Development of a wireless ultrasonic brain stimulation system for concurrent bilateral neuromodulation in freely moving rodents.

Bilateral brain stimulation is an important modality used to investigate brain circuits and treat neurological conditions. Recently, low-intensity pulsed ultrasound (LIPUS) received significant attention as a novel non-invasive neurostimulation technique with high spatial specificity. Despite the growing interest, the typical ultrasound brain stimulation study, especially for small animals, is limited to a single target of sonication. The constraint is associated with the complexity and the cost of the hardware system required to achieve multi-regional sonication. This work presented the development of a low-cost LIPUS system with a pair of single-element ultrasound transducers to address the above problem. The system was built with a multicore processor with an RF amplifier circuit. In addition, LIPUS device was incorporated with a wireless module (bluetooth low energy) and powered by a single 3.7 V battery. As a result, we achieved an ultrasound transmission with a central frequency of 380 kHz and a peak-to-peak pressure of 480 kPa from each ultrasound transducer. The developed system was further applied to anesthetized rats to investigate the difference between uni- and bilateral stimulation. A significant difference in cortical power density extracted from electroencephalogram signals was observed between uni- and bilateral LIPUS stimulation. The developed device provides an affordable solution to investigate the effects of LIPUS on functional interhemispheric connection.

Trans-Spinal Focused Ultrasound Stimulation Selectively Modulates Descending Motor Pathway.

Compared to current non-invasive methods utilizing magnetic and electrical means, focused ultrasound provides greater spatial resolution and penetration depth. Despite the broad application of ultrasound stimulation, there is a lack of studies dedicated to the investigation of acoustic neuromodulation on the spinal cord. This study aims to apply focused ultrasound on the spinal cord to modulate the descending pathways in a non-invasive fashion. The application of trans-spinal focused ultrasound (tsFUS) was examined on the motor deficit mouse model. tsFUS was achieved using a single-element focused ultrasound transducer operating at 3 MHz. The sonication was performed on anesthetized 6 week-old mice targeting T12 and L3 vertebrae. The effect was analyzed by comparing electromyography responses from the hindlimb induced by electrical stimulation of the motor cortex. Further, the mouse model with the Harmaline-induced essential tremor (ET) was selected to investigate the potential clinical application of tsFUS. The safety was verified by histological assessment. Sonication at the T12 area inhibited motor response, while sonication over the L3 region provided signal enhancement. Sonication of T12 of the ET mouse also showed the ability of ultrasound to suppress tremors. Meanwhile, the histological examination did not show any abnormalities with the highest applied acoustic pressure. In this work, a non-invasive motor signal modulation was achieved using tsFUS. Moreover, the results showed the ability of focused ultrasound to manage tremors in a safe manner. This study provides a stepping stone for the trans-spinal application of focused ultrasound to motor-related disorders.

Stretchable Surface Electrode Arrays Using an Alginate/PEDOT:PSS-Based Conductive Hydrogel for Conformal Brain Interfacing.

An electrocorticogram (ECoG) is the electrical activity obtainable from the cerebral cortex and an informative source with considerable potential for future advanced applications in various brain-interfacing technologies. Considerable effort has been devoted to developing biocompatible, conformal, soft, and conductive interfacial materials for bridging devices and brain tissue; however, the implementation of brain-adaptive materials with optimized electrical and mechanical characteristics remains challenging. Herein, we present surface electrode arrays using the soft tough ionic conductive hydrogel (STICH). The newly proposed STICH features brain-adaptive softness with Young's modulus of ~9.46 kPa, which is sufficient to form a conformal interface with the cortex. Additionally, the STICH has high toughness of ~36.85 kJ/mm3, highlighting its robustness for maintaining the solid structure during interfacing with wet brain tissue. The stretchable metal electrodes with a wavy pattern printed on the elastomer were coated with the STICH as an interfacial layer, resulting in an improvement of the impedance from 60 kΩ to 10 kΩ at 1 kHz after coating. Acute in vivo experiments for ECoG monitoring were performed in anesthetized rodents, thereby successfully realizing conformal interfacing to the animal's cortex and the sensitive recording of electrical activity using the STICH-coated electrodes, which exhibited a higher visual-evoked potential (VEP) amplitude than that of the control device.

Wearable Transcranial Ultrasound System for Remote Stimulation of Freely Moving Animal.

OBJECTIVE: Transcranial focused ultrasound (tFUS) has drawn considerable attention in the neuroscience field as a noninvasive approach to modulate brain circuits. However, the conventional approach requires the use of anesthetized or immobilized animal models, which places considerable restrictions on behavior and affects treatment. Thus, this work presents a wireless, wearable system to achieve ultrasound brain stimulation in freely behaving animals. METHODS: The wearable tFUS system was developed based on a microcontroller and amplifier circuit. Brain activity induced by tFUS was monitored through cerebral hemodynamic changes using near-infrared spectroscopy. The system was also applied to stroke rehabilitation after temporal middle cerebral artery occlusion (tMCAO) in rats. Temperature calculations and histological results showed the safety of the application even with prolonged 40 min sonication. RESULTS: The output ultrasonic wave produced from a custom PZT transducer had a central frequency of 457 kHz and peak to peak pressure of 426 kPa. The device weight was 20 g, allowing a full range of motion. The stimulation was found to induce hemodynamic changes in the sonicated area, while open-field tests showed that ultrasound applied to the ipsilateral hemisphere for 5 consecutive days after the stroke facilitated recovery. CONCLUSION: The wearable tFUS system has been designed and implemented on moving rats. The results showed the ability of device to cause both short- and long lasting effects. SIGNIFICANCE: The proposed device provides a more natural environment to investigate the effects of tFUS for behavioral and long-term studies.

Neural Dynamics of Olfactory Perception: Low- and High-Frequency Modulations of Local Field Potential Spectra in Mice Revealed by an Oddball Stimulus.

Recent brain connectome studies have evidenced distinct and overlapping brain regions involved in processing olfactory perception. However, neural correlates of hypo- or anosmia in olfactory disorder patients are poorly known. Furthermore, the bottom-up and top-down processing of olfactory perception have not been well-documented, resulting in difficulty in locating the disease foci of olfactory disorder patients. The primary aim of this study is to characterize the bottom-up process of the neural dynamics across peripheral and central brain regions in anesthetized mice. We particularly focused on the neural oscillations of local field potential (LFP) in olfactory epithelium (OE), olfactory blub (OB), prefrontal cortex (PFC), and hippocampus (HC) during an olfactory oddball paradigm in urethane anesthetized mice. Odorant presentations evoked neural oscillations across slow and fast frequency bands including delta (1-4 Hz), theta (6-10 Hz), beta (15-30 Hz), low gamma (30-50 Hz), and high gamma (70-100 Hz) in both peripheral and central nervous systems, and the increases were more prominent in the infrequently presented odorant. During 5 s odorant exposures, the oscillatory responses in power were persistent in OE, OB, and PFC, whereas neural oscillations of HC increased only for short time at stimulus onset. These oscillatory responses in power were insignificant in both peripheral and central regions of the ZnSO4-treated anosmia model. These results suggest that olfactory stimulation induce LFP oscillations both in the peripheral and central nervous systems and suggest the possibility of linkage of LFP oscillations in the brain to the oscillations in the peripheral olfactory system.