A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans.

Low intensity transcranial focused ultrasound (LIFU) is a promising method of non-invasive neuromodulation that uses mechanical energy to affect neuronal excitability. LIFU confers high spatial resolution and adjustable focal lengths for precise neuromodulation of discrete regions in the human brain. Before the full potential of low intensity ultrasound for research and clinical application can be investigated, data on the safety of this technique is indicated. Here, we provide an evaluation of the safety of LIFU for human neuromodulation through participant report and neurological assessment with a comparison of symptomology to other forms of non-invasive brain stimulation. Participants (N = 120) that were enrolled in one of seven human ultrasound neuromodulation studies in one laboratory at the University of Minnesota (2015-2017) were queried to complete a follow-up Participant Report of Symptoms questionnaire assessing their self-reported experience and tolerance to participation in LIFU research (Isppa 11.56-17.12 W/cm2) and the perceived relation of symptoms to LIFU. A total of 64/120 participant (53%) responded to follow-up requests to complete the Participant Report of Symptoms questionnaire. None of the participants experienced serious adverse effects. From the post-hoc assessment of safety using the questionnaire, 7/64 reported mild to moderate symptoms, that were perceived as 'possibly' or 'probably' related to participation in LIFU experiments. These reports included neck pain, problems with attention, muscle twitches and anxiety. The most common unrelated symptoms included sleepiness and neck pain. There were initial transient reports of mild neck pain, scalp tingling and headache that were extinguished upon follow-up. No new symptoms were reported upon follow up out to 1 month. The profile and incidence of symptoms looks to be similar to other forms of non-invasive brain stimulation.

Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis.

Targeted noninvasive control of the nervous system and end-organs may enable safer and more effective treatment of multiple diseases compared to invasive devices or systemic medications. One target is the cholinergic anti-inflammatory pathway that consists of the vagus nerve to spleen circuit, which has been stimulated with implantable devices to improve autoimmune conditions such as rheumatoid arthritis. Here we report that daily noninvasive ultrasound (US) stimulation targeting the spleen significantly reduces disease severity in a mouse model of inflammatory arthritis. Improvements are observed only with specific parameters, in which US can provide both protective and therapeutic effects. Single cell RNA sequencing of splenocytes and experiments in genetically-immunodeficient mice reveal the importance of both T and B cell populations in the anti-inflammatory pathway. These findings demonstrate the potential for US stimulation of the spleen to treat inflammatory diseases.

Effects of transcranial focused ultrasound on human primary motor cortex using 7T fMRI: a pilot study.

BACKGROUND: Transcranial focused ultrasound (tFUS) is a new non-invasive neuromodulation technique that uses mechanical energy to modulate neuronal excitability with high spatial precision. tFUS has been shown to be capable of modulating EEG brain activity in humans that is spatially restricted, and here, we use 7T MRI to extend these findings. We test the effect of tFUS on 7T BOLD fMRI signals from individual finger representations in the human primary motor cortex (M1) and connected cortical motor regions. Participants (N = 5) performed a cued finger tapping task in a 7T MRI scanner with their thumb, index, and middle fingers to produce a BOLD signal for individual M1 finger representations during either tFUS or sham neuromodulation to the thumb representation. RESULTS: Results demonstrated a statistically significant increase in activation volume of the M1 thumb representation for the tFUS condition as compared to sham. No differences in percent BOLD changes were found. This effect was spatially confined as the index and middle finger M1 finger representations did not show similar significant changes in either percent change or activation volume. No effects were seen during tFUS to M1 in the supplementary motor area or the dorsal premotor cortex. CONCLUSIONS: Single element tFUS can be paired with high field MRI that does not induce significant artifact. tFUS increases activation volumes of the targeted finger representation that is spatially restricted within M1 but does not extend to functionally connected motor regions. Trial registration ClinicalTrials.gov NCT03634631 08/14/18.

Transcranial focused ultrasound neuromodulation of the human primary motor cortex.

Transcranial focused ultrasound is an emerging form of non-invasive neuromodulation that uses acoustic energy to affect neuronal excitability. The effect of ultrasound on human motor cortical excitability and behavior is currently unknown. We apply ultrasound to the primary motor cortex in humans using a novel simultaneous transcranial ultrasound and magnetic stimulation paradigm that allows for concurrent and concentric ultrasound stimulation with transcranial magnetic stimulation (TMS). This allows for non-invasive inspection of the effect of ultrasound on motor neuronal excitability using the motor evoked potential (MEP). We test the effect of ultrasound on single pulse MEP recruitment curves and paired pulse protocols including short interval intracortical inhibition (SICI) and intracortical facilitation (ICF). In addition, we test the effect of ultrasound to motor cortex on a stimulus response reaction time task. Results show ultrasound inhibits the amplitude of single-pulse MEPs and attenuates intracortical facilitation but does not affect intracortical inhibition. Ultrasound also reduces reaction time on a simple stimulus response task. This is the first report of the effect of ultrasound on human motor cortical excitability and motor behavior and confirms previous results in the somatosensory cortex that ultrasound results in effective neuronal inhibition that confers a performance advantage.

