MRI and MRS of the human brain at magnetic fields of 14T to 20T: Technical feasibility, safety, and neuroscience horizons.

The three goals of this paper are: 1) to evaluate the improvements in technology for increasing magnetic flux density (magnetic field) to 14T in the next few years and eventually to 20T; 2) to highlight neuroscience opportunities enabled by these advances; and, 3) to evaluate the physiological and biophysical effects associated with MRI at very high performance levels. Substantial recent advances in magnet technology including superconductor developments enable neuroscience goals that are not obtainable at contemporary magnetic fields. Ten areas of brain neuroscience include potential improvements in resolution for functional MRI(BOLD), diffusion weighted MRI, tractography, susceptibility weighted MR, neuronal architecture patterns related to human behavior, proton spectroscopy of small brain biochemicals, chemical exchange saturation transfer (CEST), dynamic contrast enhanced MRI, brain energy metabolism using 13C, 17O, and 31P; and brain electrolyte physiology using 23Na, 35Cl, and 39K. Physiological phenomena and safety aspects include: absorbed RF power, acoustic sound pressure levels, induced electric fields, Lorentz forces, magnetohydrodynamic forces, and biophysical phenomena in cells and tissues. Where feasible, effects are quantified for magnetic fields beyond 7T with the conclusion that there are no foreseen barriers either in the technical or human safety aspects of brain MRI and MRS at fields up to 20T. This conclusion is conditioned on results of recommended experiments to verify the predicted level of physiological effects beyond 9.4T. This technology is predicted to enable quantification of biochemical components of the functioning brain not detectable heretofore.

Comparison of potassium and sodium binding in vivo and in agarose samples using TQTPPI pulse sequence.

Potassium and sodium specific binding in vivo were explored at 21.1T by triple quantum (TQ) magnetic resonance (MR) signals without filtration to achieve high sensitivities and precise quantifications. The pulse sequence used time proportional phase increments (TPPI). During simultaneous phase-time increments, it provided total single quantum (SQ) and TQ MR signals in the second dimension at single and triple quantum frequencies, respectively. The detection of both TQ and SQ signals was performed at identical experimental conditions and the resulting TQ signal equals 60±3% of the SQ signal when all ions experience sufficient time for binding. In a rat head in vivo the TQ percentage relative to SQ for potassium is 41.5±3% and for sodium is 16.1±1%. These percentages were compared to the matching values in an agarose tissue model with MR relaxation times similar to those of mammalian brain tissue. The sodium TQ signal in agarose samples decreased in the presence of potassium, suggesting a competitive binding of potassium relative to sodium ions for the same binding sites. The TQTPPI signals correspond to almost two times more effective binding of potassium than sodium. In vivo, up to ∼69% of total potassium and ∼27% of total sodium can be regarded as bound or experiencing an association time in the range of several milliseconds. Experimental data analyses show that more than half of the in vivo total sodium TQ signal could be from extracellular space, which is an important factor for quantification of intracellular MR signals.

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

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

Measurement of brachial artery endothelial function using a standard blood pressure cuff.

The integrity of endothelial function in major arteries (EFMA) is a powerful independent predictor of heart attack and stroke. Existing ultrasound-based non-invasive assessment methods are technically challenging and suitable only for laboratory settings. EFMA, like blood pressure (BP), is both acutely and chronically affected by factors such as lifestyle and medication. Consequently, laboratory-based measurements cannot fully gauge the effects of medical interventions on EFMA. EFMA and BP have, arguably, comparable (but complementary) value in the assessment of cardiovascular health. Widespread deployment of EFMA assessment is thus a desirable clinical goal. To this end, we propose a device based on modifying the measurement protocol of a standard electronic sphygmomanometer. The protocol involves inflating the cuff to sub-diastolic levels to enable recording of the pulse waveform before and after vasodilatory stimulus. The mechanical unloading of the arterial wall provided by the cuff amplifies the distension that occurs with each pulse, which is measured as a pressure variation in the cuff. We show that the height of the rising edge of each pulse is proportional to the change in lumen area between diastole and systole. This allows the effect of vasodilatory stimuli on the artery to be measured with high sensitivity. We compare the proposed cuff flow-mediated dilation (cFMD) method to ultrasound flow-mediated dilation (uFMD). We find significant correlation (r = 0.55, p = 0.003, N = 27) between cFMD- and uFMD-based metrics obtained when the release of a 5 min cuff occlusion is employed to induce endothelial stimulus via reactive hyperemia. cFMD is approximately proportional to the square of uFMD, representing a typical increase in sensitivity to vasodilation of 300-600%. This study illustrates the potential for an individual to conveniently measure his/her EFMA by using a low-cost reprogrammed home sphygmomanometer.

