitudes and temporal profiles of signals in GM and WM regions involved in the task coupled strongly across different task parameters. These findings reveal the network of WM tracts engaged in object (face) recognition and confirm that WM BOLD signals may be directly affected by neural activity in GM regions to which they connect.

PURPOSE: Pediatric and adult patients with sickle cell anemia (SCA) are at increased risk of stroke and cerebrovascular accident. In the general adult population, there is a relationship between arterial hemodynamics and pathology; however, this relationship in SCA patients remains to be elucidated. The aim of this work was to characterize circle of Willis hemodynamics in patients with SCA and quantify the impact of viscosity choice on pathophysiologically-relevant hemodynamics measures. METHODS: Based on measured vascular geometries, time-varying flow rates, and blood parameters, detailed patient-specific simulations of the circle of Willis were conducted for SCA patients (n=6). Simulations quantified the impact of patient-specific and standard blood viscosities on wall shear stress (WSS). RESULTS: These results demonstrated that use of a standard blood viscosity introduces large errors into the estimation of pathophysiologically-relevant hemodynamic parameters. Standard viscosity models overpredicted peak WSS by 55% and 49% for steady and pulsatile flow, respectively. Moreover, these results demonstrated non-uniform, spatial patterns of positive and negative WSS errors related to viscosity, and standard viscosity simulations overpredicted the time-averaged WSS by 32% (standard deviation=7.1%). Finally, differences in shear rate demonstrated that the viscosity choice alters the simulated near-wall flow field, impacting hemodynamics measures. CONCLUSIONS: This work presents simulations of circle of Willis arterial flow in SCA patients and demonstrates the importance and feasibility of using a patient-specific viscosity in these simulations. Accurately characterizing cerebrovascular hemodynamics in SCA populations has potential for elucidating the pathophysiology of large-vessel occlusion, aneurysms, and tissue damage in these patients.

BACKGROUND: Schizophrenia, characterized by cognitive impairments, arises from a disturbance of brain network. Pathological changes in white matter (WM) have been indicated as playing a role in disturbing neural connectivity in schizophrenia. However, deficits of functional connectivity (FC) in individual WM bundles in schizophrenia have never been explored; neither have cognitive correlates with those deficits. METHODS: Resting-state and spatial working memory task fMRI images were acquired on 67 healthy subjects and 84 patients with schizophrenia. The correlations in blood-oxygenation-level-dependent (BOLD) signals between 46 WM and 82 gray matter regions were quantified, analyzed and compared between groups under three scenarios (i.e., resting state, retention period and entire time of a spatial working memory task). Associations of FC in WM with cognitive assessment scores were evaluated for three scenarios. RESULTS: FC deficits were significant (p

The hemodynamic response function (HRF) characterizes temporal variations of blood oxygenation level-dependent (BOLD) signals. Although a variety of HRF models have been proposed for gray matter responses to functional demands, few studies have investigated HRF profiles in white matter particularly under resting conditions. In the present work we quantified the nature of the HRFs that are embedded in resting state BOLD signals in white matter, and which modulate the temporal fluctuations of baseline signals. We demonstrate that resting state HRFs in white matter could be derived by referencing to intrinsic avalanches in gray matter activities, and the derived white matter HRFs had reduced peak amplitudes and delayed peak times as compared with those in gray matter. Distributions of the time delays and correlation profiles in white matter depend on gray matter activities as well as white matter tract distributions, indicating that resting state BOLD signals in white matter encode neural activities associated with those of gray matter. This is the first investigation of derivations and characterizations of resting state HRFs in white matter and their relations to gray matter activities. Findings from this work have important implications for analysis of BOLD signals in the brain.

PURPOSE: Phospholipids are key constituents of cell membranes and serve vital functions in the regulation of cellular processes; thus, a method for in vivo detection and characterization could be valuable for detecting changes in cell membranes that are consequences of either normal or pathological processes. Here, we describe a new method to map the distribution of partially restricted phospholipids in tissues. METHODS: The phospholipids were measured by signal changes caused by relayed nuclear Overhauser enhancement-mediated CEST between the phospholipid Cho headgroup methyl protons and water at around −1.6 ppm from the water resonance. The biophysical basis of this effect was examined by controlled manipulation of head group, chain length, temperature, degree of saturation, and presence of cholesterol. Additional experiments were performed on animal tumor models to evaluate potential applications of this novel signal while correcting for confounding contributions. RESULTS: Negative relayed nuclear Overhauser dips in Z-spectra were measured from reconstituted Cho phospholipids with cholesterol but not for other Cho-containing metabolites or proteins. Significant contrast was found between tumor and contralateral normal tissue signals in animals when comparing both the measured saturation transfer signal and a more specific imaging metric. CONCLUSION: We demonstrated specific relayed nuclear Overhauser effects in partially restricted phospholipid phantoms and similar effects in solid brain tumors after correcting for confounding signal contributions, suggesting possible translational applications of this novel molecular imaging method, which we name restricted phospholipid transfer.

