Guofeng Li

Improved Anatomical Specificity of Non-invasive Neuro-stimulation by High Frequency (5 MHz) Ultrasound.

Low frequency ultrasound (<1 MHz) has been demonstrated to be a promising approach for non-invasive neuro-stimulation. However, the focal width is limited to be half centimeter scale. Minimizing the stimulation region with higher frequency ultrasound will provide a great opportunity to expand its application. This study first time examines the feasibility of using high frequency (5 MHz) ultrasound to achieve neuro-stimulation in brain, and verifies the anatomical specificity of neuro-stimulation in vivo. 1 MHz and 5 MHz ultrasound stimulation were evaluated in the same group of mice. Electromyography (EMG) collected from tail muscles together with the motion response videos were analyzed for evaluating the stimulation effects. Our results indicate that 5 MHz ultrasound can successfully achieve neuro-stimulation. The equivalent diameter (ED) of the stimulation region with 5 MHz ultrasound (0.29 ± 0.08 mm) is significantly smaller than that with 1 MHz (0.83 ± 0.11 mm). The response latency of 5 MHz ultrasound (45 ± 31 ms) is also shorter than that of 1 MHz ultrasound (208 ± 111 ms). Consequently, high frequency (5 MHz) ultrasound can successfully activate the brain circuits in mice. It provides a smaller stimulation region, which offers improved anatomical specificity for neuro-stimulation in a non-invasive manner.

A Novel Modulated Excitation Imaging System for Microultrasound

Microultrasound (micro-US), also known as ultrasound biomicroscope, is able to delineate small structures with fine spatial resolution. However, micro-US suffers limited depth of penetration due to significantly large attenuation at high frequencies. Modulated excitation imaging has displayed the capability to improve the penetration depth, while maintaining the spatial resolution. But the effectiveness of this technique in micro-US has not been fully demonstrated. In addition, the current modulated excitation imaging systems for micro-US are designed for specific excitation method, therefore, lack of flexibility, and are typically bulky and expensive. This paper presents the development of a novel system to achieve modulated excitation imaging with high programmability and flexibility to satisfy various micro-US studies. It incorporates a high-voltage arbitrary waveform generator for producing desired excitation waveform, and a programmable imaging receiver implemented by the state-of-the-art electronics and field-programmable gate array. Test results show that the proposed modulated excitation imaging system can acquire up to 20 dB signal-to-noise ratio improvement and 83% increase of penetration depth in contrast to traditional short-pulse imaging method. In vivo experiment on the dorsal skin of a human hand demonstrates good performance of the programmable modulated excitation imaging system.

Noninvasive Ultrasonic Neuromodulation in Freely Moving Mice

Neuromodulation is a fundamental method for obtaining basic information about neuronal circuits for use in treatments for neurological and psychiatric disorders. Ultrasound stimulation has become a promising approach for noninvasively inducing neuromodulation in animals and humans. However, the previous investigations were subject to substantial limitations, due to most of them involving anesthetized and fixed small-animal models. Studies of awake and freely moving animals are needed, but the currently used ultrasound devices are too bulky to be applied to a freely moving animal. This study is the first time to design and fabricate a miniature and lightweight head-mounted ultrasound stimulator for inducing neuromodulation in freely moving mice. The main components of the stimulator include a miniature piezoelectric ceramic, a concave epoxy acoustic lens, and housing and connection components. The device was able to induce action potentials recorded in situ and evoke head-turning behaviors by stimulating the primary somatosensory cortex barrel field of the mouse. These findings indicate that the proposed method can be used to induce noninvasive neuromodulation in freely moving mice. This novel method could potentially lead to the application of ultrasonic neuromodulation in more-extensive neuroscience investigations.

A Portable Ultrasound System for Non-Invasive Ultrasonic Neuro-Stimulation

Fundamental insights into the function of the neural circuits often follows from the advances in methodologies and tools for neuroscience. Electrode- and optical- based stimulation methods have been used widely for neuro-modulation with high resolution. However, they are suffering from inherent invasive surgical procedure. Ultrasound has been proved as a promising technology for neuro-stimulation in a non-invasive manner. However, no portable ultrasound system has been developed particularly for neuro-stimulation. The utilities used currently are assembled by traditional functional generator, power amplifier, and general transducer, therefore, resulting in lack of flexibility. This paper presents a portable system to achieve ultrasonic neuro-stimulation to satisfy various studies. The system incorporated a high voltage waveform generator and a matching circuit that were optimized for neuro-stimulation. A new switching mode power amplifier was designed and fabricated. The noise generated by the power amplifier was reduced (about 30 dB), and the size and weight were smaller in contrast with commercial equipment. In addition, a miniaturized ultrasound transducer was fabricated using Pb(Mg1/3Nb2/3)O3-PbTiO3(PMN-PT) 1–3 composite single crystal for the improved ultrasonic performance. The spatial peak temporal average pressure was higher than 250 kPa in the range of 0.5–5 MHz. In vitro and in vivo studies were conducted to show the performance of the system.

