Super-resolution techniques for biomedical applications and challenges.

Super-resolution (SR) techniques have revolutionized the field of biomedical applications by detailing the structures at resolutions beyond the limits of imaging or measuring tools. These techniques have been applied in various biomedical applications, including microscopy, magnetic resonance imaging (MRI), computed tomography (CT), X-ray, electroencephalogram (EEG), ultrasound, etc. SR methods are categorized into two main types: traditional non-learning-based methods and modern learning-based approaches. In both applications, SR methodologies have been effectively utilized on biomedical images, enhancing the visualization of complex biological structures. Additionally, these methods have been employed on biomedical data, leading to improvements in computational precision and efficiency for biomedical simulations. The use of SR techniques has resulted in more detailed and accurate analyses in diagnostics and research, essential for early disease detection and treatment planning. However, challenges such as computational demands, data interpretation complexities, and the lack of unified high-quality data persist. The article emphasizes these issues, underscoring the need for ongoing development in SR technologies to further improve biomedical research and patient care outcomes.

tFUSFormer: Physics-guided super-resolution Transformer for simulation of transcranial focused ultrasound propagation in brain stimulation.

Transcranial focused ultrasound (tFUS) has emerged as a new mode of non-invasive brain stimulation (NIBS), with its exquisite spatial precision and capacity to reach the deep regions of the brain. The placement of the acoustic focus onto the desired part of the brain is critical for successful tFUS procedures; however, acoustic wave propagation is severely affected by the skull, distorting the focal location/shape and the pressure level. High-resolution (HR) numerical simulation allows for monitoring of acoustic pressure within the skull but with a considerable computational burden. To address this challenge, we employed a 4x super-resolution (SR) Swin Transformer method to improve the precision of estimating tFUS acoustic pressure field, targeting operator-defined brain areas. The training datasets were obtained through numerical simulations at both ultra-low (2.0 mm) and high (0.5 mm) resolutions, conducted on in vivo CT images of 12 human skulls. Our multivariable datasets, which incorporate physical properties of the acoustic pressure field, wave velocity, and skull CT images, were utilized to train three-dimensional SR models. We found that our method yielded 87.99?4.28% accuracy in terms of focal volume conformity under foreseen skull data, and accuracy of 82.32?5.83% for unforeseen skulls, respectively. Moreover, a significant improvement of 99.4% in computational efficiency compared to the traditional 0.5 mm HR numerical simulation was shown. The presented technique, when adopted in guiding the placement of the FUS transducer to engage specific brain targets, holds great potential in enhancing the safety and effectiveness of tFUS therapy.

Non-invasive enhancement of intracortical solute clearance using transcranial focused ultrasound.

Transport of interstitial fluid and solutes plays a critical role in clearing metabolic waste from the brain. Transcranial application of focused ultrasound (FUS) has been shown to promote localized cerebrospinal fluid solute uptake into the brain parenchyma; however, its effects on the transport and clearance of interstitial solutes remain unknown. We demonstrate that pulsed application of low-intensity FUS to the rat brain enhances the transport of intracortically injected fluorescent tracers (ovalbumin and high molecular-weight dextran), yielding greater parenchymal tracer volume distribution compared to the unsonicated control group (ovalbumin by 40.1% and dextran by 34.6%). Furthermore, FUS promoted the drainage of injected interstitial ovalbumin to both superficial and deep cervical lymph nodes (cLNs) ipsilateral to sonication, with 78.3% higher drainage observed in the superficial cLNs compared to the non-sonicated hemisphere. The application of FUS increased the level of solute transport visible from the dorsal brain surface, with ~ 43% greater area and ~ 19% higher fluorescence intensity than the unsonicated group, especially in the pial surface ipsilateral to sonication. The sonication did not elicit tissue-level neuronal excitation, measured by an electroencephalogram, nor did it alter the molecular weight of the tracers. These findings suggest that nonthermal transcranial FUS can enhance advective transport of interstitial solutes and their subsequent removal in a completely non-invasive fashion, offering its potential non-pharmacological utility in facilitating clearance of waste from the brain.

