Optimal timing for drug delivery into the hippocampus by focused ultrasound: A comparison of hydrophilic and lipophilic compounds.

Aims: Previous studies have reported that focused ultrasound (FUS) helps modulate the blood-brain barrier (BBB). These studies have generally used the paracellular pathway owing to tight junction proteins (TJPs) regulation. However, BBB transport pathways also include diffusion and transcytosis. Few studies have examined transcellular transport across endothelial cells. We supposed that increased BBB permeability caused by FUS may affect transcytosis. We investigated drug delivery through transcytosis and paracellular transport to the brain after BBB modulation using FUS. Main methods: FUS and microbubbles were applied to the hippocampus of rats, and were euthanized at 1, 4, 24, and 48 h after sonication. To investigate paracellular transport, we analyzed TJPs, including zona occludens-1 (ZO-1) and occludin. We also investigated caveola-mediated transcytosis by analyzing caveola formation and major facilitator superfamily domain-containing 2a (Mfsd2a) levels, which inhibit caveola vesicle formation. Key findings: One hour after FUS, ZO-1 and occludin expression was the lowest and gradually increased over time, returning to baseline 24 h after FUS treatment. Compared with that of TJPs, caveola formation started to increase 1 h after FUS treatment and peaked at 4 h after FUS treatment before returning to baseline by 48 h after FUS treatment. Decreased Mfsd2a levels were observed at 1 h and 4 h after FUS treatment, indicating increased caveola formation. Significance: FUS induces BBB permeability changes and regulates both paracellular transport and caveola-mediated transcytosis. However, a time difference was observed between these two mechanisms. Hence, when delivering drugs into the brain after FUS, the optimal drug administration timing should be determined by the mechanism by which each drug passes through the BBB.

Power-integrated, wireless neural recording systems on the cranium using a direct printing method for deep-brain analysis.

Conventional power-integrated wireless neural recording devices suffer from bulky, rigid batteries in head-mounted configurations, hindering the precise interpretation of the subject's natural behaviors. These power sources also pose risks of material leakage and overheating. We present the direct printing of a power-integrated wireless neural recording system that seamlessly conforms to the cranium. A quasi-solid-state Zn-ion microbattery was 3D-printed as a built-in power source geometrically synchronized to the shape of a mouse skull. Soft deep-brain neural probes, interconnections, and auxiliary electronics were also printed using liquid metals on the cranium with high resolutions. In vivo studies using mice demonstrated the reliability and biocompatibility of this wireless neural recording system, enabling the monitoring of neural activities across extensive brain regions without notable heat generation. This all-printed neural interface system revolutionizes brain research, providing bio-conformable, customizable configurations for improved data quality and naturalistic experimentation.

In-vivo integration of soft neural probes through high-resolution printing of liquid electronics on the cranium.

Current soft neural probes are still operated by bulky, rigid electronics mounted to a body, which deteriorate the integrity of the device to biological systems and restrict the free behavior of a subject. We report a soft, conformable neural interface system that can monitor the single-unit activities of neurons with long-term stability. The system implements soft neural probes in the brain, and their subsidiary electronics which are directly printed on the cranial surface. The high-resolution printing of liquid metals forms soft neural probes with a cellular-scale diameter and adaptable lengths. Also, the printing of liquid metal-based circuits and interconnections along the curvature of the cranium enables the conformal integration of electronics to the body, and the cranial circuit delivers neural signals to a smartphone wirelessly. In the in-vivo studies using mice, the system demonstrates long-term recording (33 weeks) of neural activities in arbitrary brain regions. In T-maze behavioral tests, the system shows the behavior-induced activation of neurons in multiple brain regions.

Amygdala electrical stimulation for operant conditioning in rat navigation.

There have been several attempts to navigate the locomotion of animals by neuromodulation. The most common method is animal training with electrical brain stimulation for directional cues and rewards; the basic principle is to activate dopamine-mediated neural reward pathways such as the medial forebrain bundle (MFB) when the animal correctly follows the external commands. In this study, the amygdala, which is the brain region responsible for fear modulation, was targeted for punishment training. The brain regions of MFB, amygdala, and barrel cortex were electrically stimulated for reward, punishment, and directional cues, respectively. Electrical stimulation was applied to the amygdala of rats when they failed to follow directional commands. First, two different amygdala regions, i.e., basolateral amygdala (BLA) and central amygdala (CeA), were stimulated and compared in terms of behavior responses, success and correction rates for training, and gene expression for learning and memory. Then, the training was performed in three groups: group R (MFB stimulation for reward), group P (BLA stimulation for punishment), and group RP (both MFB and BLA stimulation for reward and punishment). In group P, after the training, RNA sequencing was conducted to detect gene expression and demonstrate the effect of punishment learning. Group P showed higher success rates than group R, and group RP exhibited the most effective locomotion control among the three groups. Gene expression results imply that BLA stimulation can be more effective as a punishment in the learning process than CeA stimulation. We developed a new method to navigate rat locomotion behaviors by applying amygdala stimulation.

