Feasibility of Magnetic Resonance-Compatible Accelerometers to Monitor Tremor Fluctuations During Magnetic Resonance-Guided Focused Ultrasound Thalamotomy: Technical Note.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is used to treat essential tremor and tremor-dominant Parkinson disease. Feedback is collected throughout the procedure to verify the location of the target and completeness of response; however, variability in clinical judgments may underestimate or overestimate treatment response. OBJECTIVE: To objectively quantify joint motion after each sonication using accelerometers secured to the contralateral upper extremity in an effort to optimize MRgFUS treatment. METHODS: Before the procedure, 3 accelerometers were secured to the patient's arm, forearm, and index finger. Throughout the procedure, tremor motion was regularly recorded during postural and kinetic tremor testing and individual joint angle measures were modeled. The joint angle from each accelerometer was compared with baseline measurements to assess changes in angles. Subsequent adjustments to the target location and sonication energy were made at the discretion of the neurosurgeon and neuroradiologist. RESULTS: Intraoperative accelerometer measurements of hand tremor from 18 patients provided quantified data regarding joint angle reduction: 87.3%, 94.2%, and 86.7% for signature writing, spiral drawing, and line drawing tests, respectively. Target adjustment based on accelerometer monitoring of the angle at each joint added substantial value toward achieving optimal tremor reduction. CONCLUSION: Real-time accelerometer recordings collected during MRgFUS thalamotomy offered objective quantification of changes in joint angle after each sonication, and these findings were consistent with clinical judgments of tremor response. These results suggest that this technique could be used for fine adjustment of the location of sonication energy and number of sonications to consistently achieve optimal tremor reduction.

Clinical Intervention Using Focused Ultrasound (FUS) Stimulation of the Brain in Diverse Neurological Disorders.

Various surgical techniques and pharmaceutical treatments have been developed to improve the current technologies of treating brain diseases. Focused ultrasound (FUS) is a new brain stimulation modality that can exert a therapeutic effect on diseased brain cells, with this effect ranging from permanent ablation of the pathological neural circuit to transient excitatory/inhibitory modulation of the neural activity depending on the acoustic energy of choice. With the development of intraoperative imaging technology, FUS has become a clinically available noninvasive neurosurgical option with visual feedback. Over the past 10 years, FUS has shown enormous potential. It can deliver acoustic energy through the physical barrier of the brain and eliminate abnormal brain cells to treat patients with Parkinson's disease and essential tremor. In addition, FUS can help introduce potentially beneficial therapeutics at the exact brain region where they need to be, bypassing the brain's function barrier, which can be applied for a wide range of central nervous system disorders. In this review, we introduce the current FDA-approved clinical applications of FUS, ranging from thermal ablation to blood barrier opening, as well as the emerging applications of FUS in the context of pain control, epilepsy, and neuromodulation. We also discuss the expansion of future applications and challenges. Broadening FUS technologies requires a deep understanding of the effect of ultrasound when targeting various brain structures in diverse disease conditions in the context of skull interface, anatomical structure inside the brain, and pathology.

A review of bioeffects induced by focused ultrasound combined with microbubbles on the neurovascular unit.

Focused ultrasound combined with circulating microbubbles (FUS+MB) can transiently enhance blood-brain barrier (BBB) permeability at targeted brain locations. Its great promise in improving drug delivery to the brain is reflected by a rapidly growing number of clinical trials using FUS+MB to treat various brain diseases. As the clinical applications of FUS+MB continue to expand, it is critical to have a better understanding of the molecular and cellular effects induced by FUS+MB to enhance the efficacy of current treatment and enable the discovery of new therapeutic strategies. Existing studies primarily focus on FUS+MB-induced effects on brain endothelial cells, the major cellular component of BBB. However, bioeffects induced by FUS+MB expand beyond the BBB to cells surrounding blood vessels, including astrocytes, microglia, and neurons. Together these cell types comprise the neurovascular unit (NVU). In this review, we examine cell-type-specific bioeffects of FUS+MB on different NVU components, including enhanced permeability in endothelial cells, activation of astrocytes and microglia, as well as increased intraneuron protein metabolism and neuronal activity. Finally, we discuss knowledge gaps that must be addressed to further advance clinical applications of FUS+MB.

Mechanical and mechanothermal effects of focused ultrasound elicited distinct electromyographic responses in mice.

