14 Aug

The microelectrode array technique - a crucial tool for studying excitable tissue disorders and drug testing: an update on recent advances

The microelectrode array (MEA) is an electronic device composed of a varying number of microelectrodes used to detect the extracellular field potential generated by excitable tissues. This technology allows for the measurement of electrical activity without damaging the cell membrane during recording. MEA offers a better way of getting long-term recordings and observing different cellular activities than the invasive patch clamp technique. Recent research demonstrates that MEA technology enables scientists to detect both cellular and subcellular events, allowing them to study cellular properties and reactions across different experimental conditions and even to identify distinct ion currents and their impact on cellular electrophysiology. The paper reviews the historical development of MEA technology along with its modern applications for electrophysiological research. The future advancement of MEA technology will improve our knowledge about neuronal and cardiac excitability and expand its use to additional electrically active tissues, advancing research in pharmacology, neuroscience, cardiology, and other fields.

31 Jul

PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson's disease

Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking, and LRRK2-activating mutations are linked to Parkinson's disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including protein phosphatase, Mg2⁺/Mn2⁺ dependent 1H (PPM1H), which acts on phosphorylated Rab 8A (phosphoRab8A) and phosphoRab10. Here, we report a phosphatome-wide small interfering RNA (siRNA) screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10. Upon knockout from cultured cells or mice, PPM1M displays selectivity for phosphoRab12. As shown previously for mice harboring LRRK2 pathway mutations, knockout of Ppm1m leads to primary cilia loss in striatal cholinergic and parvalbumin interneurons. We also identified a rare PPM1M mutation in patients with Parkinson's disease that is catalytically inactive when tested in vitro and in cells. These findings identify PPM1M as a key player in the LRRK2 signaling pathway and provide a new therapeutic target for the possible benefit of patients with Parkinson's disease.

2 Jul

Correction of Physiological Artifacts in Multi-Echo fMRI Data-Evaluation of Possible RETROICOR Implementations

Keywords: RETROICOR; denoising; fMRI; multi‐echo.

2 Jul

Accelerated Epigenetic Aging and Its Role in Brain Dynamics and Cognition in Young Adulthood

Accelerated epigenetic aging has been associated with changes in cognition. However, due to the lack of neuroimaging epigenetics studies, it is still unclear whether accelerated epigenetic. Aging in young adulthood might underlie the relationship between altered brain dynamics and cognitive functioning. We conducted neuroimaging epigenetics follow-up of the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) prenatal birth cohort in young adulthood and tested the possible mediatory role of accelerated epigenetic aging in the relationship between dynamic functional connectivity (DFC) and worse cognition. A total of 240 young adults (51% men; 28-30 years, all of European ancestry) participated in the neuroimaging epigenetics follow-up. Buccal swabs were collected to assess DNA methylation and calculate epigenetic aging using Horvath's epigenetic clock. Full-scale IQ was assessed using the Wechsler adult intelligence scale (WAIS). Resting-state functional magnetic resonance imaging (rs-fMRI) was acquired using a 3T Siemens Prisma MRI scanner, and DFC was assessed using mixture factor analysis, revealing information about the coverage of different DFC states. In women (but not men), lower coverage of DFC state 4 and thus lower frequency of epochs with high connectivity within the default mode network and between default mode, fronto-parietal, and visual networks was associated with lower full-scale IQ (AdjR² = 0.05, std. beta = 0.245, p = 0.008).

18 Jun

crossNN is an explainable framework for cross-platform DNA methylation-based classification of tumors

DNA methylation-based classification of (brain) tumors has emerged as a powerful and indispensable diagnostic technique. Initial implementations used methylation microarrays for data generation, while most current classifiers rely on a fixed methylation feature space. This makes them incompatible with other platforms, especially different flavors of DNA sequencing.

Here, we describe crossNN, a neural network-based machine learning framework that can accurately classify tumors using sparse methylomes obtained on different platforms and with different epigenome coverage and sequencing depth. It outperforms other deep and conventional machine learning models regarding accuracy and computational requirements while still being explainable.

