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Background: Chronic hemiparetic stroke patients have very limited benefits from current therapies. Brain-computer interface (BCI) engaging the unaffected hemisphere has emerged as a promising novel therapeutic approach for chronic stroke rehabilitation., Objectives: This study investigated the effectiveness of contralesionally-controlled BCI therapy in chronic stroke patients with impaired upper extremity motor function. We further explored neurophysiological features of motor recovery driven by BCI. We hypothesized that BCI therapy would induce a broad motor recovery in the upper extremity, and there would be corresponding changes in baseline theta and gamma oscillations, which have been shown to be associated with motor recovery., Methods: Twenty-six prospectively enrolled chronic hemiparetic stroke patients performed a therapeutic BCI task for 12 weeks. Motor function assessment data and resting state electroencephalogram signals were acquired before initiating BCI therapy and across BCI therapy sessions. The Upper Extremity Fugl-Meyer assessment served as a primary motor outcome assessment tool. Theta-gamma cross-frequency coupling (CFC) was computed and correlated with motor recovery., Results: Chronic stroke patients achieved significant motor improvement in both proximal and distal upper extremity with BCI therapy. Motor function improvement was independent of Botox application. Theta-gamma CFC enhanced bilaterally over the C3/C4 motor electrodes and positively correlated with motor recovery across BCI therapy sessions., Conclusions: BCI therapy resulted in significant motor function improvement across the proximal and distal upper extremities of patients, which significantly correlated with theta-gamma CFC increases in the motor regions. This may represent rhythm-specific cortical oscillatory mechanism for BCI-driven rehabilitation in chronic stroke patients., Trial Registration: Advarra Study: https://classic.clinicaltrials.gov/ct2/show/NCT04338971 and Washington University Study: https://classic.clinicaltrials.gov/ct2/show/NCT03611855., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: E.C.L. owns stock in Neurolutions, Inner Cosmos, and Sora Neuroscience. Washington University owns stock in Neurolutions. This work and E.C.L. have had their conflict of interest rigorously evaluated and managed throughout this study and with the creation of this manuscript. Other authors have nothing to disclose.

Motor rehabilitation is a therapeutic process to facilitate functional recovery in people with spinal cord injury (SCI). However, its efficacy is limited to areas with remaining sensorimotor function. Spinal cord stimulation (SCS) creates a temporary prosthetic effect that may allow further rehabilitation-induced recovery in individuals without remaining sensorimotor function, thereby extending the therapeutic reach of motor rehabilitation to individuals with more severe injuries. In this work, we report our first steps in developing a non-invasive brain-spine interface (BSI) based on electroencephalography (EEG) and transcutaneous spinal cord stimulation (tSCS). The objective of this study was to identify EEG-based neural correlates of lower limb movement in the sensorimotor cortex of unimpaired individuals and to quantify the performance of a linear discriminant analysis (LDA) decoder in detecting movement onset from these neural correlates. Our results show that initiation of knee extension was associated with event-related desynchronization in the central-medial cortical regions at frequency bands between 4-44 Hz. Our neural decoder using µ (8-12 Hz), low β (16-20 Hz), and high β (24-28 Hz) frequency bands achieved an average area under the curve (AUC) of 0.83 ± 0.06 s.d. (n = 7) during a cued movement task offline. Generalization to imagery and uncued movement tasks served as positive controls to verify robustness against movement artifacts and cue-related confounds, respectively. With the addition of real-time decoder-modulated tSCS, the neural decoder performed with an average AUC of 0.81 ± 0.05 s.d. (n = 9) on cued movement and 0.68 ± 0.12 s.d. (n = 9) on uncued movement. Our results suggest that the decrease in decoder performance in uncued movement may be due to differences in underlying cortical strategies between conditions. Furthermore, we explore alternative applications of the BSI system by testing neural decoders trained on uncued movement and imagery tasks. By developing a non-invasive BSI, tSCS can be timed to be delivered only during voluntary effort, which may have implications for improving rehabilitation.

Introduction: Subarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia. Given the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation (taVNS) and its ability to promote brain plasticity, taVNS has emerged as a promising therapeutic option for SAH patients. However, the effects of taVNS on cardiovascular dynamics in critically ill patients, like those with SAH, have not yet been investigated. Given the association between cardiac complications and elevated risk of poor clinical outcomes after SAH, it is essential to characterize the cardiovascular effects of taVNS to ensure this approach is safe in this fragile population. Therefore, we assessed the impact of both acute taVNS and repetitive taVNS on cardiovascular function in this study., Methods: In this randomized clinical trial, 24 SAH patients were assigned to either a taVNS treatment or a Sham treatment group. During their stay in the intensive care unit, we monitored patient electrocardiogram (ECG) readings and vital signs. We compared long-term changes in heart rate, heart rate variability, QT interval, and blood pressure between the two groups. Additionally, we assessed the effects of acute taVNS by comparing cardiovascular metrics before, during, and after the intervention. We also explored acute cardiovascular biomarkers in patients exhibiting clinical improvement., Results: We found that repetitive taVNS did not significantly alter heart rate, QT interval, blood pressure, or intracranial pressure. However, taVNS increased overall heart rate variability and parasympathetic activity compared to the sham treatment. The increase in parasympathetic activity was most pronounced from 2-4 days after initial treatment (Cohen's d = 0.50). Acutely, taVNS increased heart rate, blood pressure, and peripheral perfusion index without affecting the corrected QT interval, intracranial pressure, or heart rate variability. The acute post-treatment elevation in heart rate was more pronounced in patients who experienced a decrease of more than one point in their Modified Rankin Score at the time of discharge., Conclusions: Our study found that taVNS treatment did not induce adverse cardiovascular effects, such as bradycardia or QT prolongation, supporting its development as a safe immunomodulatory treatment approach for SAH patients. The observed acute increase in heart rate after taVNS treatment may serve as a biomarker for SAH patients who could derive greater benefit from this treatment., Trial Registration: NCT04557618., Competing Interests: Declaration of competing interest Eric Leuthardt has stock ownership in Neurolutions, Face to Face Biometrics, Caeli Vascular, Acera, Sora Neuroscience, Inner Cosmos, Kinetrix, NeuroDev, Inflexion Vascular, Aurenar, Cordance Medical, Silent Surgical, and Petal Surgical. He is a consultant for E15, Neurolutions, Inc., Petal Surgical. Washington University owns equity in Neurolutions. Anna Huguenard has stock ownership in Aurenar.

