Remote targeted electrical stimulation

Abstract

Objective:The ability to generate electric fields in specific targets remotely would transform manipulations of processes that rest on electrical signaling.Approach:This article shows that focal electric fields are generated from distance by combining two orthogonal, remotely applied energies-magnetic and focused ultrasonic fields. The effect derives from the Lorentz force equation applied to magnetic and ultrasonic fields.Main results:We elicited this effect using standard hardware and confirmed that the generated electric fields align with the Lorentz equation. The effect significantly and safely modulated human peripheral nerves and deep brain regions of non-human primates.Significance:This approach opens a new set of applications in which electric fields are generated at high spatiotemporal resolution within intact biological tissues or materials, thus circumventing the limitations of traditional electrode-based procedures.

Keywords: Lorentz force; incisionless; induction; magnetic field; neuromodulation; noninvasive; ultrasound.

Figure 1.

Remote generation of focal electrical fields. (A) Concept. An ultrasonic transducer array programmatically focuses ultrasound into a target of interest. An ultrasound wave, focused into a target with acoustic impedance Z, induces in the target motions of molecules with velocity $v=\frac{P}{Z}$. The pressure P (and so the velocity v) are maximal at the target. When the wave is emitted in a direction perpendicular to magnetic field B, so that the velocity vector is perpendicular to B, the target experiences localized electric field $E=\frac{PB}{Z}$. (B) Validation. Electric field at target measured with a pair of electrodes inside a 7 T field when a 258 kHz focused ultrasound of the pressure amplitude indicated on the abscissa is delivered into the target (figure 2(A) and methods). The measurements align with the theoretical values computed from the Lorentz equation for this magnetic field strength (n = 100 measurements, mean ± s.e.m.; the error bars are smaller than the symbols).

Figure 2.

Apparatus and stimuli. (A) Apparatus used for recordings. A focused ultrasound transducer delivered a 258 kHz stimulus into a target inside a 7 T scanner. Two electrodes positioned into the target measured the induced electric field. The measurements were performed in the indicated geometry and following a rotation of the setup 90^∘ with respect to the magnetic field. The coupling cone was filled with saline. The inter-electrode distance was 3 mm. (B) Apparatus used for nerve stimulation. A focused ultrasound transducer delivered a 258 kHz stimulus into a subject’s thumb using a coupling cone filled with degassed water. The stimulation was performed inside a 7 T scanner or 3 m away from it. Subjects were instructed to place the thumb so that it pointed perpendicularly to the magnetic and ultrasonic fields. (C) Peak-normalized ultrasound pressure field. The pressure profile was averaged over the x and y dimensions. The dotted lines show the 0.707 (0.5) pressure (intensity) levels to characterize the fields using full-width-at-half-maximum values. The full-width-at-half-maximum (FWHM) diameter was 6.5 mm in the xy-dimension, and focal length (z-dimension) 3.3 mm. (D) Peripheral nerve stimulation parameters. Each subject experienced ten repetitions of ten distinct stimuli, including sham. The stimuli, 200 ms in duration, were selected randomly and delivered every 8–12 s. We tested three pressure levels and continuous and pulsed (500 Hz, 10 kHz frequency, 50% duty) stimuli.

Figure 3.

Remote targeted modulation of the peripheral nervous system. (A) Lstim modulates human peripheral nervous system. Mean ± s.e.m. response magnitude (see section 2) for ultrasound alone (0 T) and ultrasound combined with magnetic field (7 T), separately for nociceptive (left) and tactile (right) responses. Data were pooled over all stimuli tested. The double stars indicate effects significant at p < 0.01. (B) Lstim-evoked nociceptive responses increase with ultrasound pressure. Mean ± s.e.m. magnitude of nociceptive responses as a function of ultrasound pressure at target and the presence (green) and absence (gray) of magnetic field. Data were pooled over all stimuli. (C) Lstim activates nerves in an orientation-specific manner. Mean ± s.e.m. magnitude of nociceptive responses as a function of the orientation of the induced electric field with respect to the subjects’ nerves. The neuromodulatory effects are maximized when the nerves are aligned with the induced electric field (green). Data were pooled over all stimuli. The star indicates that the modulation by the magnetic field and its orientation was significant (p < 0.05).

Figure 4.

Remote targeted modulation of the brain. (A) A 256-element, MRI-compatible phased array (Webb et al 2022, 2023) is inserted into a frame that is mounted into four titanium posts attached to the skull of two non-human primates. Each animal was positioned in a standard sphinx position. In this position, the magnetic field of the scanner (green arrow) points toward the reader. Since the ultrasound is delivered from the top, the induced Lstim field points along the animal’s left-right axis. (B) Example validation of the LGN targeting using MRI thermometry. The images represent the selective targeting of the left and right LGN (Webb et al 2022, 2023) (C) Mean ± s.e.m. high gamma activity recorded from the two posterior pins in response to 100 ms stimuli (480 kHz carrier frequency, 2 MPa amplitude) applied every 4 s to each LGN in a strictly alternating manner. The stimuli were either continuous or pulsed at 200 Hz pulse repetition frequency. Since there was no statistically significant difference, we pooled the data across these two conditions. Data are shown separately for the animals positioned inside the MRI (green) and 2 m outside of the MRI bore (black). The responses are aligned to the offset of each ultrasound stimulus (blue bar) and contain data of seven sessions recorded in the two monkeys.