INTRODUCTION AND OBJECTIVE:Low grade (LG) upper tract urothelial cancer (UTUC) accounts for 40% of all UTUC diagnosed in the US. Although LG UTUC has a low risk of progression, radical nephroureter...

INTRODUCTION AND OBJECTIVE:One out of five patients with muscle-invasive bladder cancer undergo radical cystectomy—a guideline-recommended treatment. Previous studies have primarily evaluated patie...

Arrays of coils are commonly used in MRI both for reception and in parallel transmission to alleviate radiofrequency field inhomogeneities at high fields. Most designs typically overlap loop elements by a critical area (approximately 10 %) to minimize mutual inductive couplings. With this geometrical constraint, loop sizes have to be reduced to accommodate large numbers of coils for a given coverage. However, the contribution of coil noise to total noise increases as each coil size decreases, which reduces overall signal-to-noise ratio (SNR), especially in deeper regions of the sample volume. Here we propose arrays designs using elements that overlap much more (over-overlapped), and using numerical calculations we investigate their performance compared to two kinds of conventionally overlapped arrays (one with the same coil size but smaller coil number, and one with the same coil number but smaller coil size). Our simulation results show that the over-overlapped array can considerably increase the central SNR when coil noise dominates.

The topological characteristics of functional networks, derived from measurements of resting-state connectivity in gray matter (GM), are associated with individual cognitive abilities or specific dysfunctions. However, blood oxygen level-dependent (BOLD) signals in white matter (WM) are usually ignored or even regressed out as nuisance factors in the data analyses that underlie network models. Recent studies have demonstrated reliable detection of WM BOLD signals and imply these reflect associated neural activities. Here we evaluate quantitatively the contributions of individual WM voxels to the identification of functional networks, which we term their engagement (or conceptually, their importance). We quantify the engagement by measuring the reductions of connectivity, produced by ignoring the signal fluctuations within each WM voxel, with respect to both the entire network (global) or a single GM node (local). We observed highly reproducible spatial distributions of global engagement maps, as well as a trend toward increased relevance of deep WM voxels at delayed times. Local engagement maps exhibit homogeneous spatial distributions with respect to internal nodes that constitute a well-recognized sub-functional network, but inhomogeneous distributions with respect to other nodes. WM voxels show distinct distributions of engagement depending on their anatomical locations. These findings demonstrate the important role of WM in network modeling, thus supporting the need for changes of conventional views that WM signal variations represent only physiological noise.

Objectives Sodium (Na+) is stored in the skin and muscle and plays an important role in immune regulation. In animal models, increased tissue Na+ is associated with activation of the immune system, and high salt intake exacerbates autoimmune disease and worsens hypertension. However, there is no information about tissue Na+ and human autoimmune disease. We hypothesized that muscle and skin Na+ content is (a) higher in patients with systemic lupus erythematosus (SLE) than in control subjects, and (b) associated with blood pressure, disease activity, and inflammation markers (interleukin (IL)-6, IL-10 and IL-17 A) in SLE. Methods Lower-leg skin and muscle Na+ content was measured in 23 patients with SLE and in 28 control subjects using 23Na+ magnetic resonance imaging. Demographic and clinical information was collected from interviews and chart review, and blood pressure was measured. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI). Plasma inflammation markers were measured by multiplex immunoassay. Results Muscle Na+ content was higher in patients with SLE (18.8 (16.7–18.3) mmol/L) than in control subjects (15.8 (14.7–18.3) mmol/L; p + content was also higher in SLE patients than in controls, but this difference was not statistically significant. Among patients with SLE, muscle Na+ was associated with SLEDAI and higher concentrations of IL-10 after adjusting for age, race, and sex. Skin Na+ was significantly associated with systolic blood pressure, but this was attenuated after covariate adjustment. Conclusion Patients with SLE had higher muscle Na+ content than control subjects. In patients with SLE, higher muscle Na+ content was associated with higher disease activity and IL-10 concentrations.