The objective of this study was to compare focused ultrasound (FUS) neuromodulation-induced motor responses under two physical mechanisms: mechanical and mechanothermal effects. Mice were divided into two groups. One group was subjected to short-duration FUS stimulation (0.3 s) that induced mechanical effects (mechanical group). The other group underwent long-duration FUS stimulation (15 s) that produced not only mechanical but also thermal effects (mechanothermal group). FUS was targeted at the deep cerebellar nucleus in the cerebellum to induce motor responses, which were evaluated by recording the evoked electromyographic (EMG) signals and tail movements. Brain tissue temperature rise associated with the FUS stimulation was quantified by noninvasive magnetic resonance thermometryin vivo. Temperature rise was negligible for the mechanical group (0.2 °C ± 0.1 °C) but did rise within the range of 0.6 °C ± 0.2 °C-3.3 °C ± 0.9 °C for the mechanothermal group. The elongated FUS beam also induced heating in the dorsal brain (below the top skull) and ventral brain (above the bottom skull) along the beam path for the mechanothermal group. Both mechanical and mechanothermal groups achieved successful FUS neuromodulation. EMG response latencies were within the range of 0.03-0.1 s at different intensity levels for the mechanical group. The mechanothermal effect of FUS could induce both short-latency EMG (0.2-1.4 s) and long-latency EMG (8.7-13.0 s) under the same intensity levels as the mechanical group. The different temporal dynamics of evoked EMG suggested that FUS-induced mechanical and mechanothermal effects could evoke different responses in the brain.

Sonothermogenetics for noninvasive and cell-type specific deep brain neuromodulation.

BACKGROUND: Critical advances in the investigation of brain functions and treatment of brain disorders are hindered by our inability to selectively target neurons in a noninvasive manner in the deep brain. OBJECTIVE: This study aimed to develop sonothermogenetics for noninvasive, deep-penetrating, and cell-type-specific neuromodulation by combining a thermosensitive ion channel TRPV1 with focused ultrasound (FUS)-induced brief, non-noxious thermal effect. METHODS: The sensitivity of TRPV1 to FUS sonication was evaluated in vitro. It was followed by in vivo assessment of sonothermogenetics in the activation of genetically defined neurons in the mouse brain by two-photon calcium imaging. Behavioral response evoked by sonothermogenetic stimulation at a deep brain target was recorded in freely moving mice. Immunohistochemistry staining of ex vivo brain slices was performed to evaluate the safety of FUS sonication. RESULTS: TRPV1 was found to be an ultrasound-sensitive ion channel. FUS sonication at the mouse brain in vivo selectively activated neurons that were genetically modified to express TRPV1. Temporally precise activation of TRPV1-expressing neurons was achieved with its success rate linearly correlated with the peak temperature within the FUS-targeted brain region as measured by in vivo magnetic resonance thermometry. FUS stimulation of TRPV1-expressing neurons at the striatum repeatedly evoked locomotor behavior in freely moving mice. FUS sonication was confirmed to be safe based on inspection of neuronal integrity, inflammation, and apoptosis markers. CONCLUSIONS: This noninvasive and cell-type-specific neuromodulation approach with the capability to stimulate deep brain has the promise to advance the study of the intact nervous system and uncover new ways to treat neurological disorders.

Deep Cerebellar Low-Intensity Focused Ultrasound Stimulation Restores Interhemispheric Balance after Ischemic Stroke in Mice.

Ischemic damage after stroke disrupts the complex balance of inhibitory and excitatory activity within cortical network causing brain functional asymmetry. Cerebellar deep nuclei with its extensive projections to cortical regions could be a prospective target for stimulation to restore inter-hemispheric balance and enhance neural plasticity after stroke. In our study, we repeatedly stimulated the lateral cerebellar nucleus (LCN) by low-intensity focused ultrasound (LIFU) for 3 days to enhance rehabilitation after middle cerebral artery occlusion (MCAO) in a mouse stroke model. The neural activity of the mice sensorimotor cortex was measured using epidural electrodes and analyzed with quantified electroencephalography (qEEG). Pairwise derived Brain Symmetry Index (pdBSI) and delta power were used to assess the neurorehabilitative effect of LIFU stimulation. Compared to the Stroke (non-treated) group, the LIFU group exhibited a decrease in cortical pathological delta activity, significant recovery in pdBSI and enhanced performance on the balance beam walking test. These results suggest that cerebellar LIFU stimulation could be a non-invasive method for stroke rehabilitation through the restoration of interhemispheric balance.

A neuroprotective brain stimulation for vulnerable cerebellar Purkinje cell after ischemic stroke: a study with low-intensity focused ultrasound.

