Reversible neuroinhibition by focused ultrasound is mediated by a thermal mechanism
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.
Section snippets
Ultrasound system
A 64-element DMUA transducer was used for transcranial imaging and delivery of tFUS neuromodulation. [5] The array was driven by a 32-channel linear amplifier with programmable independent waveforms in both imaging and therapy modes. The arbitrary driving waveforms were synthesized based on the desired target (focus) point and modulation scheme using previously described focusing algorithms. [11] A custom designed MATLAB (R2016a, The MathWorks, Inc., Natick, Massachusetts) interface was used to
Ultrasound characterization
A 64-element DMUA prototype was used to generate modulated tFUS patterns in the thalamus, Fig. 1. The transmitted FUS field patterns were first measured in degassed water. Measurements were made using a 3.2 MHz carrier frequency, 50 kHz modulation frequency, and pulse-repetition frequency of 500 Hz (waveform in Appendix A). Reference focal plane patterns were measured on a grid with 0.05 (medial-latera)l x 0.1 (elevation) mm2, Fig. 2 (a and c). In each experiment, a 3D image of the skull
Discussion
Low-intensity, focused, transcranial ultrasound is an ideal modality for reversible neuromodulation with high temporal and spatial resolution. Having the ability to inhibit specific neural circuits noninvasively could supplant existing neuromodulation platforms and provide unprecedented access to discover new treatments and understand functional connectivity of the brain in vivo. Despite the variety of reported effects and proposed mechanisms of FUS neuromodulation, uncertainty has remained.
Sources of funding
This work was funded by the United States National Institutes of Health National Institute of Neurological Disorders and Stroke (NINDS) R01 NS098781 and University of Minnesota MNDrive Neuromodulation.
Conflicts of interest
A provisional patent application (U.S. 62/738,420) has been filed concerning the technology presented in this work.
Acknowledgements
We would like to acknowledge Brent Clark, MD, PhD, Flaviu Tabaran, DVM, PhD, and Gerrald O'Sullivan, MVB, PhD for their expertise and help with histology.
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2023, Fundamental ResearchCitation Excerpt :The mechanisms through which UDBS modulates telomere length were not elucidated in the current study and, thus, further research is needed. The biological effects of ultrasound are relatively complex and include cavitation as well as thermal and mechanical effects [45–47]. Cavitation can usually be produced through ultrasound with microbubble injection, which can cause hemorrhaging and tissue damage.