Low-frequency (5-Hz) stimulation of ventrolateral periaqueductal gray modulates the descending serotonergic system in the peripheral neuropathic pain.

ABSTRACT: Neuropathic pain is a type of chronic pain that entails severe prolonged sensory dysfunctions caused by a lesion of the somatosensory system. Many of those suffering from the condition do not experience significant improvement with existing medications, resulting in various side effects. In this study, Sprague-Dawley male rats were used, and long-term deep brain stimulation of the ventrolateral periaqueductal gray was conducted in a rat model of spared nerve injury. We found that 5-Hz deep brain stimulation effectively modulated mechanical allodynia and induced neuronal activation in the rostral ventromedial medulla, restoring impaired descending serotonergic system. At the spinal level, glial cells were still activated but only the 5-HT1a receptor in the spinal cord was activated, implying its inhibitory role in mechanical allodynia. This study found that peripheral neuropathy caused dysfunction in the descending serotonergic system, and prolonged stimulation of ventrolateral periaqueductal gray can modulate the pathway in an efficient manner. This work would provide new opportunities for the development of targeted and effective treatments for this debilitating disease, possibly giving us lower chances of side effects from repeated high-frequency stimulation or long-term use of medication.

A Single Injection of rAAV-shmTOR in Peripheral Nerve Persistently Attenuates Nerve Injury-Induced Mechanical Allodynia.

Activation of mammalian target of rapamycin (mTOR) has been known as one of the contributing factors in nociceptive sensitization after peripheral injury. Its activation followed by the phosphorylation of downstream effectors causes hyperexcitability of primary sensory neurons in the dorsal root ganglion. We investigated whether a single injection of rAAV-shmTOR would effectively downregulate both complexes of mTOR in the long-term and glial activation as well. Male SD rats were categorized into shmTOR (n = 29), shCON (n = 23), SNI (n = 13), and Normal (n = 8) groups. Treatment groups were injected with rAAV-shmTOR or rAAV-shCON, respectively. DRG tissues and sciatic nerve were harvested for Western blot and immunohistochemical analyses. Peripheral sensitization was gradually attenuated in the shmTOR group, and it reached a peak on PID 21. Western blot analysis showed that both p-mTORC1 and p-mTORC2 were downregulated in the DRG compared to shCON and SNI groups. We also found decreased expression of phosphorylated p38 and microglial activation in the DRG. We first attempted a therapeutic strategy for neuropathic pain with a low dose of AAV injection by interfering with the mTOR signaling pathway, suggesting its potential application in pain treatment.

Liquid Crystal Polymer-Based Miniaturized Fully Implantable Deep Brain Stimulator.

A significant challenge in improving the deep brain stimulation (DBS) system is the miniaturization of the device, aiming to integrate both the stimulator and the electrode into a compact unit with a wireless charging capability to reduce invasiveness. We present a miniaturized, fully implantable, and battery-free DBS system designed for rats, using a liquid crystal polymer (LCP), a biocompatible and long-term reliable material. The system integrates the simulator circuit, the receiver coil, and a 20 mm long depth-type microelectrode array in a dome-shaped LCP package that is 13 mm in diameter and 5 mm in height. Wireless powering and control via an inductive link enable device miniaturization, allowing for full implantation and, thus, the free behavior of untethered animals. The eight-channel stimulation electrode array was microfabricated on an LCP substrate to form a multilayered system substrate, which was monolithically encapsulated by a domed LCP lid using a specialized spot-welding process. The device functionality was validated via an in vivo animal experiment using a neuropathic pain model in rats. This experiment demonstrated an increase in the mechanical withdrawal threshold of the rats with microelectrical stimulation delivered using the fully implanted device, highlighting the effectiveness of the system.

Long-term results on the suppression of secondary brain injury by early administered low-dose baclofen in a traumatic brain injury mouse model.

