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.

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.

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.

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.

Clinical application of deep learning-based synthetic CT from real MRI to improve dose planning accuracy in Gamma Knife radiosurgery: a proof of concept study.

Dose planning for Gamma Knife radiosurgery (GKRS) uses the magnetic resonance (MR)-based tissue maximum ratio (TMR) algorithm, which calculates radiation dose without considering heterogeneous radiation attenuation in the tissue. In order to plan the dose considering the radiation attenuation, the Convolution algorithm should be used, and additional radiation exposure for computed tomography (CT) and registration errors between MR and CT are entailed. This study investigated the clinical feasibility of synthetic CT (sCT) from GKRS planning MR using deep learning. The model was trained using frame-based contrast-enhanced T1-weighted MR images and corresponding CT slices from 54 training subjects acquired for GKRS planning. The model was applied prospectively to 60 lesions in 43 patients including benign tumor such as meningioma and pituitary adenoma, metastatic brain tumors, and vascular disease of various location for evaluating the model and its application. We evaluated the sCT and compared between treatment plans made with MR only (TMR 10 plan), MR and real CT (rCT; Convolution with rCT [Conv-rCT] plan), and MR and synthetic CT (Convolution with sCT [Conv-sCT] plan). The mean absolute error (MAE) of 43 sCT was 107.35 ± 16.47 Hounsfield units. The TMR 10 treatment plan differed significantly from plans made by Conv-sCT and Conv-rCT. However, the Conv-sCT and Conv-rCT plans were similar. This study showed the practical applicability of deep learning based on sCT in GKRS. Our results support the possibility of formulating GKRS treatment plans while considering radiation attenuation in the tissue using GKRS planning MR and no radiation exposure.

Pseudoprogression and peritumoral edema due to intratumoral necrosis after Gamma knife radiosurgery for meningioma.

Peritumoral cerebral edema is reported to be a side effect that can occur after stereotactic radiosurgery. We aimed to determine whether intratumoral necrosis (ITN) is a risk factor for peritumoral edema (PTE) when gamma knife radiosurgery (GKRS) is performed in patients with meningioma. In addition, we propose the concept of pseudoprogression: a temporary volume expansion that can occur after GKRS in the natural course of meningioma with ITN. This retrospective study included 127 patients who underwent GKRS for convexity meningioma between January 2019 and December 2020. Risk factors for PTE and ITN were investigated using logistic regression analysis. Analysis of variance was used to determine whether changes in tumor volume were statistically significant. After GKRS, ITN was observed in 34 (26.8%) patients, and PTE was observed in 10 (7.9%) patients. When postoperative ITN occurred after GKRS, the incidence of postoperative PTE was 18.970-fold (p = 0.009) greater. When a 70% dose volume ≥ 1 cc was used, the possibility of ITN was 5.892-fold (p < 0.001) higher. On average, meningiomas with ITN increased in volume by 128.5% at 6 months after GKRS and then decreased to 94.6% at 12 months. When performing GKRS in meningioma, a 70% dose volume ≥ 1 cc is a risk factor for ITN. At 6 months after GKRS, meningiomas with ITN may experience a transient volume expansion and PTE, which are characteristics of pseudoprogression. These characteristics typically improve at 12 months following GKRS.

Percutaneous Procedures for Trigeminal Neuralgia.

Microvascular decompression is the gold standard for the treatment of trigeminal neuralgia (TN). However, percutaneous techniques still play a role in treating patients with TN and offer several important advantages and efficiency in obtaining immediate pain relief, which is also durable in a less invasive and safe manner. Patients' preference for a less invasive method can influence the procedure they will undergo. Neurovascular conflict is not always a prerequisite for patients with TN. In addition, recurrence and failure of the previous procedure can influence the decision to follow the treatment. Therefore, indications for percutaneous procedures for TN persist when patients experience idiopathic and episodic sharp shooting pain. In this review, we provide an overview of percutaneous procedures for TN and its outcome and complication.