Global sonication of the human intracranial space via a jumbo planar transducer.

Contrary to conditioning a Focused Ultrasound (FUS) beam to sonicate a localized region of the human brain, the goal of this investigation was to explore the prospect of distributing homogeneous ultrasound energy over the entire brain space with a large cranium-wide ultrasound beam. Recent ultrasound preclincal studies utilizing large or whole brain stimulation regions create a demand for expanding the treatment envelope of transcranial pulsed-low intensity ultrasound towards Global Brain Sonication (GBS) for potential human investigation. Here, we conduct ultrasound field characterizations when transmitting pulsed ultrasound through human skull specimens using a 1-3 piezocomposite planar transducer operating at 464 kHz with an active single-element surface of 30 × 30 cm. Through computational simulation and hydrophone scanning methodology, ultrasound wave behavior and dose homogeneity in the brain space were evaluated under various trajectories of sonication using the planar transducer. Clinically relevant pulse parameters used for transcranial therapeutic ultrasound applications were used in the experiments. Simulations and empirical testing revealed that dose homogeneity and acoustic intensity over the brain space are influenced by sonication trajectory, skull lens effects, and acoustic wave reflections. The transducer can emit a spatial peak pulse average intensity of 4.03 W/cm2 (0.24 MPa) measured in the free-field at 464 kHz with electrical power of 1 kW. The simulation showed that approximately 99 % of the cranial volume was exposed with <30 % of the maximum external acoustic intensity being transmitted into the skull. The transmission loss across all sonication trajectories is similar to previously reported FUS studies. A marker for GBS dose homogeneity is introduced to score the ultrasound pressure field uniformity in the intracranial space. Results of this study identify the initial challenges of exposing the entire human brain space with ultrasound using a large cranium-wide sonication beam intended for global brain therapeutic modulation.

Aging Property of Halide Solid Electrolyte at the Cathode Interface.

Halide solid electrolytes have recently emerged as a promising option for cathode-compatible catholytes in solid-state batteries (SSBs), owing to their superior oxidation stability at high voltage and their interfacial stability. However, their day- to month-scale aging at the cathode interface has remained unexplored until now, while its elucidation is indispensable for practical deployment. Herein, the stability of halide solid electrolytes (e.g., Li3 InCl6 ) when used with conventional layered oxide cathodes during extended calendar aging is investigated. It is found that, contrary to their well-known oxidation stability, halide solid electrolytes can be vulnerable to reductive side reactions with oxide cathodes (e.g., LiNi0.8 Co0.1 Mn0.1 O2 ) in the long term. More importantly, the calendar aging at a low state of charge or as-fabricated state causes more significant degradation than at a high state of charge, in contrast to typical lithium-ion batteries, which are more susceptible to high-state-of-charge calendar aging. This unique characteristic of halide-based SSBs is related to the reduction propensity of metal ions in halide solid electrolytes and correlated to the formation of an interphase due to the reductive decomposition triggered by the oxide cathode in a lithiated state. This understanding of the long-term aging properties provides new guidelines for the development of cathode-compatible halide solid electrolytes.

Multivariable-incorporating super-resolution residual network for transcranial focused ultrasound simulation.

