An analysis of RNA quality metrics in human brain tissue.

Human brain tissue studies have historically used a range of metrics to assess RNA quality. However, few large-scale cross-comparisons of pre-sequencing quality metrics with RNA-seq quality have been published. Here, we analyze how well metrics gathered before RNA sequencing (post-mortem interval (PMI) and RNA integrity number RIN) relate to analyses of RNA quality after sequencing (Percent of counts in Top Ten genes (PTT), 5' bias, and 3' bias) as well as with individual gene counts across the transcriptome. We conduct this analysis across four different human cortical brain tissue collections sequenced with varying library preparation protocols. PMI and RIN have a low inverse correlation, and both PMI and RIN show consistent and opposing correlations with PTT. Unlike PMI, RIN shows strong consistent correlations with measurements of 3' and 5' bias, and RIN also correlates with 3,933 genes across datasets, in comparison to 138 genes for PMI. Neuronal and immune response genes correlate positively and negatively with RIN respectively, suggesting that different gene sets have divergent relationships with RIN in brain tissue. In summary, these analyses suggest that conventional metrics of RNA quality have varying degrees of value, and that PMI has an overall minimal but reproducible effect on RNA quality.

Temporal integration in human auditory cortex is predominantly yoked to absolute time, not structure duration.

Sound structures such as phonemes and words have highly variable durations. Thus, there is a fundamental difference between integrating across absolute time (e.g., 100 ms) vs. sound structure (e.g., phonemes). Auditory and cognitive models have traditionally cast neural integration in terms of time and structure, respectively, but the extent to which cortical computations reflect time or structure remains unknown. To answer this question, we rescaled the duration of all speech structures using time stretching/compression and measured integration windows in the human auditory cortex using a new experimental/computational method applied to spatiotemporally precise intracranial recordings. We observed significantly longer integration windows for stretched speech, but this lengthening was very small (~5%) relative to the change in structure durations, even in non-primary regions strongly implicated in speech-specific processing. These findings demonstrate that time-yoked computations dominate throughout the human auditory cortex, placing important constraints on neurocomputational models of structure processing.

Brain-Controlled Augmented Hearing for Spatially Moving Conversations in Multi-Talker Environments.

Focusing on a specific conversation amidst multiple interfering talkers is challenging, especially for those with hearing loss. Brain-controlled assistive hearing devices aim to alleviate this problem by enhancing the attended speech based on the listener's neural signals using auditory attention decoding (AAD). Departing from conventional AAD studies that relied on oversimplified scenarios with stationary talkers, a realistic AAD task that involves multiple talkers taking turns as they continuously move in space in background noise is presented. Invasive electroencephalography (iEEG) data are collected from three neurosurgical patients as they focused on one of the two moving conversations. An enhanced brain-controlled assistive hearing system that combines AAD and a binaural speaker-independent speech separation model is presented. The separation model unmixes talkers while preserving their spatial location and provides talker trajectories to the neural decoder to improve AAD accuracy. Subjective and objective evaluations show that the proposed system enhances speech intelligibility and facilitates conversation tracking while maintaining spatial cues and voice quality in challenging acoustic environments. This research demonstrates the potential of this approach in real-world scenarios and marks a significant step toward developing assistive hearing technologies that adapt to the intricate dynamics of everyday auditory experiences.

Optimizing Surgical Outcomes for Intracranial Epidermoid Tumors: A Retrospective Analysis of Clinical Predictors, Surgical Decisions, and Patient Clustering.

