Kristin F. Bing

Contrast‐enhanced in vivo magnetic resonance microscopy of the mouse brain enabled by noninvasive opening of the blood‐brain barrier with ultrasound

The use of contrast agents for neuroimaging is limited by the blood‐brain barrier (BBB), which restricts entry into the brain. To administer imaging agents to the brain of rats, intracarotid infusions of hypertonic mannitol have been used to open the BBB. However, this technically challenging approach is invasive, opens only a limited region of the BBB, and is difficult to extend to mice. In this work, the BBB was opened in mice, using unfocused ultrasound combined with an injection of microbubbles. This technique has several notable features: it (a) can be performed transcranially in mice; (b) takes only 3 min and uses only commercially available components; (c) opens the BBB throughout the brain; (d) causes no observed histologic damage or changes in behavior (with peak‐negative acoustic pressures of 0.36 MPa); and (e) allows recovery of the BBB within 4 h. Using this technique, Gadopentetate Dimeglumine (Gd‐DTPA) was administered to the mouse brain parenchyma, thereby shortening T1 and enabling the acquisition of high‐resolution (52 × 52 × 100 micrometers3) images in 51 min in vivo. By enabling the administration of both existing anatomic contrast agents and the newer molecular/sensing contrast agents, this technique may be useful for the study of mouse models of neurologic function and pathology with MRI. Magn Reson Med, 2010.

Blood-Brain Barrier (BBB) Disruption Using a Diagnostic Ultrasound Scanner and Definity® in Mice

The objective of this work was to determine whether diagnostic ultrasound and contrast agent could be used to transcranially and nondestructively disrupt the blood-brain barrier (BBB) in mice under ultrasound image guidance and to quantify that disruption using magnetic resonance imaging (MRI) and magnetic resonance (MR) contrast agent. Each mouse was placed under isoflurane anesthesia and the hair on top of its skull was removed before treatment. A diagnostic ultrasound transducer was placed in a water bag coupled with gel on the mouse skull. Definity (ultrasound [US] contrast) and Magnevist (MR contrast) were injected concurrent with the start of a custom ultrasound transmission sequence. The transducer was translated along the rostral-caudal axis to insonify three spatial locations (2mm apart) along one half of the brain for each sequence. T1-weighted MR images were used to quantify the volume of tissue over which the BBB disruption allowed Magnevist to enter the brain, based upon increases in MR contrast-to-noise ratio (CNR) compared with the noninsonified portions of the brain. Ultrasonic frequency, pressure and pulse duration, as well as Definity dose and injection time were varied. Preliminary results suggest that a threshold exists for BBB opening dependent upon both pressure and pulse duration (consistent with reports in the literature performed at lower frequencies). A range of typical diagnostic frequencies (e.g., 5.0-8.0 MHz) generated BBB disruption. Comparable BBB opening was noted with varied delays between Definity injection and insonification (0-2 min) for a range of Definity concentrations (400-2400 microL/kg). The low-pressure, custom sequences (mechanical index [MI]< or =0.65) had minimal blood cell extravasation as determined by histologic evaluation. This study has shown the ability of a diagnostic ultrasound system, in conjunction with Definity, to open the BBB transcranially in a mouse model for molecules approximately 0.5 kDa in size. Opening was achieved at higher frequencies than previously reported and was localized under ultrasound image guidance. A typical, ultrasound imaging mode (pulsed wave [PW] Doppler) with specific settings (transmit frequency=5.7 MHz, gate size=15 mm, pulse repetition frequency=100 Hz, system power=15%) successfully opened the BBB, which facilitates implementation using the most of commercially available clinical diagnostic scanners. Localized opening of the BBB may have potential clinical utility for the delivery of diagnostic or therapeutic agents to the brain.

Combined ultrasonic thermal ablation with interleaved ARFI image monitoring using a single diagnostic curvilinear array: A feasibility study

The goal of this work is to demonstrate the feasibility of using a diagnostic ultrasound system (Siemens Antares™ and CH6–2 curvilinear array) to ablate ex vivo liver with a custom M-mode sequence and monitor the resulting tissue stiffening with 2-D Acoustic Radiation Force Impulse (ARFI) imaging. Images were taken before and after ablation, as well as in 5- s intervals during the ablation sequence in order to monitor the ablation lesion formation temporally. Ablation lesions were generated at depths up to 1.5 cm from the surface of the liver and were not visible in B-mode. ARFI images showed liver stiffening with heating that corresponded to discolored regions in gross pathology. As expected, the contrast of ablation lesions in ARFI images is observed to increase with ablation lesion size. This study demonstrated the ability of a diagnostic system using custom beam sequences to localize an ablation site, heat the site to the point of irreversible damage and monitor the formation of the ablation lesion with ARFI imaging.

Imaging arrays with improved transmit power capability

Bonded multilayer ceramics and composites incorporating low-loss piezoceramics have been applied to arrays for ultrasound imaging to improve acoustic transmit power levels and to reduce internal heating. Commercially available hard PZT from multiple vendors has been characterized for microstructure, ability to be processed, and electroacoustic properties. Multilayers using the best materials demonstrate the tradeoffs compared with the softer PZT5-H typically used for imaging arrays. Three-layer PZT4 composites exhibit an effective dielectric constant that is three times that of single layer PZT5H, a 50% higher mechanical Q, a 30% lower acoustic impedance, and only a 10% lower coupling coefficient. Application of low-loss multilayers to linear phased and large curved arrays results in equivalent or better element performance. A 3-layer PZT4 composite array achieved the same transmit intensity at 40% lower transmit voltage and with a 35% lower face temperature increase than the PZT-5 control. Although B-mode images show similar quality, acoustic radiation force impulse (ARFI) images show increased displacement for a given drive voltage. An increased failure rate for the multilayers following extended operation indicates that further development of the bond process will be necessary. In conclusion, bonded multilayer ceramics and composites allow additional design freedom to optimize arrays and improve the overall performance for increased acoustic output while maintaining image quality.

