Lack of a region-specific brain stimulation modality having both spatial specificity and depth penetration has limited clinicians to explore novel non-pharmacological treatment options in neurorehabilitation. Focused ultrasound (FUS) has shown excitatory and suppressive modulatory effects on neural tissues in both central and peripheral nervous systems by transcranially delivering low-intensity highly focused acoustic pressure waves to region-specific neural structures in a completely non-invasive fashion. This emerging technique, with exquisite spatial selectively and depth penetration, is considered as a new mode of brain stimulation that may significantly improve existing brain stimulation modalities. This review aims to provide the perspectives of FUS-mediated brain stimulation in neurorehabilitation, along with potential pitfalls and cautions that need to be taken into consideration. When combined with the intravascular introduction of microbubble-based ultrasound contrast agents, the technique adds therapeutic potentials in delivering drug/genes/cells across the blood-brain barrier, which may open new opportunities for neurorehabilitation. Efforts are being made to construct FUS devices appropriate for routine clinical use, to investigate its fundamental mechanisms, and to optimize the sonication parameters. Repeated administration of the technique for inducing neuroplasticity, including the assessment of long-term safety, is warranted to reveal its utility in neurorehabilitation.
Acoustics ; Blood-Brain Barrier ; Brain* ; Contrast Media ; Neurological Rehabilitation* ; Neuronal Plasticity ; Peripheral Nervous System ; Sensitivity and Specificity ; Sonication ; Ultrasonography*

ABSTRACT OBJECTIVES: We report event-related functional magnetic resonance imaging(fMRI) methodology to investigate human brain activity during motor imagery. METHODS: A 1.5 Tesla clinical MR scanner was used in the acquisition of a series of T2* weighted MR images covering the whole brain. Blood oxygenation level-dependent(BOLD) signal changes associated with the imagery event were subsequently detected while healthy right-handed subjects imagined clenching of a right hand cued by auditory stimulus. RESULTS: Group analysis across nine right-handed subjects revealed activations in the medial and superior frontal gyri, cuneus, insula, middle/superior temporal gyri, and anterior cingulate gyri. Bilateral primary motor, premotor and supplementary motor areas exhibited event-related MR signal changes. Although unilateral hand clenching was imagined, bilateral activation of eloquent motor areas was observed. The proposed method also allowed for the visualization of subcortical areas, such as putamen, globus pallidus and thalamus, responsive to the event of motor imagery. CONCLUSION: The major cortical and subcortical areas in the motor pathways were identified and visualized during motor imagery event. Our results suggest that motor imagery and actual movement share common neural substrates.
Brain ; Brain Mapping ; Efferent Pathways ; Globus Pallidus ; Hand ; Humans ; Magnetic Resonance Imaging* ; Oxygen ; Putamen ; Thalamus

Ultrasound is an important theragnostic modality in modern medicine. Technical advancement of both acoustic focusing and transcranial delivery have enabled administration of ultrasound waves to localized brain areas with few millimeters of spatial specificity and penetration depth sufficient to reach the thalamus. Transcranial focused ultrasound (tFUS) given at a low acoustic intensity has been shown to increase or suppress the excitability of region-specific brain areas. The neuromodulatory effects can outlast the sonication, suggesting the possibility of inducing neural plasticity needed for neurorehabilitation.Increasing numbers of studies have shown the efficacy and excellent safety profile of the technique, yet comparisons among the safety-related parameters have not been compiled.This review aims to provide safety information and perspectives of tFUS brain stimulation.First, the acoustic parameters most relevant to thermal/mechanical tissue damage are discussed along with regulated parameters for existing ultrasound therapies/diagnostic imaging. Subsequently, the parameters used in studies of large animals, non-human primates, and humans are surveyed and summarized in terms of the acoustic intensity and the mechanical index. The pulse-mode operation and the use of low ultrasound frequency for tFUS-mediated brain stimulation warrant the establishment of new safety guidelines/ recommendations for the use of the technique among healthy volunteers, with additional cautionary requirements for its clinical translation.

