Miniaturized MR-compatible ultrasound system for real-time monitoring of acoustic effects in mice using high-resolution MRI.

Visualization of focused ultrasound in high spatial and temporal resolution is crucial for accurately and precisely targeting brain regions noninvasively. Magnetic resonance imaging (MRI) is the most widely used noninvasive tool for whole-brain imaging. However, focused ultrasound studies employing high-resolution (> 9.4 T) MRI in small animals are limited by the small size of the radiofrequency (RF) volume coil and the noise sensitivity of the image to external systems such as bulky ultrasound transducers. This technical note reports a miniaturized ultrasound transducer system packaged directly above a mouse brain for monitoring ultrasound-induced effects using high-resolution 9.4 T MRI. Our miniaturized system integrates MR-compatible materials with electromagnetic (EM) noise reduction techniques to demonstrate echo-planar imaging (EPI) signal changes in the mouse brain at various ultrasound acoustic intensities. The proposed ultrasound-MRI system will enable extensive research in the expanding field of ultrasound therapeutics.

Transcranial focused ultrasound stimulation in the infralimbic cortex facilitates extinction of conditioned fear in rats.

Transcranial focused ultrasound (tFUS) neuromodulation emerges as a promising non-invasive approach for improving neurological conditions. Extinction of conditioned fear has served as a prime model for exposure-based therapies for anxiety disorders. We investigated whether tFUS stimulation to a critical brain area, the infralimbic subdivision of the prefrontal cortex (IL), could facilitate fear extinction using rats. In a series of experiments, tFUS was delivered to the IL of a freely-moving rat and compared to sham stimulation (tFUS vs. SHAM). Initially, Fos expression in the IL was measured shortly after the stimulation. The results show that Fos expression was significantly increased in the IL but not in the neighboring regions compared to SHAM. Subsequently, two groups of rats were subjected to fear conditioning, extinction, and retention while receiving stimulation during the extinction. Rats in the tFUS group froze significantly less than SHAM during both extinction and retention tests. Importantly, the reduced freezing in the tFUS group was not attributable to non-specific effect such as auditory noise, as both groups demonstrated a similar level of locomotive activity in an open field regardless of the stimulation condition. Finally, we replicated the procedure with a shortened conditioning-to-extinction interval (15 min) to induce immediate extinction deficit. The tFUS group showed a facilitated reduction in freezing during the extinction, which persisted in the subsequent retention session compared to SHAM. In summary, the current findings suggest that tFUS stimulation in the IL facilitates fear extinction, offering a potential therapeutic regimen for fear-related psychiatric disorders.

Multifocal skull-compensated transcranial focused ultrasound system for neuromodulation applications based on acoustic holography.

Transcranial focused ultrasound stimulation is a promising therapeutic modality for human brain disorders because of its noninvasiveness, long penetration depth, and versatile spatial control capability through beamforming and beam steering. However, the skull presents a major hurdle for successful applications of ultrasound stimulation. Specifically, skull-induced focal aberration limits the capability for accurate and versatile targeting of brain subregions. In addition, there lacks a fully functional preclinical neuromodulation system suitable to conduct behavioral studies. Here, we report a miniature ultrasound system for neuromodulation applications that is capable of highly accurate multiregion targeting based on acoustic holography. Our work includes the design and implementation of an acoustic lens for targeting brain regions with compensation for skull aberration through time-reversal recording and a phase conjugation mirror. Moreover, we utilize MEMS and 3D-printing technology to implement a 0.75-g lightweight neuromodulation system and present in vivo characterization of the packaged system in freely moving mice. This preclinical system is capable of accurately targeting the desired individual or multitude of brain regions, which will enable versatile and explorative behavior studies using ultrasound neuromodulation to facilitate widespread clinical adoption.

A PVT-Robust AFE-Embedded Error-Feedback Noise-Shaping SAR ADC With Chopper-Based Passive High-Pass IIR Filtering for Direct Neural Recording.

This paper presents a PVT-robust error-feedback (EF) noise-shaping SAR (NS-SAR) ADC for direct neural-signal recording. For closed-loop bidirectional neural interfaces enabling the next generation neurological devices, a wide-dynamic-range neural recording circuit is required to accommodate stimulation artifacts. A recording structure using an NS-SAR ADC can be a good candidate because the high resolution and wide dynamic range can be obtained with a low oversampling ratio and power consumption. However, NS-SAR ADCs require an additional gain stage to obtain a well-shaped noise transfer function (NTF), and a dynamic amplifier is often used as the gain stage to minimize power overhead at the cost of vulnerability to PVT variations. To overcome this limitation, the proposed work reutilizes the capacitive-feedback amplifier, which is the analog front-end of the neural recording circuit, as a PVT-robust gain stage to achieve a reliable NS performance. In addition, a new chopper-based implementation of a passive high-pass IIR filter is proposed, achieving an improved NTF compared to prior EF NS-SAR ADCs. Fabricated in a 180-nm CMOS process, the proposed NS-SAR ADC consumes 4.3-µW power and achieves a signal-to-noise-and-distortion ratio (SNDR) of 71.7 dB and 82.7 dB for a bandwidth of 5 kHz and 300 Hz, resulting in a Schreier figure of merit (FOM) of 162.4 dB and 162.1 dB, respectively. Direct neural recording using the proposed NS-SAR ADC is demonstrated successfully in vivo, and also its tolerance against stimulation artifacts is validated in vitro.