BACKGROUND/OBJECTIVE: Intracranial epidermoid tumors (ETs) are rare, benign lesions that present significant challenges in neurosurgical management due to their propensity to encase vital neurovascular structures. We aimed to evaluate the impact of clinical, demographic, and tumor-specific factors on surgical decisions (gross total resection [GTR] vs. subtotal resection [STR]) and outcomes and identify patient clusters with distinct profiles and outcomes post-resection. METHODS: We retrospectively analyzed 72 patients with ET treated from 1998 to 2022, employing multivariable logistic regression for GTR versus STR predictors and Kaplan-Meier curves for progression-free survival (PFS). K-prototype clustering classified patients based on clinical data. RESULTS: The mean age of our cohort was 39.8 ± 20.1 years. About 13.9% of patients had a recurrence, with a median PFS of 108 months (interquartile range: 57 -206). Seizures significantly predicted GTR (P < 0.05), whereas adherence to critical structures reduced GTR likelihood (P < 0.05). Initial surgeries more often achieved GTR, correlating with longer PFS (P < 0.0001) and reduced recurrence (P < 0.01) versus re-operations. Cluster analysis identified three distinct groups, with the initial GTR cluster showing superior PFS and the lowest recurrence (P < 0.0001 and P < 0.01, respectively). Statistically significant predictors of PFS included age and preoperative seizure presence, with older age favoring longer PFS (P < 0.01) and seizures associated with reduced PFS (P < 0.01). In addition, patients with previous surgeries showed a trend toward shorter PFS (P < 0.05). CONCLUSIONS: This study emphasizes the importance of tailored surgical strategies in managing intracranial ETs, advocating for GTR to optimize long-term outcomes where possible. Future prospective studies are essential to further refine treatment approaches, enhancing survival for ET patients.

Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

INTRODUCTION: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early Alzheimer's disease (AD) pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify cerebrospinal fluid  (CSF) biomarkers for AD-related central nervous system (CNS) pathophysiologic changes using tissue and fluids with early pathology, free of post mortem artifact. METHODS: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. RESULTS: AD pathology on biopsy correlates with CSF ß-amyloid-42/40, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/ß-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights seven core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data. DISCUSSION: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking. HIGHLIGHTS: AD CSF biomarkers correlate with CNS pathology and transcriptomic changes. Seven proteins correlate with CNS pathology and gene expression changes. Inflammatory and neuronal gene expression changes correlate with YKL-40 and NPTXR, respectively. CSF metabolomic analysis identifies pathways that correlate with biopsy data. Fatty acid metabolic pathways correlate with ß-amyloid pathology.

Spectral-switching analysis reveals real-time neuronal network representations of concurrent spontaneous naturalistic behaviors in human brain.

Despite abundant evidence of functional networks in the human brain, their neuronal underpinnings, and relationships to real-time behavior have been challenging to resolve. Analyzing brain-wide intracranial-EEG recordings with video monitoring, acquired in awake subjects during clinical epilepsy evaluation, we discovered the tendency of each brain region to switch back and forth between 2 distinct power spectral densities (PSDs 2-55Hz). We further recognized that this 'spectral switching' occurs synchronously between distant sites, even between regions with differing baseline PSDs, revealing long-range functional networks that would be obscured in analysis of individual frequency bands. Moreover, the real-time PSD-switching dynamics of specific networks exhibited striking alignment with activities such as conversation and hand movements, revealing a multi-threaded functional network representation of concurrent naturalistic behaviors. Network structures and their relationships to behaviors were stable across days, but were altered during N3 sleep. Our results provide a new framework for understanding real-time, brain-wide neural-network dynamics.

Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

INTRODUCTION: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early AD pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify CSF biomarkers for AD-related CNS pathophysiologic changes using tissue and fluids with early pathology, free of post-mortem artifact. METHODS: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. RESULTS: AD pathology on biopsy correlates with CSF ß-amyloid-40/42, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/ß-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights 7 core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data.. DISCUSSION: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking.

CHD2 Regulates Neuron-Glioma Interactions in Pediatric Glioma.

