Threshold of somatic mosaicism leading to brain dysfunction with focal epilepsy.

Somatic mosaicism in a fraction of brain cells causes neurodevelopmental disorders, including childhood intractable epilepsy. However, the threshold for somatic mosaicism leading to brain dysfunction is unknown. In this study, we induced various mosaic burdens in focal cortical dysplasia type II (FCD II) mice, featuring mTOR somatic mosaicism and spontaneous behavioral seizures. The mosaic burdens ranged from approximately 1,000 to 40,000 neurons expressing the mTOR mutant in the somatosensory (SSC) or medial prefrontal (PFC) cortex. Surprisingly, approximately 8,000 to 9,000 neurons expressing the MTOR mutant, which are extrapolated to constitute 0.08-0.09% of total cells or roughly 0.04% of variant allele frequency (VAF) in the mouse hemicortex, were sufficient to trigger epileptic seizures. The mutational burden was correlated with seizure frequency and onset, with a higher tendency for electrographic inter-ictal spikes and beta- and gamma-frequency oscillations in FCD II mice exceeding the threshold. Moreover, mutation-negative FCD II patients in deep sequencing of their bulky brain tissues revealed somatic mosaicism of the mTOR pathway genes as low as 0.07% in resected brain tissues through ultra-deep targeted sequencing (up to 20 million reads). Thus, our study suggests that extremely low levels of somatic mosaicism can contribute to brain dysfunction.

Focused Ultrasound as a Novel Non-Invasive Method for the Delivery of Gold Nanoparticles to Retinal Ganglion Cells.

Purpose: The blood-retinal barrier (BRB) restricts the delivery of intravenous therapeutics to the retina, necessitating innovative approaches for treating retinal disorders. This study sought to explore the potential of focused ultrasound (FUS) to non-invasively deliver intravenously administered gold nanoparticles (AuNPs) across the BRB. FUS-BRB modulation can offer a novel method for targeted retinal therapy. Methods: AuNPs of different sizes and shapes were characterized, and FUS parameters were optimized to permeate the BRB without causing retinal damage in a rodent model. The delivery of 70-kDa dextran and AuNPs to the retinal ganglion cell (RGC) layer was visualized using confocal and two-photon microscopy, respectively. Histological and statistical analyses were conducted to assess the effectiveness and safety of the procedure. Results: FUS-BRB modulation resulted in the delivery of dextran and AuNPs to the RGC and inner nuclear layer. Smaller AuNPs reached the retinal layers to a greater extent than larger ones. The delivery of dextran and AuNPs across the BRB with FUS was achieved without significant retinal damage. Conclusions: This investigation provides the first evidence, to our knowledge, of FUS-mediated AuNP delivery across the BRB, establishing a foundation for a targeted and non-invasive approach to retinal treatment. The results contribute to developing promising non-invasive therapeutic strategies in ophthalmology to treat retinal diseases. Translational Relevance: Modifying the BRB with ultrasound offers a targeted and non-invasive delivery strategy of intravenous therapeutics to the retina.

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.

Case report: Intrathecal baclofen therapy improved gait pattern in a stroke patient with spastic dystonia.