Purpose: Acoustic streaming induced by applying transcranial focused ultrasound (FUS) promotes localized advective solute transport in the brain and has recently garnered research interest for drug delivery and enhancement of brain waste clearance. The acoustic streaming behavior in brain tissue is difficult to model numerically and thus warrants an in vitro examination of the effects of using different sonication parameters, in terms of frequency, intensity, and pulse duration (PD). Methods: Melamine and polyvinyl alcohol (PVA) foams were used to mimic the porous brain tissue, which contains leptomeningeal fenestrations and perivascular space, while agar hydrogel was used to emulate denser neuropil. FUS was delivered to these media, which were immersed in a phosphate-buffered saline containing toluidine blue O dye, across various frequencies (400, 500, and 600 kHz; applicable to transcranial delivery) in a pulsed mode at two different spatialpeak pulse-average intensities (3 and 4 W/cm2). Results: Image analysis showed that the use of 400 kHz yielded the greatest dye infiltration in melamine foam, while sonication had no impact on infiltration in the agar hydrogel due to the dominance of diffusional transport. Using a fixed spatial-peak temporal-average intensity of 0.4 W/cm2 at 400 kHz, a PD of 75 ms resulted in the greatest infiltration depth in both melamine and PVA foams among the tested range (50-150 ms). Conclusion These findings suggest the existence of a specific frequency and PD that induce greater enhancement of solute/fluid movement, which may contribute to eventual in vivo applications in promoting waste clearance from the brain.

Purpose: Acoustic streaming induced by applying transcranial focused ultrasound (FUS) promotes localized advective solute transport in the brain and has recently garnered research interest for drug delivery and enhancement of brain waste clearance. The acoustic streaming behavior in brain tissue is difficult to model numerically and thus warrants an in vitro examination of the effects of using different sonication parameters, in terms of frequency, intensity, and pulse duration (PD). Methods: Melamine and polyvinyl alcohol (PVA) foams were used to mimic the porous brain tissue, which contains leptomeningeal fenestrations and perivascular space, while agar hydrogel was used to emulate denser neuropil. FUS was delivered to these media, which were immersed in a phosphate-buffered saline containing toluidine blue O dye, across various frequencies (400, 500, and 600 kHz; applicable to transcranial delivery) in a pulsed mode at two different spatialpeak pulse-average intensities (3 and 4 W/cm2). Results: Image analysis showed that the use of 400 kHz yielded the greatest dye infiltration in melamine foam, while sonication had no impact on infiltration in the agar hydrogel due to the dominance of diffusional transport. Using a fixed spatial-peak temporal-average intensity of 0.4 W/cm2 at 400 kHz, a PD of 75 ms resulted in the greatest infiltration depth in both melamine and PVA foams among the tested range (50-150 ms). Conclusion These findings suggest the existence of a specific frequency and PD that induce greater enhancement of solute/fluid movement, which may contribute to eventual in vivo applications in promoting waste clearance from the brain.

Purpose: Acoustic streaming induced by applying transcranial focused ultrasound (FUS) promotes localized advective solute transport in the brain and has recently garnered research interest for drug delivery and enhancement of brain waste clearance. The acoustic streaming behavior in brain tissue is difficult to model numerically and thus warrants an in vitro examination of the effects of using different sonication parameters, in terms of frequency, intensity, and pulse duration (PD). Methods: Melamine and polyvinyl alcohol (PVA) foams were used to mimic the porous brain tissue, which contains leptomeningeal fenestrations and perivascular space, while agar hydrogel was used to emulate denser neuropil. FUS was delivered to these media, which were immersed in a phosphate-buffered saline containing toluidine blue O dye, across various frequencies (400, 500, and 600 kHz; applicable to transcranial delivery) in a pulsed mode at two different spatialpeak pulse-average intensities (3 and 4 W/cm2). Results: Image analysis showed that the use of 400 kHz yielded the greatest dye infiltration in melamine foam, while sonication had no impact on infiltration in the agar hydrogel due to the dominance of diffusional transport. Using a fixed spatial-peak temporal-average intensity of 0.4 W/cm2 at 400 kHz, a PD of 75 ms resulted in the greatest infiltration depth in both melamine and PVA foams among the tested range (50-150 ms). Conclusion These findings suggest the existence of a specific frequency and PD that induce greater enhancement of solute/fluid movement, which may contribute to eventual in vivo applications in promoting waste clearance from the brain.

Purpose: Acoustic streaming induced by applying transcranial focused ultrasound (FUS) promotes localized advective solute transport in the brain and has recently garnered research interest for drug delivery and enhancement of brain waste clearance. The acoustic streaming behavior in brain tissue is difficult to model numerically and thus warrants an in vitro examination of the effects of using different sonication parameters, in terms of frequency, intensity, and pulse duration (PD). Methods: Melamine and polyvinyl alcohol (PVA) foams were used to mimic the porous brain tissue, which contains leptomeningeal fenestrations and perivascular space, while agar hydrogel was used to emulate denser neuropil. FUS was delivered to these media, which were immersed in a phosphate-buffered saline containing toluidine blue O dye, across various frequencies (400, 500, and 600 kHz; applicable to transcranial delivery) in a pulsed mode at two different spatialpeak pulse-average intensities (3 and 4 W/cm2). Results: Image analysis showed that the use of 400 kHz yielded the greatest dye infiltration in melamine foam, while sonication had no impact on infiltration in the agar hydrogel due to the dominance of diffusional transport. Using a fixed spatial-peak temporal-average intensity of 0.4 W/cm2 at 400 kHz, a PD of 75 ms resulted in the greatest infiltration depth in both melamine and PVA foams among the tested range (50-150 ms). Conclusion These findings suggest the existence of a specific frequency and PD that induce greater enhancement of solute/fluid movement, which may contribute to eventual in vivo applications in promoting waste clearance from the brain.