General-Purpose Ultrasound Neuromodulation System for Chronic, Closed-Loop Preclinical Studies in Freely Behaving Rodents.

Transcranial focused ultrasound stimulation (tFUS) is an effective noninvasive treatment modality for brain disorders with high clinical potential. However, the therapeutic effects of ultrasound neuromodulation are not widely explored due to limitations in preclinical systems. The current preclinical studies are head-fixed, anesthesia-dependent, and acute, limiting clinical translatability. Here, this work reports a general-purpose ultrasound neuromodulation system for chronic, closed-loop preclinical studies in freely behaving rodents. This work uses microelectromechanical systems (MEMS) technology to design and fabricate a small and lightweight transducer capable of artifact-free stimulation and simultaneous neural recording. Using the general-purpose system, it can be observed that state-dependent ultrasound neuromodulation of the prefrontal cortex increases rapid eye movement (REM) sleep and protects spatial working memory to REM sleep deprivation. The system will allow explorative studies in brain disease therapeutics and neuromodulation using ultrasound stimulation for widespread clinical adoption.

Calcium-Modified Silk Patch as a Next-Generation Ultrasound Coupling Medium.

There is an increasing interest in developing next-generation wearable ultrasound patch systems because of their wide range of applications, such as home healthcare systems and continuous monitoring systems for physiological conditions. A wearable ultrasound patch system requires a stable interface to the skin, an ultrasound coupling medium, a flexible transducer array, and miniaturized operating circuitries. In this study, we proposed a patch composed of calcium (Ca)-modified silk, which serves as both a stable interface and a coupling medium for ultrasound transducer arrays. The Ca-modified silk patch provided not only a stable and conformal interface between the epidermal ultrasound transducer and human skin with high adhesion but also offered acoustic impedance close to that of human skin. The Ca-modified silk patch was flexible and stretchable (∼400% strain) and could be attached to various materials. In addition, because the acoustic impedance of the Ca-modified silk patch was 2.15 MRayl, which was similar to that of human skin (1.99 MRayl), the ultrasound transmission loss of the proposed patch was relatively low (∼0.002 dB). We also verified the use of the Ca-modified silk patch in various ultrasound applications, including ultrasound imaging, ultrasound heating, and transcranial ultrasound stimulation for neuromodulation. The comparable performance of the Ca-modified patch to that of a commercial ultrasound gel and its durability against various environmental conditions confirmed that the Ca-modified silk patch could be a promising candidate as a coupling medium for next-generation ultrasound patch systems.

Transcranial focused ultrasound stimulation with high spatial resolution.

BACKGROUND: Low-intensity transcranial focused ultrasound stimulation is a promising candidate for noninvasive brain stimulation and accurate targeting of brain circuits because of its focusing capability and long penetration depth. However, achieving a sufficiently high spatial resolution to target small animal sub-regions is still challenging, especially in the axial direction. OBJECTIVE: To achieve high axial resolution, we designed a dual-crossed transducer system that achieved high spatial resolution in the axial direction without complex microfabrication, beamforming circuitry, and signal processing. METHODS: High axial resolution was achieved by crossing two ultrasound beams of commercially available piezoelectric curved transducers at the focal length of each transducer. After implementation of the fixture for the dual-crossed transducer system, three sets of in vivo animal experiments were conducted to demonstrate high target specificity of ultrasound neuromodulation using the dual-crossed transducer system (n = 38). RESULTS: The full-width at half maximum (FWHM) focal volume of our dual-crossed transducer system was under 0.52 µm3. We report a focal diameter in both lateral and axial directions of 1 mm. To demonstrate successful in vivo brain stimulation of wild-type mice, we observed the movement of the forepaws. In addition, we targeted the habenula and verified the high spatial specificity of our dual-crossed transducer system. CONCLUSIONS: Our results demonstrate the ability of the dual-crossed transducer system to target highly specific regions of mice brains using ultrasound stimulation. The proposed system is a valuable tool to study the complex neurological circuitry of the brain noninvasively.