Abstract
Transcranial application of pulsed low-intensity focused ultrasound (FUS) modulates the excitability of region-specific brain areas, and anesthetic confounders on brain activity warrant the evaluation of the technique in awake animals. We examined the neuromodulatory effects of FUS in unanesthetized sheep by developing a custom-fit headgear capable of reproducibly placing an acoustic focus on the unilateral motor cortex (M1) and corresponding thalamic area. The efferent responses to sonication, based on the acoustic parameters previously identified in anesthetized sheep, were measured using electromyography (EMG) from both hind limbs across three experimental conditions: on-target sonication, off-target sonication, and without sonication. Excitatory sonication yielded greater amplitude of EMG signals obtained from the hind limb contralateral to sonication than that from the ipsilateral limb. Spurious appearance of motion-related EMG signals limited the amount of analyzed data (~ 10% selection of acquired data) during excitatory sonication, and the averaged EMG response rates elicited by the M1 and thalamic stimulations were 7.5 ± 1.4% and 6.7 ± 1.5%, respectively. Suppressive sonication, while sheep walked on the treadmill, temporarily reduced the EMG amplitude from the limb contralateral to sonication. No significant change was found in the EMG amplitudes during the off-target sonication. Behavioral observation throughout the study and histological analysis showed no sign of brain tissue damage caused by the acoustic stimulation. Marginal response rates observed during excitatory sonication call for technical refinement to reduce motion artifacts during EMG acquisitions as well as acoustic aberration correction schemes to improve spatial accuracy of sonication. Yet, our results indicate that low-intensity FUS modulated the excitability of regional brain tissues reversibly and safely in awake sheep, supporting its potential in theragnostic applications.
Highlights
Transcranial application of pulsed low-intensity focused ultrasound (FUS) modulates the excitability of region-specific brain areas, and anesthetic confounders on brain activity warrant the evaluation of the technique in awake animals
Anatomical and functional magnetic resonance imaging (MRI)-based navigation provided guidance on sonicating the unilateral primary motor cortical (M1) and the thalamic areas while electromyography (EMG) was acquired wirelessly from both hind limbs to evaluate the efferent outcome of the FUS stimulation of the brain by measuring changes in EMG amplitude obtained across three experimental conditions—sonication of the target, sonication of an off-target non-motor area, and without sonication
We found that the sonication parameters used in the present study, which were previously identified from anesthetized sheep, generated bimodal neuromodulatory effects in awake sheep
Summary
Transcranial application of pulsed low-intensity focused ultrasound (FUS) modulates the excitability of region-specific brain areas, and anesthetic confounders on brain activity warrant the evaluation of the technique in awake animals. While non-human primates can be trained to immobilize their head (often using a head fixation apparatus) for the application of FUS, reproducible and precise sonication to a desired brain location is a challenging task when using awake sheep. Anatomical and functional MRI-based navigation provided guidance on sonicating the unilateral primary motor cortical (M1) and the thalamic areas while electromyography (EMG) was acquired wirelessly from both hind limbs to evaluate the efferent outcome of the FUS stimulation of the brain by measuring changes in EMG amplitude obtained across three experimental conditions—sonication of the target, sonication of an off-target non-motor area, and without sonication. We report similarities and differences in the neuromodulatory outcomes to the ones previously demonstrated in anesthetized sheep, along with a safety evaluation through behavioral monitoring and histological assessment
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