Background: Intrathecal baclofen (ITB) therapy, a viable alternative for unsuitable candidates of conventional spasticity medications, is a preferred method of administration over the oral route. Owing to its enhanced bioavailability, ITB ensures a more effective delivery at the target site. Objective: There is a lack of conclusive evidence regarding the use of ITB treatment in managing ambulatory patients with spastic dystonia. Before ITB pump implantation, patients commonly undergo an ITB bolus injection trial to rule out potential adverse reactions and verify the therapeutic effects on hypertonic issues. In this report, we highlight a case of spastic dystonia, particularly focusing on an ambulatory patient who demonstrated significant improvement in both the modified Ashworth scale (MAS) score and gait pattern following the ITB injection trial. Case report: This case report outlines the medical history of a 67-year-old male diagnosed with left-side hemiplegia and spastic dystonia, resulting from his second episode of intracranial hemorrhage in the right thalamus. An ITB injection trial was initiated because the patient was not suitable for continued botulinum toxin injections and oral medications. This was due to the persistent occurrence of spastic dystonia in both the upper and lower extremities. The patient underwent a four-day ITB injection trial with progressively increasing doses, resulting in improved MAS scores and gait parameters, including cadence, step length, step time, stride length, and stride time were increased. Particularly, kinematic gait analysis demonstrates a substantial improvement of increased knee flexion in the swing phase in stiff knee gait pattern. These findings indicated a gradual reduction in spasticity-related symptoms, signifying the positive effect of the ITB injection trial. The patient eventually received an ITB pump implantation. Conclusion: In this post-stroke patient with spastic dystonia, ITB therapy has demonstrated effective and substantial management of spasticity, along with improvement in gait patterns.

Next-Generation Sequencing of Vitreoretinal Lymphoma by Vitreous Liquid Biopsy: Diagnostic Potential and Genotype/Phenotype Correlation.

Purpose: To determine the diagnostic potential of next-generation sequencing (NGS) in vitreous samples, analyze genotype-phenotype characteristics, and compare NGS of matched vitreous and brain samples in patients with associated central nervous system lymphoma (CNSL). Methods: A total of 32 patients suspected of vitreoretinal lymphoma (VRL) who underwent diagnostic vitrectomy and NGS were included in this retrospective observational case-series. Fresh vitreous specimens from diagnostic vitrectomy of VRL-suspected patients underwent NGS using a custom panel targeting 747 candidate genes for lymphoma. They also underwent malignancy cytology, interleukin (IL)-10/IL-6, immunoglobulin heavy chain (IGH)/immunoglobulin kappa light chain (IGK) monoclonality testing. MYD88 L265P mutation was examined from anterior chamber tap samples. The diagnosis of VRL was made based on typical clinical characteristics for VRL, as well as malignant cytology, IGH/IGK clonality, or IL-10/IL-6 > 1. Sensitivity and specificity of NGS were compared with conventional diagnostic tests. Brain tissues suspected of lymphoma were collected by stereotactic biopsy and underwent NGS. Genetic variations detected in NGS of vitreous and brain tissue specimens were compared. Results: The sensitivity values for cytology, IL-10/IL-6 > 1, clonality assays for IGH and IGK, MYD88 L265P detection in anterior chamber tap samples, and vitreous NGS were 0.23, 0.83, 0.68, 0.79, 0.67, and 0.85, with specificity values of 1.00, 0.83, 0.50, 0.25, 0.83, and 0.83, respectively. The sensitivity (0.85) of vitreous NGS was the highest compared to other conventional diagnostic tests for VRL. The most common mutations were MYD88 (91%), CDKN2A (36%), PIM1 (32%), IGLL5 (27%), and ETV6 (23%). Although several gene alterations demonstrated heterogeneity between the brain and eyes, some common mutational profiles were observed in matched vitreous and brain samples. Conclusions: Overall, NGS of the vitreous demonstrated high sensitivity among conventional diagnostic tests. VRL and CNSL appeared to have both shared and distinct genetic variations, which may suggest site-specific variations from a common origin.

Stereotactic radiosurgery for noncavernous sinus dural arteriovenous fistulas: treatment outcomes and their predictors.

