Auricular Vagus Nerve Stimulation Mitigates Inflammation and Vasospasm in Subarachnoid Hemorrhage: A Randomized Trial.

Background: Inflammation contributes to morbidity following subarachnoid hemorrhage (SAH). Transauricular vagus nerve stimulation (taVNS) offers a noninvasive approach to target the inflammatory response following SAH. Methods: In this prospective, triple-blinded, randomized, controlled trial, twenty-seven patients were randomized to taVNS or sham stimulation. Blood and cerebrospinal fluid (CSF) were collected to quantify inflammatory markers. Cerebral vasospasm severity and functional outcomes (modified Rankin Scale, mRS) were analyzed. Results: No adverse events occurred. Radiographic vasospasm was significantly reduced (p = 0.018), with serial vessel caliber measurements demonstrating a more rapid return to normal than sham (p < 0.001). In the taVNS group, TNF-α was significantly reduced in both plasma (days 7 and 10) and CSF (day 13); IL-6 was also significantly reduced in plasma (day 4) and CSF (day 13) (p < 0.05). Patients receiving taVNS had higher rates of favorable outcomes at discharge (38.4% vs 21.4%) and first follow-up (76.9% vs 57.1%), with significant improvement from admission to first follow-up (p = 0.014), unlike the sham group (p = 0.18). The taVNS group had a significantly lower rate of discharge to skilled nursing facility or hospice (p = 0.04). Conclusion: taVNS is a non-invasive method of neuro- and systemic immunomodulation. This trial supports that taVNS following SAH can mitigate the inflammatory response, reduce radiographic vasospasm, and potentially improve functional and neurological outcomes. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04557618.

The effect of transcutaneous auricular vagus nerve stimulation on cardiovascular function in subarachnoid hemorrhage patients: a safety study.

Objective: Subarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia.2,6,7 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.3,8,9 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 population4. 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 rapidly responsive cardiovascular biomarkers in patients exhibiting clinical improvement. Results: We found that repetitive taVNS did not significantly alter heart rate, corrected QT interval, blood pressure, or intracranial pressure. However, taVNS increased overall heart rate variability and parasympathetic activity from 5-10 days after initial treatment, as compared to the sham treatment. 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 1 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.

Does Vibrotactile Stimulation of the Auricular Vagus Nerve Enhance Working Memory? A Behavioral and Physiological Investigation.

Background: Working memory is essential to a wide range of cognitive functions and activities. Transcutaneous auricular VNS (taVNS) is a promising method to improve working memory performance. However, the feasibility and scalability of electrical stimulation are constrained by several limitations, such as auricular discomfort and inconsistent electrical contact. Objective: We aimed to develop a novel and practical method, vibrotactile taVNS, to improve working memory. Further, we investigated its effects on arousal, measured by skin conductance and pupil diameter. Method: This study included 20 healthy participants. Behavioral response, skin conductance, and eye tracking data were concurrently recorded while the participants performed N-back tasks under three conditions: vibrotactile taVNS delivered to the cymba concha, earlobe (sham control), and no stimulation (baseline control). Results: In 4-back tasks, which demand maximal working memory capacity, active vibrotactile taVNS significantly improved the performance metric d ' compared to the baseline but not to the sham. Moreover, we found that the reduction rate of d ' with increasing task difficulty was significantly smaller during vibrotactile taVNS sessions than in both baseline and sham conditions. Arousal, measured as skin conductance and pupil diameter, declined over the course of the tasks. Vibrotactile taVNS rescued this arousal decline, leading to arousal levels corresponding to optimal working memory levels. Moreover, pupil diameter and skin conductance level were higher during high-cognitive-load tasks when vibrotactile taVNS was delivered to the concha compared to baseline and sham. Conclusion: Our findings suggest that vibrotactile taVNS modulates the arousal pathway and could be a potential intervention for enhancing working memory. Highlights: Vibrotactile stimulation of the auricular vagus nerve increases general arousal.Vibrotactile stimulation of the auricular vagus nerve mitigates arousal decreases as subjects continuously perform working memory tasks.6 Hz Vibrotactile auricular vagus nerve stimulation is a potential intervention for enhancing working memory performance.

Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH): Protocol for a prospective, triple-blinded, randomized controlled trial.

Background: Inflammation has been implicated in driving the morbidity associated with subarachnoid hemorrhage (SAH). Despite understanding the important role of inflammation in morbidity following SAH, there is no current effective way to modulate this deleterious response. There is a critical need for a novel approach to immunomodulation that can be safely, rapidly, and effectively deployed in SAH patients. Vagus nerve stimulation (VNS) provides a non-pharmacologic approach to immunomodulation, with prior studies demonstrating VNS can reduce systemic inflammatory markers, and VNS has had early success treating inflammatory conditions such as arthritis, sepsis, and inflammatory bowel diseases. The aim of the Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH) trial is to translate the use of non-invasive transcutaneous auricular VNS (taVNS) to spontaneous SAH, with our central hypothesis being that implementing taVNS in the acute period following spontaneous SAH attenuates the expected inflammatory response to hemorrhage and curtails morbidity associated with inflammatory-mediated clinical endpoints. Materials and methods: The overall objectives for the NAHSaH trial are to 1) Define the impact that taVNS has on SAH-induced inflammatory markers in the plasma and cerebrospinal fluid (CSF), 2) Determine whether taVNS following SAH reduces radiographic vasospasm, and 3) Determine whether taVNS following SAH reduces chronic hydrocephalus. Following presentation to a single enrollment site, enrolled SAH patients are randomly assigned twice daily treatment with either taVNS or sham stimulation for the duration of their intensive care unit stay. Blood and CSF are drawn before initiation of treatment sessions, and then every three days during a patient's hospital stay. Primary endpoints include change in the inflammatory cytokine TNF-α in plasma and cerebrospinal fluid between day 1 and day 13, rate of radiographic vasospasm, and rate of requirement for long-term CSF diversion via a ventricular shunt. Secondary outcomes include exploratory analyses of a panel of additional cytokines, number and type of hospitalized acquired infections, duration of external ventricular drain in days, interventions required for vasospasm, continuous physiology data before, during, and after treatment sessions, hospital length of stay, intensive care unit length of stay, and modified Rankin Scale score (mRS) at admission, discharge, and each at follow-up appointment for up to two years following SAH. Discussion: Inflammation plays a central role in morbidity following SAH. This NAVSaH trial is innovative because it diverges from the pharmacologic status quo by harnessing a novel non-invasive neuromodulatory approach and its known anti-inflammatory effects to alter the pathophysiology of SAH. The investigation of a new, effective, and rapidly deployable intervention in SAH offers a new route to improve outcomes following SAH. Trial registration: Clinical Trials Registered, NCT04557618. Registered on September 21, 2020, and the first patient was enrolled on January 4, 2021.