BACKGROUND AND OBJECTIVE: Transcranial focused ultrasound (tFUS) has emerged as a new non-invasive brain stimulation (NIBS) modality, with its exquisite ability to reach deep brain areas at a high spatial resolution. Accurate placement of an acoustic focus to a target region of the brain is crucial during tFUS treatment; however, the distortion of acoustic wave propagation through the intact skull casts challenges. High-resolution numerical simulation allows for monitoring of the acoustic pressure field in the cranium but also demands extensive computational loads. In this study, we adopt a super-resolution residual network technique based on a deep convolution to enhance the prediction quality of the FUS acoustic pressure field in the targeted brain regions. METHODS: The training dataset was acquired by numerical simulations performed at low-(1.0 mm) and high-resolutions (0.5mm) on three ex vivo human calvariae. Five different super-resolution (SR) network models were trained by using a multivariable dataset in 3D, which incorporated information on the acoustic pressure field, wave velocity, and localized skull computed tomography (CT) images. RESULTS: The accuracy of 80.87±4.50% in predicting the focal volume with a substantial improvement of 86.91% in computational cost compared to the conventional high-resolution numerical simulation was achieved. The results suggest that the method can greatly reduce the simulation time without sacrificing accuracy and improve the accuracy further with the use of additional inputs. CONCLUSIONS: In this research, we developed multivariable-incorporating SR neural networks for transcranial focused ultrasound simulation. Our super-resolution technique may contribute to promoting the safety and efficacy of tFUS-mediated NIBS by providing on-site feedback information on the intracranial pressure field to the operator.

Deep Neural Network for Navigation of a Single-Element Transducer During Transcranial Focused Ultrasound Therapy: Proof of Concept.

Transcranial focused ultrasound (tFUS) has gained attention in the field of brain stimulation owing to its non-invasive neurotherapeutic potentials. However, complex interactions between acoustic waves and the cranium may introduce misalignment of the acoustic focus from a geometric target location, thus, necessitate on-site feedback of real-time navigational information of the transducer (spatial coordinates and angular orientation) for the operators to accurately place the acoustic focus to the desired brain area. In this study, we propose a deep-learning-based network model that can provide spatial navigational information of a single-element FUS transducer with respect to the targeted brain region. The training dataset were acquired through forward simulations that reflect the different tFUS transmissions for each skull structure using cranial computed tomography (CT) image data. The performance of the network was evaluated through three ex vivo calvaria. As a result show that the presented neural network-based method can an accurately navigate the FUS transducer with the conformity of ∼99.59% in placement of the transducer and ∼74.49% in the focal volume and an average difference of ∼0.96 mm in the focal point, all capable of real-time operation (∼10 ms).

Enhancement of cerebrospinal fluid tracer movement by the application of pulsed transcranial focused ultrasound.

Efficient transport of solutes in the cerebrospinal fluid (CSF) plays a critical role in their clearance from the brain. Convective bulk flow of solutes in the CSF in the perivascular space (PVS) is considered one of the important mechanisms behind solute movement in the brain, before their ultimate drainage to the systemic lymphatic system. Acoustic pressure waves can impose radiation force on a medium in its path, inducing localized and directional fluidic flow, known as acoustic streaming. We transcranially applied low-intensity focused ultrasound (FUS) to rats that received an intracisternal injection of fluorescent CSF tracers (dextran and ovalbumin, having two different molecular weights-Mw). The sonication pulsing parameter was determined on the set that propelled the aqueous solution of toluidine blue O dye into a porous media (melamine foam) at the highest level of infiltration. Fluorescence imaging of the brain showed that application of FUS increased the uptake of ovalbumin at the sonicated plane, particularly around the ventricles, whereas the uptake of high-Mw dextran was unaffected. Numerical simulation showed that the effects of sonication were non-thermal. Sonication did not alter the animals' behavior or disrupt the blood-brain barrier (BBB) while yielding normal brain histology. The results suggest that FUS may serve as a new non-invasive means to promote interstitial CSF solute transport in a region-specific manner without disrupting the BBB, providing potential for enhanced clearance of waste products from the brain.

Design of a lithiophilic and electron-blocking interlayer for dendrite-free lithium-metal solid-state batteries.

All-solid-state batteries are a potential game changer in the energy storage market; however, their practical employment has been hampered by premature short circuits caused by the lithium dendritic growth through the solid electrolyte. Here, we demonstrate that a rational layer-by-layer strategy using a lithiophilic and electron-blocking multilayer can substantially enhance the performance/stability of the system by effectively blocking the electron leakage and maintaining low electronic conductivity even at high temperature (60°C) or under high electric field (3 V) while sustaining low interfacial resistance (13.4 ohm cm2). It subsequently results in a homogeneous lithium plating/stripping, thereby aiding in achieving one of the highest critical current densities (~3.1 mA cm-2) at 60°C in a symmetric cell. A full cell paired with a commercial-level cathode exhibits exceptionally long durability (>3000 cycles) and coulombic efficiency (99.96%) at a high current density (2 C; ~1.0 mA cm-2), which records the highest performance among all-solid-state lithium metal batteries reported to date.