Selective inversion recovery (SIR) is a quantitative magnetization transfer (qMT) method that provides estimates of parameters related to myelin content in white matter, namely the macromolecular pool-size-ratio (PSR) and the spin-lattice relaxation rate of the free pool (R1f), without the need for independent estimates of ∆B0, B1+, and T1. Although the feasibility of performing SIR in the human brain has been demonstrated, the scan times reported previously were too long for whole-brain applications. In this work, we combined optimized, short-TR acquisitions, SENSE/partial-Fourier accelerations, and efficient 3D readouts (turbo spin-echo, SIR-TSE; echo-planar imaging, SIR-EPI; and turbo field echo, SIR-TFE) to obtain whole-brain data in 18, 10, and 7 min for SIR-TSE, SIR-EPI, SIR-TFE, respectively. Based on numerical simulations, all schemes provided accurate parameter estimates in large, homogenous regions; however, the shorter SIR-TFE scans underestimated focal changes in smaller lesions due to blurring. Experimental studies in healthy subjects (n = 8) yielded parameters that were consistent with literature values and repeatable across scans (coefficient of variation: PSR = 2.2–6.4%, R1f = 0.6–1.4%) for all readouts. Overall, SIR-TFE parameters exhibited the lowest variability, while SIR-EPI parameters were adversely affected by susceptibility-related image distortions. In patients with relapsing remitting multiple sclerosis (n = 2), focal changes in SIR parameters were observed in lesions using all three readouts; however, contrast was reduced in smaller lesions for SIR-TFE, which was consistent with the numerical simulations. Together, these findings demonstrate that efficient, accurate, and repeatable whole-brain SIR can be performed using 3D TFE, EPI, or TSE readouts; however, the appropriate readout should be tailored to the application.

Whereas resting state BOLD (blood oxygenation-level dependent) functional MRI (fMRI) has been widely used to assess functional connectivity between cortical regions, the laminar specificity of such measures is poorly understood. This study aims to determine (a) whether the resting state functional connectivity (rsFC) between two functionally related cortical regions varies with depth, (b) the relationship between layer-resolved tactile stimulus-evoked activation pattern and inter-layer rsFC pattern between two functionally distinct but related areas 3b and 1, and (c) the effects of spatial resolution on rsFC measures. We examined the inter-layer rsFC between somatosensory areas 3b and 1 of squirrel monkeys under anesthesia using tactile stimulus-driven and resting state BOLD acquisitions at sub-millimeter resolution. Consistent with previous observations in the areas 3b and 1, we detected robust stimulus-evoked BOLD activations with foci confined mainly to the upper layers (centered at 21% of the cortical depth). By carefully placing seeds in upper, middle and lower layers of areas 3b and 1, we observed strong rsFC between superficial and middle layers of these two areas. The layer-resolved activation patterns in areas 3b and 1 agree with their inter-layer rsFC patterns, and are consistent with the known anatomical connections between layers. In summary, using BOLD rsFC pattern we identified an inter-layer inter-areal microcircuit that shows strong intrinsic functional connections between superficial and middle layer somatosensory areas 3b and 1 of monkeys. RsFC can be used as a robust invasive tool to probe inter-layer cortico-cortical microcircuits.

Purpose Functional magnetic resonance imaging with BOLD contrast is widely used for detecting brain activity in the cortex. Recently, several studies have described anisotropic correlations of resting-state BOLD signals between voxels in white matter (WM). These local WM correlations have been modeled as functional-correlation tensors, are largely consistent with underlying WM fiber orientations derived from diffusion MRI, and appear to change during functional activity. However, functional-correlation tensors have several limitations. The use of only nearest-neighbor voxels makes functional-correlation tensors sensitive to noise. Furthermore, adjacent voxels tend to have higher correlations than diagonal voxels, resulting in orientation-related biases. Finally, the tensor model restricts functional correlations to an ellipsoidal bipolar-symmetric shape, and precludes the ability to detect complex functional orientation distributions (FODs). Methods We introduce high-angular-resolution functional-correlation imaging (HARFI) to address these limitations. In the same way that high-angular-resolution diffusion imaging (HARDI) techniques provide more information than diffusion tensors, we show that the HARFI model is capable of characterizing complex FODs expected to be present in WM. Results We demonstrate that the unique radial and angular sampling strategy eliminates orientation biases present in tensor models. We further show that HARFI FODs are able to reconstruct known WM pathways. Finally, we show that HARFI allows asymmetric "bending" and "fanning" distributions, and propose asymmetric and functional indices which may increase fiber tracking specificity, or highlight boundaries between functional regions. Conclusions The results suggest the HARFI model could be a robust, new way to evaluate anisotropic BOLD signal changes in WM.