Local field potentials responses of ultrasonic neuromodulation in freely moving mouse

Ultrasound (US) brain stimulation has been demonstrated to be a promising approach for noninvasive neuromodulation. However, traditional methods always demand animals to be under anesthesia and body constraint to achieve stable operation with bulky US transducer, while those demands would result in interference to the neural activity related to perception, cognition, and behavior. Appling a miniature US stimulator in freely moving mouse will greatly benefit for obtaining credible neural response from brain modulation. This study investigates the local field potentials (LFPs) responses of ultrasonic neuromodulation on freely moving mouse with a customized head-mounted US transducer. The stimulator mainly consist of a tiny piezoelectric ceramic, a concave epoxy acoustic lens, and some affiliated accessories for housing and connecting. The decrease of power spectral density at theta band and increase of power at delta band of local field potentials, indicate that the proposed head-mounted ultrasound stimulator can perform noninvasive neuromodulation on freely moving mouse. The proposed head-mounted US device could potentially promote the development of ultrasonic neuromodulation to more extensive neuroscience studies.

A programmable ultrasound platform for multi-gate Doppler measurement

Noninvasive visualization of blood flow with high frequency Doppler ultrasound has been extensively used to assess the morphology and hemodynamics of the microcirculation. A completely digital implementation of multi-gate pulsed-wave (PW) Doppler method was proposed in this paper for high frequency ultrasound applications. Analog mixer was eliminated by a digital demodulator and same data acquisition path was shared with traditional B-mode imaging which made the design compact and flexible. Hilbert transform based quadrature demodulation scheme was employed to achieve the multi-gate Doppler acquisition. Parabolic velocity gradient inside the vessel phantom and velocity profile with different time slots were acquired to demonstrate the functionality of the multi-gate Doppler.

Temporal Neuromodulation of Retinal Ganglion Cells by Low-Frequency Focused Ultrasound Stimulation

Significant progress has been made recently in treating neurological blindness using implantable visual prostheses. However, implantable medical devices are highly invasive and subject to many safety, efficacy, and cost issues. The discovery that ultrasound (US) may be useful as a noninvasive neuromodulation tool has aroused great interest in the field of acoustic retinal prostheses (ARPs). We have investigated the responsiveness of rat retinal ganglion cells (RGCs) to low-frequency focused US stimulation (LFUS) at 2.25 MHz and characterized the neurophysiological properties of US responses by performing in vitro multielectrode array recordings. The results show that LFUS can reliably activate RGCs. The US-induced responses did not correspond to the standard light responses and varied greatly among cell types. Moreover, dual-peak responses to US stimulation were observed that have not been reported previously. The temporal response properties of RGCs, including their latency, firing rate, and response type, were modulated by the acoustic intensity. These findings suggest the presence of a temporal neuromodulation effect of LFUS and potentially open a new avenue in the development of ARP.

Local field potentials responses to ultrasonic neuromodulaton on freely moving mouse

Ultrasound (US) brain stimulation has been demonstrated to be a promising approach for noninvasive neuromodulation. However, traditional methods always demand animals to be under anesthesia and body constraint to achieve stable operation with bulky US transducer, while those demands would result in interference to the neural activity related to perception, cognition, and behavior. Appling a miniature US stimulator on freely moving mouse will greatly benefit for obtaining credible neural response from ultrasonic neuromodulation. This study investigates the local field potentials (LFPs) responses to ultrasonic neuromodulation on freely moving mouse by using a customized head-mounted US transducer.

Retina stimulation on rat in vivo with low-frequency ultrasound

More and more researches are exploring the neurostimulation effect of ultrasound (US) on the central nervous system (e.g. brain and retina) and the peripheral nervous system (such as skin). US stimulation has been regarded as a new noninvasive neurostimulation approach by many researchers. Our previous studies had shown that the temporal response patterns of RGCs could be stimulated by US in vitro. In this article, we apply low-frequency (2.25 MHz) focused US stimulation to the rat retina in vivo to investigate the effect on the primary visual cortex.

Simulation Study of an Ultrasound Retinal Prosthesis With a Novel Contact-Lens Array for Noninvasive Retinal Stimulation

Millions of people around the world suffer from varying degrees of vision loss (including complete blindness) because of retinal degenerative diseases. Artificial retinal prosthesis, which is usually based on electrical neurostimulation, is the most advanced technology for different types of retinal degeneration. However, this technology involves placing a device into the eyeball, and such a highly invasive procedure is inevitably highly risk and expensive. Ultrasound has been demonstrated to be a promising technology for noninvasive neurostimulation, making it possible to stimulate the retina and induce action potentials similar to those elicited by light stimulation. However, the technology of ultrasound retinal stimulation still requires considerable developments before it could be applied clinically. This paper proposes a novel contact-lens array transducer for use in an ultrasound retinal prosthesis (USRP). The transducer was designed in the shape of a contact lens so as to facilitate acoustic coupling with the eye liquid. The key parameters of the ultrasound transducer were simulated, and results are presented that indicate the achievement of 2-D pattern generation and that the proposed contact-lens array is suitable for multiple-focus neurostimulation, and can be used in a USRP.