OBJECTIVE: Stereotactic radiosurgery (SRS) has emerged as a safe and effective treatment modality for dural arteriovenous fistulas (dAVFs), particularly cavernous sinus (CS) dAVFs. However, the long-term outcomes of non-CS dAVFs are not well known. This study aimed to evaluate the efficacy and safety of SRS for non-CS dAVFs and to investigate the risk factors for incomplete obliteration. METHODS: Between 2007 and 2020, 65 non-CS dAVFs in 63 patients were treated using SRS at a single institution. Demographic characteristics, initial clinical presentations, clinical outcomes, and radiological findings were retrospectively reviewed. The procedure-related complications were assessed. Radiological outcomes were evaluated as complete obliteration, incomplete obliteration, and angiographic worsening, whereas clinical outcomes were evaluated for symptom recovery. RESULTS: At a median follow-up of 17 months, the overall complete obliteration rate was 63.1%, and the cumulative obliteration rates were 24.6%, 60.0%, 70.0%, and 74.3% at 12, 24, 36, and 48 months, respectively. Six patients underwent retreatment due to angiographic worsening; in 5 of these patients, recruitment of arterial feeders was newly observed in the adjacent sinus, which was not treated in the initial SRS. In the multivariate analysis, high-flow shunt and venous ectasia were associated with incomplete obliteration. No adverse events occurred after SRS. CONCLUSIONS: SRS for non-CS dAVFs is safe, and its efficacy is highly variable according to location. High-flow shunts may indicate greater radioresistance. In the retreated cases, new fistulas tended to be accompanied by sinus steno-occlusion and formed in the adjacent sinus segments.

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.

Real-Time Acoustic Simulation Framework for tFUS: A Feasibility Study Using Navigation System.

Transcranial focused ultrasound (tFUS), in which acoustic energy is focused on a small region in the brain through the skull, is a non-invasive therapeutic method with high spatial resolution and depth penetration. Image-guided navigation has been widely utilized to visualize the location of acoustic focus in the cranial cavity. However, this system is often inaccurate because of the significant aberrations caused by the skull. Therefore, acoustic simulations using a numerical solver have been widely adopted to compensate for this inaccuracy. Although the simulation can predict the intracranial acoustic pressure field, real-time application during tFUS treatment is almost impossible due to the high computational cost. In this study, we propose a neural network-based real-time acoustic simulation framework and test its feasibility by implementing a simulation-guided navigation (SGN) system. Real-time acoustic simulation is performed using a 3D conditional generative adversarial network (3D-cGAN) model featuring residual blocks and multiple loss functions. This network was trained by the conventional numerical acoustic simulation program (i.e., k-Wave). The SGN system is then implemented by integrating real-time acoustic simulation with a conventional image-guided navigation system. The proposed system can provide simulation results with a frame rate of 5 Hz (i.e., about 0.2 s), including all processing times. In numerical validation (3D-cGAN vs. k-Wave), the average peak intracranial pressure error was 6.8 ± 5.5%, and the average acoustic focus position error was 5.3 ± 7.7 mm. In experimental validation using a skull phantom (3D-cGAN vs. actual measurement), the average peak intracranial pressure error was 4.5%, and the average acoustic focus position error was 6.6 mm. These results demonstrate that the SGN system can predict the intracranial acoustic field according to transducer placement in real-time.

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.

Quasi-seamless stitching for large-area micropatterned surfaces enabled by Fourier spectral analysis of moiré patterns.

The main challenge in preparing a flexible mold stamp using roll-to-roll nanoimprint lithography is to simultaneously increase the imprintable area with a minimized perceptible seam. However, the current methods for stitching multiple small molds to fabricate large-area molds and functional surfaces typically rely on the alignment mark, which inevitably produces a clear alignment mark and stitched seam. In this study, we propose a mark-less alignment by the pattern itself method inspired by moiré technique, which uses the Fourier spectral analysis of moiré patterns formed by superposed identical patterns for alignment. This method is capable of fabricating scalable functional surfaces and imprint molds with quasi-seamless and alignment mark-free patterning. By harnessing the rotational invariance property in the Fourier transform, our approach is confirmed to be a simple and efficient method for extracting the rotational and translational offsets in overlapped periodic or nonperiodic patterns with a minimized stitched region, thereby allowing for the large-area and quasi-seamless fabrication of imprinting molds and functional surfaces, such as liquid-repellent film and micro-optical sheets, that surpass the conventional alignment and stitching limits and potentially expand their application in producing large-area metasurfaces.