The medical specialty radiology has experienced a number of extremely important and influential technical developments in the past that have affected how medical imaging is deployed. Artificial intelligence (AI) is potentially another such development that will introduce fundamental changes into the practice of radiology. In this commentary the historical evolution of some major changes in radiology are traced as background to how AI may also be embraced into practice. Potential new capabilities provided by AI offer exciting prospects for more efficient and effective use of medical images.

Arrays of radiofrequency coils are widely used in magnetic resonance imaging to achieve high signal-to-noise ratios and flexible volume coverage, to accelerate scans using parallel reception, and to mitigate field non-uniformity using parallel transmission. However, conventional coil arrays require complex decoupling technologies to reduce electromagnetic coupling between coil elements, which would otherwise amplify noise and limit transmitted power. Here we report a novel self-decoupled RF coil design with a simple structure that requires only an intentional redistribution of electrical impedances around the length of the coil loop. We show that self-decoupled coils achieve high inter-coil isolation between adjacent and non-adjacent elements of loop arrays and mixed arrays of loops and dipoles. Self-decoupled coils are also robust to coil separation, making them attractive for size-adjustable and flexible coil arrays., Conventional coil arrays require complex decoupling technologies to reduce electromagnetic coupling between coil elements. Here, the authors report a self-decoupled RF coil design that achieves high inter-coil isolation between adjacent and non-adjacent elements and mixed arrays of loops and dipoles

ObjectiveWhile epilepsy studies rarely examine brainstem, we sought to examine the hypothesis that temporal lobe epilepsy (TLE) leads to subcortical arousal center dysfunction, contributing to neocortical connectivity and neurocognitive disturbances.MethodsIn this case-control study of 26 adult patients with TLE and 26 controls, we used MRI to measure structural and functional connectivity of the cuneiform/subcuneiform nuclei (CSC), pedunculopontine nucleus, and ventral tegmental area. Ascending reticular activating system connectivity patterns were related to neuropsychological and disease measures.ResultsCompared to controls, patients with TLE demonstrated reductions in ascending reticular activating system structural and functional connectivity, most prominently to neocortical regions (p < 0.05, unpaired t tests, corrected). While reduced CSC structural connectivity was related to impaired performance IQ and visuospatial memory, diminished CSC functional connectivity was associated with impaired verbal IQ and language abilities (p < 0.05, Spearman ρ, t tests). Finally, CSC structural connectivity decreases were quantitatively associated with consciousness-impairing seizure frequency (p < 0.05, Spearman ρ) and the presence of generalized seizures (p < 0.05, unpaired t test), suggesting a relationship to disease severity.ConclusionsConnectivity perturbations in brainstem arousal centers are present in TLE and may contribute to neurocognitive problems. These studies demonstrate the underappreciated role of brainstem networks in epilepsy and may lead to novel neuromodulation targets to treat or prevent deleterious brain network effects of seizures in TLE.

Purpose Renal fibrosis is a hallmark of progressive renal disease; however, current clinical tests are insufficient for assessing renal fibrosis. Here we evaluated the utility of quantitative magnetization transfer MRI in detecting renal fibrosis in a murine model of progressive diabetic nephropathy (DN). Methods The db/db eNOS-/- mice, a well-recognized model of progressive DN, and normal wild-type mice were imaged at 7T. The quantitative magnetization transfer data were collected in coronal plane using a 2D magnetization transfer prepared spoiled gradient echo sequence with a Gaussian-shaped presaturation pulse. Parameters were derived using a two-pool fitting model. A normal range of cortical pool size ratio (PSR) was defined as Mean±2SD of wild-type kidneys (N = 20). The cortical regions whose PSR values exceeded this threshold (threshold PSR) were assessed. The correlations between the PSR-based and histological (collagen IV or picrosirius red stain) fibrosis measurements were evaluated. Results Compared with wild-type mice, moderate increases in mean PSR values and scattered clusters of high PSR region were observed in cortex of DN mouse kidneys. Abnormally high PSR regions (% area) that were detected by the threshold PSR were significantly increased in renal cortexes of DN mice. These regions progressively increased on aging and highly correlated with histological fibrosis measures, while the mean PSR values correlated much less. Conclusion Renal fibrosis in DN can be assessed by the quantitative magnetization transfer MRI and threshold analysis. This technique may be used as a novel imaging biomarker for DN and other renal diseases.