Dual-mode intracranial catheter integrating 3D ultrasound imaging and hyperthermia for neuro-oncology: feasibility study.

In this study, we investigated the feasibility of an intracranial catheter transducer with dual-mode capability of real-time 3D (RT3D) imaging and ultrasound hyperthermia, for application in the visualization and treatment of tumors in the brain. Feasibility is demonstrated in two ways: first by using a 50-element linear array transducer (17 mm × 3.1 mm aperture) operating at 4.4 MHz with our Volumetrics diagnostic scanner and custom, electrical impedance-matching circuits to achieve a temperature rise over 4°C in excised pork muscle, and second, by designing and constructing a 12 Fr, integrated matrix and linear-array catheter transducer prototype for combined RT3D imaging and heating capability. This dual-mode catheter incorporated 153 matrix array elements and 11 linear array elements diced on a 0.2 mm pitch, with a total aperture size of 8.4 mm × 2.3 mm. This 3.64 MHz array achieved a 3.5°C in vitro temperature rise at a 2 cm focal distance in tissue-mimicking material. The dual-mode catheter prototype was compared with a Siemens 10 Fr AcuNav™ catheter as a gold standard in experiments assessing image quality and therapeutic potential and both probes were used in an in vivo canine brain model to image anatomical structures and color Doppler blood flow and to attempt in vivo heating.

Detecting concussion impairment with radar using gait analysis techniques

Several studies have shown that measuring changes in gait could provide an easier method of diagnosing and monitoring concussions. The purpose of this study was to measure radar signal returns to explore if differences in gait patterns between normal and “concussed” individuals could be identified from radar spectrogram data. Access to concussed individuals was not available during this feasibility study. Instead, based on research that demonstrated a blood alcohol content (BAC) of 0.05% was equivalent to concussion impairment, BAC impairment goggles were used to visually simulate a concussion. Both “impaired” and “not impaired” individuals were asked to complete only motor skill tasks and then complete motor skill and cognitive skill tasks simultaneously. These results were analyzed using informationtheoretic (IT) techniques. IT algorithms were chosen because of their potential to identify similarities and differences without having the requirement of a priori knowledge on an individual. Receiver operating characteristic (ROC) curves were created to select the appropriate decision index, D(Q), values for acceptable true positive and false positive percentages.

Electromagnetic human body modeling with physiological motion for radar applications

Radar has the potential to be used for both therapeutic and diagnostic medical applications, such as vital sign detection. To date, the focus of research in radar medical applications has been predominantly in algorithm development. Improved performance may, however, be achieved through the optimal selection of radar system parameters. In this paper, we present the implementation and validation of electromagnetic human body models for the purpose of selecting application-specific parameters, such as frequency. Higher fidelity in the models leads to valuable physical insight into how the absorption and reflectivity of the human body phantom may be effectively used for vital sign detection. Toward this goal, the validation of two high fidelity models against each other is presented as well as a representative example of vital sign detection modeling.

STAP application in mountainous terrain: Challenges and strategies

This paper describes the results of a study to evaluate ground moving target indication (GMTI) challenges in mountainous terrain and identify new exploitation methods to enhance the capabilities of a nominal X-band radar system. Through simulation and analysis we describe the difficulties inherent in space-time adaptive processing (STAP) GMTI in highly mountainous terrain. We use intermediate performance metrics, such as detection rate and signal-to-interference-plus-noise ratio (SINR) losses over range and Doppler, to identify physical mechanisms leading to STAP inefficiency and characterize the benefits of improvement strategies, such as Power Comparable Training (PCT), a data-dependent training method. The focus of this effort is to understand factors adversely affecting the detection of surface targets, including vehicles and dismounts; document the performance impacts; and, identify a plausible solution space.

Exploitation of radar Doppler signatures for gait analysis

The purpose of this study was to measure radar signal returns to explore if differences in gait patterns of individuals under certain conditions could be exploited from radar Doppler signatures. Abnormalities in gait associated with some forms of concussion as well as other neurological diseases that manifest in the walking gait could be a future avenue for analysis with this methodology. Access to clinically diagnosed concussed individuals was not available during this proof-of-concept study. Instead, based on research that demonstrated a blood alcohol content (BAC) of 0.05% was comparable to concussion impairment, BAC visual impairment goggles were employed. Healthy individuals with and without visually simulated impairment conditions were asked to complete only motor skill tasks and then complete motor skill and cognitive skill tasks simultaneously. These results were analyzed using information theoretic (IT) techniques. IT algorithms were chosen because of their potential to identify similarities and differences without the requirement of any a priori knowledge. Using statistical processing techniques, initial results show that gait anomalies could be quantitatively distinguished between the described conditions.

Parametric extraction of cardiac and respiratory rates from radar measurements of the human body

Cardiac and respiratory motion of the chest cavity, crucial to vital sign detection, has not been considered in the study of electromagnetic (EM) wave interaction with tissues using phantom models commonly found in commercial EM software packages. The volume and physical composition of the tissue layers near the surface change with physiological motion, thereby imparting time dependence to the constitutive parameters. In this paper, we consider a human body phantom model that includes physiological motion and develop a new algorithm based on the state-space method to extract cardiac and respiration rates. The method is applied to simulated data as well as 24 GHz radar measurements on a sedentary subject. It is shown that the state-space method accurately estimates vital signs without producing harmonics and inter-modulation products that plague signal resolution in commonly used auto-correlated FFT spectrograms relying on peak detection.