Effects of focused ultrasound pulse duration on stimulating cortical and subcortical motor circuits in awake sheep
Hyun-Chul Kim, Wonhye Lee, Kavin Kowsari, Daniel S. Weisholtz, Seung-Schik Yoo
PLOS ONE 2022 · 10.1371/journal.pone.0278865
Abstract
Low-intensity transcranial focused ultrasound (tFUS) offers new functional neuromodulation opportunities, enabling stimulation of cortical as well as deep brain areas with high spatial resolution. Brain stimulation of awake sheep, in the absence of the confounding effects of anesthesia on brain function, provides translational insight into potential human applications with safety information supplemented by histological analyses. We examined the effects of tFUS pulsing parameters, particularly regarding pulse durations (PDs), on stimulating the cortical motor area (M1) and its thalamic projection in unanesthetized, awake sheep (n = 8). A wearable tFUS headgear, custom-made for individual sheep, enabled experiments to be conducted without using anesthesia. FUS stimuli, each 200 ms long, were delivered to the M1 and the thalamus using three different PDs (0.5, 1, and 2 ms) with the pulse repetition frequency (PRF) adjusted to maintain a 70% duty cycle at a derated in situ spatial-peak temporal-average intensity (Ispta) of 3.6 W/cm2. Efferent electromyography (EMG) responses to stimulation were quantified from both hind limbs. Group-averaged EMG responses from each of the hind limbs across the experimental conditions revealed selective responses from the hind limb contralateral to sonication. The use of 0.5 and 1 ms PDs generated higher EMG signal amplitudes compared to those obtained using a 2 ms PD. Faster efferent response was also observed from thalamic stimulation than that from stimulating the M1. Post-sonication behavioral observation and histological assessment performed 24 h and 1 month after sonication were not indicative of any abnormalities. The results suggest the presence of pulsing scheme-dependent effects of tFUS on brain stimulation and attest its safety in awake large animals.
Abstract via europepmc.
Exposures
Exposure 1: M1 stimulation, three pulse durations
Target: primary motor cortex — “M1”
Device: Ultran · Ultran Group · GPS200-MR
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 250 | ✓✓✓ |
| Pulse duration (ms) | 0.5, 1, 2swept | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 1,400, 700, 350swept | ✓✓✓ |
| Duty cycle (%) | 70 | ✓✓✓ |
| Sonication duration (s) | 0.2 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | 5.2 | ✓✓✓⚑ |
| In-situ Ispta (W/cm²) | 3.6 | ✓✓✓ |
200 ms stimuli at 70% duty cycle with pulse durations 0.5, 1 and 2 ms (PRF 1,400, 700, 350 Hz respectively), randomised with no-FUS trials at 4.8 s intervals; 50 trials per parameter per session, 5 sessions per animal.
Exposure 2: Thalamic stimulation, three pulse durations
Target: thalamus — “thalamus”
Device: Ultran · Ultran Group · GPS200-MR
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 250 | ✓✓✓ |
| Pulse duration (ms) | 0.5, 1, 2swept | ✓✓✓ |
| Pulse repetition frequency (Hz) | 1,400, 700, 350swept | ✓✓✓ |
| Duty cycle (%) | 70 | ✓✓✓ |
| Sonication duration (s) | 0.2 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | 5.2 | ✓✓✓ |
| In-situ Ispta (W/cm²) | 3.6 | ✓✓✓ |
200 ms stimuli at 70% duty cycle with pulse durations 0.5, 1 and 2 ms (PRF 1,400, 700, 350 Hz respectively), randomised with no-FUS trials at 4.8 s intervals; 50 trials per parameter per session, 5 sessions per animal.
Flags from extraction
exposures[0].in_situ.isppa_w_cm2— In situ Isppa estimated with a 25.6% intensity transmission derived from ovine skull in a previous study; free-field intensity not stated.sham_type— No-FUS trials were interleaved randomly; how they were produced is not described.auditory_control— Paper notes auditory confounds were not controlled and need future study; only short-latency EMG (<25 ms) was excluded.exposures[0].timing.pulse_duration_ms— Pulse duration, PRF vary together to keep 70% duty cycle; lists are aligned (0.5/1400, 1/700, 2/350).exposures[1].target— Thalamic target not specified further than thalamus.