Differential evolution method to find optimal location of a single-element transducer for transcranial focused ultrasound therapy.

BACKGROUND AND OBJECTIVE: Focused ultrasound (FUS) has been receiving growing attention as a noninvasive brain stimulation tool because of its superior spatial specificity and depth penetrability. However, the large mismatch of acoustic properties between the skull and water can disrupt and shift the acoustic focus in the brain. In this paper, we present a numerical method to find the optimal location of a single-element FUS transducer, which creates focus on the target region. METHODS: The score function, representing the superposition of acoustic waves according to the relative phase difference and transmissibility, was defined based on time-reversal invariance of acoustic waves and depending on the spatial location of the transducer. The optimal location of the transducer was then determined using a differential evolution algorithm. To assess the proposed method, we conducted a forward simulation and compared the resulting focal location to the desired target point. We also performed experimental validation by measuring the acoustic pressure field through an ex vivo human skull in a water tank. RESULTS: The numerical results indicated that the score function had a positive proportional relationship with the acoustic pressure at the target. Moreover, for the optimized transducer location, both the numerical and experimental results showed that the normalized acoustic pressure at the target was higher than 0.9. CONCLUSIONS: In this study, we developed an optimization method to place a single-element transducer that effectively transmits acoustic energy to the targeted region in the brain. Our numerical and experimental results demonstrate that the proposed method can provide an optimal transducer location for safe and efficient FUS treatment.

High-energy and durable lithium metal batteries using garnet-type solid electrolytes with tailored lithium-metal compatibility.

Lithium metal batteries using solid electrolytes are considered to be the next-generation lithium batteries due to their enhanced energy density and safety. However, interfacial instabilities between Li-metal and solid electrolytes limit their implementation in practical batteries. Herein, Li-metal batteries using tailored garnet-type Li7-xLa3-aZr2-bO12 (LLZO) solid electrolytes is reported, which shows remarkable stability and energy density, meeting the lifespan requirements of commercial applications. We demonstrate that the compatibility between LLZO and lithium metal is crucial for long-term stability, which is accomplished by bulk dopant regulating and dopant-specific interfacial treatment using protonation/etching. An all-solid-state with 5 mAh cm-2 cathode delivers a cumulative capacity of over 4000 mAh cm-2 at 3 mA cm-2, which to the best of our knowledge, is the highest cycling parameter reported for Li-metal batteries with LLZOs. These findings are expected to promote the development of solid-state Li-metal batteries by highlighting the efficacy of the coupled bulk and interface doping of solid electrolytes.

Feasibility of Upper Cranial Nerve Sonication in Human Application via Neuronavigated Single-Element Pulsed Focused Ultrasound.

Sonicating deep brain regions with pulsed focused ultrasound using magnetic resonance imaging-guided neuronavigation single-element piezoelectric transducers is a new area of exploration for neuromodulation. Upper cranial nerves such as the trigeminal nerve and other nerves responsible for sensory/motor functions in the head may be potential targets for ultrasound pain therapy. The location of upper cranial nerves close to the skull base poses additional challenges when compared with conventional cortical or middle brain targets. In the work described here, a series of computational and empirical testing methods using human skull specimens were conducted to assess the feasibility of sonicating the trigeminal pathway near the sphenoid bone region. The results indicate a transducer with a focal length of 120 mm and diameter of 85 mm (350 kHz) can deliver sonication to upper cranial nerve regions with spatial accuracy comparable to that of focused ultrasound brain targets used in previous human studies. Temperature measurements in cortical bone and in the skull base with embedded thermocouples yield evidence of minimal bone heating. Conventional pulse parameters were found to cause reverberation interference patterns near the cranial floor; therefore, changes in pulse cycles and pulse repetition frequency were examined for reducing standing waves. Limitations and considerations for conducting ultradeep focal targeting in human applications are discussed.