High-grade gliomas (HGG) are deadly diseases for both adult and pediatric patients. Recently, it has been shown that neuronal activity promotes the progression of multiple subgroups of HGG. However, epigenetic mechanisms that govern this process remain elusive. Here we report that the chromatin remodeler chromodomain helicase DNA-binding protein 2 (CHD2) regulates neuron-glioma interactions in diffuse midline glioma (DMG) characterized by onco-histone H3.1K27M. Depletion of CHD2 in H3.1K27M DMG cells compromises cell viability and neuron-to-glioma synaptic connections in vitro, neuron-induced proliferation of H3.1K27M DMG cells in vitro and in vivo, activity-dependent calcium transients in vivo, and extends the survival of H3.1K27M DMG-bearing mice. Mechanistically, CHD2 coordinates with the transcription factor FOSL1 to control the expression of axon-guidance and synaptic genes in H3.1K27M DMG cells. Together, our study reveals a mechanism whereby CHD2 controls the intrinsic gene program of the H3.1K27M DMG subtype, which in turn regulates the tumor growth-promoting interactions of glioma cells with neurons. Significance: Neurons drive the proliferation and invasion of glioma cells. Here we show that chromatin remodeler chromodomain helicase DNA-binding protein 2 controls the epigenome and expression of axon-guidance and synaptic genes, thereby promoting neuron-induced proliferation of H3.1K27M diffuse midline glioma and the pathogenesis of this deadly disease.

Use of Recommended Neurodiagnostic Evaluation Among Patients With Drug-Resistant Epilepsy.

Importance: Interdisciplinary practice parameters recommend that patients with drug-resistant epilepsy (DRE) undergo comprehensive neurodiagnostic evaluation, including presurgical assessment. Reporting from specialized centers suggests long delays to referral and underuse of surgery; however, longitudinal data are limited to characterize neurodiagnostic evaluation among patients with DRE in more diverse US settings and populations. Objective: To examine the rate and factors associated with neurodiagnostic studies and comprehensive evaluation among patients with DRE within 3 US cohorts. Design, Setting, and Participants: A retrospective cross-sectional study was conducted using the Observational Medical Outcomes Partnership Common Data Model including US multistate Medicaid data, commercial claims data, and Columbia University Medical Center (CUMC) electronic health record data. Patients meeting a validated computable phenotype algorithm for DRE between January 1, 2015, and April 1, 2020, were included. No eligible participants were excluded. Exposure: Demographic and clinical variables were queried. Main Outcomes and Measures: The proportion of patients receiving a composite proxy for comprehensive neurodiagnostic evaluation, including (1) magnetic resonance or other advanced brain imaging, (2) video electroencephalography, and (3) neuropsychological evaluation within 2 years of meeting the inclusion criteria. Results: A total of 33 542 patients with DRE were included in the Medicaid cohort, 22 496 in the commercial insurance cohort, and 2741 in the CUMC database. A total of 31 516 patients (53.6%) were women. The proportion of patients meeting the comprehensive evaluation main outcome in the Medicaid cohort was 4.5% (n = 1520); in the commercial insurance cohort, 8.0% (n = 1796); and in the CUMC cohort, 14.3% (n = 393). Video electroencephalography (24.9% Medicaid, 28.4% commercial, 63.2% CUMC) and magnetic resonance imaging of the brain (35.6% Medicaid, 43.4% commercial, 52.6% CUMC) were performed more regularly than neuropsychological evaluation (13.0% Medicaid, 16.6% commercial, 19.2% CUMC) or advanced imaging (3.2% Medicaid, 5.4% commercial, 13.1% CUMC). Factors independently associated with greater odds of evaluation across all 3 data sets included the number of inpatient and outpatient nonemergency epilepsy visits and focal rather than generalized epilepsy. Conclusions and Relevance: The findings of this study suggest there is a gap in the use of diagnostic studies to evaluate patients with DRE. Care setting, insurance type, frequency of nonemergency visits, and epilepsy type are all associated with evaluation. A common data model can be used to measure adherence with best practices across a variety of observational data sources.

Awake intraoperative mapping for the prevention of amusia.

The authors describe the awake surgical mapping of music skills for patients who require resection in brain areas that may support musical abilities. A 65-year-old man was diagnosed with an anterolateral right temporal nonenhancing lesion, likely a diffusely infiltrating glioma, after presenting with several episodes of altered taste and smell and one episode of loss of consciousness. The patient specializes in music and music technology and has composed scores for films. An awake surgery was planned in a semiseated position. Prerecorded melodies were designed preoperatively as a surrogate for a composition skill task. These consisted of 10- to 15-second musical clips played during bipolar electrical stimulation of the overlying cortex and were divided into three segments: listen, play, and accuracy check. During the "listen" phase, the patient listened to a musical prompt. During the "play" phase, he played a musical response on a keyboard. Stimulation at multiple temporal neocortical sites was negative for any alteration in task performance. The patient did well postoperatively with excellent clinical and radiographic results and returned to composing music without functional compromise. Musical composition tasks can be performed safely intraoperatively for patients with musical expertise. Whether stimulating more posterior nondominant temporal neocortex or other cortical or white matter locations can disrupt this task remains undetermined.