Entropy measures are increasingly being used to analyze the structure of neural activity observed by functional magnetic resonance imaging (fMRI), with resting-state networks (RSNs) being of interest for their reproducible descriptions of the brain's functional architecture. Temporal correlations have shown a dichotomy among these networks: those that engage with the environment, known as extrinsic, which include the visual and sensorimotor networks; and those associated with executive control and self-referencing, known as intrinsic, which include the default mode network and the frontoparietal control network. While these inter-voxel temporal correlations enable the assessment of synchrony among the components of individual networks, entropic measures introduce an intra-voxel assessment that quantifies signal features encoded within each blood oxygen level-dependent (BOLD) time series. As a result, this framework offers insights into comprehending the representation and processing of information within fMRI signals. Multiscale entropy (MSE) has been proposed as a useful measure for characterizing the entropy of neural activity across different temporal scales. This measure of temporal entropy in BOLD data is dependent on the length of the time series; thus, high-quality data with fine-grained temporal resolution and a sufficient number of time frames is needed to improve entropy precision. We apply MSE to the Midnight Scan Club, a highly sampled and well-characterized publicly available dataset, to analyze the entropy distribution of RSNs and evaluate its ability to distinguish between different functional networks. Entropy profiles are compared across temporal scales and RSNs. Our results have shown that the spatial distribution of entropy at infra-slow frequencies (0.005-0.1 Hz) reproduces known parcellations of RSNs. We found a complexity hierarchy between intrinsic and extrinsic RSNs, with intrinsic networks robustly exhibiting higher entropy than extrinsic networks. Finally, we found new evidence that the topography of entropy in the posterior cerebellum exhibits high levels of entropy comparable to that of intrinsic RSNs., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Purpose: High-grade glioma (HGG) is the most common and deadly malignant glioma of the central nervous system. The current standard of care includes surgical resection of the tumor, which can lead to functional and cognitive deficits. The aim of this study is to develop models capable of predicting functional outcomes in HGG patients before surgery, facilitating improved disease management and informed patient care., Methods: Adult HGG patients (N = 102) from the neurosurgery brain tumor service at Washington University Medical Center were retrospectively recruited. All patients completed structural neuroimaging and resting state functional MRI prior to surgery. Demographics, measures of resting state network connectivity (FC), tumor location, and tumor volume were used to train a random forest classifier to predict functional outcomes based on Karnofsky Performance Status (KPS < 70, KPS ≥ 70)., Results: The models achieved a nested cross-validation accuracy of 94.1% and an AUC of 0.97 in classifying KPS. The strongest predictors identified by the model included FC between somatomotor, visual, auditory, and reward networks. Based on location, the relation of the tumor to dorsal attention, cingulo-opercular, and basal ganglia networks were strong predictors of KPS. Age was also a strong predictor. However, tumor volume was only a moderate predictor., Conclusion: The current work demonstrates the ability of machine learning to classify postoperative functional outcomes in HGG patients prior to surgery accurately. Our results suggest that both FC and the tumor's location in relation to specific networks can serve as reliable predictors of functional outcomes, leading to personalized therapeutic approaches tailored to individual patients., (© 2024. The Author(s).)

Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing with paired V(D)J sequencing, respectively, on TILs from two cohorts of patients totaling 15 patients with high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared with matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T-cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T-cell subset within the GBM microenvironment and may harbor potential therapeutic implications., Significance: To understand the limited efficacy of immune-checkpoint blockade in GBM, we applied a multiomics approach to understand the TIL landscape. By highlighting the enrichment of GZMK+ effector T cells and the lack of exhausted T cells, we provide a new potential mechanism of resistance to immunotherapy in GBM. This article is featured in Selected Articles from This Issue, p. 897., (©2024 American Association for Cancer Research.)

Background: Focused ultrasound (FUS) combined with microbubbles is a promising technique for noninvasive, reversible, and spatially targeted blood-brain barrier opening, with clinical trials currently ongoing. Despite the fast development of this technology, there is a lack of established quality assurance (QA) strategies to ensure procedure consistency and safety. To address this challenge, this study presents the development and clinical evaluation of a passive acoustic detection-based QA protocol for FUS-induced blood-brain barrier opening (FUS-BBBO) procedure., Methods: Ten glioma patients were recruited to a clinical trial for evaluating a neuronavigation-guided FUS device. An acoustic sensor was incorporated at the center of the FUS device to passively capture acoustic signals for accomplishing three QA functions: FUS device QA to ensure the device functions consistently, acoustic coupling QA to detect air bubbles trapped in the acoustic coupling gel and water bladder of the transducer, and FUS procedure QA to evaluate the consistency of the treatment procedure., Findings: The FUS device passed the device QA in 9/10 patient studies. 4/9 cases failed acoustic coupling QA on the first try. The acoustic coupling procedure was repeatedly performed until it passed QA in 3/4 cases. One case failed acoustic coupling QA due to time constraints. Realtime passive cavitation monitoring was performed for FUS procedure QA, which captured variations in FUS-induced microbubble cavitation dynamics among patients., Interpretation: This study demonstrated that the proposed passive acoustic detection could be integrated with a clinical FUS system for the QA of the FUS-BBBO procedure., Funding: National Institutes of Health R01CA276174, R01MH116981, UG3MH126861, R01EB027223, R01EB030102, and R01NS128461., Competing Interests: Declaration of interests ECL and HC are inventors on an awarded US patent filed by Washington University in St. Louis on the sonobiopsy technique (US11667975B2), which covers the overall methods and systems for noninvasive and localized brain liquid biopsy using focused ultrasound. ECL and HC serve as advisors and shareholders of Cordance Medical, Inc., which is involved in commercializing the sonobiopsy technique. This relationship did not influence the design, execution, or interpretation of the study presented in this manuscript. The conflict of interest has been rigorously managed by Washington University in St. Louis. ECL received consulting fee from Neurolutions E15 and own stock from Neurolutions, Osteovantage, Face to Face Biometrics, Caeli Vascular, Acera, Sora Neuroscience, Inner Cosmos, Kinetrix, NeuroDev, Inflexion Vascular, Aurenar, Petal Surgical, which are not related to the present study. UA has K08 grant (K08NS125038) and Brain aneurysm foundation grant (GR0026849). This relationship did not influence the design, execution, or interpretation of the study presented in this manuscript. Other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Limitations in chronic pain therapies necessitate novel interventions that are effective, accessible, and safe. Brain-computer interfaces (BCIs) provide a promising modality for targeting neuropathology underlying chronic pain by converting recorded neural activity into perceivable outputs. Recent evidence suggests that increased frontal theta power (4-7 Hz) reflects pain relief from chronic and acute pain. Further studies have suggested that vibrotactile stimulation decreases pain intensity in experimental and clinical models. This longitudinal, non-randomized, open-label pilot study's objective was to reinforce frontal theta activity in six patients with chronic upper extremity pain using a novel vibrotactile neurofeedback BCI system. Patients increased their BCI performance, reflecting thought-driven control of neurofeedback, and showed a significant decrease in pain severity (1.29 ± 0.25 MAD, p = 0.03, q = 0.05) and pain interference (1.79 ± 1.10 MAD p = 0.03, q = 0.05) scores without any adverse events. Pain relief significantly correlated with frontal theta modulation. These findings highlight the potential of BCI-mediated cortico-sensory coupling of frontal theta with vibrotactile stimulation for alleviating chronic pain., (© 2024. The Author(s).)