Does vibrotactile stimulation of the auricular vagus nerve enhance working memory? A behavioral and physiological investigation.

BACKGROUND: Working memory is essential to a wide range of cognitive functions and activities. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising method to improve working memory performance. However, the feasibility and scalability of electrical stimulation are constrained by several limitations, such as auricular discomfort and inconsistent electrical contact. OBJECTIVE: We aimed to develop a novel and practical method, vibrotactile taVNS, to improve working memory. Further, we investigated its effects on arousal, measured by skin conductance and pupil diameter. METHOD: This study included 20 healthy participants. Behavioral response, skin conductance, and eye tracking data were concurrently recorded while the participants performed N-back tasks under three conditions: vibrotactile taVNS delivered to the cymba concha, earlobe (sham control), and no stimulation (baseline control). RESULTS: In 4-back tasks, which demand maximal working memory capacity, active vibrotactile taVNS significantly improved the performance metric d' compared to the baseline but not to the sham. Moreover, we found that the reduction rate of d' with increasing task difficulty was significantly smaller during vibrotactile taVNS sessions than in both baseline and sham conditions. Arousal, measured as skin conductance and pupil diameter, declined over the course of the tasks. Vibrotactile taVNS rescued this arousal decline, leading to arousal levels corresponding to optimal working memory levels. Moreover, pupil diameter and skin conductance level were higher during high-cognitive-load tasks when vibrotactile taVNS was delivered to the concha compared to baseline and sham. CONCLUSION: Our findings suggest that vibrotactile taVNS modulates the arousal pathway and could be a potential intervention for enhancing working memory.

Quality assurance for focused ultrasound-induced blood-brain barrier opening procedure using passive acoustic detection.

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.

Glioblastoma-infiltrating CD8+ T cells are predominantly a clonally expanded GZMK+ effector population.

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 (CITE-seq) and single-cell RNA sequencing (scRNA-seq) with paired V(D)J sequencing, respectively, on TIL 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 to 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 which may harbor potential therapeutic implications.

A novel theta-controlled vibrotactile brain-computer interface to treat chronic pain: a pilot study.

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.

Optimal approaches to analyzing functional MRI data in glioma patients.

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.

Single-pulse electrical stimulation artifact removal using the novel matching pursuit-based artifact reconstruction and removal method (MPARRM).

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.

IpsiHand Brain-Computer Interface Therapy Induces Broad Upper Extremity Motor Recovery in Chronic Stroke.

Background and Purpose: 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. This study investigated the effectiveness of the IpsiHand System, a contralesionally-controlled BCI therapy in chronic stroke patients with impaired upper extremity motor function. We further explored neurophysiological features of motor recovery affected by BCI. We hypothesized that BCI therapy would induce a broad motor recovery in the upper extremity (proximal and distal), and there would be corresponding changes in baseline theta and gamma oscillations, which have been shown to be associated with motor recovery. Methods: Thirty chronic hemiparetic stroke patients performed a therapeutic BCI task for 12 weeks. Motor function assessment data and resting state electroencephalogram (EEG) signals were acquired before initiating BCI therapy and across BCI therapy sessions. The Upper Extremity Fugl-Meyer assessment (UEFM) 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 with BCI therapy. We found significant improvement in both proximal and distal upper extremity motor function. Importantly, motor function improvement was independent of Botox application. Theta-gamma CFC enhanced bilaterally over the C3 and C4 motor electrodes following BCI therapy. We observed significant positive correlations between motor recovery and theta gamma CFC increase across BCI therapy sessions. Conclusions: BCI therapy resulted in significant motor function improvement across the proximal and distal upper extremities of patients. This therapy was significantly correlated with changes in baseline cortical dynamics, specifically theta-gamma CFC increases in both the right and left motor regions. This may represent rhythm-specific cortical oscillatory mechanism for BCI-driven motor rehabilitation in chronic stroke patients.

Predicting survival in glioblastoma with multimodal neuroimaging and machine learning.

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.

First-in-human prospective trial of sonobiopsy in high-grade glioma patients using neuronavigation-guided focused ultrasound.

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.

Precision functional MRI mapping reveals distinct connectivity patterns for depression associated with traumatic brain injury.

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.

Glioblastoma induces whole-brain spectral change in resting state fMRI: Associations with clinical comorbidities and overall survival.

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.

Slow-wave modulation analysis during states of unconsciousness using the novel tau-modulation method.

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.

Structural gray matter alterations in glioblastoma and high-grade glioma-A potential biomarker of survival.

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.

Data-efficient resting-state functional magnetic resonance imaging brain mapping with deep learning.

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.