Complications After Deep Brain Stimulation: A 21-Year Experience in 426 Patients.

Background: Deep brain stimulation is an established treatment for movement disorders such as Parkinson's disease, essential tremor, and dystonia. However, various complications that occur after deep brain stimulation are a major concern for patients and neurosurgeons. Objective: This study aimed to analyze various complications that occur after deep brain stimulation. Methods: We reviewed the medical records of patients with a movement disorder who underwent bilateral deep brain stimulation between 2000 and 2020. Among them, patients requiring revision surgery were analyzed. Results: A total of 426 patients underwent bilateral deep brain stimulation for a movement disorder. The primary disease was Parkinson's disease in 315 patients, followed by dystonia in 71 patients and essential tremor in 40 patients. Twenty-six (6.1%) patients had complications requiring revision surgery; the most common complication was infection (12 patients, 2.8%). Conclusion: Various complications may occur after deep brain stimulation, and patient prognosis should be improved by reducing complications.

Epidural grid, a new methodology of invasive intracranial EEG monitoring: A technical note and experience of a single center.

INTRODUCTION: Subdural grid monitoring (SDG) has the advantage to provide continuous coverage over a larger area of cortex, direct visualization of electrode location and functional mapping. However, SDG can cause direct irritation of the cortex or postoperative headaches due to cerebrospinal fluid (CSF) leakage. Epidural grid monitoring (EDG) without opening the dura is thought to reduce the possibility of these complications. We report our experience with EDG. METHODS: We described our surgical technique of EDG in invasive intracranial electroencephalography (iEEG) monitoring. A retrospective review of 30 patients who underwent grid placement of iEEG between March 2019 and December 2020 was performed to compare SDG and EDG. RESULTS: Of the 30 patients, 10 patients underwent SDG and 20 patients underwent EDG. There was no difference in age between SDG and EDG groups (p = 0.13). Also, there was no difference in the number of grid electrodes, craniotomy size, number of electrodes per craniotomy area and postoperative complication rate (p = 0.32, 0.84, 0.58 and 0.40). However, the maximum number of electrodes that have been undermined from the bone margin was much higher in SDG group (SDG 4.6 ± 2.2 vs. EDG 2.0 ± 0.9; p = 0.001). The demand for postoperative analgesics was significantly lower in EDG group (SDG 13.4 ± 9.1 vs. EDG 4.1 ± 4.3; p = 0.012); and the demand for postoperative antiemetics also tended to be low (SDG 4.6 ± 3.6 vs. EDG 1.8 ± 1.6; p = 0.078). CONCLUSIONS: There was no significant difference in craniotomy and electrode insertion between the two groups; however, the EDG group showed less postoperative headache and nausea. Though not in direct contact with the cortex, the quality of the electrophysiological signal received through the electrode in EDG is comparable to that of the SDG. The EDG enables to detect the onset of seizure and delineate the epileptogenic zone sufficiently. Moreover, functional mapping is possible with EDG. Therefore, EDG has the sufficient potential to replace SDG for monitoring of the lateral surface of brain.

Permeability-controlled migration of induced seismicity to deeper depths near Venus in North Texas.

Migration of seismic events to deeper depths along basement faults over time has been observed in the wastewater injection sites, which can be correlated spatially and temporally to the propagation or retardation of pressure fronts and corresponding poroelastic response to given operation history. The seismicity rate model has been suggested as a physical indicator for the potential of earthquake nucleation along faults by quantifying poroelastic response to multiple well operations. Our field-scale model indicates that migrating patterns of 2015-2018 seismicity observed near Venus, TX are likely attributed to spatio-temporal evolution of Coulomb stressing rate constrained by the fault permeability. Even after reducing injection volumes since 2015, pore pressure continues to diffuse and steady transfer of elastic energy to the deep fault zone increases stressing rate consistently that can induce more frequent earthquakes at large distance scales. Sensitivity tests with variation in fault permeability show that (1) slow diffusion along a low-permeability fault limits earthquake nucleation near the injection interval or (2) rapid relaxation of pressure buildup within a high-permeability fault, caused by reducing injection volumes, may mitigate the seismic potential promptly.