Neuromodulation with single-element transcranial focused ultrasound in human thalamus.

Transcranial focused ultrasound (tFUS) has proven capable of stimulating cortical tissue in humans. tFUS confers high spatial resolutions with deep focal lengths and as such, has the potential to noninvasively modulate neural targets deep to the cortex in humans. We test the ability of single-element tFUS to noninvasively modulate unilateral thalamus in humans. Participants (N = 40) underwent either tFUS or sham neuromodulation targeted at the unilateral sensory thalamus that contains the ventro-posterior lateral (VPL) nucleus of thalamus. Somatosensory evoked potentials (SEPs) were recorded from scalp electrodes contralateral to median nerve stimulation. Activity of the unilateral sensory thalamus was indexed by the P14 SEP generated in the VPL nucleus and cortical somatosensory activity by subsequent inflexions of the SEP and through time/frequency analysis. Participants also under went tactile behavioral assessment during either the tFUS or sham condition in a separate experiment. A detailed acoustic model using computed tomography (CT) and magnetic resonance imaging (MRI) is also presented to assess the effect of individual skull morphology for single-element deep brain neuromodulation in humans. tFUS targeted at unilateral sensory thalamus inhibited the amplitude of the P14 SEP as compared to sham. There is evidence of translation of this effect to time windows of the EEG commensurate with SI and SII activities. These results were accompanied by alpha and beta power attenuation as well as time-locked gamma power inhibition. Furthermore, participants performed significantly worse than chance on a discrimination task during tFUS stimulation.

Numerical evaluation of the skull for human neuromodulation with transcranial focused ultrasound.

OBJECTIVE: Transcranial focused ultrasound is an emerging field for human non-invasive neuromodulation, but its dosing in humans is difficult to know due to the skull. The objective of the present study was to establish modeling methods based on medical images to assess skull differences between individuals on the wave propagation of ultrasound. APPROACH: Computational models of transcranial focused ultrasound were constructed using CT and MR scans to solve for intracranial pressure. We explored the effect of including the skull base in models, different transducer placements on the head, and differences between 250 kHz or 500 kHz acoustic frequency for both female and male models. We further tested these features using linear, nonlinear, and elastic simulations. To better understand inter-subject skull thickness and composition effects we evaluated the intracranial pressure maps between twelve individuals at two different skull sites. MAIN RESULTS: Nonlinear acoustic simulations resulted in virtually identical intracranial pressure maps with linear acoustic simulations. Elastic simulations showed a difference in max pressures and full width half maximum volumes of 15% at most. Ultrasound at an acoustic frequency of 250 kHz resulted in the creation of more prominent intracranial standing waves compared to 500 kHz. Finally, across twelve model human skulls, a significant linear relationship to characterize intracranial pressure maps was not found. SIGNIFICANCE: Despite its appeal, an inherent problem with the use of a noninvasive transcranial ultrasound method is the difficulty of knowing intracranial effects because of the skull. Here we develop detailed computational models derived from medical images of individuals to simulate the propagation of neuromodulatory ultrasound across the skull and solve for intracranial pressure maps. These methods allow for a much better understanding of the intracranial effects of ultrasound for an individual in order to ensure proper targeting and more tightly control dosing.

Computational exploration of wave propagation and heating from transcranial focused ultrasound for neuromodulation.

OBJECTIVE: While ultrasound is largely established for use in diagnostic imaging, its application for neuromodulation is relatively new and crudely understood. The objective of the present study was to investigate the effects of tissue properties and geometry on the wave propagation and heating in the context of transcranial neuromodulation. APPROACH: A computational model of transcranial-focused ultrasound was constructed and validated against empirical data. The models were then incrementally extended to investigate a number of issues related to the use of ultrasound for neuromodulation, including the effect on wave propagation of variations in geometry of skull and gyral anatomy as well as the effect of multiple tissue and media layers, including scalp, skull, CSF, and gray/white matter. In addition, a sensitivity analysis was run to characterize the influence of acoustic properties of intracranial tissues. Finally, the heating associated with ultrasonic stimulation waveforms designed for neuromodulation was modeled. MAIN RESULTS: The wave propagation of a transcranially focused ultrasound beam is significantly influenced by the cranial domain. The half maximum acoustic beam intensity profiles are insensitive overall to small changes in material properties, though the inclusion of sulci in models results in greater peak intensity values compared to a model without sulci (1%-30% greater). Finally, heating using currently employed stimulation parameters in humans is highest in bone (0.16 °C) and is negligible in brain (4.27 × 10(-3) °C) for a 0.5 s exposure. SIGNIFICANCE: Ultrasound for noninvasive neuromodulation holds great promise and appeal for its non-invasiveness, high spatial resolution and deep focal lengths. Here we show gross brain anatomy and biological material properties to have limited effect on ultrasound wave propagation and to result in safe heating levels in the skull and brain.

