Transcranial focused ultrasound (tFUS) is a promising neuromodulation technique, but its mechanisms remain unclear. We hypothesize that if tFUS parameters exhibit distinct modulation effects in different neuron populations, then the mechanism can be understood through identifying unique features in these neuron populations. In this work, we investigate the effect of tFUS stimulation on different functional neuron types in in vivo anesthetized rodent brains. Single neuron recordings were separated into regular-spiking and fast-spiking units based on their extracellular spike shapes acquired through intracranial electrophysiological recordings, and further validated in transgenic optogenetic mice models of light-excitable excitatory and inhibitory neurons. We show that excitatory and inhibitory neurons are intrinsically different in response to ultrasound pulse repetition frequency (PRF). The results suggest that we can preferentially target specific neuron types noninvasively by tuning the tFUS PRF. Chemically deafened rats and genetically deafened mice were further tested for validating the directly local neural effects induced by tFUS without potential auditory confounds.

For last decade, low-intensity transcranial focused ultrasound (tFUS) has been rapidly developed for a myriad of successful applications in neuromodulation. tFUS possesses high spatial resolution, focality and depth penetration as a noninvasive neuromodulation tool. Despite the promise, confounding activation can be observed in rodents when stimulation parameters are not selected carefully. Here we summarize the existing classes of observations for ultrasound neuromodulation: ultrasound directly activates a localized area, or ultrasound indirectly activates auditory pathways, which further propagates to other cortical networks. We also present control in vivo animal studies, which suggest that underlying tFUS brain modulation is characterized by localized activation independent of auditory networks activations.

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Transcranial focused ultrasound (tFUS) neuromodulation provides a promising emerging non-invasive therapy for the treatment of neurological disorders. Many studies have demonstrated the ability of tFUS to elicit transient changes in neural responses. However, the ability of tFUS to induce sustained changes need to be carefully examined. In this study, we use the long-term potentiation/long term depression (LTP/LTD) model in the rat hippocampus, the medial perforant path (mPP) to dentate gyrus (DG) pathway, to explore whether tFUS is capable of encoding frequency specific information to induce plasticity. Single-element focused transducers were used for tFUS stimulation with ultrasound fundamental frequency of 0.5 MHz and nominal focal distance of 38 mm tFUS stimulation is directed to mPP. Measurement of synaptic connectivity is achieved through the slope of field excitatory post synaptic potentials (fEPSPs), which are elicited using bipolar electrical stimulation electrodes and recorded at DG using extracellular electrodes to quantify degree of plasticity. We applied pulsed tFUS stimulation with total duration of 5 min, with 5 levels of pulse repetition frequencies each administered at 50 Hz sonication frequency at the mPP. Baseline fEPSP is recorded 10 min prior, and 30þ minutes after tFUS administration. In N ¼ 16 adult wildtype rats, we observed sustained depression of fEPSP slope after 5 min of tFUS focused at the presynaptic field mPP. Across all PRFs, no significant difference in maximum fEPSP slope change was observed, average tFUS induced depression level was observed at 19.6%. When compared to low frequency electrical stimulation (LFS) of 1 Hz delivered to the mPP, the sustained changes induced by tFUS stimulation show no statistical difference to LFS for up to 24 min after tFUS stimulation. When both the maximum depression effects and the duration of sustained effects are both taken into account, PRF 3 kHz can induce significantly larger effects than other PRFs tested. tFUS stimulation is measured with a spatial-peak pressure amplitude of 99 kPa, translating to an estimation of 0.43 C temperature increase when assuming no loss of heat. The results suggest the ability of tFUS to encode sustained changes in synaptic connectivity through mechanism which are unlikely to involve thermal changes.

A patient's capacity for tissue regeneration varies based on age, nutritional status, disease state, lifestyle, and gender. Because regeneration cannot be predicted prior to biomaterial implantation, there is a need for responsive biomaterials with adaptive, personalized degradation profiles to improve regenerative outcomes. This study reports a new approach to use therapeutic ultrasound as a means of altering the degradation profile of silk fibroin biomaterials noninvasively postimplantation. By evaluating changes in weight, porosity, surface morphology, compressive modulus, and chemical structure, it is concluded that therapeutic ultrasound can trigger enhanced degradation of silk fibroin scaffolds noninvasively. By removing microbubbles on the scaffold surface, it is found that acoustic cavitation is the mechanism responsible for changing the degradation profile. This method is proved to be safe for human cells with no negative effects on cell viability or metabolism. Sonication through human skin also effectively triggers scaffold degradation, increasing the clinical relevance of these results. These findings suggest that silk is an ultrasound-responsive biomaterial, where the degradation profile can be adjusted noninvasively to improve regenerative outcomes.

Transcranial focused ultrasound (tFUS) is an emerging non-invasive brain stimulation tool for safely and reversibly modulating brain circuits. The effectiveness of tFUS on human brain has been demonstrated, but how tFUS influences the human voluntary motor processing in the brain remains unclear. Methods: We apply low-intensity tFUS to modulate the movement-related cortical potential (MRCP) originating from human subjects practicing a voluntary foot tapping task. 64channel electroencephalograph (EEG) is recorded concurrently and further used to reconstruct the brain source activity specifically at the primary leg motor cortical area using the electrophysiological source imaging (ESI). Results: The ESI illustrates the ultrasound modulated MRCP source dynamics with high spatiotemporal resolutions. The MRCP source is imaged and its source profile is further evaluated for assessing the tFUS neuromodulatory effects on the voluntary MRCP. Moreover, the effect of ultrasound pulse repetition frequency (UPRF) is further assessed in modulating the MRCP. The ESI results show that tFUS significantly increases the MRCP source profile amplitude (MSPA) comparing to a sham ultrasound condition, and further, a high UPRF enhances the MSPA more than a low UPRF does. Conclusion: The present results demonstrate the neuromodulatory effects of the low-intensity tFUS on enhancing the human voluntary movement-related cortical activities evidenced through the ESI imaging. Significance: This work provides the first evidence of tFUS enhancing the human endogenous motor cortical activities through excitatory modulation.

1Transcranial focused ultrasound (tFUS) is an emerging non-invasive brain 2 stimulation tool for safely and reversibly modulating brain circuits. The 3 effectiveness of tFUS on human brain has been demonstrated, but how tFUS 4 influences the human voluntary motor processing in the brain remains 5 unclear. We apply low-intensity tFUS to modulate the movement-related 6 cortical potential (MRCP) originating from human subjects practicing a 7 voluntary foot tapping task. 64-channel electroencephalograph (EEG) is 8 recorded concurrently and further used to reconstruct the brain source 9 activity specifically at the primary leg motor cortical area using the 10 electrophysiological source imaging (ESI). The ESI illustrates the ultrasound 11 modulated MRCP source dynamics with high spatiotemporal resolutions. 12The MRCP source is imaged and its source profile is further evaluated for 13 assessing the tFUS neuromodulatory effects on the voluntary MRCP. 14 Moreover, the effect of ultrasound pulse repetition frequency (UPRF) is 15 further assessed in modulating the MRCP. ESI results show that tFUS 16 significantly increases the MRCP source profile amplitude (MSPA) 17 comparing to a sham ultrasound condition, and further, a high UPRF 18 enhances the MSPA more than a low UPRF. This work provides the first 19 evidence of tFUS enhancing the human voluntary movement-related cortical 20 activity through excitatory modulation.21 485

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