Purpose To test the ability of a novel pulse sequence applied in vivo at 3 Tesla to separate the contributions to the water signal from amide proton transfer (APT) and relayed nuclear Overhauser enhancement (rNOE) from background direct water saturation and semisolid magnetization transfer (MT). The lack of such signal source isolation has confounded conventional chemical exchange saturation transfer (CEST) imaging. Methods We quantified APT and rNOE signals using a chemical exchange rotation transfer (CERT) metric, MTRdouble . A range of duty cycles and average irradiation powers were applied, and results were compared with conventional CEST analyses using asymmetry (MTRasym ) and extrapolated magnetization transfer (EMR). Results Our results indicate that MTRdouble is more specific than MTRasym and, because it requires as few as 3 data points, is more rapid than methods requiring a complete Z-spectrum, such as EMR. In white matter, APT (1.5 ± 0.5%) and rNOE (2.1 ± 0.7%) were quantified by using MTRdouble with a 30% duty cycle and a 0.5-µT average power. In addition, our results suggest that MTRdouble is insensitive to B0 inhomogeneity, further magnifying its speed advantage over CEST metrics that require a separate B0 measurement. However, MTRdouble still has nontrivial sensitivity to B1 inhomogeneities. Conclusion We demonstrated that MTRdouble is an alternative metric to evaluate APT and rNOE, which is fast, robust to B0 inhomogeneity, and easy to process.

Background and purpose An imaging biomarker of myelin integrity is an unmet need in multiple sclerosis (MS). Selective inversion recovery (SIR) quantitative magnetization transfer imaging (qMT) provides assays of myelin content in the human brain. We previously translated the SIR method to 7T and incorporated a rapid turbo field echo (TFE) readout for whole-brain imaging within clinically acceptable scan times. We herein provide histological validation and test in vivo feasibility and applicability of the SIR-TFE protocol in MS. Methods Clinical (T1 - and T2 -weighted) and SIR-TFE MRI scans were performed at 7T in a postmortem MS brain and MRI data were acquired in 10 MS patients and 14 heathy volunteers in vivo. The following parameters were estimated from SIR data: the macromolecular-to-free water pool-size-ratio (PSR), the spin-lattice relaxation rate of water (R1f ), and the MT exchange rate (kmf ). Differences in SIR parameters across tissue types, eg, white matter lesions (WM-Ls) and normal appearing WM (NAWM) in patients, and normal white matter (NWM) in heathy volunteers were evaluated. Associations between SIR parameters and disability scores were assessed. Results For postmortem scans, correspondence was observed between WM-Ls and NAWM from histology and PSR/R1f values. In vivo differences were detected for PSR, R1f , and kmf between WM-Ls and NWM (P ≤ .041). Associations were seen between WM-Ls/ NAWM PSR and disability scores (r ≤ -.671, P ≤ .048). Conclusions SIR-qMT at 7T provides sensitive, quantitative measures of myelin integrity for clinical and research applications.

PURPOSE: To evaluate the ability of spin-lock imaging to detect the uptake of 3-o-methyl-D-glucose (3oMG) in normal brain and brain tumors in animals. METHODS: Measurements of the longitudinal relaxation rate in the rotating frame (R(1ρ)) were made over a range of spin-lock powers in rat brains bearing 9L tumors. The dispersion of R(1ρ) values was quantified by ΔR(1ρ), the difference of R(1ρ) values acquired with low and high locking powers. The glucose analogue 3-o-methyl-D-glucose (3oMG) was administered intravenously and the differences of ΔR(1ρ) values (ΔR(1ρ)(diff)) before and as a function of time after administration were calculated to isolate the contribution of 3oMG to the dispersions, which at high fields mainly reflects chemical exchange effects. In addition, the ratio of image signals from low and high locking fields (the spin-lock ratio, SLR), which requires fewer acquisitions and varies directly with ΔR(1ρ), was computed as an alternative measure of the variation with locking power, and changes in SLR (SLR(diff)) after 3oMG were evaluated. RESULTS: Both ΔR(1ρ)(diff) and SLR(diff) in tumors increased rapidly after injection, whereas intact brain showed a gradual increase up to 1h. ΔR(1ρ)(diff) and SLR(diff) were significantly different between tumors and contralateral normal tissues. CONCLUSION: Spin-lock methods can be used to detect 3oMG in vivo after injection, and appropriate analyses of MRI signals allow tumors to be distinguished from normal brain.