Imaging and modeling of flow in porous media using clinical nuclear emission tomography systems and computational fluid dynamics.

This paper presents experimental and modeling aspects of applying nuclear emission tomography to study fluid flow in laboratory packed porous media columns of the type frequently used in geophysics, geochemistry and hydrology research. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are used as non-invasive tools to obtain dynamic 3D images of radioactive tracer concentrations. Dynamic sequences obtained using 18F-FDG PET are used to trace flow through a 5 cm diameter × 20 cm tall sand packed column with and without an impermeable obstacle. In addition, a custom-made rotating column setup placed in a clinical two-headed SPECT camera is used to image 99mTc-DTPA tracer propagation in a through-flowing column (10 cm diameter × 30 cm tall) packed with recovered aquifer sediments. A computational fluid dynamics software package FLUENT is used to model the observed flow dynamics. Tracer distributions obtained in the simulations in the smaller column uniformly packed with sand and in the column with an obstacle are remarkably similar to the reconstructed images in the PET experiments. SPECT results demonstrate strongly non-uniform flow patterns for the larger column slurry-packed with sub-surface sediment and slow upward flow. In the numerical simulation of the SPECT study, two symmetric channels with increased permeability are prescribed along the column walls, which result in the emergence of two well-defined preferential flow paths. Methods and results of this work provide new opportunities in hydrologic and biogeochemical research. The primary target application for developed technologies is non-destructive, non-perturbing, quantitative imaging of flow dynamics within laboratory scale porous media systems.

Dynamic single photon emission computed tomography--basic principles and cardiac applications.

The very nature of nuclear medicine, the visual representation of injected radiopharmaceuticals, implies imaging of dynamic processes such as the uptake and wash-out of radiotracers from body organs. For years, nuclear medicine has been touted as the modality of choice for evaluating function in health and disease. This evaluation is greatly enhanced using single photon emission computed tomography (SPECT), which permits three-dimensional (3D) visualization of tracer distributions in the body. However, to fully realize the potential of the technique requires the imaging of in vivo dynamic processes of flow and metabolism. Tissue motion and deformation must also be addressed. Absolute quantification of these dynamic processes in the body has the potential to improve diagnosis. This paper presents a review of advancements toward the realization of the potential of dynamic SPECT imaging and a brief history of the development of the instrumentation. A major portion of the paper is devoted to the review of special data processing methods that have been developed for extracting kinetics from dynamic cardiac SPECT data acquired using rotating detector heads that move as radiopharmaceuticals exchange between biological compartments. Recent developments in multi-resolution spatiotemporal methods enable one to estimate kinetic parameters of compartment models of dynamic processes using data acquired from a single camera head with slow gantry rotation. The estimation of kinetic parameters directly from projection measurements improves bias and variance over the conventional method of first reconstructing 3D dynamic images, generating time-activity curves from selected regions of interest and then estimating the kinetic parameters from the generated time-activity curves. Although the potential applications of SPECT for imaging dynamic processes have not been fully realized in the clinic, it is hoped that this review illuminates the potential of SPECT for dynamic imaging, especially in light of new developments that enable measurement of dynamic processes directly from projection measurements.