Background: Resting-state fMRI is increasingly used to study the effects of gliomas on the functional organization of the brain. A variety of preprocessing techniques and functional connectivity analyses are represented in the literature. However, there so far has been no systematic comparison of how alternative methods impact observed results., New Method: We first surveyed current literature and identified alternative analytical approaches commonly used in the field. Following, we systematically compared alternative approaches to atlas registration, parcellation scheme, and choice of graph-theoretical measure as regards differentiating glioma patients (N = 59) from age-matched reference subjects (N = 163)., Results: Our results suggest that non-linear, as opposed to affine registration, improves structural match to an atlas, as well as measures of functional connectivity. Functionally- as opposed to anatomically-derived parcellation schemes maximized the contrast between glioma patients and reference subjects. We also demonstrate that graph-theoretic measures strongly depend on parcellation granularity, parcellation scheme, and graph density., Comparison With Existing Methods and Conclusions: Our current work primarily focuses on technical optimization of rs-fMRI analysis in glioma patients and, therefore, is fundamentally different from the bulk of papers discussing glioma-induced functional network changes. We report that the evaluation of glioma-induced alterations in the functional connectome strongly depends on analytical approaches including atlas registration, choice of parcellation scheme, and graph-theoretical measures., Competing Interests: Declaration of Competing Interest KYP, JSS, PHL, AZS, report the following conflict of interest. Licensing of Intellectual Property: Sora Neuroscience. AS reports the following conflict of interest. Stock ownership: TheraPanacea. DSM reports the following conflict of interest. Stock ownership: Sora Neuroscience, Flywheel Exchange LLC. ECL reports the following conflicts of interest. Stock ownership: Neurolutions, General Sensing, Osteovantage, Pear Therapeutics, Face to Face Biometrics, Immunovalent, Caeli Vascular, Acera, Sora Neuroscience, Inner Cosmos, Kinetrix, NeuroDev. Petal Surgical. Consultant: Monteris Medical, E15, Acera, Alcyone, Intellectual Ventures, Medtronic, Neurolutions, Osteovantage, Pear Therapeutics, Sante Ventures, Microbot. Licensing of Intellectual Property: Neurolutions, Osteovantage, Caeli Vascular, Sora Neuroscience. Washington University owns equity in Neurolutions. The other authors report they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective. Single-pulse electrical stimulation (SPES) has been widely used to probe effective connectivity. However, analysis of the neural response is often confounded by stimulation artifacts. We developed a novel matching pursuit-based artifact reconstruction and removal method (MPARRM) capable of removing artifacts from stimulation-artifact-affected electrophysiological signals. Approach. To validate MPARRM across a wide range of potential stimulation artifact types, we performed a bench-top experiment in which we suspended electrodes in a saline solution to generate 110 types of real-world stimulation artifacts. We then added the generated stimulation artifacts to ground truth signals (stereoelectroencephalography signals from nine human subjects recorded during a receptive speech task), applied MPARRM to the combined signal, and compared the resultant denoised signal with the ground truth signal. We further applied MPARRM to artifact-affected neural signals recorded from the hippocampus while performing SPES on the ipsilateral basolateral amygdala in nine human subjects. Main results. MPARRM could remove stimulation artifacts without introducing spectral leakage or temporal spread. It accommodated variable stimulation parameters and recovered the early response to SPES within a wide range of frequency bands. Specifically, in the early response period (5-10 ms following stimulation onset), we found that the broadband gamma power (70-170 Hz) of the denoised signal was highly correlated with the ground truth signal (R=0.98±0.02, Pearson), and the broadband gamma activity of the denoised signal faithfully revealed the responses to the auditory stimuli within the ground truth signal with94%±1.47%sensitivity and99%±1.01%specificity. We further found that MPARRM could reveal the expected temporal progression of broadband gamma activity along the anterior-posterior axis of the hippocampus in response to the ipsilateral amygdala stimulation. Significance. MPARRM could faithfully remove SPES artifacts without confounding the electrophysiological signal components, especially during the early-response period. This method can facilitate the understanding of the neural response mechanisms of SPES., (Creative Commons Attribution license.)

Sonobiopsy is an emerging technology that combines focused ultrasound (FUS) with microbubbles to enrich circulating brain disease-specific biomarkers for noninvasive molecular diagnosis of brain diseases. Here, we report the first-in-human prospective trial of sonobiopsy in high-grade glioma patients to evaluate its feasibility and safety in enriching plasma circulating tumor biomarkers. A nimble FUS device integrated with a clinical neuronavigation system was used to perform sonobiopsy following an established clinical workflow for neuronavigation. Analysis of blood samples collected before and after FUS sonication showed that sonobiopsy enriched plasma circulating tumor DNA (ctDNA), including a maximum increase of 1.6-fold for the mononucleosome cell-free DNA (cfDNA) fragments (120-280 bp), 1.9-fold for the patient-specific tumor variant ctDNA level, and 5.6-fold for the TERT mutation ctDNA level. Histological analysis of surgically resected tumors confirmed the safety of the procedure. Transcriptome analysis of sonicated and nonsonicated tumor tissues found that FUS sonication modulated cell physical structure-related genes. Only 2 out of 17,982 total detected genes related to the immune pathways were upregulated. These feasibility and safety data support the continued investigation of sonobiopsy for noninvasive molecular diagnosis of brain diseases., (© 2023. Nature Publishing Group UK.)

Purpose: Glioblastoma (GBM) is the most common and aggressive malignant glioma, with an overall median survival of less than two years. The ability to predict survival before treatment in GBM patients would lead to improved disease management, clinical trial enrollment, and patient care., Methods: GBM patients (N = 133, mean age 60.8 years, median survival 14.1 months, 57.9% male) were retrospectively recruited from the neurosurgery brain tumor service at Washington University Medical Center. All patients completed structural neuroimaging and resting state functional MRI (RS-fMRI) before surgery. Demographics, measures of cortical thickness (CT), and resting state functional network connectivity (FC) were used to train a deep neural network to classify patients based on survival (< 1y, 1-2y, >2y). Permutation feature importance identified the strongest predictors of survival based on the trained models., Results: The models achieved a combined cross-validation and hold out accuracy of 90.6% in classifying survival (< 1y, 1-2y, >2y). The strongest demographic predictors were age at diagnosis and sex. The strongest CT predictors of survival included the superior temporal sulcus, parahippocampal gyrus, pericalcarine, pars triangularis, and middle temporal regions. The strongest FC features primarily involved dorsal and inferior somatomotor, visual, and cingulo-opercular networks., Conclusion: We demonstrate that machine learning can accurately classify survival in GBM patients based on multimodal neuroimaging before any surgical or medical intervention. These results were achieved without information regarding presentation symptoms, treatments, postsurgical outcomes, or tumor genomic information. Our results suggest GBMs have a global effect on the brain's structural and functional organization, which is predictive of survival., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Many groups have reported lymphatic and glymphatic structures in animal and human brains, but tracer injection into the human brain to demonstrate real-time lymphatic drainage and mapping has not been described. We enrolled patients undergoing standard-of-care resection or stereotactic biopsy for suspected intracranial tumors. Patients received peritumoral injections of 99m Tc-tilmanocept followed by planar or tomographic imaging. Fourteen patients with suspected brain tumors were enrolled. One was excluded from analysis because of tracer leakage during injection. There was no drainage of 99m Tc-tilmanocept to regional lymph nodes in any of the patients. On average, after correcting for radioactive decay, 70.7% (95% CI: 59.9%, 81.6%) of the tracer in the injection site and 78.1% (95% CI: 71.1%, 85.1%) in the whole-head on the day of surgery remained the morning after, with variable radioactivity in the subarachnoid space. The retained fraction was much greater than expected based on the clearance rate from non-brain injection sites. In this pilot study, the lymphatic tracer 99m Tc-tilmanocept was injected into the brain parenchyma, and there was no drainage outside the brain to the cervical lymph nodes. Our work demonstrates an inefficiency of drainage from peritumoral brain parenchyma and highlights a therapeutic opportunity to improve immunosurveillance of the brain.

