Ultrasound does not activate but can inhibit in vivo mammalian nerves across a wide range of parameters.

Ultrasound (US) has been shown to stimulate brain circuits, however, the ability to excite peripheral nerves with US remains controversial. To the best of our knowledge, there is still no in vivo neural recording study that has applied US stimulation to a nerve isolated from surrounding tissue to confirm direct activation effects. Here, we show that US cannot excite an isolated mammalian sciatic nerve in an in vivo preparation, even at high pressures (relative to levels recommended in the FDA guidance for diagnostic ultrasound) and for a wide range of parameters, including different pulse patterns and center frequencies. US can, however, reliably inhibit nerve activity whereby greater suppression is correlated with increases in nerve temperature. By prohibiting the nerve temperature from increasing during US application, we did not observe suppressive effects. Overall, these findings demonstrate that US can reliably inhibit nerve activity through a thermal mechanism that has potential for various health disorders, though future studies are needed to evaluate the long-term safety of therapeutic ultrasound applications.

Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis.

Targeted noninvasive control of the nervous system and end-organs may enable safer and more effective treatment of multiple diseases compared to invasive devices or systemic medications. One target is the cholinergic anti-inflammatory pathway that consists of the vagus nerve to spleen circuit, which has been stimulated with implantable devices to improve autoimmune conditions such as rheumatoid arthritis. Here we report that daily noninvasive ultrasound (US) stimulation targeting the spleen significantly reduces disease severity in a mouse model of inflammatory arthritis. Improvements are observed only with specific parameters, in which US can provide both protective and therapeutic effects. Single cell RNA sequencing of splenocytes and experiments in genetically-immunodeficient mice reveal the importance of both T and B cell populations in the anti-inflammatory pathway. These findings demonstrate the potential for US stimulation of the spleen to treat inflammatory diseases.

Ultrasound Produces Extensive Brain Activation via a Cochlear Pathway.

Ultrasound (US) can noninvasively activate intact brain circuits, making it a promising neuromodulation technique. However, little is known about the underlying mechanism. Here, we apply transcranial US and perform brain mapping studies in guinea pigs using extracellular electrophysiology. We find that US elicits extensive activation across cortical and subcortical brain regions. However, transection of the auditory nerves or removal of cochlear fluids eliminates the US-induced activity, revealing an indirect auditory mechanism for US neural activation. Our findings indicate that US activates the ascending auditory system through a cochlear pathway, which can activate other non-auditory regions through cross-modal projections. This cochlear pathway mechanism challenges the idea that US can directly activate neurons in the intact brain, suggesting that future US stimulation studies will need to control for this effect to reach reliable conclusions.

Development and optimization of hardware for delta relaxation enhanced MRI.

PURPOSE: Delta relaxation enhanced magnetic resonance (dreMR) imaging requires an auxiliary B0 electromagnet capable of shifting the main magnetic field within a clinical 1.5 Tesla (T) MR system. In this work, the main causes of interaction between an actively shielded, insertable resistive B0 electromagnet and a 1.5T superconducting system are systematically identified and mitigated. METHODS: The effects of nonideal fabrication of the field-shifting magnet are taken into consideration through careful measurement during winding and improved accuracy in the design of the associated active shield. The shielding performance of the resultant electromagnet is compared against a previously built system in which the shield design was based on an ideal primary coil model. Hardware and software approaches implemented to eliminate residual image artifacts are presented in detail. RESULTS: The eddy currents produced by the newly constructed dreMR system are shown to have a significantly smaller "long-time-constant" component, consistent with the hypothesis that less energy is deposited into the cryostat of the MR system. CONCLUSION: With active compensation, the dreMR imaging system is capable of 0.22T field shifts within a clinical 1.5T MRI with no significant residual eddy-current fields.

Molecular MR imaging of liver fibrosis: a feasibility study using rat and mouse models.

BACKGROUND & AIMS: Liver biopsy, the current clinical gold standard for fibrosis assessment, is invasive and has sampling errors, and is not optimal for screening, monitoring, or clinical decision-making. Fibrosis is characterized by excessive accumulation of extracellular matrix proteins including type I collagen. We hypothesize that molecular magnetic resonance imaging (MRI) with a probe targeted to type I collagen could provide a direct and non-invasive method of fibrosis assessment. METHODS: Liver fibrosis was induced in rats with diethylnitrosamine and in mice with carbon tetrachloride. Animals were imaged prior to and immediately following i.v. administration of either collagen-targeted probe EP-3533 or non-targeted control Gd-DTPA. Magnetic resonance (MR) signal washout characteristics were evaluated from T1 maps and T1-weighted images. Liver tissue was subjected to pathologic scoring of fibrosis and analyzed for gadolinium and hydroxyproline. RESULTS: EP-3533-enhanced MR showed greater signal intensity on delayed imaging (normalized signal enhancement mice: control=0.39 ± 0.04, fibrotic=0.55 ± 0.03, p<0.01) and slower signal washout in the fibrotic liver compared to controls (liver t(1/2)=51.3 ± 3.6 vs. 42.0 ± 2.5 min, p<0.05 and 54.5 ± 1.9 vs. 44.1 ± 2.9 min, p<0.01 for fibrotic vs. controls in rat and mouse models, respectively). Gd-DTPA-enhanced MR could not distinguish fibrotic from control animals. EP-3533 gadolinium concentration in the liver showed strong positive correlations with hydroxyproline levels (r=0.74 (rats), r=0.77 (mice)) and with Ishak scoring (r=0.84 (rats), r=0.79 (mice)). CONCLUSIONS: Molecular MRI of liver fibrosis with a collagen-specific probe identifies fibrotic tissue in two rodent models of disease.

