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.

4 Jun

Assessing Laryngeal Neuromotor Activity from Phonation

Neurodegenerative motor disorders affect the neuromuscular system challenging daily life and normal activity. Parkinson's Disease (PD) is among the most prevalent ones, with a large impact and rising prevalence rates. Speech is most affected by PD as far as phonatory and articulatory performance is concerned. Neuromotor activity (NMA) alterations have an impact on larynx muscles responsible for vocal fold adduction and abduction, hampering phonation stability and regularity. The main muscular articulators involved in phonation control are the cricothyroid (tensor) and thyroarytenoid (relaxer) systems, regulated by two distinct direct neuromotor pathways, activated by the precentral gyrus laryngeal control areas. These articulations control the musculus vocalis, directly responsible for regular vocal fold vibration. An indirect estimation of the muscular tension produced by inverse filtering may split into two independent channels, assumed to be the tensor and relaxer neuromotor pathways such as the differential neuromotor activity (DNMA). The amplitude distributions of both DNMA channels allow comparing phonations from PD-affected persons (PDPs) and age-matched healthy control participants (HCPs) with respect to a set of reference mid-age normative participants (RSPs). The comparisons are carried out by Jensen-Shannon distributions of PDP and HCP phonations with respect to those of RSPs. A dataset of 96 phonation samples from participants balanced by gender is used to train a set of decision tree classifiers (DTCs) to distinguish PDP from HCP phonation.

4 Jun

Human brain local field potential recordings during a battery of multilingual cognitive and eye-tracking tasks

Intracranial human brain recordings from multiple implanted depth electrodes using stereo-EEG (sEEG) technology for seizure localization provide unique local field potential signals (LFP) sampled with standard macro- and special micro-electrode contacts. Over one hundred macro- and micro-contact LFP signals localized in particular brain regions were recorded from each sEEG monitoring case as patients engaged in an automated battery of verbal memory and non-verbal gaze movement tasks. Subject eye and vocal responses in both visual and auditory task versions were automatically detected in Polish, Czech, and Slovak languages with accurate timing of the correct and incorrect verbal responses using our web-based transcription tool. The behavioral events, LFP and pupillometric signals were synchronized and stored in a standard BIDS data structure with corresponding metadata. Each dataset contains recordings from at least one battery task performed over at least one day. The same set of 180 common nouns in the three languages was used across different battery tasks and recording days to enable the analysis of selective responses to specific word stimuli.

19 May

Multicentre analysis of seizure outcome predicted by removal of high-frequency oscillations

In drug-resistant focal epilepsy, planning surgical resection can involve presurgical intracranial EEG (iEEG) recordings to detect seizures and other iEEG patterns to improve postsurgical seizure outcome. We hypothesized that resection of tissue generating interictal high-frequency oscillations (HFOs, 80-500 Hz) in the iEEG predicts surgical outcome. In eight international epilepsy centres, iEEG was recorded during the presurgical evaluation of patients. The patients were of all ages, had epilepsy of all types, and underwent surgical resection of a single focus aiming at seizure freedom. In a prospective analysis, we applied a fully automated definition of HFO that was independent of the dataset. Using an observational cohort design that was blinded to postsurgical seizure outcome, we analysed HFO rates during non-rapid-eye-movement sleep. If channels had consistently high rates over multiple epochs, they were labelled the 'HFO area'. After HFO analysis, centres provided the electrode contacts located in the resected volume and the seizure outcome at follow-up ≥24 months after surgery. The study was registered at www.clinicaltrials.gov (NCT05332990). We received 160 iEEG datasets. In 146 datasets (91%), the HFO area could be defined. The patients with a completely resected HFO area were more likely to achieve seizure freedom in comparison to those without [odds ratio 2.61, 95% confidence interval (CI) 1.15-5.91, P = 0.02]. 

19 May

Subcutaneous Ocrelizumab in Patients With Multiple Sclerosis: Results of the Phase 3 OCARINA II Study

Background and objectives: IV-administered ocrelizumab (OCR) is approved for the treatment of relapsing and primary progressive multiple sclerosis (RMS/PPMS). OCARINA II (NCT05232825) was designed to demonstrate noninferiority in drug exposure of OCR subcutaneous (SC) vs IV administration.

Methods: This phase 3, randomized, open-label study enrolled OCR-naive patients aged 18-65 years with RMS/PPMS and an Expanded Disability Status Scale score of 0-6.5. Patients received OCR IV 600 mg or OCR SC 920 mg (controlled period), followed by OCR SC 920 mg every 24 weeks, up to week 96 (OCR IV/SC and OCR SC/SC). The primary end point was OCR area under the serum concentration-time curve from day 1 to week 12 (AUC_W1‒12); other end points included clinical, biomarker, and pharmacodynamic outcomes and safety data.

