Ultrasonic neuromodulation is a rapidly growing field, in which low-intensity ultrasound (US) is delivered to nervous system tissue, resulting in transient modulation of neural activity. This review summarizes the findings in the central and peripheral nervous systems from mechanistic studies in cell culture to cognitive behavioral studies in humans. The mechanisms by which US mechanically interacts with neurons and could affect firing are presented. An in-depth safety assessment of current studies shows that parameters for the human studies fall within the safety envelope for US imaging. Challenges associated with accurately targeting US and monitoring the response are described. In conclusion, the literature supports the use of US as a safe, non-invasive brain stimulation modality with improved spatial localization and depth targeting compared with alternative methods. US neurostimulation has the potential to be used both as a scientific instrument to investigate brain function and as a therapeutic modality to modulate brain activity.

Ultrasound Neuromodulation: A Review of Results, Mechanisms and Safety.

Ultrasonic Neuromodulation Causes Widespread Cortical Activation via an Indirect Auditory Mechanism

To understand brain circuits it is necessary both to record and manipulate their activity. Transcranial ultrasound stimulation (TUS) is a promising non-invasive brain stimulation technique. To date, investigations report short-lived neuromodulatory effects, but to deliver on its full potential for research and therapy, ultrasound protocols are required that induce longer-lasting 'offline' changes. Here, we present a TUS protocol that modulates brain activation in macaques for more than one hour after 40 s of stimulation, while circumventing auditory confounds. Normally activity in brain areas reflects activity in interconnected regions but TUS caused stimulated areas to interact more selectively with the rest of the brain. In a within-subject design, we observe regionally specific TUS effects for two medial frontal brain regions - supplementary motor area and frontal polar cortex. Independently of these site-specific effects, TUS also induced signal changes in the meningeal compartment. TUS effects were temporary and not associated with microstructural changes.

/pdf/offline-impact-of-transcranial-focused-ultrasound-on-epjsoitcs5.pdf

Offline impact of transcranial focused ultrasound on cortical activation in primates.

https://pr.ibs.re.kr/bitstream/8788114/6831/1/Ultrasonic%20Neuromodulation%20via%20Astrocytic%20TRPA1.pdf

Ultrasonic Neuromodulation via Astrocytic TRPA1.

The understanding of brain function and the capacity to treat neurological and psychiatric disorders rest on the ability to intervene in neuronal activity in specific brain circuits Current methods of neuromodulation incur a tradeoff between spatial focus and the level of invasiveness Transcranial focused ultrasound (FUS) is emerging as a neuromodulation approach that combines noninvasiveness with focus that can be relatively sharp even in regions deep in the brain This may enable studies of the causal role of specific brain regions in specific behaviors and behavioral disorders In addition to causal brain mapping, the spatial focus of FUS opens new avenues for treatments of neurological and psychiatric conditions This review introduces existing and emerging FUS applications in neuromodulation, discusses the mechanisms of FUS effects on cellular excitability, considers the effects of specific stimulation parameters, and lays out the directions for future work

/pdf/neuromodulation-with-transcranial-focused-ultrasound-3fmmfkzeh5.pdf

Neuromodulation with transcranial focused ultrasound

Purpose: Ultrasound neuromodulation is a promising noninvasive technique for controlling neural activity. Previous small animal studies suffered from low targeting specificity because of the low ultrasound frequencies (<690 kHz) used. In this study, the authors demonstrated the capability of focused ultrasound (FUS) neuromodulation in the megahertz-range to achieve superior targeting specificity in the murine brain as well as demonstrate modulation of both motor and sensory responses. Methods: FUS sonications were carried out at 1.9 MHz with 50% duty cycle, pulse repetition frequency of 1 kHz, and duration of 1 s. The robustness of the FUS neuromodulation was assessed first in sensorimotor cortex, where elicited motor activities were observed and recorded on videos and electromyography. Deeper brain regions were then targeted where pupillary dilation served as an indicative of successful modulation of subcortical brain structures. Results: Contralateral and ipsilateral movements of the hind limbs were repeatedly observed when the FUS was targeted at the sensorimotor cortex. Induced trunk and tail movements were also observed at different coordinates inside the sensorimotor cortex. At deeper targeted-structures, FUS induced eyeball movements (superior colliculus) and pupillary dilation (pretectal nucleus, locus coeruleus, and hippocampus). Histological analysis revealed no tissue damage associated with the FUS sonications. Conclusions: The motor movements and pupillary dilation observed in this study demonstrate the capability of FUS to modulate cortical and subcortical brain structures without inducing any damage. The variety of responses observed here demonstrates the capability of FUS to perform functional brain mapping.

Focused ultrasound neuromodulation of cortical and subcortical brain structures using 1.9 MHz

Brain diseases including neurological disorders and tumors remain under treated due to the challenge to access the brain, and blood-brain barrier (BBB) restricting drug delivery which, also profoundly limits the development of pharmacological treatment. Focused ultrasound (FUS) with microbubbles is the sole method to open the BBB noninvasively, locally, and transiently and facilitate drug delivery, while translation to the clinic is challenging due to long procedure, targeting limitations, or invasiveness of current systems. In order to provide rapid, flexible yet precise applications, we have designed a noninvasive FUS and monitoring system with the protocol tested in monkeys (from in silico preplanning and simulation, real-time targeting and acoustic mapping, to post-treatment assessment). With a short procedure (30 min) similar to current clinical imaging duration or radiation therapy, the achieved targeting (both cerebral cortex and subcortical structures) and monitoring accuracy was close to the predicted 2-mm lower limit. This system would enable rapid clinical transcranial FUS applications outside of the MRI system without a stereotactic frame, thereby benefiting patients especially in the elderly population.