We use crossNN to train a pan-cancer classifier that can discriminate more than 170 tumor types across all organ sites. Validation in more than 5,000 tumors profiled on different platforms, including nanopore and targeted bisulfite sequencing, demonstrates its robustness and scalability with 99.1% and 97.8% precision for the brain tumor and pan-cancer models, respectively.

18 Jun

The Jugular Foramen is Rather a Canal With Distinctive Morphological Configuration Concerning Its Clinical Anatomy and Surgical Implications: Morphological Analysis

Background and objectives: The jugular foramen (JF) is rather a complex anatomical structure with internal configuration. Its osteomorphology was assessed to redefine this rather long bony passage as a jugular canal (JC) based on its morphometric data.

Methods: The JF was endocranially and exocranially observed and measured by a digital Vernier caliper bilaterally in 402 dry skulls with opened cranial cavity. The following parameters were measured and analyzed statistically: (1) external and internal widths in the mediolateral dimension, (2) external and internal lengths in the anteroposterior dimension, and (3) depth between the external and internal planes of the foramen. The JF/canal was classified based on its appearance and its morphometric features.

Results: The mean length of the JC was approximately 12 mm (12.25 mm-right, 11.76 mm-left) and was longer on the right side (P = .05, 95% CI). Its external opening was found to be slightly larger than the internal opening (P = .07-right, P = .06-left). The JC took 3 distinctive course patterns of straight (47.6%), curved (45.5%), and angulated (6.9%). Its openings exhibited 3 types based on their morphometric analysis: 14.4% Type-I (width = length ±1 mm), 9.8% Type-II (width > length), and 75.9% Type-III (width < length).

18 Jun

Visual Features in Stereo-Electroencephalography to Predict Surgical Outcome: A Multicenter Study

Objective: Epilepsy surgery needs predictive features that are easily implemented in clinical practice. Previous studies are limited by small sample sizes, lack of external validation, and complex computational approaches. We aimed to identify and validate visually stereo-electroencephalography (SEEG) features with the highest predictive value for surgical outcome, and assess the reliability of their visual extraction.

Methods: We included 177 patients with drug-resistant epilepsy who underwent SEEG-guided surgery at 4 epilepsy centers. We assessed the predictive performance of 10 SEEG features from various SEEG periods for surgical outcome, using the area under the receiver operating characteristic curve, and considering resected channels and surgical outcome as the gold standard. Findings were validated externally using balanced accuracy. Six experts, blinded to outcome, evaluated the visual reliability of the optimal feature using interrater reliability, percentage agreement (standard deviation ± SD) and Gwet's kappa (κ ± SD).

Results: The derivation cohort comprised 100 consecutive patients, each with at least 1-year of postoperative follow up (40% temporal lobe epilepsy; 42% Engel Ia). Spatial co-occurrence of gamma spikes and preictal spikes emerged as the optimal predictive feature of surgical outcome (area under the receiver operating characteristic curve 0.82). 

4 Jun

Focused ultrasound-induced blood-brain barrier opening: A comparative analysis of permeability quantification based on K trans and PS

Purpose: Focused ultrasound-induced blood-brain barrier (BBB) opening is a promising method for neurotherapeutic delivery. The standard for quantifying induced BBB permeability is the $K^{\text{trans}}$ parameter, which reflects both permeability and plasma flow. The influence of plasma flow can be eliminated by estimating the PS parameter. However, this parameter has been largely unexplored in this application. This study aims to compare permeability estimates based on $K^{\text{trans}}$ and PS in focused ultrasound-induced BBB opening experiments.

Methods: We used the extended Tofts model (ETM) and the two-compartment exchange model (2CXM) to estimate $K^{\text{trans}}$ and PS parameters, respectively. Permeability estimates were compared using simulated concentration curves, simulated DCE-MRI data, and real datasets. We explored the influence of spatially-regularized model fitting on the results.

Results: For opened BBB, $K^{\text{trans}}$ was minimally influenced by plasma flow under the tested conditions. However, fitting the ETM often introduced outliers in $K^{\text{trans}}$ estimates in regions with closed BBB. The 2CXM outperformed the ETM at high signal-to-noise ratios, but its higher complexity led to lower precision at low signal-to-noise ratios. Both these issues were successfully compensated by spatially-regularized model fitting.