Transcranial ultrasound neuromodulation of the thalamic visual pathway in a large animal model and the dose-response relationship with MR-ARFI
Morteza Mohammadjavadi, Ryan T. Ash, Ningrui Li, Pooja Gaur, Jan Kubanek, Yamil Saenz, Gary H. Glover, Gerald R. Popelka, Anthoney M. Norcia, Kim Butts Pauly
Scientific Reports 2022, 12 · 10.1038/s41598-022-20554-4
Abstract
Neuromodulation of deep brain structures via transcranial ultrasound stimulation (TUS) is a promising, but still elusive approach to non-invasive treatment of brain disorders. The purpose of this study was to confirm that MR-guided TUS of the lateral geniculate nucleus (LGN) can modulate visual evoked potentials (VEPs) in the intact large animal; and to study the impact on cortical brain oscillations. The LGN on one side was identified with T2-weighted MRI in sheep (all male, n = 9). MR acoustic radiation force imaging (MR-ARFI) was used to confirm localization of the targeted area in the brain. Electroencephalographic (EEG) signals were recorded, and the visual evoked potential (VEP) peak-to-peak amplitude (N70 and P100) was calculated for each trial. Time-frequency spectral analysis was performed to elucidate the effect of TUS on cortical brain dynamics. The VEP peak-to-peak amplitude was reversibly suppressed relative to baseline during TUS. Dynamic spectral analysis demonstrated a change in cortical oscillations when TUS is paired with visual sensory input. Sonication-associated microscopic displacements, as measured by MR-ARFI, correlated with the TUS-mediated suppression of visual evoked activity. TUS non-invasively delivered to LGN can neuromodulate visual activity and oscillatory dynamics in large mammalian brains.
Abstract via europepmc.
Exposures
Exposure 1: MR-guided TUS of the lateral geniculate nucleus (LGN), with non-LGN (medial putamen/internal capsule) active control sonication
Target: lateral geniculate nucleus — “lateral geniculate nucleus (LGN) of the thalamus, unilateral”
Device: Insightec · Insightec Ltd. · ExAblate 2100 (1024-element phased array) ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 550 | ✓✓✓ |
| 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 | measurementmean or range across subjects | |
| In-situ pressure (kPa) | 550, 1,000swept | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | 19.3, 63.8swept | ✓✓✓ |
| In-situ Ispta (W/cm²) | 2.8, 9.57swept | ✓✓✓ |
Nine male sheep (6 LGN-TUS experiments on 5 animals; 5 sham experiments on 4 animals, including one animal given zero TUS intensity and three 'Active Sham' animals where the transducer was unintentionally off-target due to movement) underwent a 5-min light-only EEG baseline, then two 20-min LGN sonication blocks, then three 20-min non-LGN control-site sonication blocks (control site ~10 mm anterior to LGN, spanning medial putamen and adjacent internal capsule). Each 20-min block cycled four interleaved 15 s conditions every minute: no stimulus, light-only, TUS-only, and light-plus-TUS (1 Hz repetition). Pulse trains had a rectangular envelope, repeated once per second.
Flags from extraction
blinding— Blinding was incidental rather than a designed protocol: 'Active Sham' cases were identified only at the end of the experiment (transducer dislocation discovered by visual/MRI inspection), so 'the experimenters were blind to the experimental conditions for Active Sham or TUS groups during the experiment.' Coded as single-blind.sham_type— The sham/control group combined three distinct mechanisms: one animal given deliberately zero TUS intensity (inactive_transducer), three animals where the transducer was unintentionally off-target due to movement (not a designed sham, coded as other), plus a within-subject active non-LGN control-site sonication used in the LGN-TUS group itself (active_control_site).auditory_control— No masking sound or deafening was used; auditory/electromagnetic confounds were instead addressed analytically via interleaved light-only vs light-plus-TUS vs TUS-only trials and a separate tofu-phantom EEG-artifact control experiment.n_sessions_per_subject— Most animals underwent the protocol once, but one LGN-TUS animal and one Active-Sham animal each underwent the full procedure twice (12 and 3 days apart respectively); recorded as [1,2] rather than a single number.exposures[0].in_situ.pressure_kpa— In-situ intensity/pressure were estimated retrospectively from ex vivo hydrophone measurements of transmission through each animal's excised skull cap, then combined with per-animal power settings; reported as a range across the 6 LGN experiments with means given in the quote.