Purpose: Acoustic streaming induced by applying transcranial focused ultrasound (FUS) promotes localized advective solute transport in the brain and has recently garnered research interest for drug delivery and enhancement of brain waste clearance. The acoustic streaming behavior in brain tissue is difficult to model numerically and thus warrants an in vitro examination of the effects of using different sonication parameters, in terms of frequency, intensity, and pulse duration (PD). Methods: Melamine and polyvinyl alcohol (PVA) foams were used to mimic the porous brain tissue, which contains leptomeningeal fenestrations and perivascular space, while agar hydrogel was used to emulate denser neuropil. FUS was delivered to these media, which were immersed in a phosphate-buffered saline containing toluidine blue O dye, across various frequencies (400, 500, and 600 kHz; applicable to transcranial delivery) in a pulsed mode at two different spatialpeak pulse-average intensities (3 and 4 W/cm2). Results: Image analysis showed that the use of 400 kHz yielded the greatest dye infiltration in melamine foam, while sonication had no impact on infiltration in the agar hydrogel due to the dominance of diffusional transport. Using a fixed spatial-peak temporal-average intensity of 0.4 W/cm2 at 400 kHz, a PD of 75 ms resulted in the greatest infiltration depth in both melamine and PVA foams among the tested range (50-150 ms). Conclusion These findings suggest the existence of a specific frequency and PD that induce greater enhancement of solute/fluid movement, which may contribute to eventual in vivo applications in promoting waste clearance from the brain.

Purpose: Increasing attention has been paid to low-intensity transcranial focused ultrasound (tFUS) for its potential therapeutic effects in Alzheimer's disease (AD). While preclinical studies have shown promising therapeutic effects of low-intensity tFUS in AD models, its efficacy and safety remain unclear in humans. In this pilot study, we investigated the effects of low-intensity tFUS on blood-brain barrier opening, the regional cerebral metabolic rate of glucose (rCMRglu), and cognition in patients with AD. Methods: After receiving institutional review board approval, four patients with AD received tFUS to the hippocampus immediately after an intravenous injection of a microbubble ultrasound contrast agent. Sonication was delivered at low-intensity, at a pressure level below the threshold for blood-brain barrier opening. Patients underwent brain magnetic resonance imaging, 18F-fluoro-2-deoxyglucose positron emission tomography, and neuropsychological assessments before and after the tFUS procedure. A whole-brain voxel-wise paired t test was conducted to compare rCMRglu before and after tFUS. Results: The sonication, as anticipated, did not show evidence of active blood-brain barrier opening on T1 dynamic contrast-enhanced magnetic resonance imaging. rCMRglu in the superior frontal gyrus (P<0.001), middle cingulate gyrus (P<0.001), and fusiform gyrus increased after tFUS (P=0.001). Patients demonstrated mild improvement in measures of memory, executive, and global cognitive function following tFUS. No adverse events were reported. Conclusion These results suggest that hippocampal sonication with low-intensity tFUS may have beneficial effects on cerebral glucose metabolism and cognitive function in patients with AD. Further larger studies are needed to confirm the therapeutic efficacy of tFUS in AD.

OBJECTIVES: We report a functional magnetic resonance imaging(fMRI) method for mapping human cerebellar activity during painful cold-stimulation. METHODS: Six healthy volunteers experienced painful thermal stimulation induced by holding an ice bag(0-3C) in their left hand while lying still in 1.5 Tesla MR scanner. In order to capture the hemodynamic BOLD(blood oxygenation level dependent) response associated with the stimuli, a series of susceptibility-weighted MR images were acquired, and a statistical parametric map was generated to visualize and quantify the eloquent areas of brain activation. RESULTS: In addition to cerebral areas including anterior/posterior cingulate gyri, prefrontal cortex, and insula, our results suggested that several cerebellar areas such as quadrangular lobule, bilateral gracile and semilunar lobules were involved in the experience of pain during cold stimulation. CONCLUSIONS: Human cerebellum, in addition to the cerebrum, is involved in the cognition and processing painful sensory stimulation.
Brain ; Cerebellum ; Cerebrum ; Cognition ; Deception ; Hand ; Healthy Volunteers ; Hemodynamics ; Humans* ; Ice ; Magnetic Resonance Imaging* ; Oxygen ; Prefrontal Cortex