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.

The emergence of new ultrasound technologies has improved our understanding of the brain functions and offered new opportunities for the treatment of brain diseases. Ultrasound has become a valuable tool in preclinical animal and clinical studies as it not only provides information about the structure and function of brain tissues but can also be used as a therapy alternative for brain diseases. High-resolution cerebral flow images with high sensitivity can be acquired using novel functional ultrasound and super-resolution ultrasound imaging techniques. The non-invasive treatment of essential tremors has been clinically approved and it has been demonstrated that the ultrasound technology can revolutionize the currently existing treatment methods. Microbubble-mediated ultrasound can remotely open the blood brain barrier enabling targeted drug delivery in the brain. More recently, ultrasound neuromodulation received a great amount of attention due to its non-invasive and deep penetration features and potential therapeutic benefits. This review provides a thorough introduction to the current state-of-the-art research on brain ultrasound and also introduces basic knowledge of brain ultrasound including the acoustic properties of the brain/skull and engineering techniques for ultrasound. Ultrasound is expected to play an increasingly important role in the diagnosis and therapy of brain diseases.

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.

Relaxor-based ferroelectric single crystals Pb(Mg_1/3Nb_2/3)O₃-PbTiO₃ (PMN-PT) have drawn much attention in the ferroelectric field because of their excellent piezoelectric properties and high electromechanical coupling coefficients (d₃₃~2000 pC/N, kt~60%) near the morphotropic phase boundary (MPB). Ternary Pb(In_1/2Nb_1/2)O₃-Pb(Mg_1/3Nb_2/3)O₃-PbTiO₃ (PIN-PMN-PT) single crystals also possess outstanding performance comparable with PMN-PT single crystals, but have higher phase transition temperatures (rhombohedral to tetragonal T_rt, and tetragonal to cubic T_c) and larger coercive field E_c. Therefore, these relaxor-based single crystals have been extensively employed for ultrasonic transducer applications. In this paper, an overview of our work and perspectives on using PMN-PT and PIN-PMN-PT single crystals for ultrasonic transducer applications is presented. Various types of single-element ultrasonic transducers, including endoscopic transducers, intravascular transducers, high-frequency and high-temperature transducers fabricated using the PMN-PT and PIN-PMN-PT crystals and their 2-2 and 1-3 composites are reported. Besides, the fabrication and characterization of the array transducers, such as phased array, cylindrical shaped linear array, high-temperature linear array, radial endoscopic array, and annular array, are also addressed.

A modified Pb(Mg _1/3 Nb _2/3 )O ₃ -PbTiO ₃ (PMN-PT) polycrystalline ceramic with ultrahigh relative clamped dielectric permittivity (ε ^S /ε ₀ = 3500) and high piezoelectric properties (d ₃₃ = 1200 pC/N, k _t = 0.55) was used to fabricate high-frequency miniature ultrasound transducers. A 39-MHz high-frequency ultrasound needle transducer with a miniature aperture of 0.4 mm × 0.4 mm was designed and successfully characterized. The fabricated needle transducer had an electromechanical coupling factor k _t of 0.55, large bandwidth of 80% at -6 dB, and low insertion loss of -13 dB. A wire phantom and porcine eyeball imaging study showed good imaging capability of this needle transducer. The transducer performance was found to be superior to that of other needle transducers with miniature apertures, making this modified PMN-PT ceramic-based needle transducer quite promising for minimally invasive procedures in medical applications.

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.