A strategy to maximize astaxanthin production from Haematococcus pluvialis in a cost-effective process by utilizing a PBR-LGP-PBR array (PLPA) hybrid system using light guide panel (LGP) and solar cells.

This study evaluated economic feasibility through production efficiency, return on investment (ROI) and payout time of a hybrid system using a photobioreactor (PBR)-light guide panel (LGP)-PBR array (PLPA) and solar cells developed for astaxanthin and ω-3 FA simultaneous production of Haematococcus pluvialis. The economic feasibility of the PLPA hybrid system (8 PBRs) and the PBR-PBR-PBR array (PPPA) system (8 PBRs) was evaluated for producing high-value products while effectively reducing CO2. Introducing a PLPA hybrid system has increased the amount of culture per area by 1.6 times. Also, the shading effect was effectively suppressed with an LGP placed between each PBR, increasing biomass and astaxanthin productivity by 3.39-fold and 4.79-fold, respectively compared to the untreated H. pluvialis cultures. In addition, ROI increased by 6.55 and 4.71 times, and the payout time was reduced by 1.34 and 1.37 times, respectively in 10 and 100-ton scale processes.

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.

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.

Preclinical Research on Focused Ultrasound-Mediated Blood-Brain Barrier Opening for Neurological Disorders: A Review.

Several therapeutic agents for neurological disorders are usually not delivered to the brain owing to the presence of the blood-brain barrier (BBB), a special structure present in the central nervous system (CNS). Focused ultrasound (FUS) combined with microbubbles can reversibly and temporarily open the BBB, enabling the application of various therapeutic agents in patients with neurological disorders. In the past 20 years, many preclinical studies on drug delivery through FUS-mediated BBB opening have been conducted, and the use of this method in clinical applications has recently gained popularity. As the clinical application of FUS-mediated BBB opening expands, it is crucial to understand the molecular and cellular effects of FUS-induced microenvironmental changes in the brain so that the efficacy of treatment can be ensured, and new treatment strategies established. This review describes the latest research trends in FUS-mediated BBB opening, including the biological effects and applications in representative neurological disorders, and suggests future directions.

Ultra-Low Level Somatic Mutations and Structural Variations in Focal Cortical Dysplasia Type II.

OBJECTIVE: Brain somatic mutations in mTOR pathway genes are a major genetic etiology of focal cortical dysplasia type II (FCDII). Despite a greater ability to detect low-level somatic mutations in the brain by deep sequencing and analytics, about 40% of cases remain genetically unexplained. METHODS: We included 2 independent cohorts consisting of 21 patients with mutation-negative FCDII without apparent mutations on conventional deep sequencing of bulk brain. To find ultra-low level somatic variants or structural variants, we isolated cells exhibiting phosphorylation of the S6 ribosomal protein (p-S6) in frozen brain tissues using fluorescence-activated cell sorting (FACS). We then performed deep whole-genome sequencing (WGS; >90×) in p-S6+ cells in a cohort of 11 patients with mutation-negative. Then, we simplified the method to whole-genome amplification and target gene sequencing of p-S6+ cells in independent cohort of 10 patients with mutation-negative followed by low-read depth WGS (10×). RESULTS: We found that 28.6% (6 of 21) of mutation-negative FCDII carries ultra-low level somatic mutations (less than 0.2% of variant allele frequency [VAF]) in mTOR pathway genes. Our method showed ~34 times increase of the average mutational burden in FACS mediated enrichment of p-S6+ cells (average VAF = 5.84%) than in bulky brain tissues (average VAF = 0.17%). We found that 19% (4 of 21) carried germline structural variations in GATOR1 complex undetectable in whole exome or targeted gene sequencing. CONCLUSIONS: Our method facilitates the detection of ultra-low level somatic mutations, in specifically p-S6+ cells, and germline structural variations and increases the genetic diagnostic rate up to ~80% for the entire FCDII cohort. ANN NEUROL 2023;93:1082-1093.