The role of established contralateral cerebrocerebellar connections on cerebellar injury during stroke has been increasingly revealed in recent years. An extensive number of studies have investigated alteration in inter-hemispheric correlation in order to find brain regions whose responses are specific to restore functional loss and enhance adaptive neural plasticity after stroke. Although, several non-invasive brain stimulation studies have proven their efficacy in the treatment of stroke recovery, finding more effective brain regions that responsible for stroke rehabilitation as well as optimizing neural stimulation protocol are the main goals of further investigations. In this study, the lateral cerebellar nucleus (LCN) was exposed to Low-Intensity Focused Ultrasound (LIFU) to reduce the cerebellar damage resulting from crossed cerebellar diaschisis (CCD) phenomenon after cerebral ischemia. A mouse brain ischemia was induced by middle cerebral artery occlusion (MCAO). A level of decrease in Purkinje cell (PC) number and a quantity of myeloperoxidase (MPO) positive neutrophils in the cerebral cortex were compared between stroke and stroke+LIFU groups after MCAO. In stroke+LIFU group, the increased ipsilateral water content due to tissue swelling was observed, showing an attenuation of brain edema. Prominently, the reduction of the neuroimmune reactivity at the infarct core and the peri-infarct regions, and the increased rate of survival among PCs clearly demonstrated primary evidence of neuroprotective effect induced by LIFU-mediated cerebellar modulation.

Modulation of Cerebellar Cortical Plasticity Using Low-Intensity Focused Ultrasound for Poststroke Sensorimotor Function Recovery.

BACKGROUND: Stroke affects widespread brain regions through interhemispheric connections by influencing bilateral motor activity. Several noninvasive brain stimulation techniques have proved their capacity to compensate the functional loss by manipulating the neural activity of alternative pathways. Over the past few decades, brain stimulation therapies have been tailored within the theoretical framework of modulation of cortical excitability to enhance adaptive plasticity after stroke. OBJECTIVE: However, considering the vast difference between animal and human cerebral cortical structures, it is important to approach specific neuronal target starting from the higher order brain structure for human translation. The present study focuses on stimulating the lateral cerebellar nucleus (LCN), which sends major cerebellar output to extensive cortical regions. METHODS: In this study, in vivo stroke mouse LCN was exposed to low-intensity focused ultrasound (LIFU). After the LIFU exposure, animals underwent 4 weeks of rehabilitative training. RESULTS: During the cerebellar LIFU session, motor-evoked potentials (MEPs) were generated in both forelimbs accompanying excitatory sonication parameter. LCN stimulation group on day 1 after stroke significantly enhanced sensorimotor recovery compared with the group without stimulation. The recovery has maintained for a 4-week period in 2 behavior tests. Furthermore, we observed a significantly decreased level of brain edema and tissue swelling in the affected hemisphere 3 days after the stroke. CONCLUSIONS: This study provides the first evidence showing that LIFU-induced cerebellar modulation could be an important strategy for poststroke recovery. A longer follow-up study is, however, necessary in order to fully confirm the effects of LIFU on poststroke recovery.

A review of low-intensity focused ultrasound for neuromodulation.

The ability of ultrasound to be focused into a small region of interest through the intact skull within the brain has led researchers to investigate its potential therapeutic uses for functional neurosurgery and tumor ablation. Studies have used high-intensity focused ultrasound to ablate tissue in localised brain regions for movement disorders and chronic pain while sparing the overlying and surrounding tissue. More recently, low-intensity focused ultrasound (LIFU) that induces reversible biological effects has been emerged as an alternative neuromodulation modality due to its bi-modal (i.e. excitation and suppression) capability with exquisite spatial specificity and depth penetration. Many compelling evidences of LIFU-mediated neuromodulatory effects including behavioral responses, electrophysiological recordings and functional imaging data have been found in the last decades. LIFU, therefore, has the enormous potential to improve the clinical outcomes as well as to replace the currently available neuromodulation techniques such as deep brain stimulation (DBS), transcranial magnetic stimulation and transcranial current stimulation. In this paper, we aim to provide a summary of pioneering studies in the field of ultrasonic neuromodulation including its underlying mechanisms that were published in the last 60 years. In closing, some of potential clinical applications of ultrasonic brain stimulation will be discussed.

Blue light aids in coping with the post-lunch dip: an EEG study.

The 'post-lunch dip' is a commonly experienced period of drowsiness in the afternoon hours. If this inevitable period can be disrupted by an environmental cue, the result will be enhanced workplace performance. Because blue light is known to be a critical cue for entraining biological rhythms, we investigated whether blue light illumination can be a practical strategy for coping with the post-lunch dip. Twenty healthy participants underwent a continuous performance test, during which the electroencephalogram (EEG) was recorded under four different illumination conditions: dark ( < 0.3 lx), 33% blue-enriched light, 66% blue-enriched light and white polychromatic light. As a result, exposure to blue-enriched light during the post-lunch dip period significantly reduced the EEG alpha activity, and increased task performance. Since desynchronisation of alpha activity reflects enhancement of vigilance, our findings imply that blue light might disrupt the post-lunch dip. Subsequent exploration of illumination parameters will be beneficial for possible chronobiological and ergonomic applications.