Effects of Electrical Stimulation in the Inferior Colliculus on Frequency Discrimination by Rhesus Monkeys and Implications for the Auditory Midbrain Implant.

UNLABELLED: Understanding the relationship between the auditory selectivity of neurons and their contribution to perception is critical to the design of effective auditory brain prosthetics. These prosthetics seek to mimic natural activity patterns to achieve desired perceptual outcomes. We measured the contribution of inferior colliculus (IC) sites to perception using combined recording and electrical stimulation. Monkeys performed a frequency-based discrimination task, reporting whether a probe sound was higher or lower in frequency than a reference sound. Stimulation pulses were paired with the probe sound on 50% of trials (0.5-80 µA, 100-300 Hz, n = 172 IC locations in 3 rhesus monkeys). Electrical stimulation tended to bias the animals' judgments in a fashion that was coarsely but significantly correlated with the best frequency of the stimulation site compared with the reference frequency used in the task. Although there was considerable variability in the effects of stimulation (including impairments in performance and shifts in performance away from the direction predicted based on the site's response properties), the results indicate that stimulation of the IC can evoke percepts correlated with the frequency-tuning properties of the IC. Consistent with the implications of recent human studies, the main avenue for improvement for the auditory midbrain implant suggested by our findings is to increase the number and spatial extent of electrodes, to increase the size of the region that can be electrically activated, and to provide a greater range of evoked percepts. SIGNIFICANCE STATEMENT: Patients with hearing loss stemming from causes that interrupt the auditory pathway after the cochlea need a brain prosthetic to restore hearing. Recently, prosthetic stimulation in the human inferior colliculus (IC) was evaluated in a clinical trial. Thus far, speech understanding was limited for the subjects and this limitation is thought to be partly due to challenges in harnessing the sound frequency representation in the IC. Here, we tested the effects of IC stimulation in monkeys trained to report the sound frequencies they heard. Our results indicate that the IC can be used to introduce a range of frequency percepts and suggest that placement of a greater number of electrode contacts may improve the effectiveness of such implants.

Transcranial focused ultrasound for BOLD fMRI signal modulation in humans.

Transcranial focused ultrasound (tFUS) is an emerging form of non-surgical human neuromodulation that confers advantages over existing electro and electromagnetic technologies by providing a superior spatial resolution on the millimeter scale as well as the capability to target sub-cortical structures non-invasively. An examination of the pairing of tFUS and blood oxygen level dependent (BOLD) functional MRI (fMRI) in humans is presented here.

Transcranial focused ultrasound modulates intrinsic and evoked EEG dynamics.

BACKGROUND: The integration of EEG recordings and transcranial neuromodulation has provided a useful construct for noninvasively investigating the modification of human brain circuit activity. Recent evidence has demonstrated that focused ultrasound can be targeted through the human skull to affect the amplitude of somatosensory evoked potentials and its associated spectral content. OBJECTIVE/HYPOTHESIS: The present study tests whether focused ultrasound transmitted through the human skull and targeted to somatosensory cortex can affect the phase and phase rate of cortical oscillatory dynamics. METHODS: A computational model was developed to gain insight regarding the insertion behavior of ultrasound induced pressure waves in the human head. The instantaneous phase and phase rate of EEG recordings before, during, and after transmission of transcranial focused ultrasound (tFUS) to human somatosensory cortex were examined to explore its effects on phase dynamics. RESULTS: Computational modeling results show the skull effectively reinforces the focusing of tFUS due to curvature of material interfaces. Neurophysiological recordings show that tFUS alters the phase distribution of intrinsic brain activity for beta frequencies, but not gamma. This modulation was accompanied by a change in phase rate of both beta and gamma frequencies. Additionally, tFUS modulated phase distributions in the beta band of early sensory-evoked activity but did not affect late sensory-evoked activity, lending support to the spatial specificity of tFUS for neuromodulation. This spatial specificity was confirmed through an additional experiment where the ultrasound transducer was moved 1 cm laterally from the original cortical target. CONCLUSIONS: Focused ultrasonic energy can alter EEG oscillatory dynamics through local mechanical perturbation of discrete cortical circuits.

A quantitative overview of biophysical forces impinging on neural function.