ZigBee-based wireless intra-oral control system for quadriplegic patients.

A human-to-computer system that includes a wireless intra-oral module, a wireless coordinator and distributed wireless controllers, is presented. The state-of-the-art ZigBee protocol is employed to achieve reliable, low-power and cost-efficient wireless communication between the tongue, computer and controllers. By manipulating five buttons on the wireless intra-oral module using the tongue, the subject can control cursors, computer menus, wheelchair, lights, TV, phone and robotic devices. The system is designed to improve the life quality of patients with stroke and patients with spinal cord injury.

Assessment of endothelial function in the radial artery using inhaled albuterol.

Endothelial dysfunction is an early indicator of developing atherosclerosis and is a strong predictor of future heart attack and stroke. At present, evaluation of endothelial function (EF) (specifically, EF mediated by nitric oxide, NO) is too technically difficult to form part of a routine clinical examination. Non-invasive methods that measure NO-dependent EF in arteries make use of a 4-5 minute blood pressure cuff occlusion of the arm in order to induce reactive hyperemia (RH) upon cuff release. The increased blood flow that results from the RH stimulates the endothelial cells to release NO and relax the surrounding vascular smooth muscle. The magnitude of the change in arterial caliber or stiffness provides a measure of EF. The cuff occlusion is uncomfortable and inflation and release inevitably move the arm, increasing the technical difficulty of obtaining reliable measurements. In beta2-adrengergic agonist albuterol induces NO-mediated vasorelaxation in resistance vessels of humans. We examine, for the first time, the effect of albuterol on conduit vessels (radial artery) by measuring changes in the transit times of artificial pulses observed after inhalation of albuterol. We conclude that albuterol is able to relax the radial artery and that this correlates with the effects of RH (r=0.62, p=0.04). However, the response to a dose of 360 micro-g is smaller and more variable when compared to the response to RH-based stimulus.

Synthetic nano-LDL with paclitaxel oleate as a targeted drug delivery vehicle for glioblastoma multiforme.

The low density lipoprotein (LDL) receptor has been shown to be upregulated in GBM tumor cells in vitro and is therefore a potential molecular target for the delivery of therapeutic agents. A synthetic nano-LDL (nLDL) particle was developed as a drug delivery vehicle targeted to GBM cells by incorporating a lipophilic prodrug, paclitaxel oleate, into the particle. Nano-LDL containing paclitaxel oleate (nLDL-PO) was constructed by combining a synthetic peptide containing a lipid binding motif and the LDL receptor (LDLR) binding domain of apolipoprotein B-100 with a lipid emulsion consisting of phosphatidyl choline, triolein, and paclitaxel oleate. Paclitaxel oleate incorporated into the core of the lipid particle. nLDL-PO cell survival in GBM cell lines was found to be time, concentration, and cell line dependent. Cell killing was observed with short drug incubations and exhibited saturation at 6 h. nLDL-PO cell survival improved in the presence of the LDL receptor inhibitor, suramin, demonstrating that the drug was delivered via the LDL receptor. Collectively, these data strongly suggest that the synthetic nano-LDLs can incorporate lipophilic drugs and are capable of killing GBM cells. nLDL-PO has the potential to serve as a selective drug delivery vehicle for targeting GBM tumors via the LDL receptor.

Synthetic nano-low density lipoprotein as targeted drug delivery vehicle for glioblastoma multiforme.