Challenges and Strategies towards Practically Feasible Solid-State Lithium Metal Batteries.

Remarkable improvement of the ionic conductivity of inorganic solid electrolytes (SEs) exceeding 10 mS cm-1 at room temperature has opened up the opportunities to realize the commercialization of solid-state batteries (SSBs). The transition to the intrinsically inflammable SEs also promises that SSBs would successfully utilize lithium metal anode thus achieving the high-energy-density lithium metal batteries without the risk of a safety hazard. However, the practical operation of solid-state lithium metal batteries (SSLMBs) still faces the challenges of the poor cycle stability and the low energy efficiency, which are coupled with the interface stability and even with the dendrite growth of lithium metal. This article overviews current understandings regarding the underlying origins of the issues in employing the lithium metal anode in SSLMBs from the five main standpoints: i) the chemical/electrochemical interfacial stability, ii) the microscopic evolution of interfacial morphology, iii) the intrinsic diffusivity of lithium atom/vacancy at the interface, iv) imperfections (defect/pores), and v) non-negligible electronic conductivity of SEs. The discussions are followed on the state-of-the-art efforts and strategies to overcome these respective challenges. Finally, the authors provide their perspectives for the future research directions toward achieving the commercial level of high-energy SSLMBs.

Transcutaneous application of ultrasound enhances the effects of finasteride in a murine model of androgenic alopecia.

PURPOSE: The purpose of this study was to evaluate if transcutaneous application of low-intensity ultrasound can locally enhance the effects of finasteride on hair growth in a murine model of androgenic alopecia (AA). METHODS: AA mice (injected twice per week with testosterone enanthate, n=11), under daily oral administration of finasteride, received 1-MHz ultrasound for 1 hour at the unilateral thigh area five times per week for 5 weeks. Non-thermal and non-cavitational ultrasound was delivered in a pulsed manner (55-ms pulse duration with a repetition frequency of 4 Hz). Skin temperature was measured during sonication, and the measurements were validated with numerical simulations of sonication-induced tissue temperature changes. Hair growth was assessed both photographically and histologically. RESULTS: We found more hair growth on the sonicated thigh area than on the unsonicated thigh, beginning from week 3 through the end of the experiment. Histological analyses showed that the number of hair follicles doubled in the skin sections that received sonication compared to the unsonicated zone, with thicker follicular diameter and skin. An over five-fold increase was also observed in the anagen/telogen ratio in the sonicated area, suggesting an enhanced anagen phase. Skin temperature was unaltered by the administered sonication. CONCLUSION: The findings of the present study suggest that pulsed application of ultrasound promotes hair growth, potentially by disrupting the binding of albumin to finasteride. This may suggest further applications to enhance the pharmacological effects of other relevant drugs exhibiting high plasma protein binding.

Transcranial focused ultrasound modulates cortical and thalamic motor activity in awake sheep.

Transcranial application of pulsed low-intensity focused ultrasound (FUS) modulates the excitability of region-specific brain areas, and anesthetic confounders on brain activity warrant the evaluation of the technique in awake animals. We examined the neuromodulatory effects of FUS in unanesthetized sheep by developing a custom-fit headgear capable of reproducibly placing an acoustic focus on the unilateral motor cortex (M1) and corresponding thalamic area. The efferent responses to sonication, based on the acoustic parameters previously identified in anesthetized sheep, were measured using electromyography (EMG) from both hind limbs across three experimental conditions: on-target sonication, off-target sonication, and without sonication. Excitatory sonication yielded greater amplitude of EMG signals obtained from the hind limb contralateral to sonication than that from the ipsilateral limb. Spurious appearance of motion-related EMG signals limited the amount of analyzed data (~ 10% selection of acquired data) during excitatory sonication, and the averaged EMG response rates elicited by the M1 and thalamic stimulations were 7.5 ± 1.4% and 6.7 ± 1.5%, respectively. Suppressive sonication, while sheep walked on the treadmill, temporarily reduced the EMG amplitude from the limb contralateral to sonication. No significant change was found in the EMG amplitudes during the off-target sonication. Behavioral observation throughout the study and histological analysis showed no sign of brain tissue damage caused by the acoustic stimulation. Marginal response rates observed during excitatory sonication call for technical refinement to reduce motion artifacts during EMG acquisitions as well as acoustic aberration correction schemes to improve spatial accuracy of sonication. Yet, our results indicate that low-intensity FUS modulated the excitability of regional brain tissues reversibly and safely in awake sheep, supporting its potential in theragnostic applications.