Secondary injury from traumatic brain injury (TBI) perpetuates cerebral damages through varied ways. Attenuating neuroinflammation, which is a key feature of TBI, is important for long-term prognosis of its patients. Baclofen, a muscle relaxant, has shown promise in reducing excessive inflammation in other neurologic disorders. However, its effectiveness in TBI remains ambiguous. Thus, our study aimed to investigate whether early administration of baclofen could elicit potential therapeutic effects by diminishing exaggerated neuroinflammation in TBI mice. In this study, 80 C57BL/6 mice were used, of which 69 mice received controlled cortical impact. The mice were divided into six groups (11-16 mice each). Baclofen, administered at dose of 0.05, 0.2 and 1 mg/kg, was injected intraperitoneally a day after TBI for 3 consecutive weeks. 3 weeks after completing the treatments, the mice were assessed histologically. The results showed that mice treated with baclofen exhibited a significantly lower volume of lesion tissue than TBI mice with normal saline. Baclofen also reduced activated glial cells with neurotoxic immune molecules and inhibited apoptotic cells. Significant recovery was observed and sustained for 6 weeks at the 0.2 mg/kg dose in the modified neurological severity score. Furthermore, memory impairment was recovered with low-doses of baclofen in the Y-maze. Our findings demonstrate that early administration of low dose baclofen can regulate neuroinflammation, prevent cell death, and improve TBI motor and cognitive abnormalities.

Altered prefrontal beta oscillatory activity during removal of information from working memory in obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is related to working memory impairment. Since patients with OCD have difficulty controlling their obsessive thoughts, removal of irrelevant information might be important in the pathophysiology of OCD. However, little is known about brain activity during the removal of information from working memory in patients with OCD. Our goal was to explore potential deficits in inhibitory function related to working memory processes in patients with OCD. METHODS: Sixteen OCD patients and 20 healthy controls (HCs) were recruited. We compared in prefrontal alpha and beta band activity derived from magnetoencephalography (MEG) between patients with OCD and HCs during multiple phases of information processing associated with working memory, especially in post-trial period of the visuospatial working memory task (the delayed matching-to-sample task), which is presumed to be related to the information removal process of working memory. RESULTS: Prefrontal post-trial beta power change (presumed to occur at high levels during the post-trial period) exhibited significant reductions in patients with OCD compared to HCs. In addition, the post-trial beta power change was negatively correlated with Obsessive-Compulsive Inventory-Revised total scores in patients with OCD. CONCLUSIONS: These findings suggest that impairment in the removal of information from working memory might be a key mechanism underlying the inability of OCD patients to rid themselves of their obsessions.

One-year outcomes of deep brain stimulation in refractory Tourette syndrome.

AIM: Deep brain stimulation (DBS) is one option for treating refractory Tourette syndrome (TS); however, it remains unclear which preoperative factors are predictive of DBS outcomes. This study investigated the efficacy of DBS targeting the anteromedial globus pallidus internus and evaluated predisposing factors affecting the outcomes of DBS in a single center in Korea. METHOD: Twenty patients who had undergone DBS for refractory TS were reviewed retrospectively. Tic symptoms were followed up at 3-month intervals for up to 1 year after surgery. The Yale Global Tic Severity Scale was used to evaluate preoperative/postoperative tic symptoms. Scores from the Yale-Brown Obsessive Compulsive Scale, Beck Depression Inventory-II, and Beck Anxiety Inventory were also evaluated. RESULTS: Patients with refractory TS achieved improvement in tic symptoms within 1 year after DBS. Initial responders who achieved a 35% reduction in Yale Global Tic Severity Scale total score within the first 3 months after DBS showed larger treatment effects during 1-year follow-up. Although no clinical or demographic factors were predictive of initial responses, patients with serious self-injurious behaviors tended to show delayed responses. CONCLUSION: This is the first study to our knowledge to report the DBS outcomes of 20 patients with TS in a single center in Asia. Our study supports the efficacy of DBS targeting anteromedial globus pallidus internus in refractory TS with no evident serious adverse events. Initial responses after DBS seem to be a predictor of long-term outcomes after surgery.

Long-lasting restoration of memory function and hippocampal synaptic plasticity by focused ultrasound in Alzheimer's disease.