Dual Pallidal and Thalamic Deep Brain Stimulation for Complex Ipsilateral Dystonia.

PURPOSE: Globus pallidus pars interna (GPi) has become an established target for deep brain stimulation (DBS) in dystonia. Previous studies suggest that targeting the ventralis oralis (Vo) complex nucleus improves dystonic tremor or even focal dystonia. Research has also demonstrated that multi-target DBS shows some benefits over single target DBS. In this study, we reviewed patients who had undergone unilateral DBS targeting the GPi and Vo. MATERIALS AND METHODS: Five patients diagnosed with medically refractory upper extremity dystonia (focal or segmental) underwent DBS. Two DBS electrodes each were inserted unilaterally targeting the ipsilateral GPi and Vo. Clinical outcomes were evaluated using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Disability Rating Scale. RESULTS: BFMDRS scores decreased by 55% at 1-month, 56% at 3-month, 59% at 6-month, and 64% at 12-month follow up. Disability Rating Scale scores decreased 41% at 1-month, 47% at 3-month, 50% at 6-month, and 60% at 12-month follow up. At 1 month after surgery, stimulating both targets improved clinical scores better than targeting GPi or Vo alone. CONCLUSION: Unilateral thalamic and pallidal dual electrode DBS may be as effective or even superior to DBS of a single target for dystonia. Although the number of patients was small, our results reflected favorable clinical outcomes.

Stereotactic biopsy for adult brainstem lesions: A surgical approach and its diagnostic value according to the 2016 World Health Organization Classification.

BACKGROUND: The brainstem has the critical role of regulating cardiac and respiratory function and it also provides motor and sensory function to the face via the cranial nerves. Despite the observation of a brainstem lesion in a radiological examination, it is difficult to obtain tissues for a pathological diagnosis because of the location and small volume of the brainstem. Thus, we aimed to share our 6-year experience with stereotactic biopsies from brainstem lesions and confirm the value and safety of stereotactic biopsy on this highly eloquent area in this study. METHODS: We retrospectively reviewed the medical records of 42 adult patients who underwent stereotactic biopsy on brainstem lesions from 2015 to 2020. The radiological findings, surgical records, pathological diagnosis, and postoperative complications of all patients were analyzed. RESULTS: Histopathological diagnoses were made in 40 (95.2%) patients. Astrocytic tumors were diagnosed in 29 (69.0%) patients, diffuse large B cell lymphoma in 5 (11.9%) patients, demyelinating disease in 4 (9.5%) patients, germinoma in 1 (2.4%) patient, and radiation necrosis in 1 (2.4%) patient. In the 40 patients with successful stereotactic biopsy, 10 (25.0%) patients had inconsistent preoperative radiological diagnosis and postoperative pathological diagnosis. In addition, there was a difference between the treatments prescribed by the radiological and pathological diagnoses in 8 out of 10 patients whose diagnoses changed after biopsy. There was no operative mortality among the 42 patients. CONCLUSIONS: A pathological diagnosis can be made safely and efficiently in brainstem lesions using stereotactic biopsy. This pathological diagnosis will enable patients to receive appropriate treatment.

Stimulation-Induced Side Effects of Deep Brain Stimulation in the Ventralis Intermedius and Posterior Subthalamic Area for Essential Tremor.