1H chemical shift magnetic resonance imaging probes with high sensitivity for multiplex imaging.

Proton-based chemical shift imaging probes were encapsulated inside nano-carriers to increase the sensivitity of the reporters. Co-encapsulation with a relaxation agent results in improved sensitivity and suppresses background signals. Simultaneous imaging of different chemical shift reporters allows multiplexed detection.

Results for diffusion-weighted imaging with a fourth-channel gradient insert.

Diffusion-weighted imaging suffers from motion artifacts and relatively low signal quality due to the long echo times required to permit the diffusion encoding. We investigated the inclusion of a noncylindrical fourth gradient coil, dedicated entirely to diffusion encoding, into the imaging system. Standard three-axis whole body gradients were used during image acquisition, but we designed and constructed an insert coil to perform diffusion encodings. We imaged three phantoms on a 3-T system with a range of diffusion coefficients. Using the insert gradient, we were able to encode b values of greater than 1300 s/mm(2) with an echo time of just 83 ms. Images obtained using the insert gradient had higher signal to noise ratios than those obtained using the whole body gradient: at 500 s/mm(2) there was a 18% improvement in signal to noise ratio, at 1000 s/mm(2) there was a 39% improvement in signal to noise ratio, and at 1350 s/mm(2) there was a 56% improvement in signal to noise ratio. Using the insert gradient, we were capable of doing diffusion encoding at high b values by using relatively short echo times.

Evaluation of a positron emission tomography (PET)-compatible field-cycled MRI (FCMRI) scanner.

Field-cycled MRI (FCMRI) uses two independent, actively controlled resistive magnets to polarize a sample and to provide the magnetic field environment during data acquisition. This separation of tasks allows for novel forms of contrast, reduction of susceptibility artifacts, and a versatility in design that facilitates the integration of a second imaging modality. A 0.3T/4-MHz FCMRI scanner was constructed with a 9-cm-wide opening through the side for the inclusion of a photomultiplier-tube-based positron emission tomography (PET) system. The performance of the FCMRI scanner was evaluated prior to integrating PET detectors. Quantitative measurements of the system's signal, phase, and temperature were recorded. The polarizing and readout magnets could be operated continuously at 100 A without risk of damage to the system. Transient instabilities in the readout magnet, caused by the pulsing of the polarizing magnet, dissipated in 50 ms; this resulted in a steady-state homogeneity of 32 Hz over a 7-cm-diameter volume. The short- and long-term phase behaviors of the readout field were sufficiently stable to prevent visible readout or phase-encode artifacts during imaging. Preliminary MR images demonstrated the potential of the FCMRI scanner and the efficacy of integrating a PET system.

Delta relaxation enhanced MR: improving activation-specificity of molecular probes through R1 dispersion imaging.

MR molecular imaging enables high-resolution, in vivo study of molecular processes frequently utilizing gadolinium-based probes that specifically bind to a particular biological molecule or tissue. While some MR probes are inactive when unbound and produce enhancement only after binding, the majority are less specific and cause enhancement in either state. Accumulation processes are then required to increase probe concentration in regions of the target molecule/tissue. Herein, a method is described for creating specificity for traditionally nonspecific probes. This method utilizes MR field-cycling methods to produce MRI contrast related to the dependence of R(1) upon magnetic field. It is shown that the partial derivative of R(1) with respect to magnetic field strength, R(1)', can be used as an unambiguous measure of probe binding. T(1)-weighted images and R(1)' images were produced for samples of albumin and buffer both enhanced with the albumin-binding agent Vasovist. For T(1) images, samples with low concentrations of Vasovist in an albumin solution could not be differentiated from samples with higher concentrations of Vasovist in buffer. Conversely, the R(1)' images showed high specificity to albumin. Albumin samples with a 10-microM concentration of Vasovist were enhanced over buffer samples containing up to 16 times more Vasovist.