Focused ultrasound enhances the anesthetic effects of topical lidocaine in rats.

BACKGROUND: High-intensity ultrasound has been used to induce acoustic cavitation in the skin and subsequently enhances skin permeability to deliver hydrophobic topical medications including lidocaine. In contrast, instead of changing skin permeability, pulsed application of low-intensity focused ultrasound (FUS) has shown to non-invasively and temporarily disrupt drug-plasma protein binding, thus has potential to enhance the anesthetic effects of hydrophilic lidocaine hydrochloride through unbinding it from serum/interstitial α1-acid glycoprotein (AAG). METHODS: FUS, operating at fundamental frequency of 500 kHz, was applied pulse-mode (55-ms pulse duration, 4-Hz pulse repetition frequency) at a spatial-peak pulse-average intensity of 5 W/cm2. In vitro equilibrium dialysis was performed to measure the unbound concentration of lidocaine (lidocaine hydrochloride) from dialysis cassettes, one located at the sonication focus and the other outside the sonication path, all immersed in phosphate-buffered saline solution containing both lidocaine (10 µg/mL) and human AAG (5 mg/mL). In subsequent animal experiments (Sprague-Dawley rats, n = 10), somatosensory evoked potential (SSEP), elicited by electrical stimulations to the unilateral hind leg, was measured under three experimental conditions-applications of FUS to the unilateral thigh area at the site of administered topical lidocaine, FUS only, and lidocaine only. Skin temperature was measured before and after sonication. Passive cavitation detection was also performed during sonication to evaluate the presence of FUS-induced cavitation. RESULTS: Sonication increased the unbound lidocaine concentration (8.7 ± 3.3 %) from the dialysis cassette, compared to that measured outside the sonication path (P < 0.001). Application of FUS alone did not alter the SSEP while administration of lidocaine reduced its P23 component (i.e., a positive peak at 23 ms latency). The FUS combined with lidocaine resulted in a further reduction of the P23 component (in a range of 21.8 - 23.4 ms after the electrical stimulations; F(2,27) = 3.2 - 4.0, P < 0.05), indicative of the enhanced anesthetic effect of the lidocaine. Administration of FUS neither induced cavitation nor altered skin conductance or temperature, suggesting that skin permeability was unaffected. CONCLUSIONS: Unbinding lidocaine from the plasma proteins by exposure to non-thermal low-intensity ultrasound is attributed as the main mechanism behind the observation.

Computational and Histological Analyses for Investigating Mechanical Interaction of Thermally Drawn Fiber Implants with Brain Tissue.

The development of a compliant neural probe is necessary to achieve chronic implantation with minimal signal loss. Although fiber-based neural probes fabricated by the thermal drawing process have been proposed as a solution, their long-term effect on the brain has not been thoroughly investigated. Here, we examined the mechanical interaction of thermally drawn fiber implants with neural tissue through computational and histological analyses. Specifically, finite element analysis and immunohistochemistry were conducted to evaluate the biocompatibility of various fiber implants made with different base materials (steel, silica, polycarbonate, and hydrogel). Moreover, the effects of the coefficient of friction and geometric factors including aspect ratio and the shape of the cross-section on the strain were investigated with the finite element model. As a result, we observed that the fiber implants fabricated with extremely softer material such as hydrogel exhibited significantly lower strain distribution and elicited a reduced immune response. In addition, the implants with higher coefficient of friction (COF) and/or circular cross-sections showed a lower strain distribution and smaller critical volume. This work suggests the materials and design factors that need to be carefully considered to develop future fiber-based neural probes to minimize mechanical invasiveness.