Objective . Slow-wave modulation occurs during states of unconsciousness and is a large-scale indicator of underlying brain states. Conventional methods typically characterize these large-scale dynamics by assuming that slow-wave activity is sinusoidal with a stationary frequency. However, slow-wave activity typically has an irregular waveform shape with a non-stationary frequency, causing these methods to be highly unpredictable and inaccurate. To address these limitations, we developed a novel method using tau-modulation, which is more robust than conventional methods in estimating the modulation of slow-wave activity and does not require assumptions on the shape or stationarity of the underlying waveform. Approach . We propose a novel method to estimate modulatory effects on slow-wave activity. Tau-modulation curves are constructed from cross-correlation between slow-wave and high-frequency activity. The resultant curves capture several aspects of modulation, including attenuation or enhancement of slow-wave activity, the temporal synchrony between slow-wave and high-frequency activity, and the rate at which the overall brain activity oscillates between states. Main results . The method's performance was tested on an open electrocorticographic dataset from two monkeys that were recorded during propofol-induced anesthesia, with electrodes implanted over the left hemispheres. We found a robust propagation of slow-wave modulation along the anterior-posterior axis of the lateral aspect of the cortex. This propagation preferentially originated from the anterior superior temporal cortex and anterior cingulate gyrus. We also found the modulation frequency and polarity to track the stages of anesthesia. The algorithm performed well, even with non-sinusoidal activity and in the presence of real-world noise. Significance . The novel method provides new insight into several aspects of slow-wave modulation that have been previously difficult to evaluate across several brain states. This ability to better characterize slow-wave modulation, without spurious correlations induced by non-sinusoidal signals, may lead to robust and physiologically-plausible diagnostic tools for monitoring brain functions during states of unconsciousness., (Creative Commons Attribution license.)

Depression associated with traumatic brain injury (TBI) is believed to be clinically distinct from primary major depressive disorder (MDD) and may be less responsive to conventional treatments. Brain connectivity differences between the dorsal attention network (DAN), default mode network (DMN), and subgenual cingulate have been implicated in TBI and MDD. To characterize these distinctions, we applied precision functional mapping of brain network connectivity to resting-state functional magnetic resonance imaging data from five published patient cohorts, four discovery cohorts ( n = 93), and one replication cohort ( n = 180). We identified a distinct brain connectivity profile in TBI-associated depression that was independent of TBI, MDD, posttraumatic stress disorder (PTSD), depression severity, and cohort. TBI-associated depression was independently associated with decreased DAN-subgenual cingulate connectivity, increased DAN-DMN connectivity, and the combined effect of both. This effect was stronger when using precision functional mapping relative to group-level network maps. Our results support the possibility of a physiologically distinct "TBI affective syndrome," which may benefit from individualized neuromodulation approaches to target its distinct neural circuitry.

Focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) is an emerging technique for the noninvasive and spatiotemporally controlled diagnosis of brain cancer by inducing blood-brain barrier (BBB) disruption to release brain tumor-specific biomarkers into the blood circulation. The feasibility, safety, and efficacy of sonobiopsy were demonstrated in both small and large animal models using magnetic resonance-guided FUS devices. However, the high cost and complex operation of magnetic resonance-guided FUS devices limit the future broad application of sonobiopsy in the clinic. In this study, a neuronavigation-guided sonobiopsy device is developed and its targeting accuracy is characterized in vitro, in vivo, and in silico. The sonobiopsy device integrated a commercially available neuronavigation system (BrainSight) with a nimble, lightweight FUS transducer. Its targeting accuracy was characterized in vitro in a water tank using a hydrophone. The performance of the device in BBB disruption was verified in vivo using a pig model, and the targeting accuracy was quantified by measuring the offset between the target and the actual locations of BBB opening. The feasibility of the FUS device in targeting glioblastoma (GBM) tumors was evaluated in silico using numerical simulation by the k-Wave toolbox in glioblastoma patients. It was found that the targeting accuracy of the neuronavigation-guided sonobiopsy device was 1.7 ± 0.8 mm as measured in the water tank. The neuronavigation-guided FUS device successfully induced BBB disruption in pigs with a targeting accuracy of 3.3 ± 1.4 mm. The targeting accuracy of the FUS transducer at the GBM tumor was 5.5 ± 4.9 mm. Age, sex, and incident locations were found to be not correlated with the targeting accuracy in GBM patients. This study demonstrated that the developed neuronavigation-guided FUS device could target the brain with a high spatial targeting accuracy, paving the foundation for its application in the clinic.

Background: Patients with glioblastoma (GBM) and high-grade glioma (HGG, World Health Organization [WHO] grade IV glioma) have a poor prognosis. Consequently, there is an unmet clinical need for accessible and noninvasively acquired predictive biomarkers of overall survival in patients. This study evaluated morphological changes in the brain separated from the tumor invasion site (ie, contralateral hemisphere). Specifically, we examined the prognostic value of widespread alterations of cortical thickness (CT) in GBM/HGG patients., Methods: We used FreeSurfer, applied with high-resolution T1-weighted MRI, to examine CT, evaluated prior to standard treatment with surgery and chemoradiation in patients (GBM/HGG, N = 162, mean age 61.3 years) and 127 healthy controls (HC; 61.9 years mean age). We then compared CT in patients to HC and studied patients' associated changes in CT as a potential biomarker of overall survival., Results: Compared to HC cases, patients had thinner gray matter in the contralesional hemisphere at the time of tumor diagnosis. patients had significant cortical thinning in parietal, temporal, and occipital lobes. Fourteen cortical parcels showed reduced CT, whereas in 5, it was thicker in patients' cases. Notably, CT in the contralesional hemisphere, various lobes, and parcels was predictive of overall survival. A machine learning classification algorithm showed that CT could differentiate short- and long-term survival patients with an accuracy of 83.3%., Conclusions: These findings identify previously unnoticed structural changes in the cortex located in the hemisphere contralateral to the primary tumor mass. Observed changes in CT may have prognostic value, which could influence care and treatment planning for individual patients., Competing Interests: E.C.L. has equity in Neurolutions, Inner Cosmos. E.C.L., D.S.M., and C.D.H. have equity in Sora Neuroscience. E.C.L, J.J.L., and J.S.S. have patent interests licensed to Sora Neuroscience. D.S.M. has equity in Radiologics, Inc. Washington University has equity in Neurolutions. B.L and E.C.L. have filed a provisional patent on the techniques described in this manuscript. All other authors declared that they had no conflicts of interest to their authorship or the publication of this article., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Objective: Resting-state functional MRI (RS-fMRI) enables the mapping of function within the brain and is emerging as an efficient tool for the presurgical evaluation of eloquent cortex. Models capable of reliable and precise mapping of resting-state networks (RSNs) with a reduced scanning time would lead to improved patient comfort while reducing the cost per scan. The aims of the present study were to develop a deep 3D convolutional neural network (3DCNN) capable of voxel-wise mapping of language (LAN) and motor (MOT) RSNs with minimal quantities of RS-fMRI data., Methods: Imaging data were gathered from multiple ongoing studies at Washington University School of Medicine and other thoroughly characterized, publicly available data sets. All study participants (n = 2252 healthy adults) were cognitively screened and completed structural neuroimaging and RS-fMRI. Random permutations of RS-fMRI regions of interest were used to train a 3DCNN. After training, model inferences were compared using varying amounts of RS-fMRI data from the control data set as well as 5 patients with glioblastoma multiforme., Results: The trained model achieved 96% out-of-sample validation accuracy on data encompassing a large age range collected on multiple scanner types and varying sequence parameters. Testing on out-of-sample control data showed 97.9% similarity between results generated using either 50 or 200 RS-fMRI time points, corresponding to approximately 2.5 and 10 minutes, respectively (96.9% LAN, 96.3% MOT true-positive rate). In evaluating data from patients with brain tumors, the 3DCNN was able to accurately map LAN and MOT networks despite structural and functional alterations., Conclusions: Functional maps produced by the 3DCNN can inform surgical planning in patients with brain tumors in a time-efficient manner. The authors present a highly efficient method for presurgical functional mapping and thus improved functional preservation in patients with brain tumors.