Functional MRI based on blood oxygenation level-dependent (BOLD) contrast is well established as a neuroimaging technique for detecting neural activity in the cortex of the human brain. While detection and characterization of BOLD signals, as well as their electrophysiological and hemodynamic/metabolic origins, have been extensively studied in gray matter (GM), the detection and interpretation of BOLD signals in white matter (WM) remain controversial. We have previously observed that BOLD signals in a resting state reveal structure-specific anisotropic temporal correlations in WM and that external stimuli alter these correlations and permit visualization of task-specific fiber pathways, suggesting variations in WM BOLD signals are related to neural activity. In this study, we provide further strong evidence that BOLD signals in WM reflect neural activities both in a resting state and under functional loading. We demonstrate that BOLD signal waveforms in stimulus-relevant WM pathways are synchronous with the applied stimuli but with various degrees of time delay and that signals in WM pathways exhibit clear task specificity. Furthermore, resting-state signal fluctuations in WM tracts show significant correlations with specific parcellated GM volumes. These observations support the notion that neural activities are encoded in WM circuits similarly to cortical responses.

Spontaneous fluctuations of Blood Oxygenation-Level Dependent (BOLD) MRI signal in a resting state have previously been detected and analyzed to describe intrinsic functional networks in the spinal cord of rodents, non-human primates and human subjects. In this study we combined high resolution imaging at high field with data-driven Independent Component Analysis (ICA) to i) delineate fine-scale functional networks within and between segments of the cervical spinal cord of monkeys, and also to ii) characterize the longitudinal effects of a unilateral dorsal column injury on these networks. Seven distinct functional hubs were revealed within each spinal segment, with new hubs detected at bilateral intermediate and gray commissure regions in addition to the bilateral dorsal and ventral horns previously reported. Pair-wise correlations revealed significantly stronger connections between hubs on the dominant hand side. Unilateral dorsal-column injuries disrupted predominantly inter-segmental rather than intra-segmental functional connectivities as revealed by correlation strengths and graph-theory based community structures. The effects of injury on inter-segmental connectivity were evident along the length of the cord both below and above the lesion region. Connectivity strengths recovered over time and there was revival of inter-segmental communities as animals recovered function. BOLD signals of frequency 0.01–0.033 Hz were found to be most affected by injury. The results in this study provide new insights into the intrinsic functional architecture of spinal cord and underscore the potential of functional connectivity measures to characterize changes in networks after an injury and during recovery.

Background: People with Alzheimer’s disease (AD) report pain less frequently and receive less pain medication than people without AD. Recent studies have begun to elucidate how pain may be altered in those with AD. However, potential sex differences in pain responsiveness have never been explored in these patients. It is unclear whether sex differences found in prior studies of healthy young and older individuals extend to people with AD. Objective: The purpose of this study was to examine sex differences in the psychophysical response to experimental thermal pain in people with AD. Methods: Cross-sectional analysis of 14 male and 14 female age-matched (≥65 years of age, median = 74) and AD severity-matched (Mini-Mental State Exam score 0.05). Conclusions: Results suggest experimental pain-related sex differences persist in older adults with AD in a different manner than those previously demonstrated in cognitively intact older adults. These findings could potentially aid in developing targeted pain management approaches in this vulnerable population. Further studies are warranted to replicate the findings from this pilot work.

The goal is to develop an imaging method where contrast reflects amide-water magnetization exchange, with minimal signal contributions from other sources. Conventional chemical exchange saturation transfer (CEST) imaging of amides (often called amide proton transfer, or APT, and quantified by the metric MTRasym) is confounded by several factors unrelated to amides, such as aliphatic protons, water relaxation, and macromolecular magnetization transfer. In this work, we examined the effects of combining our previous chemical exchange rotation (CERT) approach with the non-linear AREX method while using different duty cycles (DC) for the label and reference scans. The dependencies of this approach, named AREXdouble,vdc, on tissue parameters, including T1, T2, semi-solid component concentration (fm), relayed nuclear Overhauser enhancement (rNOE), and nearby amines, were studied through numerical simulations and control sample experiments at 9.4 T and 1 µT irradiation. Simulations and experiments show that AREXdouble,vdc is sensitive to amide-water exchange effects, but is relatively insensitive to T1, T2, fm, nearby amine, and distant aliphatic protons, while the conventional metric MTRasym, as well as several other APT imaging methods, are significantly affected by at least some of these confounding factors.