Deep brain stimulation (DBS) targeting the ventralis intermedius (VIM) nucleus of the thalamus and the posterior subthalamic area (PSA) has been shown to be an effective treatment for essential tremor (ET). The aim of this study was to compare the stimulation-induced side effects of DBS targeting the VIM and PSA using a single electrode. Patients with medication-refractory ET who underwent DBS electrode implantation between July 2011 and October 2020 using a surgical technique that simultaneously targets the VIM and PSA with a single electrode were enrolled in this study. A total of 93 patients with ET who had 115 implanted DBS electrodes (71 unilateral and 22 bilateral) were enrolled. The Clinical Rating Scale for Tremor (CRST) subscores improved from 20.0 preoperatively to 4.3 (78.5% reduction) at 6 months, 6.3 (68.5% reduction) at 1 year, and 6.5 (67.5% reduction) at 2 years postoperation. The best clinical effect was achieved in the PSA at significantly lower stimulation amplitudes. Gait disturbance and clumsiness in the leg was found in 13 patients (14.0%) upon stimulation of the PSA and in significantly few patients upon stimulation of the VIM (p = 0.0002). Fourteen patients (15.1%) experienced dysarthria when the VIM was stimulated; this number was significantly more than that with PSA stimulation (p = 0.0233). Transient paresthesia occurred in 13 patients (14.0%) after PSA stimulation and in six patients (6.5%) after VIM stimulation. Gait disturbance and dysarthria were significantly more prevalent in patients undergoing bilateral DBS than in those undergoing unilateral DBS (p = 0.00112 and p = 0.0011, respectively). Paresthesia resolved either after reducing the amplitude or switching to bipolar stimulation. However, to control gait disturbance and dysarthria, some loss of optimal tremor control was necessary at that particular electrode contact. In the present study, the most common stimulation-induced side effect associated with VIM DBS was dysarthria, while that associated with PSA DBS was gait disturbance. Significantly, more side effects were associated with bilateral DBS than with unilateral DBS. Therefore, changing active DBS contacts to simultaneous targeting of the VIM and PSA may be especially helpful for ameliorating stimulation-induced side effects.

Predictive Factors of Radiation-Induced Changes Following Single-Session Gamma Knife Radiosurgery for Arteriovenous Malformations.

We evaluated for possible predictors of radiation-induced changes (RICs) after gamma knife radiosurgery (GKRS) for arteriovenous malformations (AVMs). We identified the nidal component within AVMs to analyze the correlation between the volume of brain parenchyma within the 50% isodose line (IDL) and RICs. We retrospectively reviewed patients with AVMs who underwent a single-session of GKRS at our institution between 2007 and 2017 with at least a 2-year minimum follow-up. Follow-up magnetic resonance images were evaluated for newly developed T2 signal changes and the proportions of nidus and intervening parenchyma were quantified. A total of 180 AVM patients (98 males and 82 females) with a median age of 34 years were included in the present study. The overall obliteration rate was 67.8%. The median target volume was 3.65 cc. The median nidus and parenchyma volumes within the 50% IDL were 1.54 cc and 2.41 cc, respectively. RICs were identified in 79 of the 180 patients (43.9%). AVMs associated with previous hemorrhages showed a significant inverse correlation with RICs. In a multivariate analysis, RICs were associated with a higher proportion of brain parenchyma within the 50% IDL (hazard ratio (HR) 169.033; p < 0.001) and inversely correlated with the proportion of nidus volume within the 50% IDL (HR 0.006; p < 0.001). Our study identified that a greater proportion of brain tissue between the nidus within the 50% IDL was significantly correlated with RICs. Nidus angioarchitectural complexity and the absence of a prior hemorrhage were also associated with RICs. The identification of possible predictors of RICs could facilitate radiosurgical planning and treatment decisions as well as the planning of appropriate follow-up after GKRS; this could minimize the risk of RICs, which would be particularly beneficial for the treatment of incidentally found asymptomatic AVMs.

Technical and operative factors affecting magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor: experience from 250 treatments.