Background Neurodegenerative disorders (such as Alzheimer disease) characterized by the deposition of various pathogenic forms of tau protein in the brain are collectively referred to as tauopathies. Identification of the molecular drivers and pathways of neurodegeneration is critical to individualized targeted treatment of these disorders. However, despite important advances in fluid biomarker detection, characterization of these molecular subtypes is limited by the blood-brain barrier. Purpose To evaluate the feasibility and safety of focused ultrasound-mediated liquid biopsy (sonobiopsy) in the detection of brain-derived protein biomarkers in a transgenic mouse model of tauopathy (PS19 mice). Materials and Methods Sonobiopsy was performed by sonicating the cerebral hemisphere in 2-month-old PS19 and wild-type mice, followed by measurement of plasma phosphorylated tau (p-tau) species (30 minutes after sonication in the sonobiopsy group). Next, spatially targeted sonobiopsy was performed by sonicating either the cerebral cortex or the hippocampus in 6-month-old PS19 mice. To detect changes in plasma neurofilament light chain (a biomarker of neurodegeneration) levels, blood samples were collected before and after sonication (15 and 45-60 minutes after sonication). Histologic staining was performed to evaluate tissue damage after sonobiopsy. The Shapiro-Wilk test, unpaired and paired t tests, and the Mann-Whitney U test were used. Results In the 2-month-old mice, sonobiopsy significantly increased the normalized levels of plasma p-tau species compared with the conventional blood-based liquid biopsy (p-tau-181-to-mouse tau [m-tau] ratio: 1.7-fold increase, P = .006; p-tau-231-to-m-tau ratio: 1.4-fold increase, P = .048). In the 6-month-old PS19 mice, spatially targeted sonobiopsy resulted in a 2.3-fold increase in plasma neurofilament light chain after sonication of the hippocampus and cerebral cortex ( P < .001). After optimization of the sonobiopsy parameters, no excess microhemorrhage was observed in the treated cerebral hemisphere compared with the contralateral side. Conclusion This study showed the feasibility of sonobiopsy to release phosphorylated tau species and neurofilament light chain to the blood circulation, potentially facilitating diagnosis of neurodegenerative disorders. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Fowlkes in this issue.

At the group level, antidepressant efficacy of rTMS targets is inversely related to their normative connectivity with subgenual anterior cingulate cortex (sgACC). Individualized connectivity may yield better targets, particularly in patients with neuropsychiatric disorders who may have aberrant connectivity. However, sgACC connectivity shows poor test-retest reliability at the individual level. Individualized resting-state network mapping (RSNM) can reliably map inter-individual variability in brain network organization. Thus, we sought to identify individualized RSNM-based rTMS targets that reliably target the sgACC connectivity profile. We used RSNM to identify network-based rTMS targets in 10 healthy controls and 13 individuals with traumatic brain injury-associated depression (TBI-D). These "RSNM targets" were compared with consensus structural targets and targets based on individualized anti-correlation with a group-mean-derived sgACC region ("sgACC-derived targets"). The TBI-D cohort was also randomized to receive active (n = 9) or sham (n = 4) rTMS to RSNM targets with 20 daily sessions of sequential high-frequency left-sided stimulation and low-frequency right-sided stimulation. We found that the group-mean sgACC connectivity profile was reliably estimated by individualized correlation with default mode network (DMN) and anti-correlation with dorsal attention network (DAN). Individualized RSNM targets were thus identified based on DAN anti-correlation and DMN correlation. These RSNM targets showed greater test-retest reliability than sgACC-derived targets. Counterintuitively, anti-correlation with the group-mean sgACC connectivity profile was also stronger and more reliable for RSNM-derived targets than for sgACC-derived targets. Improvement in depression after RSNM-targeted rTMS was predicted by target anti-correlation with the portions of sgACC. Active treatment also led to increased connectivity within and between the stimulation sites, the sgACC, and the DMN. Overall, these results suggest that RSNM may enable reliable individualized rTMS targeting, although further research is needed to determine whether this personalized approach can improve clinical outcomes., (© 2023. The Author(s).)

Background: Rapid growth in smartphone use has expanded opportunities to use mobile health (mHealth) technology to collect real-time patient-reported and objective biometric data. These data may have important implication for personalized treatments of degenerative spine disease. However, no large-scale study has examined the feasibility and acceptability of these methods in spine surgery patients., Objective: To evaluate the feasibility and acceptability of a multimodal preoperative mHealth assessment in patients with degenerative spine disease., Methods: Adults undergoing elective spine surgery were provided with Fitbit trackers and sent preoperative ecological momentary assessments (EMAs) assessing pain, disability, mood, and catastrophizing 5 times daily for 3 weeks. Objective adherence rates and a subjective acceptability survey were used to evaluate feasibility of these methods., Results: The 77 included participants completed an average of 82 EMAs each, with an average completion rate of 86%. Younger age and chronic pulmonary disease were significantly associated with lower EMA adherence. Seventy-two (93%) participants completed Fitbit monitoring and wore the Fitbits for an average of 247 hours each. On average, participants wore the Fitbits for at least 12 hours per day for 15 days. Only worse mood scores were independently associated with lower Fitbit adherence. Most participants endorsed positive experiences with the study protocol, including 91% who said they would be willing to complete EMAs to improve their preoperative surgical guidance., Conclusion: Spine fusion candidates successfully completed a preoperative multimodal mHealth assessment with high acceptability. The intensive longitudinal data collected may provide new insights that improve patient selection and treatment guidance., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Background: Direct current electrical stimulation may serve as a promising nonpharmacological adjunct promoting osteogenesis and fusion. The aim of this study was to evaluate the utility of electroactive spine instrumentation in the focal delivery of therapeutic electrical stimulation to enhance lumbar bone formation and interbody fusion., Methods: A finite element model of adult human lumbar spine (L4-L5) instrumented with single-level electroactive pedicle screws was simulated. Direct current electrical stimulation was routed through anodized electroactive pedicle screws to target regions of fusion. The electrical fields generated by electroactive pedicle screws were evaluated in various tissue compartments including isotropic tissue volumes, cortical, and trabecular bone. Electrical field distributions at various stimulation amplitudes (20-100 µA) and pedicle screw anodization patterns were analyzed in target regions of fusion (eg, intervertebral disc space, vertebral body, and pedicles)., Results: Electrical stimulation with electroactive pedicle screws at various stimulation amplitudes and anodization patterns enabled modulation of spatial distribution and intensity of electric fields within the target regions of lumbar spine. Anodized screws (50%) vs unanodized screws (0%) induced high-amplitude electric fields within the intervertebral disc space and vertebral body but negligible electric fields in spinal canal. Direct current electrical stimulation via anodized screws induced electrical fields, at therapeutic threshold of >1 mV/cm, sufficient for osteoinduction within the target interbody region., Conclusions: Selective anodization of electroactive pedicle screws may enable focal delivery of therapeutic electrical stimulation in the target regions in human lumbar spine. This study warrants preclinical and clinical testing of integrated electroactive system in inducing target lumbar fusion in vivo., Clinical Relevance: The findings of this study provide a foundation for clinically investigating electroactive intrumentation to enhance spine fusion., (This manuscript is generously published free of charge by ISASS, the International Society for the Advancement of Spine Surgery. Copyright © 2023 ISASS. To see more or order reprints or permissions, see http://ijssurgery.com.)