Results: Baseline demographics were balanced across OCR IV/SC and OCR SC/SC arms (N = 118/118, 40.0 ± 11.9/39.9 ± 11.4 years, 59.3%/65.3% female, 89.0%/89.0% with RMS). The study demonstrated noninferiority of OCR SC 920 mg to OCR IV 600 mg for the primary end point AUC_W1-12 and also over the dosing interval for AUC_W1‒24 (geometric mean ratios [90% CI] 1.29 [1.23-1.35] and 1.27 [1.21-1.34], respectively). At week 48, 111 of 118 (OCR IV/SC) and 114 of 118 (OCR SC/SC) had received OCR SC. 

5 May

A Systematic Review of Current Terminology for Conditions Preceding Degenerative Cervical Myelopathy: Evidence Synthesis to Inform an AO Spine Expert Opinion Statement

Study DesignSystematic review.ObjectivesThe pre-symptomatic state of Degenerative Cervical Myelopathy (DCM), wherein degenerative changes and spinal cord compression are seen without clinical findings, is poorly understood and inconsistently categorised. Clear identification may elucidate the temporality of DCM development. Therefore, a systematic assessment was undertaken of current terminology for pre-DCM states, with the objective of standardising definitions and informing an AO Spine expert position statement.MethodsMedline and Embase were searched for all studies on asymptomatic spinal compression or clinical findings preceding DCM, returning 3585 studies. After screening, 96 studies were included in the final analysis. The terminology used for pre-DCM states and their definitions were extracted, along with their frequencies or speciality/country of author in the literature.ResultsMultiple terms were used to represent pre-DCM stages, including "asymptomatic" (86 studies), "non-myelopathic" (26 studies), "without myelopathy" (15 studies), "pre-symptomatic" (9 studies) and "sub-clinical" (7 studies). "asymptomatic" was associated with the greatest inconsistency. Some defined this as patients with radiological signs of spinal degeneration with/without spinal cord compression but no clinical signs of myelopathy, whereas others used the term synonymously with healthy controls.

5 May

Search for Mutations Connected With Non-Response to Anti-EGFR Therapy in mCRC in the Morphologically Defined Regions of Primary Tumours

Background: Emerging evidence suggests that tumour morphological heterogeneity may influence mutational profiles relevant to therapy response. In this pilot study, we aimed to assess whether mutations identified within specific morphological patterns or at the invasion front correlate with shorter time to progression after anti-EGFR therapy, as compared to whole-tissue analysis.

Methods: We investigated genetic mutations in 142 samples from primary tumours of 39 KRAS wild-type metastatic colorectal cancer (CRC) patients receiving anti-EGFR therapy. Deep next-generation sequencing was performed on whole-tumour sections and six morphology-defined tumour regions.

Results: Mutations in genes linked to anti-EGFR therapy response (KRAS, BRAF, NRAS, PTEN and PI3KCA) were found uniquely in the non-responder group, with substantial variability across morphological sub-regions. BRAF mutations were aligned with serrated and mucinous morphologies, while KRAS mutations (p.Lys147Glu and p.Ala146Thr) were associated with mucinous and desmoplastic morphologies. In all cases, the cumulative mutational profile from sub-regions provided more details than that of the whole-tumour profile.

24 Apr

Non-invasive therapeutic drug monitoring: LC-MS validation for lamotrigine quantification in dried blood spot and oral fluid/saliva

Epilepsy, affecting over 50 million people globally, presents a significant neurological challenge. Effective prevention of epileptic seizures relies on proper administration and monitoring of Anti-Seizure Medication (ASMs). Therapeutic Drug Monitoring (TDM) ensures optimal dosage adjustment, minimizing adverse effects and potential drug interactions. While traditional venous blood collection for TDM may be stressful, emerging alternative sampling methods, particularly Dried Blood Spot (DBS) or oral fluid offer less invasive way of sampling. This study aimed to develop and validate an analytical method for the determination of lamotrigine in such alternative samples. The sample, either DBS or oral fluid, was subjected to extraction, evaporation, and reconstitution in 15 % acetonitrile containing 0.1 % formic acid. A Kinetex C18 Polar column was used for liquid chromatographic separation and MS in ESI+ mode was used for detection and quantitation of lamotrigine using an isotopically labelled internal standard according to EMA guidelines. The calibration range of the developed method enables the determination of lamotrigine in the concentration range of 1-30 μg/mL in DBS and 0.5-20 μg/mL in oral fluid. Oral fluid and DBS samples from patients treated with lamotrigine analysed by the developed method were compared to plasma concentrations measured by the hospital's accredited laboratory.