The fundamentals of neuronal membrane excitability are globally described using the Hodgkin-Huxley (HH) model. The HH model, however, does not account for a number of biophysical phenomena associated with action potentials or propagating nerve impulses. Physical mechanisms underlying these processes, such as reversible heat transfer and axonal swelling, have been compartmentalized and separately investigated to reveal neuronal activity is not solely influenced by electrical or biochemical factors. Instead, mechanical forces and thermodynamics also govern neuronal excitability and signaling. To advance our understanding of neuronal function and dysfunction, compartmentalized analyses of electrical, chemical, and mechanical processes need to be revaluated and integrated into more comprehensive theories. The present perspective is intended to provide a broad overview of biophysical forces that can influence neural function, but which have been traditionally underappreciated in neuroscience. Further, several examples where mechanical forces have been shown to exert their actions on nervous system development, signaling, and plasticity are highlighted to underscore their importance in sculpting neural function. By considering the collective actions of biophysical forces influencing neuronal activity, our working models can be expanded and new paradigms can be applied to the investigation and characterization of brain function and dysfunction.

Simultaneous transcranial magnetic stimulation and single-neuron recording in alert non-human primates.

Transcranial magnetic stimulation (TMS) is a widely used, noninvasive method for stimulating nervous tissue, yet its mechanisms of effect are poorly understood. Here we report new methods for studying the influence of TMS on single neurons in the brain of alert non-human primates. We designed a TMS coil that focuses its effect near the tip of a recording electrode and recording electronics that enable direct acquisition of neuronal signals at the site of peak stimulus strength minimally perturbed by stimulation artifact in awake monkeys (Macaca mulatta). We recorded action potentials within ∼1 ms after 0.4-ms TMS pulses and observed changes in activity that differed significantly for active stimulation as compared with sham stimulation. This methodology is compatible with standard equipment in primate laboratories, allowing easy implementation. Application of these tools will facilitate the refinement of next generation TMS devices, experiments and treatment protocols.

Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans.

Improved methods of noninvasively modulating human brain function are needed. Here we probed the influence of transcranial focused ultrasound (tFUS) targeted to the human primary somatosensory cortex (S1) on sensory-evoked brain activity and sensory discrimination abilities. The lateral and axial spatial resolution of the tFUS beam implemented were 4.9 mm and 18 mm, respectively. Electroencephalographic recordings showed that tFUS significantly attenuated the amplitudes of somatosensory evoked potentials elicited by median nerve stimulation. We also found that tFUS significantly modulated the spectral content of sensory-evoked brain oscillations. The changes produced by tFUS on sensory-evoked brain activity were abolished when the acoustic beam was focused 1 cm anterior or posterior to S1. Behavioral investigations showed that tFUS targeted to S1 enhanced performance on sensory discrimination tasks without affecting task attention or response bias. We conclude that tFUS can be used to focally modulate human cortical function.

Is sham cTBS real cTBS? The effect on EEG dynamics.

Increasing sensitivity of modern evaluation tools allows for the study of weaker electric stimulation effects on neural populations. In the current study we examined the effects of sham continuous theta burst (cTBS) transcranial magnetic stimulation to the left dorsolateral prefrontal cortex (DLPFC) upon somatosensory evoked potentials (SEP) and frontal-parietal phase coupling of alpha and beta bands. Sham TMS results in an induced electric field amplitude roughly 5% that of real TMS with a similar spatial extent in cortex. Both real and sham cTBS reduced the amplitude of the frontal P14-N30 SEP and increased local phase coupling in the alpha-beta frequency bands of left frontal cortex. In addition, both sham and real cTBS increased frontal-parietal phase coupling in the alpha-beta bands concomitant with an increase in amplitude of parietal P50-N70 complex. These data suggest that weak electric fields from sham cTBS can affect both local and downstream neuronal circuits, though in a different manner than high strength TMS.

Model-based analysis of multiple electrode array stimulation for epiretinal visual prostheses.

OBJECTIVE: Epiretinal stimulation, which uses an array of electrodes implanted on the inner retinal surface to relay a representation of the visual scene to the neuronal elements of the retina, has seen considerable success. The objective of the present study was to quantify the effects of multi-electrode stimulation on the patterns of neural excitation in a computational model of epiretinal stimulation. APPROACH: A computational model of retinal ganglion cells was modified to represent the morphology of human retinal ganglion cells and validated against published experimental data. The ganglion cell model was then combined with a model of an axon of the nerve fiber layer to produce a population model of the inner retina. The response of the population of model neurons to epiretinal stimulation with a multi-electrode array was quantified across a range of electrode geometries using a novel means to quantify the model response-the minimum radius circle bounding the activated model neurons as a proxy for the evoked phosphene. MAIN RESULTS: Multi-electrode stimulation created unique phosphenes, uch that the number of potential phosphenes can far exceed the number of electrode contacts. SIGNIFICANCE: The ability to exploit the spatial and temporal interactions of stimulation may be critical to improvements in the performance of epiretinal prostheses.