BACKGROUND: Focused ultrasound (FUS) is a medical technology that non-invasively stimulates the brain and has been applied in thermal ablation, blood-brain barrier (BBB) opening, and neuromodulation. In recent years, numerous experiences and indications for the use of FUS in clinical and preclinical studies have rapidly expanded. Focused ultrasound-mediated BBB opening induces cognitive enhancement and neurogenesis; however, the underlying mechanisms have not been elucidated. METHODS: Here, we investigate the effects of FUS-mediated BBB opening on hippocampal long-term potentiation (LTP) and cognitive function in a 5xFAD mouse model of Alzheimer's disease (AD). We applied FUS with microbubble to the hippocampus and LTP was measured 6 weeks after BBB opening using FUS. Field recordings were made with a concentric bipolar electrode positioned in the CA1 region using an extracellular glass pipette filled with artificial cerebrospinal fluid. Morris water maze and Y-maze was performed to test cognitive function. RESULTS: Our results demonstrated that FUS-mediated BBB opening has a significant impact on increasing LTP at Schaffer collateral - CA1 synapses and rescues cognitive dysfunction and working memory. These effects persisted for up to 7 weeks post-treatment. Also, FUS-mediated BBB opening in the hippocampus increased PKA phosphorylation. CONCLUSION: Therefore, it could be a promising treatment for neurodegenerative diseases as it remarkably increases LTP, thereby improving working memory.

Endogenous Neural Stem Cell Activation after Low-Intensity Focused Ultrasound-Induced Blood-Brain Barrier Modulation.

Endogenous neural stem cells (eNSCs) in the adult brain, which have the potential to self-renew and differentiate into functional, tissue-appropriate cell types, have raised new expectations for neurological disease therapy. Low-intensity focused ultrasound (LIFUS)-induced blood-brain barrier modulation has been reported to promote neurogenesis. Although these studies have reported improved behavioral performance and enhanced expression of brain biomarkers after LIFUS, indicating increased neurogenesis, the precise mechanism remains unclear. In this study, we evaluated eNSC activation as a mechanism for neurogenesis after LIFUS-induced blood-brain barrier modulation. We evaluated the specific eNSC markers, Sox-2 and nestin, to confirm the activation of eNSCs. We also performed 3'-deoxy-3'[18F] fluoro-L-thymidine positron emission tomography ([18F] FLT-PET) to evaluate the activation of eNSCs. The expression of Sox-2 and nestin was significantly upregulated 1 week after LIFUS. After 1 week, the upregulated expression decreased sequentially; after 4 weeks, the upregulated expression returned to that of the control group. [18F] FLT-PET images also showed higher stem cell activity after 1 week. The results of this study indicated that LIFUS could activate eNSCs and induce adult neurogenesis. These results show that LIFUS may be useful as an effective treatment for patients with neurological damage or neurological disorders in clinical settings.

Combined Effects of Focused Ultrasound and Photodynamic Treatment for Malignant Brain Tumors Using C6 Glioma Rat Model.

PURPOSE: Glioblastoma (GBM) is an intractable disease for which various treatments have been attempted, but with little effect. This study aimed to measure the effect of photodynamic therapy (PDT) and sonodynamic therapy (SDT), which are currently being used to treat brain tumors, as well as sono-photodynamic therapy (SPDT), which is the combination of these two. MATERIALS AND METHODS: Four groups of Sprague-Dawley rats were injected with C6 glioma cells in a cortical region and treated with PDT, SDT, and SPDT. Gd-MRI was monitored weekly and 18F-FDG-PET the day before and 1 week after the treatment. The acoustic power used during sonication was 5.5 W/cm² using a 0.5-MHz single-element transducer. The 633-nm laser was illuminated at 100 J/cm². Oxidative stress and apoptosis markers were evaluated 3 days after treatment using immunohistochemistry (IHC): 4-HNE, 8-OhdG, and Caspase-3. RESULTS: A decrease in tumor volume was observed in MRI imaging 12 days after the treatment in the PDT group (p<0.05), but the SDT group showed a slight increase compared to the 5-Ala group. The high expression rates of reactive oxygen species-related factors, such as 8-OhdG (p<0.001) and Caspase-3 (p<0.001), were observed in the SPDT group compared to other groups in IHC. CONCLUSION: Our findings show that light with sensitizers can inhibit GBM growth, but not ultrasound. Although SPDT did not show the combined effect in MRI, high oxidative stress was observed in IHC. Further studies are needed to investigate the safety parameters to apply ultrasound in GBM.

Advances in Technical Aspects of Deep Brain Stimulation Surgery.