The low density lipoprotein (LDL) receptor has been shown to be upregulated in GBM tumor cells and is therefore a potential molecular target for the delivery of therapeutic agents. A synthetic nano-LDL (nLDL) particle was developed and tested to determine its utility as a drug delivery vehicle targeted to GBM tumors. nLDL particles were constructed by combining a synthetic peptide containing a lipid binding motif and the LDL receptor (LDLR) binding domain of apolipoprotein B-100 with a lipid emulsion consisting of phosphatidyl choline, triolein, and cholesteryl oleate. Composition analysis, fast protein liquid chromatography, and electron microscopy revealed that nLDL was highly reproducible and intermediate in size between high density lipoprotein and LDL particles (10.5+/-2.8 nm diameter). The binding and uptake of fluorescently labeled nLDL particles was assessed using fluorescence microscopy. Uptake of nLDL was time dependent, exhibiting saturation at approximately 3 h, and concentration dependent, exhibiting saturation at concentrations greater than 5 microM peptide. Using Lysotracker as a cellular marker, nLDL co-localized with lysosomes. nLDL binding was eliminated by blocking LDLRs with suramin and nLDL inhibited binding of plasma LDL to LDLRs. Collectively these data strongly suggest that the synthetic nano-LDLs described here are taken up by LDLR and can serve as a drug delivery vehicle for targeting GBM tumors via the LDLR.

Evaluation of arterial endothelial function using transit times of artificially induced pulses.

Impairment of arterial endothelial function is an early event in atherosclerosis and correlates with the major risk factors for cardiovascular disease. The most widely employed non-invasive measure of endothelial function involves brachial artery (BA) diameter measurement using ultrasound imaging before and after several minutes of blood flow occlusion. The change in arterial diameter is a measure of flow-mediated vasorelaxation (FMVR). The high between-laboratory variability of results and cost of instrumentation render this technique unsuitable for routine clinical use. We induce artificial pulses at the superficial radial artery using a linear actuator. An ultrasonic Doppler stethoscope detects these pulses 10-30 cm proximal to the point of pulse induction. The delay between pulse application and detection provides the pulse transit time (PTT). By measuring PTT before and after 5 min of BA occlusion and ensuing reactive hyperemia, FMVR may be measured based on the changes in PTT caused by changes in vessel caliber, smooth muscle tone and wall thickness. We (1) validate the sensitivity of this technique to arterial wall tone using sublingual nitroglycerin and (2) compare measurements of endothelial function to ultrasound BA diameter measurements in 12 human subjects. The PTT-based method is verified to measure arterial wall tone and is shown to provide 37% greater sensitivity (p < 0.05) to FMVR than BA diameter measurements. By measuring the change in pulse transit time before and after endothelial stimulus, a sensitive, reproducible and convenient measure of endothelial function may be obtained at a low cost.

The Trauma Patient Tracking System: implementing a wireless monitoring infrastructure for emergency response.

In mass trauma situations, emergency personnel are challenged with the task of prioritizing the care of many injured victims. We propose a trauma patient tracking system (TPTS) where first-responders tag all patients with a wireless monitoring device that continuously reports the location of each patient. The system can be used not only to prioritize patient care, but also to determine the time taken for each patient to receive treatment. This is important in training emergency personnel and in identifying bottlenecks in the disaster response process. In situations where biochemical agents are involved, a TPTS may be employed to determine sites of cross-contamination. In order to track patient location in both outdoor and indoor environments, we employ both Global Positioning System (GPS) and Television/ Radio Frequency (TVRF) technologies. Each patient tag employs IEEE 802.11 (Wi-Fi)/TCP/IP networking to communicate with a central server via any available Wi-Fi basestation. A key component to increase TPTS fault-tolerance is a mobile Wi-Fi basestation that employs redundant Internet connectivity to ensure that tags at the disaster scene can send information to the central server even when local infrastructure is unavailable for use. We demonstrate the robustness of the system in tracking multiple patients in a simulated trauma situation in an urban environment.

High-resolution NMR of static samples by rotation of the magnetic field.