Introduction: Resting state functional MRI (RS-fMRI) is currently used in numerous clinical and research settings. The localization of resting state networks (RSNs) has been utilized in applications ranging from group analysis of neurodegenerative diseases to individual network mapping for pre-surgical planning of tumor resections. Reproducibility of these results has been shown to require a substantial amount of high-quality data, which is not often available in clinical or research settings., Methods: In this work, we report voxelwise mapping of a standard set of RSNs using a novel deep 3D convolutional neural network (3DCNN). The 3DCNN was trained on publicly available functional MRI data acquired in n = 2010 healthy participants. After training, maps that represent the probability of a voxel belonging to a particular RSN were generated for each participant, and then used to calculate mean and standard deviation (STD) probability maps, which are made publicly available. Further, we compared our results to previously published resting state and task-based functional mappings., Results: Our results indicate this method can be applied in individual subjects and is highly resistant to both noisy data and fewer RS-fMRI time points than are typically acquired. Further, our results show core regions within each network that exhibit high average probability and low STD., Discussion: The 3DCNN algorithm can generate individual RSN localization maps, which are necessary for clinical applications. The similarity between 3DCNN mapping results and task-based fMRI responses supports the association of specific functional tasks with RSNs., Competing Interests: The Washington University in St. Louis may receive royalty income based on a technology developed by PL, JS, JL, EL, and BA and licensed by Washington University to Sora Neuroscience. That technology is used in this research. EL owns stock in Neurolutions, General Sensing, Osteovantage, Pear Therapeutics, Face to Face Biometrics, Caeli Vascular, Acera, Sora Neuroscience, Inner Cosmos, Kinetrix, NeuroDev, and Petal Surgical. Washington University has an equity ownership of Neurolutions. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luckett, Lee, Park, Raut, Meeker, Gordon, Snyder, Ances, Leuthardt and Shimony.)

The central nervous system (CNS) antigen-presenting cell (APC) that primes antitumor CD8+ T-cell responses remains undefined. Elsewhere in the body, the conventional dendritic cell 1 (cDC1) performs this role. However, steady-state brain parenchyma cDC1 are extremely rare; cDCs localize to the choroid plexus and dura. Thus, whether the cDC1 play a function in presenting antigen derived from parenchymal sources in the tumor setting remains unknown. Using preclinical glioblastoma (GBM) models and cDC1-deficient mice, we explored the presently unknown role of cDC1 in CNS antitumor immunity. We determined that, in addition to infiltrating the brain tumor parenchyma itself, cDC1 prime neoantigen-specific CD8+ T cells against brain tumors and mediate checkpoint blockade-induced survival benefit. We observed that cDC, including cDC1, isolated from the tumor, the dura, and the CNS-draining cervical lymph nodes harbored a traceable fluorescent tumor antigen. In patient samples, we observed several APC subsets (including the CD141+ cDC1 equivalent) infiltrating glioblastomas, meningiomas, and dura. In these same APC subsets, we identified a tumor-specific fluorescent metabolite of 5-aminolevulinic acid, which fluorescently labeled tumor cells during fluorescence-guided GBM resection. Together, these data elucidate the specialized behavior of cDC1 and suggest that cDC1 play a significant role in CNS antitumor immunity., (©2022 American Association for Cancer Research.)

Glioblastoma, a highly aggressive form of brain tumor, is a brain-wide disease. We evaluated the impact of tumor burden on whole brain resting-state functional magnetic resonance imaging (rs-fMRI) activity. Specifically, we analyzed rs-fMRI signals in the temporal frequency domain in terms of the power-law exponent and fractional amplitude of low-frequency fluctuations (fALFF). We contrasted 189 patients with newly-diagnosed glioblastoma versus 189 age-matched healthy reference participants from an external dataset. The patient and reference datasets were matched for age and head motion. The principal finding was markedly flatter spectra and reduced grey matter fALFF in the patients as compared to the reference dataset. We posit that the whole-brain spectral change is attributable to global dysregulation of excitatory and inhibitory balance and metabolic demand in the tumor-bearing brain. Additionally, we observed that clinical comorbidities, in particular, seizures, and MGMT promoter methylation, were associated with flatter spectra. Notably, the degree of change in spectra was predictive of overall survival. Our findings suggest that frequency domain analysis of rs-fMRI activity provides prognostic information in glioblastoma patients and offers a means of noninvasively studying the effects of glioblastoma on the whole brain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To identify factors, including the use of intraoperative magnetic resonance imaging (iMRI), impacting overall survival (OS) and progression-free survival (PFS) after resections of newly diagnosed intracranial grade II ependymomas performed across 4 different institutions., Methods: Analyses of a multicenter mixed retrospective/prospective database assessed the impact of patient, treatment, and tumor characteristics on OS and PFS. iMRI workflow and logistics were also outlined., Results: Forty-three patients were identified (mean age 25.4 years, mean follow-up 52.8 months). The mean OS was 52.8 ± 44.7 months. Univariate analyses failed to identify prognostic factors associated with OS, likely due to relatively shorter follow-up time for this less aggressive glioma subtype. The mean PFS was 43.7 ± 39.8 months. Multivariate analyses demonstrated that gross-total resection was associated with prolonged PFS compared to both subtotal resection (STR) (P = 0.005) and near-total resection (P = 0.01). Infratentorial location was associated with improved PFS compared to supratentorial location (P = 0.04). Log-rank analyses of Kaplan-Meier survival curves showed that increasing extent of resection (EOR) led to improved OS specifically for supratentorial tumors (P = 0.02) and improved PFS for all tumors (P < 0.001). Thirty cases (69.8%) utilized iMRI, of which 12 (27.9%) involved additional resection after iMRI. Of these, 8/12 (66.7%) resulted in gross-total resection, while 2/12 (16.7%) were near-total resection and 2/12 (16.7%) were subtotal resection. iMRI was not an independent prognosticator of PFS (P = 0.72)., Conclusions: Greater EOR and infratentorial location were associated with increased PFS for grade II ependymomas. Greater EOR was associated with longer OS only for supratentorial tumors. A longer follow-up is needed to establish prognostic factors for this cohort, including use of iMRI., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: For patients with surgically accessible solitary metastases or oligometastatic disease, treatment often involves resection followed by postoperative stereotactic radiosurgery (SRS). This strategy has several potential drawbacks, including irregular target delineation for SRS and potential tumor "seeding" away from the resection cavity during surgery. A neoadjuvant (preoperative) approach to radiation therapy avoids these limitations and offers improved patient convenience. This study assessed the efficacy of neoadjuvant SRS as a new treatment paradigm for patients with brain metastases., Methods: A retrospective review was performed at a single institution to identify patients who had undergone neoadjuvant SRS (specifically, Gamma Knife radiosurgery) followed by resection of a brain metastasis. Kaplan-Meier survival and log-rank analyses were used to evaluate risks of progression and death. Assessments were made of local recurrence and leptomeningeal spread. Additionally, an analysis of the contemporary literature of postoperative and neoadjuvant SRS for metastatic disease was performed., Results: Twenty-four patients who had undergone neoadjuvant SRS followed by resection of a brain metastasis were identified in the single-institution cohort. The median age was 64 years (range 32-84 years), and the median follow-up time was 16.5 months (range 1 month to 5.7 years). The median radiation dose was 17 Gy prescribed to the 50% isodose. Rates of local disease control were 100% at 6 months, 87.6% at 12 months, and 73.5% at 24 months. In 4 patients who had local treatment failure, salvage therapy included repeat resection, laser interstitial thermal therapy, or repeat SRS. One hundred thirty patients (including the current cohort) were identified in the literature who had been treated with neoadjuvant SRS prior to resection. Overall rates of local control at 1 year after neoadjuvant SRS treatment ranged from 49% to 91%, and rates of leptomeningeal dissemination from 0% to 16%. In comparison, rates of local control 1 year after postoperative SRS ranged from 27% to 91%, with 7% to 28% developing leptomeningeal disease., Conclusions: Neoadjuvant SRS for the treatment of brain metastases is a novel approach that mitigates the shortcomings of postoperative SRS. While additional prospective studies are needed, the current study of 130 patients including the summary of 106 previously published cases supports the safety and potential efficacy of preoperative SRS with potential for improved outcomes compared with postoperative SRS.