BACKGROUND: Deep brain stimulation has become an established technology for the treatment of patients with a wide variety of conditions, including movement disorders, psychiatric disorders, epilepsy, and pain. Surgery for implantation of DBS devices has enhanced our understanding of human physiology, which in turn has led to advances in DBS technology. Our group has previously published on these advances, proposed future developments, and examined evolving indications for DBS. SUMMARY: The crucial roles of structural MR imaging pre-, intra-, and post-DBS procedure in target visualization and confirmation of targeting are described, with discussion of new MR sequences and higher field strength MRI enabling direct visualization of brain targets. The incorporation of functional and connectivity imaging in procedural workup and their contribution to anatomical modelling is reviewed. Various tools for targeting and implanting electrodes, including frame-based, frameless, and robot-assisted, are surveyed, and their pros and cons are described. Updates on brain atlases and various software used for planning target coordinates and trajectories are presented. The pros and cons of asleep versus awake surgery are discussed. The role and value of microelectrode recording and local field potentials are described, as well as the role of intraoperative stimulation. Technical aspects of novel electrode designs and implantable pulse generators are presented and compared.

Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson's Disease.

BACKGROUND: Unilateral focused ultrasound ablation of the internal segment of globus pallidus has reduced motor symptoms of Parkinson's disease in open-label studies. METHODS: We randomly assigned, in a 3:1 ratio, patients with Parkinson's disease and dyskinesias or motor fluctuations and motor impairment in the off-medication state to undergo either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. The primary outcome was a response at 3 months, defined as a decrease of at least 3 points from baseline either in the score on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), for the treated side in the off-medication state or in the score on the Unified Dyskinesia Rating Scale (UDysRS) in the on-medication state. Secondary outcomes included changes from baseline to month 3 in the scores on various parts of the MDS-UPDRS. After the 3-month blinded phase, an open-label phase lasted until 12 months. RESULTS: Of 94 patients, 69 were assigned to undergo ultrasound ablation (active treatment) and 25 to undergo the sham procedure (control); 65 patients and 22 patients, respectively, completed the primary-outcome assessment. In the active-treatment group, 45 patients (69%) had a response, as compared with 7 (32%) in the control group (difference, 37 percentage points; 95% confidence interval, 15 to 60; P = 0.003). Of the patients in the active-treatment group who had a response, 19 met the MDS-UPDRS III criterion only, 8 met the UDysRS criterion only, and 18 met both criteria. Results for secondary outcomes were generally in the same direction as those for the primary outcome. Of the 39 patients in the active-treatment group who had had a response at 3 months and who were assessed at 12 months, 30 continued to have a response. Pallidotomy-related adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness. CONCLUSIONS: Unilateral pallidal ultrasound ablation resulted in a higher percentage of patients who had improved motor function or reduced dyskinesia than a sham procedure over a period of 3 months but was associated with adverse events. Longer and larger trials are required to determine the effect and safety of this technique in persons with Parkinson's disease. (Funded by Insightec; ClinicalTrials.gov number, NCT03319485.).

Evaluation of changes in neural oscillation after bilateral capsulotomy in treatment refractory obsessive-compulsive disorder using magnetoencephalogram.

Bilateral thermal capsulotomy with magnetic resonance-guided focused ultrasound (MRgFUS-capsulotomy) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Herein, we investigated the effects of bilateral thermal capsulotomy with MRgFUS on neural oscillations in treatment-refractory OCD patients. Eight patients underwent resting-state MEG with repeated recordings before and 1 and 6 months after MRgFUS-capsulotomy, and the oscillatory power and phase coherence over the entire cortical sensor area were measured. After MRgFUS-capsulotomy, the high beta band power in the fronto-central and temporal areas decreased at 1 month and remained stable for 6 months. Cortical connectivity of the high beta band gradually decreased over the entire cortical area during the following 6 months. At 1 month, improvement in anxiety and depression symptoms was significantly correlated with changes in high beta band power in both the frontotemporal and temporal areas. The treatment effect of MRgFUS-capsulotomy may be attributed to the cortical high beta band. Our results provide an advanced understanding of the neural mechanisms underlying MRgFUS-capsulotomy and other neuromodulatory interventions for treatment-refractory OCD.

Comparison of Single-Session, Neoadjuvant, and Adjuvant Embolization Gamma Knife Radiosurgery for Arteriovenous Malformation.

