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: 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

Objective: Low-intensity transcranial focused ultrasound (tFUS) has emerged as a promising non-invasive brain stimulation modality with high spatial selectivity and the ability to reach deep brain areas. The present study aimed to investigate the safety and effectiveness of low-intensity tFUS in treating major depressive disorder. Methods: Participants were recruited in an outpatient clinic and randomly assigned to either the verum tFUS or sham stimulation group. The intervention group received six sessions of tFUS stimulation to the left dorsolateral prefrontal cortex over two weeks. Neuropsychological assessments were conducted before and after the sessions. Resting-state functional magnetic resonance imaging (rsfMRI) was also performed to evaluate changes in functional connectivity (FC). The primary outcome measure was the change in depressive symptoms, assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS). Results: The tFUS stimulation sessions were well tolerated without any undesirable side effects. The analysis revealed a significant main effect of session sequence on the MADRS scores and significant interactions between the session sequences and groups. The rsfMRI analysis showed a higher FC correlation between the right superior part of the subgenual anterior cingulate cortex (sgACC) and several other brain regions in the verum group compared with the sham group. Conclusion Our results reveal that tFUS stimulation clinically improved MADRS scores with network-level modulation of a sgACC subregion. This randomized, sham-controlled clinical trial, the first study of its kind, demonstrated the safety and probable efficacy of tFUS stimulation for the treatment of depression.

Objective: Low-intensity transcranial focused ultrasound (tFUS) has emerged as a promising non-invasive brain stimulation modality with high spatial selectivity and the ability to reach deep brain areas. The present study aimed to investigate the safety and effectiveness of low-intensity tFUS in treating major depressive disorder. Methods: Participants were recruited in an outpatient clinic and randomly assigned to either the verum tFUS or sham stimulation group. The intervention group received six sessions of tFUS stimulation to the left dorsolateral prefrontal cortex over two weeks. Neuropsychological assessments were conducted before and after the sessions. Resting-state functional magnetic resonance imaging (rsfMRI) was also performed to evaluate changes in functional connectivity (FC). The primary outcome measure was the change in depressive symptoms, assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS). Results: The tFUS stimulation sessions were well tolerated without any undesirable side effects. The analysis revealed a significant main effect of session sequence on the MADRS scores and significant interactions between the session sequences and groups. The rsfMRI analysis showed a higher FC correlation between the right superior part of the subgenual anterior cingulate cortex (sgACC) and several other brain regions in the verum group compared with the sham group. Conclusion Our results reveal that tFUS stimulation clinically improved MADRS scores with network-level modulation of a sgACC subregion. This randomized, sham-controlled clinical trial, the first study of its kind, demonstrated the safety and probable efficacy of tFUS stimulation for the treatment of depression.

Objective: Low-intensity transcranial focused ultrasound (tFUS) has emerged as a promising non-invasive brain stimulation modality with high spatial selectivity and the ability to reach deep brain areas. The present study aimed to investigate the safety and effectiveness of low-intensity tFUS in treating major depressive disorder. Methods: Participants were recruited in an outpatient clinic and randomly assigned to either the verum tFUS or sham stimulation group. The intervention group received six sessions of tFUS stimulation to the left dorsolateral prefrontal cortex over two weeks. Neuropsychological assessments were conducted before and after the sessions. Resting-state functional magnetic resonance imaging (rsfMRI) was also performed to evaluate changes in functional connectivity (FC). The primary outcome measure was the change in depressive symptoms, assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS). Results: The tFUS stimulation sessions were well tolerated without any undesirable side effects. The analysis revealed a significant main effect of session sequence on the MADRS scores and significant interactions between the session sequences and groups. The rsfMRI analysis showed a higher FC correlation between the right superior part of the subgenual anterior cingulate cortex (sgACC) and several other brain regions in the verum group compared with the sham group. Conclusion Our results reveal that tFUS stimulation clinically improved MADRS scores with network-level modulation of a sgACC subregion. This randomized, sham-controlled clinical trial, the first study of its kind, demonstrated the safety and probable efficacy of tFUS stimulation for the treatment of depression.

Objective: Low-intensity transcranial focused ultrasound (tFUS) has emerged as a promising non-invasive brain stimulation modality with high spatial selectivity and the ability to reach deep brain areas. The present study aimed to investigate the safety and effectiveness of low-intensity tFUS in treating major depressive disorder. Methods: Participants were recruited in an outpatient clinic and randomly assigned to either the verum tFUS or sham stimulation group. The intervention group received six sessions of tFUS stimulation to the left dorsolateral prefrontal cortex over two weeks. Neuropsychological assessments were conducted before and after the sessions. Resting-state functional magnetic resonance imaging (rsfMRI) was also performed to evaluate changes in functional connectivity (FC). The primary outcome measure was the change in depressive symptoms, assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS). Results: The tFUS stimulation sessions were well tolerated without any undesirable side effects. The analysis revealed a significant main effect of session sequence on the MADRS scores and significant interactions between the session sequences and groups. The rsfMRI analysis showed a higher FC correlation between the right superior part of the subgenual anterior cingulate cortex (sgACC) and several other brain regions in the verum group compared with the sham group. Conclusion Our results reveal that tFUS stimulation clinically improved MADRS scores with network-level modulation of a sgACC subregion. This randomized, sham-controlled clinical trial, the first study of its kind, demonstrated the safety and probable efficacy of tFUS stimulation for the treatment of depression.