Introduction: There is a need to identify objective cortical electrophysiological correlates for pain relief that could potentially contribute to a better pain management. However, the field of developing brain biomarkers for pain relief is still largely underexplored., Objectives: The objective of this study was to investigate cortical electrophysiological correlates associated with relief from chronic pain. Those features of pain relief could serve as potential targets for novel therapeutic interventions to treat pain., Methods: In 12 patients with chronic pain in the upper or lower extremity undergoing a clinically indicated nerve block procedure, brain activity was recorded by means of electroencephalogram before and 30 minutes after the nerve block procedure. To determine the specific cortical electrophysiological correlates of relief from chronic pain, 12 healthy participants undergoing cold-pressor test to induce experimental acute pain were used as a control group. The data were analyzed to characterize power spectral density patterns of pain relief and identify their source generators at cortical level., Results: Chronic pain relief was associated with significant delta, theta, and alpha power increase at the frontal area. However, only midfrontal theta power increase showed significant positive correlation with magnitude of reduction in pain intensity. The sources of theta power rebound were located in the left dorsolateral prefrontal cortex (DLPFC) and midline frontal cortex. Furthermore, theta power increase in the midline frontal cortex was significantly higher with chronic vs acute pain relief., Conclusion: These findings may provide basis for targeting chronic pain relief via modulation of the midline frontal theta oscillations., Competing Interests: E.C. Leuthardt has stock ownership in Neurolutions, Inner Cosmos, and Sora Neuroscience. Washington University also owns stock in Neurolutions. This work and E.C. Leuthardt have had their conflict of interest rigorously evaluated and managed throughout this study and with creation of this manuscript. The remaining authors have no conflicts of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Price transparency is an increasingly popular solution for high healthcare expenditures in the United States, but little is known about its potential to facilitate patient price shopping. Our objective was to analyze interhospital and interpayer price variability in spine surgery and spine imaging using newly public payer-specific negotiated charges (PNCs). We selected a subset of billing codes for spine surgery and spine imaging at 12 hospitals within a Saint Louis metropolitan area healthcare system. We then compared PNCs for these procedures and tested for significant differences in interhospital and interinsurer IQR using the Mann-Whitney U Test. We found significantly greater IQRs of PNCs as a factor of the insurance plan than as a factor of the hospital for cervical spinal fusions (interinsurer IQR $8256; interhospital IQR $533; P < .0001), noncervical spinal fusions (interinsurer IQR $28 423; interhospital IQR $5512; P < .001), computed tomographies of the lower spine (interinsurer IQR $595; interhospital IQR $113; P < .0001), and MRIs lower spinal canal (interinsurer IQR $1010; interhospital IQR $158; P < .0001). There was no significant difference between the interinsurer IQR and the interhospital IQR for lower spine x-rays (interinsurer IQR $107; interhospital IQR $67; P = .0543). Despite some between-hospital heterogeneity, we show significantly higher price variability between insurers than between hospitals. Our single system analysis limits our ability to generalize, but our results suggest that savings depend more on hospital and provider negotiations than patient price shopping, given the difficulty of switching insurers., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Background: Improved survival for patients with brain metastases has been accompanied by a rise in tumor recurrence after stereotactic radiotherapy (SRT). Laser interstitial thermal therapy (LITT) has emerged as an effective treatment for SRT failures as an alternative to open resection or repeat SRT. We aimed to evaluate the efficacy of LITT followed by SRT (LITT+SRT) in recurrent brain metastases., Methods: A multicenter, retrospective study was performed of patients who underwent treatment for biopsy-proven brain metastasis recurrence after SRT at an academic medical center. Patients were stratified by "planned LITT+SRT" versus "LITT alone" versus "repeat SRT alone." Index lesion progression was determined by modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria., Results: Fifty-five patients met inclusion criteria, with a median follow-up of 7.3 months (range: 1.0-30.5), age of 60 years (range: 37-86), Karnofsky Performance Status (KPS) of 80 (range: 60-100), and pre-LITT/biopsy contrast-enhancing volume of 5.7 cc (range: 0.7-19.4). Thirty-eight percent of patients underwent LITT+SRT, 45% LITT alone, and 16% SRT alone. Median time to index lesion progression (29.8, 7.5, and 3.7 months [ P = .022]) was significantly improved with LITT+SRT. When controlling for age in a multivariate analysis, patients treated with LITT+SRT remained significantly less likely to have index lesion progression ( P = .004)., Conclusions: These data suggest that LITT+SRT is superior to LITT or repeat SRT alone for treatment of biopsy-proven brain metastasis recurrence after SRT failure. Prospective trials are warranted to validate the efficacy of using combination LITT+SRT for treatment of recurrent brain metastases., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Objective: Localization of focal epilepsy is critical for surgical treatment of refractory seizures. There remains a great need for noninvasive techniques to localize seizures for surgical decision-making. We investigate the use of deep learning using resting state functional magnetic resonance imaging (RS-fMRI) to identify the hemisphere of seizure onset in temporal lobe epilepsy (TLE) patients., Methods: A total of 2132 healthy controls and 32 preoperative TLE patients were studied. All participants underwent structural MRI and RS-fMRI. Healthy control data were used to generate training samples for a three-dimensional convolutional neural network (3DCNN). RS-fMRI was synthetically altered in randomly lateralized regions in the healthy control participants. The model was then trained to classify the hemisphere containing synthetic noise. Finally, the model was tested on TLE patients to assess its performance for detecting biological seizure onset zones, and gradient-weighted class activation mapping (Grad-CAM) identified the strongest predictive regions., Results: The 3DCNN classified healthy control hemispheres known to contain synthetic noise with 96% accuracy, and TLE hemispheres clinically identified to be seizure onset zones with 90.6% accuracy. Grad-CAM identified a range of temporal, frontal, parietal, and subcortical regions that were strong anatomical predictors of the seizure onset zone, and the resting state networks that colocalized with Grad-CAM results included default mode, medial temporal, and dorsal attention networks. Lastly, in an analysis of a subset of patients with postsurgical outcomes, the 3DCNN leveraged a more focal set of regions to achieve classification in patients with Engel Class >I compared to Engel Class I., Significance: Noninvasive techniques capable of localizing the seizure onset zone could improve presurgical planning in patients with intractable epilepsy. We have demonstrated the ability of deep learning to identify the correct hemisphere of the seizure onset zone in TLE patients using RS-fMRI with high accuracy. This approach represents a novel technique of seizure lateralization that could improve preoperative surgical planning., (© 2022 International League Against Epilepsy.)