/pdf/efficient-blood-brain-barrier-opening-in-primates-with-330vws3vku.pdf

Efficient Blood-Brain Barrier Opening in Primates with Neuronavigation-Guided Ultrasound and Real-Time Acoustic Mapping.

Objective. Focused ultrasound (FUS) has recently been demonstrated capable of exciting motor neuronal activity. However, comprehensive understanding of elucidated excitatory and inhibitory effects is required to better assess FUS-mediated modulation. In this study, we demonstrate that image-guided FUS can selectively modulate motor neuron activity in the mouse sciatic nerve in vivo and attribute motor responses to thermal effects. Approach. FUS was applied on the sciatic nerve of anesthetized mice in vivo through the intact skin and muscle using ultrasound imaging for targeting. Both excitatory and inhibitory effects were recorded using electromyography (EMG) along with muscle response of the hind limb. The effects of FUS modulation vs heating by invasive alternative heating source (AHS) on electrically evoked EMG responses in the sciatic nerve in vivo were also investigated. The safety and reversibility of the technique were validated using histology and EMG recovery. Main results. The FUS was capable of eliciting motor neuronal activity comparable to electrical stimulation, and facilitating motor neuronal response on electrically evoked potentials with temperature elevation up to 11.5 ± 0.3 oC (PRF ≤ 40 Hz). On the other hand, FUS-induced temperature elevations above 15.1 ± 1.6 oC (PRF ≥ 100 Hz) resulted in the suppression of electrically-evoked motor neuronal activity along with a decrease in EMG latency and area under the curve (AUC), which was validated against the invasive AHS with temperature elevation of 18.1 ± 8.5 oC instead of FUS modulation. Histological findings along with EMG responses after FUS modulation demonstrated a reversible or irreversible modulation. Significance. The findings reported herein indicate that image-guided FUS (PRF ≤ 100 Hz) induces safe and controllable modulation of involuntarily evoked motor neuron activity in vivo.

https://iopscience.iop.org/article/10.1088/1741-2552/ab6be6/pdf

Image-guided focused ultrasound modulates electrically evoked motor neuronal activity in the mouse peripheral nervous system in vivo.

The past decade has seen rapid growth in the application of focused ultrasound (FUS) as a tool for basic neuroscience research and potential treatment of brain disorders. Here, we review recent developments in our understanding of how FUS can alter brain activity, perception, and behavior when applied to the central nervous system, either alone or in combination with circulating agents. Focused ultrasound in the central nervous system can directly excite or inhibit neuronal activity, as well as affect perception and behavior. Combining FUS with intravenous microbubbles to open the blood-brain barrier also affects neural activity and behavior, and the effects may be more sustained than FUS alone. Opening the BBB also allows delivery of drugs that do not cross the intact BBB including viral vectors for gene delivery. While further research is needed to elucidate the biophysical mechanisms, focused ultrasound, alone or in combination with other factors, is rapidly maturing as an effective technology for altering brain activity. Future challenges include refining control over targeting specificity, the volume of affected tissue, cell-type specificity (excitatory or inhibitory), and the duration of neural and behavioral effects.

/pdf/modulation-of-brain-function-and-behavior-by-focused-42jfgu2ptl.pdf

Modulation of Brain Function and Behavior by Focused Ultrasound.

Measuring temperature during focused ultrasound (FUS) procedures is critical for characterization, calibration, and monitoring to ultimately ensure safety and efficacy. Despite the low cost and the high spatial and temporal resolutions of temperature measurements using thermocouples, the viscous heating (VH) artifact at the thermocouple-tissue interface requires reading corrections for correct thermometric analysis. In this study, a simulation pipeline is proposed to correct the VH artifact arising from temperature measurements using thermocouples in FUS fields. The numerical model consists of simulating a primary source of heating due to ultrasound absorption and a secondary source of heating from viscous forces generated by the thermocouple in the FUS field. Our numerical validation found that up to 90% of the measured temperature rise was due to VH effects. Experimental temperature measurements were performed using thermocouples embedded in fresh chicken breast samples. Temperature corrections were demonstrated for single high-intensity FUS pulses at 3.1 MHz and for multiple pulses (3.1 MHz, 100 Hz, and 500 Hz pulse repetition frequency). The VH accumulated during sonications and produced a temperature increase of 3.1 °C and 15.3 °C for the single and multiple pulse sequences, respectively. The methodology presented here enables the decoupling of the temperature increase generated by absorption and VH. Thus, more reliable temperature measurements can be extracted from thermocouple measurements by correcting for VH.

/pdf/numerical-modeling-of-ultrasound-heating-for-the-correction-3t7mdes9cj.pdf

Christian Aurup

Papers

Focused ultrasound neuromodulation of cortical and subcortical brain structures using 1.9 MHz

Efficient Blood-Brain Barrier Opening in Primates with Neuronavigation-Guided Ultrasound and Real-Time Acoustic Mapping.

Image-guided focused ultrasound modulates electrically evoked motor neuronal activity in the mouse peripheral nervous system in vivo.

Modulation of Brain Function and Behavior by Focused Ultrasound.

Numerical modeling of ultrasound heating for the correction of viscous heating artifacts in soft tissue temperature measurements.