Aberrant fast spiking interneuronal activity precedes seizure transitions in humans.

There is active debate regarding how GABAergic function changes during seizure initiation and propagation, and whether interneuronal activity drives or impedes the pathophysiology. Here, we track cell-type specific firing during spontaneous human seizures to identify neocortical mechanisms of inhibitory failure. Fast-spiking interneuron activity was maximal over 1 second before equivalent excitatory increases, and showed transitions to out-of-phase firing prior to local tissue becoming incorporated into the seizure-driving territory. Using computational modeling, we linked this observation to transient saturation block as a precursor to seizure invasion, as supported by multiple lines of evidence in the patient data. We propose that transient blocking of inhibitory firing due to selective fast-spiking interneuron saturation-resulting from intense excitatory synaptic drive-is a novel mechanism that contributes to inhibitory failure, allowing seizure propagation.

Glioma-Induced Alterations in Excitatory Neurons are Reversed by mTOR Inhibition.

Gliomas are highly aggressive brain tumors characterized by poor prognosis and composed of diffusely infiltrating tumor cells that intermingle with non-neoplastic cells in the tumor microenvironment, including neurons. Neurons are increasingly appreciated as important reactive components of the glioma microenvironment, due to their role in causing hallmark glioma symptoms, such as cognitive deficits and seizures, as well as their potential ability to drive glioma progression. Separately, mTOR signaling has been shown to have pleiotropic effects in the brain tumor microenvironment, including regulation of neuronal hyperexcitability. However, the local cellular-level effects of mTOR inhibition on glioma-induced neuronal alterations are not well understood. Here we employed neuron-specific profiling of ribosome-bound mRNA via 'RiboTag,' morphometric analysis of dendritic spines, and in vivo calcium imaging, along with pharmacological mTOR inhibition to investigate the impact of glioma burden and mTOR inhibition on these neuronal alterations. The RiboTag analysis of tumor-associated excitatory neurons showed a downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development, and an upregulation of transcripts encoding cytoskeletal proteins involved in dendritic spine turnover. Light and electron microscopy of tumor-associated excitatory neurons demonstrated marked decreases in dendritic spine density. In vivo two-photon calcium imaging in tumor-associated excitatory neurons revealed progressive alterations in neuronal activity, both at the population and single-neuron level, throughout tumor growth. This in vivo calcium imaging also revealed altered stimulus-evoked somatic calcium events, with changes in event rate, size, and temporal alignment to stimulus, which was most pronounced in neurons with high-tumor burden. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed the glioma-induced alterations on the excitatory neurons, including the alterations in ribosome-bound transcripts, dendritic spine density, and stimulus evoked responses seen by calcium imaging. These results point to mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma - manifested by alterations in ribosome-bound mRNA, dendritic spine density, and stimulus-evoked neuronal activity. Collectively, our work identifies the pathological changes that tumor-associated excitatory neurons experience as both hyperlocal and reversible under the influence of mTOR inhibition, providing a foundation for developing therapies targeting neuronal signaling in glioma.

The Matrix Receptor CD44 Is Present in Astrocytes throughout the Human Central Nervous System and Accumulates in Hypoxia and Seizures.