Chronic stroke patients with upper-limb motor disabilities are now beginning to see treatment options that were not previously available. To date, the two options recently approved by the United States Food and Drug Administration include vagus nerve stimulation and brain-computer interface therapy. While the mechanisms for vagus nerve stimulation have been well defined, the mechanisms underlying brain-computer interface-driven motor rehabilitation are largely unknown. Given that cross-frequency coupling has been associated with a wide variety of higher-order functions involved in learning and memory, we hypothesized this rhythm-specific mechanism would correlate with the functional improvements effected by a brain-computer interface. This study investigated whether the motor improvements in chronic stroke patients induced with a brain-computer interface therapy are associated with alterations in phase-amplitude coupling, a type of cross-frequency coupling. Seventeen chronic hemiparetic stroke patients used a robotic hand orthosis controlled with contralesional motor cortical signals measured with EEG. Patients regularly performed a therapeutic brain-computer interface task for 12 weeks. Resting-state EEG recordings and motor function data were acquired before initiating brain-computer interface therapy and once every 4 weeks after the therapy. Changes in phase-amplitude coupling values were assessed and correlated with motor function improvements. To establish whether coupling between two different frequency bands was more functionally important than either of those rhythms alone, we calculated power spectra as well. We found that theta-gamma coupling was enhanced bilaterally at the motor areas and showed significant correlations across brain-computer interface therapy sessions. Importantly, an increase in theta-gamma coupling positively correlated with motor recovery over the course of rehabilitation. The sources of theta-gamma coupling increase following brain-computer interface therapy were mostly located in the hand regions of the primary motor cortex on the left and right cerebral hemispheres. Beta-gamma coupling decreased bilaterally at the frontal areas following the therapy, but these effects did not correlate with motor recovery. Alpha-gamma coupling was not altered by brain-computer interface therapy. Power spectra did not change significantly over the course of the brain-computer interface therapy. The significant functional improvement in chronic stroke patients induced by brain-computer interface therapy was strongly correlated with increased theta-gamma coupling in bihemispheric motor regions. These findings support the notion that specific cross-frequency coupling dynamics in the brain likely play a mechanistic role in mediating motor recovery in the chronic phase of stroke recovery., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples., Methods: Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers., Results: In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples., Conclusions: Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura., (© 2022. The Author(s).)

Laser interstitial thermal therapy (LITT) has become an increasingly utilized alternative to surgical resection for the treatment of glioma in patients. However, treatment outcomes in isocitrate dehydrogenase 1 and 2 ( IDH1/2 ) mutant glioma, specifically, have not been reported. The objective of this study was to characterize a single institution's cohort of IDH1/2 mutant grade 2/3 glioma patients treated with LITT. We collected data on patient presentation, radiographic features, tumor molecular profile, complications, and outcomes. We calculated progression-free survival (PFS) and tested factors for significant association with longer PFS. Overall, 22.7% of our cohort experienced progression at a median follow up of 1.8 years. The three- and five-year estimates of PFS were 72.5% and 54.4%, respectively. This is the first study to characterize outcomes in patients with IDH1/2 mutant glioma after LITT. Our results suggest that LITT is an effective treatment option for IDH1/2 mutant glioma.

Background: Treatment options for unresectable new and recurrent glioblastoma remain limited. Laser ablation has demonstrated safety as a surgical approach to treating primary brain tumors. The LAANTERN prospective multicenter registry (NCT02392078) data were analyzed to determine clinical outcomes for patients with new and recurrent IDH wild-type glioblastoma., Methods: Demographics, intraprocedural data, adverse events, KPS, health economics, and survival data were prospectively collected and then analyzed on IDH wild-type newly diagnosed and recurrent glioblastoma patients who were treated with laser ablation at 14 US centers between January 2016 and May 2019. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable differences in survival, and median survival numbers., Results: A total of 29 new and 60 recurrent IDH wild-type WHO grade 4 glioblastoma patients were treated. Positive MGMT promoter methylation status was present in 5/29 of new and 23/60 of recurrent patients. Median physician-estimated extent of ablation was 91%-99%. Median overall survival (OS) was 9.73 months (95% confidence interval: 5.16, 15.91) for newly diagnosed patients and median post-procedure survival was 8.97 months (6.94, 12.36) for recurrent patients. Median OS for newly diagnosed patients receiving post-LITT chemo/radiation was 16.14 months (6.11, not reached). Factors associated with improved survival were MGMT promoter methylation, adjuvant chemotherapy within 12 weeks, and tumor volume <3 cc., Conclusions: Laser ablation is a viable option for patients with new and recurrent glioblastoma. Median OS for IDH wild-type newly diagnosed glioblastoma is comparable to outcomes observed in other tumor resection studies when those patients undergo radiation and chemotherapy following LITT., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Despite the improved understanding of the molecular and genetic heterogeneity of glioblastoma, there is still an unmet need for better therapeutics, as treatment approaches have remained unchanged in recent years. Research into the role of the immune microenvironment has generated enthusiasm for testing immunotherapy (specifically, immune checkpoint inhibitors). However, to date, trials of immunotherapy in glioblastoma have not demonstrated a survival advantage. Combination approaches aimed at optimally inducing response to immune checkpoint inhibitors with radiotherapy are currently being investigated. Herein, the authors describe their experience of the potential benefit and clinical outcomes of using combination pembrolizumab (an immune checkpoint inhibitor) and laser interstitial thermal therapy in a case series of patients with recurrent IDH -wild-type glioblastoma.

Background: Many factors impact survival in patients with glioblastoma, including age, Karnofsky Performance Status, postoperative chemoradiation, IDH1/2 mutation status, MGMT promoter methylation status, and extent of resection. High-throughput next-generation sequencing is a widely available diagnostic tool, but the independent impact of tumors harboring specific mutant genes on survival and the efficacy of extent of resection are not clear., Methods: We utilized a widely available diagnostic platform (FoundationOne CDx) to perform high-throughput next-generation sequencing on 185 patients with newly diagnosed glioblastoma in our tertiary care center. We performed multivariate analysis to control for clinical parameters with known impact on survival to elucidate the independent prognostic value of prevalent mutant genes and the independent impact of gross total resection., Results: When controlling for factors with known prognostic significance including IDH1/2 mutation and after multiple comparisons analysis, CDKN2B and EGFR mutations were associated with reduced overall survival while PTEN mutation was associated with improved overall survival. Gross total resection, compared to other extent of resection, was associated with improved overall survival in patients with tumors harboring mutations in CDKN2A , CDKN2B , EGFR , PTEN , TERT promoter, and TP53 . All patients possessed at least one of these 6 mutant genes., Conclusions: This study verifies the independent prognostic value of several mutant genes in glioblastoma. Six commonly found mutant genes were associated with improved survival when gross total resection was achieved. Thus, even when accounting for known predictors of survival and multiple mutant gene comparisons, extent of resection continues to be strongly associated with survival., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)