BACKGROUND: The purpose of intracranial arteriovenous malformations (AVMs) treatment is to prevent bleeding or subsequent hemorrhage with complete obliteration. For large, difficult-to-treat AVMs, multimodal approaches including surgery, endovascular embolization, and gamma knife radiosurgery (GKRS) are frequently used. OBJECTIVE: To analyze the outcomes of AVMs treated with single-session, neoadjuvant, and adjuvant embolization GKRS. METHODS: We retrospectively reviewed a database of 453 patients with AVMs who underwent GKRS between January 2007 and December 2017 at our facility. The obliteration rate, incidence of latent period bleeding, cyst formation, and radiation-induced changes were compared among the 3 groups, neoadjuvant-embolized, adjuvant-embolized, nonembolized group. In addition, the variables predicting AVM obliteration and complications were investigated. RESULTS: A total of 228 patients were enrolled in this study. The neoadjuvant-embolized, adjuvant-embolized, and nonembolized groups comprised 29 (12.7%), 19 (8.3%), and 180 (78.9%) patients, respectively. Significant differences were detected among the 3 groups in the history of previous hemorrhage and the presence of aneurysms ( P < .0001). Multivariate Cox regression analyses revealed a significant inverse correlation between neoadjuvant embolization and obliteration occurring 36 months after GKRS (hazard ratio, 0.326; P = .006). CONCLUSION: GKRS with either neoadjuvant or adjuvant embolization is a beneficial approach for the treatment of AVMs with highly complex angioarchitectures that are at risk for hemorrhage during the latency period. Embolization before GKRS may be a negative predictive factor for late-stage obliteration (>36 months). To confirm our conclusions, further studies involving a larger number of patients and continuous follow-up are necessary.

Somatosensory ECoG-based brain-machine interface with electrical stimulation on medial forebrain bundle.

Brain-machine interface (BMI) provides an alternative route for controlling an external device with one's intention. For individuals with motor-related disability, the BMI technologies can be used to replace or restore motor functions. Therefore, BMIs for movement restoration generally decode the neural activity from the motor-related brain regions. In this study, however, we designed a BMI system that uses sensory-related neural signals for BMI combined with electrical stimulation for reward. Four-channel electrocorticographic (ECoG) signals were recorded from the whisker-related somatosensory cortex of rats and converted to extract the BMI signals to control the one-dimensional movement of a dot on the screen. At the same time, we used operant conditioning with electrical stimulation on medial forebrain bundle (MFB), which provides a virtual reward to motivate the rat to move the dot towards the desired center region. The BMI task training was performed for 7 days with ECoG recording and MFB stimulation. Animals successfully learned to move the dot location to the desired position using S1BF neural activity. This study successfully demonstrated that it is feasible to utilize the neural signals from the whisker somatosensory cortex for BMI system. In addition, the MFB electrical stimulation is effective for rats to learn the behavioral task for BMI.

Differences in intrinsic functional networks in patients with essential tremor who had good and poor long-term responses after thalamotomy performed using MR-guided ultrasound.

OBJECTIVE: Thalamotomy at the nucleus ventralis intermedius using MR-guided focused ultrasound has been an effective treatment method for essential tremor (ET). However, this is not true for all cases, even for successful ablation. How the brain differs in patients with ET between those with long-term good and poor outcomes is not clear. To analyze the functional connectivity difference between patients in whom thalamotomy was effective and those in whom thalamotomy was ineffective and its prognostic role in ET treatment, the authors evaluated preoperative resting-state functional MRI in thalamotomy-treated patients. METHODS: Preoperative resting-state functional MRI data in 85 patients with ET, who were experiencing tremor relief at the time of treatment and were followed up for a minimum of 6 months after the procedure, were collected for the study. The authors conducted a graph independent component analysis of the functional connectivity matrices of tremor-related networks. The patients were divided into thalamotomy-effective and thalamotomy-ineffective groups (thalamotomy-effective group, ≥ 50% motor symptom reduction; thalamotomy-ineffective group, < 50% motor symptom reduction at 6 months after treatment) and the authors compared network components between groups. RESULTS: Seventy-two (84.7%) of the 85 patients showed ≥ 50% tremor reduction from baseline at 6 months after thalamotomy. The network analysis shows significant suppression of functional network components with connections between the areas of the cerebellum and the basal ganglia and thalamus, but enhancement of those between the premotor cortex and supplementary motor area in the noneffective group compared to the effective group. CONCLUSIONS: The present study demonstrates that patients in the noneffective group have suppressed functional subnetworks in the cerebellum and subcortex regions and have enhanced functional subnetworks among motor-sensory cortical networks compared to the thalamotomy-effective group. Therefore, the authors suggest that the functional connectivity pattern might be a possible predictive factor for outcomes of MR-guided focused ultrasound thalamotomy.