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.

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.

Characteristics of Focused Ultrasound Mediated Blood-Brain Barrier Opening in Magnetic Resonance Images.

OBJECTIVE: The blood-brain barrier (BBB) is an obstacle for molecules to pass through from blood to the brain. Focused ultrasound is a new method which temporarily opens the BBB, which makes pharmaceutical delivery or removal of neurodegenerative proteins possible. This study was demonstrated to review our BBB opening procedure with magnetic resonance guided images and find specific patterns in the BBB opening. METHODS: In this study, we reviewed the procedures and results of two clinical studies on BBB opening using focused ultrasound regarding its safety and clinical efficacy. Magnetic resonance images were also reviewed to discover any specific findings. RESULTS: Two clinical trials showed clinical benefits. All clinical trials demonstrated safe BBB opening, with no specific side effects. Magnetic resonance imaging showed temporary T1 contrast enhancement in the sonication area, verifying the BBB opening. Several low-signal intensity spots were observed in the T2 susceptibility-weighted angiography images, which were also reversible and temporary. Although these spots can be considered as microbleeding, evidence suggests these are not ordinary microbleeding but an indicator for adequate BBB opening. CONCLUSION: Magnetic resonance images proved safe and efficient BBB opening in humans, using focused ultrasound.

Efficacy and safety of stereotactic radiosurgery versus endovascular treatment for symptomatic cavernous sinus dural arteriovenous fistula without ophthalmological emergency: a single-center 10-year experience.

OBJECTIVE: Stereotactic radiosurgery (SRS) is emerging as a treatment option for cavernous sinus dural arteriovenous fistula (CS dAVF); it is less invasive and has a lower complication rate than conventional surgeries. However, little is known regarding the advantages and limitations of SRS compared to those of endovascular treatment (EVT). The aim of this study was to compare the efficacy and safety between EVT and SRS for treatment of CS dAVF. METHODS: Between January 2011 and April 2021, a total of 86 consecutive patients diagnosed with CS dAVF were treated with EVT or SRS. Among them, 8 patients with ophthalmological emergency and 8 without follow-up data at ≥ 12 months were excluded. During the same period, no neurological deficit due to intracranial hemorrhage or seizure was noted in any of the patients. Ultimately, 70 patients (EVT 33, SRS 37) were included in this study. Demographic characteristics, initial clinical presentations, clinical outcomes, and radiological findings were retrospectively reviewed and compared. Procedure-related complications were also assessed after the treatments. RESULTS: The patients' baseline characteristics (except conjunctival symptoms) and angiographic features of CS dAVF were not significantly different between the EVT and SRS groups. Conjunctival symptoms were more frequently noted in the EVT than in the SRS group (69.7% vs 40.5%, p = 0.015). After EVT, initial complete obliteration was achieved in 20 cases (60.6%). Complete obliteration was achieved at 6 months in 86.4% of cases with EVT and in 77.8% of those treated with SRS (p = 0.507), and at 12 months in 86.4% cases with EVT and in 94.4% of those treated with SRS (p = 0.357). Worsening of symptoms developed at 1 month in 24.2% of cases with EVT and in 5.4% of those treated with SRS (p = 0.038); at 6 months in 22.6% of cases with EVT and in 10.8% of those treated with SRS; and at 12 months in 30.0% of cases with EVT and in 13.5% of those treated with SRS (p = 0.099). The angioarchitecture of CS dAVF did not affect angiographic obliteration after SRS. Procedure-related morbidity and mortality occurred more frequently in the EVT than in the SRS group (27.3% vs 8.1%, p = 0.034). CONCLUSIONS: Both EVT and SRS were effective for the treatment of CS dAVF without ophthalmological emergency. However, procedure-related morbidity and mortality was less frequent in SRS than in EVT, and consequently SRS may be more advantageous in terms of safety.

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.