Image-Guided Focused Ultrasound-Mediated Regional Brain Stimulation in Sheep
Wonhye Lee, Stephanie D. Lee, Michael Y. Park, Lori Foley, Erin Purcell-Estabrook, Hyungmin Kim, Krisztina Fischer, Lee-So Maeng, Seung-Schik Yoo
Ultrasound in Medicine & Biology 2016, 42, 459-470 · 10.1016/j.ultrasmedbio.2015.10.001
Abstract
Non-invasive brain stimulation using focused ultrasound has largely been carried out in small animals. In the present study, we applied stimulatory focused ultrasound transcranially to the primary sensorimotor (SM1) and visual (V1) brain areas in sheep (Dorset, all female, n = 8), under the guidance of magnetic resonance imaging, and examined the electrophysiologic responses. By use of a 250-kHz focused ultrasound transducer, the area was sonicated in pulsed mode (tone-burst duration of 1 ms, duty cycle of 50%) for 300 ms. The acoustic intensity at the focal target was varied up to a spatial peak pulse-average intensity (Isppa) of 14.3 W/cm(2). Sonication of SM1 elicited electromyographic responses from the contralateral hind leg, whereas stimulation of V1 generated electroencephalographic potentials. These responses were detected only above a certain acoustic intensity, and the threshold intensity, as well as the degree of responses, varied among sheep. Post-sonication animal behavior was normal, but minor microhemorrhages were observed from the V1 areas exposed to highly repetitive sonication (every second for ≥500 times for electroencephalographic measurements, Isppa = 6.6-10.5 W/cm(2), mechanical index = 0.9-1.2). Our results suggest the potential translational utility of focused ultrasound as a new brain stimulation modality, yet also call for caution in the use of an excessive number of sonications.
Abstract via europepmc.
Exposures
Exposure 1: Primary sensorimotor cortex (SM1) stimulation, EMG-based motor evoked potentials
Target: sensorimotor cortex — “primary sensorimotor (SM1)”
Device: custom-built · Channel Industries (piezo-ceramic element; custom transducer assembly) · single-element ceramic piezo-electric FUS transducer, 250 kHz, 6-cm outer diameter, 7-cm radius of curvature ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 250 | ✓✓✓ |
| Pulse duration (ms) | 1 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 500 | ✓✓✓ |
| Duty cycle (%) | 50pulse duration × PRF gives 50% | ✓✓✓ |
| Sonication duration (s) | 0.3 | ✓✓✓ |
| 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) | 0.5, 11.8swept | ✓✓✓⚑ |
| In-situ Ispta (W/cm²) | not reported |
During each FUS session, batches of sonication were given in 5-s intervals (for MEP measurement) to the target area in the brain. The minimum AI eliciting tangible responses was searched for by increasing the AI from 0.5 W/cm^2 Isppa with 30 s between trials, then increased (in-situ, skull-attenuation corrected) up to 11.8 W/cm^2 Isppa for SM1. Focused ultrasound was administered to the left hemisphere of the SM1 area and EMG-based MEP measurements were taken from both hind legs.
Exposure 2: Primary visual cortex (V1) stimulation, EEG-based sonication-triggered visual evoked potentials
Target: primary visual cortex — “primary visual (V1)”
Device: custom-built · Channel Industries (piezo-ceramic element; custom transducer assembly) · single-element ceramic piezo-electric FUS transducer, 250 kHz, 6-cm outer diameter, 7-cm radius of curvature ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 250 | ✓✓✓ |
| Pulse duration (ms) | 1 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 500 | ✓✓✓ |
| Duty cycle (%) | 50pulse duration × PRF gives 50% | ✓✓✓ |
| Sonication duration (s) | 0.3 | ✓✓✓ |
| 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) | 0.5, 14.3swept | ✓✓✓ |
| In-situ Ispta (W/cm²) | not reported |
During each FUS session, batches of sonication were given in 1-s intervals (for sVEP measurement) to the target area in the brain. The minimum AI eliciting tangible responses was searched for by increasing the AI from 0.5 W/cm^2 Isppa with 30 s between trials, then increased (in-situ, skull-attenuation corrected) up to 14.3 W/cm^2 Isppa for V1. A total of four to eight multiple FUS sessions were performed on each sheep to acquire the sVEPs, with EEG responses averaged (n=100, every second for each sonication) to derive the sVEP; a subset of sheep additionally received highly repetitive sonication (500 or more sonications, every second) to probe prolonged-exposure effects.
Flags from extraction
exposures[0].in_situ.isppa_w_cm2— The 0.5 W/cm^2 starting value of the intensity search is not explicitly stated to be pre- or post-skull-correction; it is grouped with the corrected in-situ maxima (11.8/14.3 W/cm^2) as the tested range, but this domain assignment for the lower bound is uncertain.n_sessions_per_subject— The '4 to 8 sessions per sheep' figure is stated specifically for the sVEP (V1) data collection; the number of SM1/MEP sessions per sheep is not given as clearly (Table 1 shows a variable number of FUS procedures per sheep).exposures[*].timing.protocol_description— Inter-sonication/inter-trial intervals (5 s for MEP, 1 s for sVEP, 30 s during threshold search) and the highly repetitive V1 sub-study (500+ sonications) are described qualitatively per the schema's protocol_description field rather than as additional numeric timing fields.