Mechanical rotation of a sample at 54.7 degrees with respect to the static magnetic field, so-called magic-angle spinning (MAS), is currently a routine procedure in nuclear magnetic resonance (NMR). The technique enhances the spectral resolution by averaging away anisotropic spin interactions thereby producing isotropic-like spectra with resolved chemical shifts and scalar couplings. It should be possible to induce similar effects in a static sample if the direction of the magnetic field is varied, e.g., magic-angle rotation of the B0 field (B0-MAS). Here, this principle is experimentally demonstrated in a static sample of solid hyperpolarized xenon at approximately 3.4 mT. By extension to moderately high fields, it is possible to foresee interesting applications in situations where physical manipulation of the sample is inconvenient or impossible. Such situations are expected to arise in many cases from materials to biomedicine and are particularly relevant to the novel approach of ex situ NMR spectroscopy and imaging.

Enhanced cutaneous vascular response in AD subjects under donepezil therapy.

OBJECTIVE: Abnormal cutaneous vasodilatory responses to the iontophoresis of vasodilators were previously observed in Alzheimer's disease (AD). We sought to replicate these observations and further identify peripheral vascular components of AD pathology. METHODS: Methacholine chloride (MCh), acetylcholine chloride (ACh), and sodium nitroprusside (SNP) were applied iontophoretically to forearm skin. Laser Doppler imaging of treated areas yielded total perfusion response values. RESULTS: Response to MCh was enhanced 78% ( P=0.003 ) in AD subjects under therapy with the acetylcholinesterase inhibitor (AChEI) donepezil ( N=9 ), relative to age- and sex-matched controls ( N=12 ). Significant increases in perfusion were also observed after application of ACh (68%, P=0.03 ) and SNP (46%, P=0.04 ). CONCLUSIONS: A previous study reported attenuated response to ACh in AD. Paradoxically, we observed a substantially enhanced response that is likely a consequence of donepezil therapy. The increased response to the endothelium-independent vasodilator SNP indicates improved general vasodilatory response, perhaps due to preservation of endogenous ACh by donepezil. Cerebral perfusion in response to functional activation may be improved in this way, suggesting a secondary therapeutic mode of donepezil.

Method for the measurement of the sensitivity of vascular beds to ischemia.

We identify a novel performance parameter of arterial beds and propose a convenient, non-invasive method for its measurement. The parameter relates the amount of reactive hyperemic flow that ensues after blood flow occlusion to the duration of occlusion and thus may be viewed as a measure of the sensitivity of the downstream vascular bed to the level of ischemia. The measurement is performed by inducing three successive progressively longer periods of ischemia in a limb using a pneumatic cuff. During the periods between occlusions, reactive hyperemic flow is measured at a finger using laser Doppler fluximetry (LDF). Total hyperemic response is calculated for each occlusion by averaging the LDF time series over the interocclusion interval. The vascular sensitivity parameter is calculated as the gradient of the line fit to the three mean response measurements. We evaluate the method in 18 subjects and find that orally administered nicotine significantly reduces the sensitivity to ischemia by 34%.

Biomonitoring with wireless communications.

Wireless biomonitoring, first used in human beings for fetal heart-rate monitoring more than 30 years ago, has now become a technology for remote sensing of patients' activity, blood pulse pressure, oxygen saturation, internal pressures, orthopedic device loading, and gastrointestinal endoscopy. Technical advances in miniaturization and wireless communications have enabled development of monitoring devices that can be made available for general use by individuals/patients and caregivers. New methods for short-range wireless communications not encumbered by radio spectrum restrictions (e.g., ultra-wideband) will enable applications of wireless monitoring without interference in ambulatory subjects, in home care, and in hospitals.

Progenitor endothelial cell involvement in Alzheimer's disease.

There is compelling evidence that endothelial cells of the brain and periphery are dysfunctional in Alzheimer's disease. There is evidence for a fundamental defect in, or abnormal aging of, endothelial progenitor cells in atherosclerosis. The possibility that endothelial cell defects are a primary cause for Alzheimer's disease or other dementias can be researched by molecular and cell biology studies as well as cell trafficking studies using recently demonstrated molecular imaging methods. The evidence for abnormal endothelial function and the methods to explore this hypothesis are presented.