Reversible neuroinhibition by focused ultrasound is mediated by a thermal mechanism
David P. Darrow, Parker O'Brien, Thomas J. Richner, Theoden I. Netoff, Emad S. Ebbini
Brain Stimulation 2019, 12, 1439-1447 · 10.1016/j.brs.2019.07.015
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.
Abstract via europepmc.
Exposures
Exposure 1: tFUS to contralateral VPL thalamus during tibial nerve SSEP
Target: ventral posterolateral nucleus — “ventral posterolateral (VPL) nucleus of the thalamus”
Device: custom-built · 64-element dual-mode ultrasound array (DMUA) ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 3,200 | ✓✓✓ |
| Pulse duration (ms) | not reported | ⚑ |
| Pulse repetition frequency (Hz) | 500 | ✓✓✓ |
| Duty cycle (%) | 5, 70swept | ✓✓✓ |
| Sonication duration (s) | 30 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Ispta, domain unspecified (W/cm²) | 20, 88swept | ✓✓✓⚑ |
Experimental epochs consisted of 120 s of baseline SSEP followed by 150 s of SSEP during ultrasound stimulation, which was followed by a 60 s washout period. Ultrasound was delivered for 30 s followed by 10 sequential periods of 50 SSEP windows. 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); amplitude and duty cycle were varied independently, and various modulation frequencies were also tested at two intensities (see Appendix A).
Flags from extraction
exposures[0].unspecified_domain.ispta_w_cm2— Intensity values (88 W/cm2 near-complete suppression; 20 W/cm2 held constant during duty-cycle sweep) are described only as 'I', consistent with I_SPTA used elsewhere in the paper, but the domain (free-field water calibration vs. skull-derated in-brain value) is not explicitly stated.exposures[0].timing.pulse_duration_ms— The paper reports carrier frequency, a separate 50 kHz modulation frequency, and a 500 Hz pulse-repetition frequency, plus a duty-cycle range (5-70%), but never states pulse duration directly, so the burst rule could not be resolved; both the modulation frequency and duty-cycle range are recorded in protocol_description instead.sham_type— Ipsilateral VPL stimulation (real ultrasound, no effect) is used as the anatomical control condition; classified as active_control_site.provenance.notes— A sentence states 'Suppression of the SSEP saturated at around 15 dB W/cm2', which mixes incompatible units (dB and W/cm2), apparently an OCR/typesetting error; this value was not extracted into a numeric field.