Reversible neuroinhibition by focused ultrasound is mediated by a thermal mechanism

Highlights

• Transcranial low-intensity focused ultrasound reversibly inhibits neural activity.

• tFUS robustly suppresses SSEPs when the thalamus (VPL) is targeted.

• Evoked responses or startle were not observed with dual-mode ultrasound arrays.

• Suppression varies with ultrasound intensity with multi-second time constants.

• A thermal effect underlies the primary mechanism of tFUS.

Abstract

Background

Transcranial focused ultrasound (tFUS) at low intensities has been reported to directly evoke responses and reversibly inhibit function in the central nervous system. While some doubt has been cast on the ability of ultrasound to directly evoke neuronal responses, spatially-restricted transcranial ultrasound has demonstrated consistent, inhibitory effects, but the underlying mechanism of reversible suppression in the central nervous system is not well understood.

Objective/hypothesis

In this study, we sought to characterize the effect of transcranial, low-intensity, focused ultrasound on the thalamus during somatosensory evoked potentials (SSEP) and investigate the mechanism by modulating the parameters of ultrasound.

Methods

TFUS was applied to the ventral posterolateral nucleus of the thalamus of a rodent while electrically stimulating the tibial nerve to induce an SSEP. Thermal changes were also induced through an optical fiber that was image-guided to the same target.

Results

Focused ultrasound reversibly suppressed SSEPs in a spatially and intensity-dependent manner while remaining independent of duty cycle, peak pressure, or modulation frequency. Suppression was highly correlated and temporally consistent with in vivo temperature changes while producing no pathological changes on histology. Furthermore, stereotactically-guided delivery of thermal energy through an optical fiber produced similar thermal effects and suppression.

Conclusion

We confirm that tFUS predominantly causes neuroinhibition and conclude that the most primary biophysical mechanism is the thermal effect of focused ultrasound.

Introduction

Reversible neuromodulation using ultrasound through a craniotomy was first reported more than 60 years ago. [1] Since then, the promise of a noninvasive method of using mechanical waves to modulate the function of the nervous system with submillimeter resolution has been fueled by substantial improvements in modeling, ultrasound transducer design, and computational power. [[2], [3], [4]] Compared to existing noninvasive neuromodulation platforms such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tcDCS), tFUS has superior spatial resolution. [3].

The skull is highly reflective, diffractive, and absorptive of ultrasound, producing a significant barrier to delivery of ultrasound to the brain, and these effects can vary widely across regions of the skull with differing thickness and concavity. [[5], [6], [7], [8]] Transcranial focused ultrasound (tFUS) incorporates strategies to account for these effects in order to minimize distortion. [4,5] Phased arrays of ultrasound transducers and modeling techniques make it possible to take into account the anatomical variation in order to focus ultrasound through the skull while distributing energy delivery across the scalp. [6] The dual-mode ultrasound array (DMUA) technology is a new paradigm in image-guided FUS interventions enabling simultaneous delivery of high resolution therapy while actively monitoring the sonicated tissue. [[9], [10], [11]] Real-time monitoring, such as ultrasound thermography, enables imaging of the temperature of the tissue heated by ultrasound and can be performed in closed-loop fashion to adjust for distortion. [5,12] Our group previously demonstrated that this technique successfully produces localized effects in a rodent model through monitoring of tFUS-induced subtherapeutic heating of brain tissues. [5] In addition to its basic (3D) image guidance capabilities, our DMUA system employs advanced multi-channel transmit control circuitry allowing investigation over a large parameter space.

While tFUS at high intensities can open the blood-brain barrier, or create lesions to ablate tumors, tFUS at lower intensities has been reported to reversibly modulate neural activity without damaging tissue. [[13], [14], [15]] Inhibition and excitation by tFUS have been reported in in vitro, in vivo in animals, in and humans. [3] The reported effects of transcranial tFUS range from evoked neural activity to modulation of sensory evoked-potentials. [8,[16], [17], [18], [19], [20], [21], [22], [23], [24]] Numerous mechanisms have been suggested based on the interaction between known ultrasound biophysical effects and neurophysiology, but the heterogeneity of effects and experimental confounds shroud our understanding of the main underlying mechanisms. [3].

A common tFUS experimental paradigm uses a laterally-restricted ultrasound focus from a single element transducer where the ventral-dorsal extent of the ultrasound beam spans the entire skull of the animal. [25] Recently, a pair of studies highlighted an important confound in this paradigm, where it was shown that delivery of ultrasound in this way results in tFUS beams with a large dorsoventral area of effect, directing ultrasound into the base of the skull to the cochlea and inner ear and therefore produces an auditory-startle response. [26,27]. This may explain, at least in part, some of the ultrasound-evoked responses previously reported. [26,27] In contrast, experiments using phased-arrays capable of restricting the ultrasound focus in all three dimensions, or in humans where the skull base remains far from the focus, report inhibitory effects on active neural circuits. [8,15,17,23] Considerable uncertainty remains regarding the mechanism of inhibition as ultrasound produces several effects within biological tissue including thermal effects and mechanical effects, such as radiation pressure, shear waves, cavitation, and microcavitation. [2,28].

Here we sought to characterize the effect of tFUS at low-intensities on a well-characterized neural circuit: the primary somatosensory afferent pathway. In this study we vary the parameters of the ultrasound beam and measure each parameter's effects on modulating the pathway to elucidate the underlying mechanism.