Localized Disruption of Blood Albumin-Phenytoin Binding Using Transcranial Focused Ultrasound.

Plasma protein binding (PPB) plays an important role in drug pharmacokinetics, particularly for central nervous system drugs, as PPB affects the blood concentration of unbound drug available to cross the blood-brain barrier (BBB). We report the non-invasive, spatially specific disruption of PPB to phenytoin, an anti-epileptic drug with high affinity to albumin, using 250-kHz focused ultrasound (FUS) delivered in a pulsed manner (55-ms tone burst duration, 4-Hz pulse repetitions). Equilibrium dialysis performed on sonicated phosphate-buffered saline solution containing phenytoin and bovine serum albumin revealed a 27.7% elevation in the unbound phenytoin concentration compared with an unsonicated control. Sonication of a unilateral brain hemisphere in rats (n = 10) after intraperitoneal phenytoin injection revealed increased parenchymal phenytoin uptake compared with the unsonicated hemisphere, without evidence of temperature change or BBB disruption. These findings illustrate the use of FUS as a novel technique for spatially selective disruption of PPB, which may be applied to a wide range of drug-plasma protein interactions.

Therapeutic Potentials of Localized Blood-Brain Barrier Disruption by Noninvasive Transcranial Focused Ultrasound: A Technical Review.

The demands for region-specific, noninvasive therapies for neurologic/psychiatric conditions are growing. The rise of transcranial focused ultrasound technology has witnessed temporary and reversible disruptions of the blood-brain barrier in the brain with exceptional control over the spatial precisions and depth, all in a noninvasive manner. Starting with small animal studies about a decade ago, the technique is now being explored in nonhuman primates and humans for the assessment of its efficacy and safety. The ability to transfer exogenous/endogenous therapeutic agents, cells, and biomolecules across the blood-brain barrier opens up new therapeutic avenues for various neurologic conditions, with a possibility to modulate the excitability of regional brain function. This review addresses the technical fundamentals, sonication parameters, experimental protocols, and monitoring techniques to examine the efficacy/safety in focused ultrasound-mediated blood-brain barrier disruption and discuss its potential translations to clinical use.

Effects of sonication parameters on transcranial focused ultrasound brain stimulation in an ovine model.

Low-intensity focused ultrasound (FUS) has significant potential as a non-invasive brain stimulation modality and novel technique for functional brain mapping, particularly with its advantage of greater spatial selectivity and depth penetration compared to existing non-invasive brain stimulation techniques. As previous studies, primarily carried out in small animals, have demonstrated that sonication parameters affect the stimulation efficiency, further investigation in large animals is necessary to translate this technique into clinical practice. In the present study, we examined the effects of sonication parameters on the transient modification of excitability of cortical and thalamic areas in an ovine model. Guided by anatomical and functional neuroimaging data specific to each animal, 250 kHz FUS was transcranially applied to the primary sensorimotor area associated with the right hind limb and its thalamic projection in sheep (n = 10) across multiple sessions using various combinations of sonication parameters. The degree of effect from FUS was assessed through electrophysiological responses, through analysis of electromyogram and electroencephalographic somatosensory evoked potentials for evaluation of excitatory and suppressive effects, respectively. We found that the modulatory effects were transient and reversible, with specific sonication parameters outperforming others in modulating regional brain activity. Magnetic resonance imaging and histological analysis conducted at different time points after the final sonication session, as well as behavioral observations, showed that repeated exposure to FUS did not damage the underlying brain tissue. Our results suggest that FUS-mediated, non-invasive, region-specific bimodal neuromodulation can be safely achieved in an ovine model, indicating its potential for translation into human studies.