In the mammalian isocortex, CD44, a cell surface receptor for extracellular matrix molecules, is present in pial-based and fibrous astrocytes of white matter but not in protoplasmic astrocytes. In the hominid isocortex, CD44+ astrocytes comprise the subpial "interlaminar" astrocytes, sending long processes into the cortex. The hippocampus also contains similar astrocytes. We have examined all levels of the human central nervous system and found CD44+ astrocytes in every region. Astrocytes in white matter and astrocytes that interact with large blood vessels but not with capillaries in gray matter are CD44+, the latter extending long processes into the parenchyma. Motor neurons in the brainstem and spinal cord, such as oculomotor, facial, hypoglossal, and in the anterior horn of the spinal cord, are surrounded by CD44+ processes, contrasting with neurons in the cortex, basal ganglia, and thalamus. We found CD44+ processes that intercalate between ependymal cells to reach the ventricle. We also found CD44+ astrocytes in the molecular layer of the cerebellar cortex. Protoplasmic astrocytes, which do not normally contain CD44, acquire it in pathologies like hypoxia and seizures. The pervasive and inducible expression of CD44 in astrocytes is a novel finding that lays the foundations for functional studies into the significance of CD44 in health and disease.

Brain tumor-related epilepsy management: A Society for Neuro-oncology (SNO) consensus review on current management.

Tumor-related epilepsy (TRE) is a frequent and major consequence of brain tumors. Management of TRE is required throughout the course of disease and a deep understanding of diagnosis and treatment is key to improving quality of life. Gross total resection is favored from both an oncologic and epilepsy perspective. Shared mechanisms of tumor growth and epilepsy exist, and emerging data will provide better targeted therapy options. Initial treatment with antiseizure medications (ASM) in conjunction with surgery and/or chemoradiotherapy is typical. The first choice of ASM is critical to optimize seizure control and tolerability considering the effects of the tumor itself. These agents carry a potential for drug-drug interactions and therefore knowledge of mechanisms of action and interactions is needed. A review of adverse effects is necessary to guide ASM adjustments and decision-making. This review highlights the essential aspects of diagnosis and treatment of TRE with ASMs, surgery, chemotherapy, and radiotherapy while indicating areas of uncertainty. Future studies should consider the use of a standardized method of seizure tracking and incorporating seizure outcomes as a primary endpoint of tumor treatment trials.

Region-Dependent Mechanical Properties of Human Brain Tissue Under Large Deformations Using Inverse Finite Element Modeling.

This study aims to facilitate intracranial simulation of traumatic events by determining the mechanical properties of different anatomical structures of the brain. Our experimental indentation paradigm used fresh, post-operative human tissue, which is highly advantageous in determining mechanical properties without being affected by postmortem time. This study employed an inverse finite element approach coupled with experimental indentation data to characterize mechanical properties of the human hippocampus (CA1, CA3, dentate gyrus), cortex white matter, and cortex grey matter. We determined that an uncoupled viscoelastic Ogden constitutive formulation was most appropriate to represent the mechanical behavior of these different regions of brain. Anatomical regions were significantly different in their mechanical properties. The cortex white matter was stiffer than cortex grey matter, and the CA1 and dentate gyrus were both stiffer than cortex grey matter. Although no sex dependency was observed, there were trends indicating that male brain regions were generally stiffer than corresponding female regions. In addition, there were no statistically significant age dependent differences. This study provides a structure-specific description of fresh human brain tissue mechanical properties, which will be an important step toward explicitly modeling the heterogeneity of brain tissue deformation during TBI through finite element modeling.

Pretrial predictors of conflict response efficacy in the human prefrontal cortex.

The ability to perform motor actions depends, in part, on the brain's initial state. We hypothesized that initial state dependence is a more general principle and applies to cognitive control. To test this idea, we examined human single units recorded from the dorsolateral prefrontal (dlPFC) cortex and dorsal anterior cingulate cortex (dACC) during a task that interleaves motor and perceptual conflict trials, the multisource interference task (MSIT). In both brain regions, variability in pre-trial firing rates predicted subsequent reaction time (RT) on conflict trials. In dlPFC, ensemble firing rate patterns suggested the existence of domain-specific initial states, while in dACC, firing patterns were more consistent with a domain-general initial state. The deployment of shared and independent factors that we observe for conflict resolution may allow for flexible and fast responses mediated by cognitive initial states. These results also support hypotheses that place dACC hierarchically earlier than dlPFC in proactive control.