Controlled noninvasive modulation of deep brain regions in humans

Abstract

Transcranial focused ultrasound provides noninvasive and reversible approaches for precise and personalized manipulations of brain circuits, with the potential to transform our understanding of brain function and treatments of brain dysfunction. However, effective applications in humans have been limited by the human head, which attenuates and distorts ultrasound severely and unpredictably. This has led to uncertain ultrasound intensities delivered into the brain. Here, we address this lingering barrier using a direct measurement approach that can be repeatedly applied to the human brain. The approach uses an ultrasonic scan of the head to measure and compensate for the attenuation of the ultrasound by all obstacles within the ultrasound path. No other imaging modality is required and the method is parameter-free and personalized to each subject. The approach accurately restores operators’ intended intensities inside ex-vivo human skulls. Moreover, the approach is critical for effective modulation of deep brain regions in humans. When applied, the approach modulates fMRI Blood Oxygen Level Dependent (BOLD) activity in disease-relevant deep brain regions. This tool unlocks the potential of emerging approaches based on low-intensity ultrasound for controlled manipulations of neural circuits in humans.

Noninvasive modulation of essential tremor with focused ultrasonic waves

“…We have developed an ultrasonic neuromodulation array that enables effective and safe modulation of deep brain circuits in humans [7,37]. Using this device, we now aim to address a key question in the ultrasonic neuromodulation field, i.e., whether low-intensity transcranial focused ultrasound can induce observable changes in overt, motor behavior of human subjects.…”

“…The frequency was also chosen to be compatible with an existing transcranial-focused ultrasound surgical device [5]. Further, the skull correction method used here [37] enabled a compensation for the increased attenuation of this relatively high frequency. Previous studies validated the neuromodulatory efficacy of this parameter, being appropriate to modulate fMRI blood oxygenation leveldependent activity at target and to induce mood changes in subjects with major depressive disorder [7,34].…”

“…The lack of an effect in one of the subjects-or just a trend toward a decrease over time-is likely caused by the targeting difficulties of precise registration and phase aberrations caused by delivering ultrasound through the human skull. The skull can strongly aberrate the beam, to the point that the delivered focal coordinate can differ markedly from the intended coordinate [37]. The VIM nucleus is approximately 4 × 4 × 6 mm in size (x, y, z) [53], making it a difficult to match the size of the ultrasound focus used in this experiment (2.4 × 3.6 × 20.4 mm; y, z, and x dimensions of the MNI coordinate system).…”

“…The ultrasound was delivered into the target (VIM of the thalamus) in 10 ms pulses (650 kHz, 0.72 MPa peak pressure following correction for the skull) every 100 ms over the 15 s total sonication duration. The device automatically calculates the attenuation of the ultrasound by the skull, scalp, and hair, and compensates for these obstacles prior to the stimulation [7,37]. This correction circumvents the need for hair shaving, so the participants' hair was not shaved.…”

Controlled ultrasonic interventions through the human skull

“…To address this issue, we have previously developed a new approach that measures the ultrasound attenuation and dephasing by the head using ultrasound (Riis et al, 2024a). Although the…”