OBJECTIVE: Magnetic resonance imaging-guided focused ultrasound (MRgFUS) provides real-time monitoring of patients to assess tremor control and document any adverse effects. MRgFUS of the ventral intermediate nucleus (VIM) of the thalamus has become an effective treatment option for medically intractable essential tremor (ET). The aim of this study was to analyze the correlations of clinical and technical parameters with 12-month outcomes after unilateral MRgFUS thalamotomy for ET to help guide future clinical treatments. METHODS: From October 2013 to January 2019, data on unilateral MRgFUS thalamotomy from the original pivotal study and continued-access studies from three different geographic regions were collected. Authors of the present study retrospectively reviewed those data and evaluated the efficacy of the procedure on the basis of improvement in the Clinical Rating Scale for Tremor (CRST) subscore at 1 year posttreatment. Safety was based on the rates of moderate and severe thalamotomy-related adverse events. Treatment outcomes in relation to various patient- and sonication-related parameters were analyzed in a large cohort of patients with ET. RESULTS: In total, 250 patients were included in the present analysis. Improvement was sustained throughout the 12-month follow-up period, and 184 (73.6%) of 250 patients had minimal or no disability due to tremor (CRST subscore < 10) at the 12-month follow-up. Younger age and higher focal temperature (Tmax) correlated with tremor improvement in the multivariate analysis (OR 0.948, p = 0.013; OR 1.188, p = 0.025; respectively). However, no single statistically significant factor correlated with Tmax in the multivariate analysis. The cutoff value of Tmax in predicting a CRST subscore < 10 was 55.8°C. Skull density ratio (SDR) was positively correlated with heating efficiency (ß = 0.005, p < 0.001), but no significant relationship with tremor improvement was observed. In the low-temperature group, 1-3 repetitions to the right target with 52°C ≤ Tmax ≤ 54°C was sufficient to generate sustained tremor suppression within the investigated follow-up period. The high-temperature group had a higher rate of balance disturbances than the low-temperature group (p = 0.04). CONCLUSIONS: The authors analyzed the data of 250 patients with the aim of improving practices for patient screening and determining treatment endpoints. These results may improve the safety, efficacy, and efficiency of MRgFUS thalamotomy for ET.

Magnetic Resonance-Guided Focused Ultrasound Surgery for Obsessive-Compulsive Disorders: Potential for use as a Novel Ablative Surgical Technique.

Surgical treatment for psychiatric disorders, such as obsessive-compulsive disorder (OCD) and depression, using ablative techniques, such as cingulotomy and capsulotomy, have historically been controversial for a number of scientific, social, and ethical reasons. Recently, with the elucidation of anatomical and neurochemical substrates of brain function in healthy controls and patients with such disorders using various functional neuroimaging techniques, these criticisms are becoming less valid. Furthermore, by using new techniques, such as deep brain stimulation (DBS), and identifying more precise targets, beneficial effects and the lack of serious complications have been demonstrated in patients with psychiatric disorders. However, DBS also has many disadvantages. Currently, magnetic resonance-guided focused ultrasound surgery (MRgFUS) is used as a minimal-invasive surgical method for generating precisely placed focal thermal lesions in the brain. Here, we review surgical techniques and their potential complications, along with anterior limb of the internal capsule (ALIC) capsulotomy by radiofrequency lesioning and gamma knife radiosurgery, for the treatment of OCD and depression. We also discuss the limitations and technical issues related to ALIC capsulotomy with MRgFUS for medically refractory OCD and depression. Through this review we hope MRgFUS could be considered as a new treatment choice for refractory OCD.

Operational and geological controls of coupled poroelastic stressing and pore-pressure accumulation along faults: Induced earthquakes in Pohang, South Korea.

Coupled poroelastic stressing and pore-pressure accumulation along pre-existing faults in deep basement contribute to recent occurrence of seismic events at subsurface energy exploration sites. Our coupled fluid-flow and geomechanical model describes the physical processes inducing seismicity corresponding to the sequential stimulation operations in Pohang, South Korea. Simulation results show that prolonged accumulation of poroelastic energy and pore pressure along a fault can nucleate seismic events larger than Mw3 even after terminating well operations. In particular the possibility of large seismic events can be increased by multiple-well operations with alternate injection and extraction that can enhance the degree of pore-pressure diffusion and subsequent stress transfer through a rigid and low-permeability rock to the fault. This study demonstrates that the proper mechanistic model and optimal well operations need to be accounted for to mitigate unexpected seismic hazards in the presence of the site-specific uncertainty such as hidden/undetected faults and stress regime.

Safety and Efficacy of Magnetic Resonance-Guided Focused Ultrasound Surgery With Autofocusing Echo Imaging.

OBJECTIVE: Magnetic resonance-guided focused ultrasound surgery (MRgFUS) lesioning is a new treatment for brain disorders. However, the skull is a major barrier of ultrasound sonication in MRgFUS because it has an irregular surface and varies its size and shape among individuals. We recently developed the concept of skull density ratio (SDR) to select candidates for MRgFUS from among patients with essential tremor (ET). However, SDR is not the only factor contributing to successful MRgFUS lesioning treatment-refining the target through exact measurement of the ultrasonic echo in the transducer also improves treatment efficacy. In the present study, we carried out MRgFUS lesioning using an autofocusing echo imaging technique. We aimed to evaluate the safety and efficacy of this new approach, especially in patients with low SDR in whom previous focusing methods have failed. METHODS: From December 2019 to March 2020, we recruited 10 patients with ET or Parkinson's disease (PD) who had a low SDR. Two patients dropped out of the trial due to the screening failure of other medical diseases. In total, eight patients were included: six with ET who underwent MRgFUS thalamotomy and two with PD who underwent MRgFUS pallidotomy. The autofocusing echo imaging technique was used in all cases. RESULTS: The mean SDR of the patients with ET was 0.34 (range: 0.29-0.39), while that of the patients with PD was 0.41 (range: 0.38-0.44). The mean skull volume of patients with ET was 280.57 cm3 (range: 227-319 cm3), while that of the patients with PD was 287.13 cm3 (range: 271-303 cm3). During MRgFUS, a mean of 15 sonications were performed, among which a mean of 5.63 used the autofocusing technique. The mean maximal temperature (Tmax) achieved was 55.88°C (range: 52-59°C), while the mean energy delivered was 34.75 kJ (range: 20-42 kJ) among all patients. No serious adverse events occurred during or after treatment. Tmax or sonication factors (skull volume, SDR, sonication number, autofocusing score, similarity score, energy range, and power) were not correlated with autofocusing technique (p > 0.05, autofocusing score showed a p-value of 0.071). CONCLUSION: Using autofocusing echo imaging lesioning, a safe and efficient MRgFUS treatment, is available even for patients with a low SDR. Therefore, the indications for MRgFUS lesioning could be expanded to include patients with ET who have an SDR < 0.4 and those with PD who have an SDR < 0.45. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, identifier: NCT03935581.

Skull Factors Affecting Outcomes of Magnetic Resonance-Guided Focused Ultrasound for Patients with Essential Tremor.

PURPOSE: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy has become a standard treatment for medically intractable essential tremor (ET). Skull density ratio (SDR) and skull volume in patients with ET are currently considered useful indicators of the successful application of MRgFUS. We compared the clinical outcomes of MRgFUS thalamotomy with SDR above 0.4 and 0.45. We also described patterns of SDR and skull volume in Korean patients with ET who were eligible to be screened for MRgFUS. MATERIALS AND METHODS: In screening 318 ET patients, we evaluated patterns of skull density and skull volume according to age and sex. Fifty patients with ET were treated with MRgFUS. We investigated the effects of SDR and skull volume on treatment parameters and the outcomes of ET. RESULTS: The mean SDR of the 318 ET patients was 0.45±0.11, and that for skull volume was 315.74±40.95 cm³. The male patients had a higher SDR than female patients (p=0.047). Skull volume significantly decreased with aging. SDR and skull volume exhibited a linear negative relationship. Among therapeutic parameters, maximal temperature was positively related to SDR, while sonication number was not related to either SDR or skull volume. Tremor outcome was also not related to SDR or skull volume. CONCLUSION: SDR varied widely from 0.11 to 0.73, and men had a higher SDR. Therapeutic parameters and clinical outcomes were not affected by SDR or skull volume.