Publications

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.

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. 

24 Apr

Repeated Administrations of Polyphenolic Extracts Prevent Chronic Reflexive and Non-Reflexive Neuropathic Pain Responses by Modulating Gliosis and CCL2-CCR2/CX3CL1-CX3CR1 Signaling in Spinal Cord-Injured Female Mice

Neuropathic pain after spinal cord injury lacks any effective treatments, often leading to chronic pain. This study tested whether the daily administration of fully characterized polyphenolic extracts from grape stalks and coffee could prevent both reflexive and non-reflexive chronic neuropathic pain in spinal cord-injured mice by modulating the neuroimmune axis. Female CD1 mice underwent mild spinal cord contusion and received intraperitoneal extracts in weeks one, three, and six post-surgery. Reflexive pain responses were assessed weekly for up to 10 weeks, and non-reflexive pain was evaluated at the study's end. Neuroimmune crosstalk was investigated, focusing on glial activation and the expression of CCL2/CCR2 and CX3CL1/CX3CR1 in supraspinal pain-related areas, including the periaqueductal gray, rostral ventromedial medulla, anterior cingulate cortex, and amygdala. Repeated treatments prevented mechanical allodynia and thermal hyperalgesia, and also modulated non-reflexive pain. Moreover, they reduced supraspinal gliosis and regulated CCL2/CCR2 and CX3CL1/CX3CR1 signaling. 

24 Apr

FGFR2 residence in primary cilia is necessary for epithelial cell signaling

Primary cilium projects from cells to provide a communication platform with neighboring cells and the surrounding environment. This is ensured by the selective entry of membrane receptors and signaling molecules, producing fine-tuned and effective responses to the extracellular cues.

In this study, we focused on one family of signaling molecules, the fibroblast growth factor receptors (FGFRs), their residence within cilia, and its role in FGFR signaling. We show that FGFR1 and FGFR2, but not FGFR3 and FGFR4, localize to primary cilia of the developing mouse tissues and in vitro cells. For FGFR2, we demonstrate that the ciliary residence is necessary for its signaling and expression of target morphogenic genes. We also show that the pathogenic FGFR2 variants have minimal cilium presence, which can be rescued for the p.P253R variant associated with the Apert syndrome by using the RLY-4008 kinase inhibitor.

Finally, we determine the molecular regulators of FGFR2 trafficking to cilia, including IFT144, BBS1, and the conserved T429V430 motif within FGFR2.

24 Apr

Dietary inflammatory index during pregnancy and its relationship with gyrification and IQ in young adult offspring

24 Apr

Enhancing stroke response in school children: Efficacy of the HOBIT program - a cluster randomized trial

Keywords: Children; Cluster randomized trial; Health education; Intervention; School; Stroke awareness.

11 Apr

Virtual Waiting Room: The New Narrative of Waiting in Oncology Care

This conceptual study introduces the "virtual waiting room," an innovative, interactive, web-based platform designed to enhance the waiting experience in oncology by providing personalized, educational, and supportive content. Central to our study is the implementation of the circular entry model, which allows for non-linear navigation of health information, empowering patients to access content based on their immediate needs and interests. This approach respects the individual journeys of patients, acknowledging the diverse pathways through which they seek understanding and manage their health. The virtual waiting room is designed not only to support patients but also to facilitate stronger communication and shared understanding between patients, caregivers, and families. By providing a shared digital space, the platform enables caregivers and family members to access the same information and resources, thereby promoting transparency and collective knowledge. This shared access is crucial in managing the emotional complexities of oncology care, where effective communication can significantly impact treatment outcomes and patient well-being. Furthermore, the study explores how the circular entry model within the virtual waiting room can enhance patient autonomy and engagement by offering customized interactions based on user feedback and preferences. This personalized approach aims to reduce anxiety, improve health literacy, and prepare patients more effectively for clinical interactions. 

11 Apr

Noninvasive Temporal Interference Stimulation of the Subthalamic Nucleus in Parkinson's Disease Reduces Beta Activity

Background: Temporal interference stimulation (TIS) is a novel noninvasive electrical stimulation technique to focally modulate deep brain regions; a minimum of two high-frequency signals (f₁ and f₂ > 1 kHz) interfere to create an envelope-modulated signal at a deep brain target with the frequency of modulation equal to the difference frequency: Δf = |f₂ - f₁|.

Objective: The goals of this study were to verify the capability of TIS to modulate the subthalamic nucleus (STN) with Δf and to compare the effect of TIS and conventional deep brain stimulation (DBS) on the STN beta oscillations in patients with Parkinson's disease (PD).

Methods: DBS leads remained externalized after implantation, allowing local field potentials (LFPs) recordings in eight patients with PD. TIS was performed initially by two pairs (f₁ = 9.00 kHz; f₂ = 9.13 kHz, 4 mA peak-peak per pair maximum) of scalp electrodes placed in temporoparietal regions to focus the envelope signal maximum (Δf = 130 Hz) at the motor part of the STN target.

Results: The comparison between the baseline LFPs and recordings after TIS and conventional DBS sessions showed substantial suppression of high beta power peak after both types of stimulation in all patients.

24 Mar

A Controlled Single-Centre Pilot Study to Evaluate the Effect of Prophylactic Surgery in Asymptomatic Degenerative Cervical Cord Compression

Study DesignSingle-centre controlled pilot study.ObjectivesTo evaluate the effect of prophylactic surgery and to review the biases of a therapeutic trial in asymptomatic degenerative cervical cord compression (ADCC) patients.MethodsPatients with ADCC and at least 1 predictor of progression to symptomatic degenerative cervical cord myelopathy (DCM) were offered either prophylactic surgery or standard structured rehabilitation. Recruited patients were clinically followed to detect the development of symptomatic DCM.ResultsForty-one patients treated surgically and 68 patients treated non-surgically completed the minimum 36 months' follow-up; 3 recruited patients were lost from evaluation. The surgical group had a higher Neck Disability Index score and more severe MRI compression. A matched subgroup of 41 non-surgical patients was created to reduce potential bias. During the follow-up period we observed progression to symptomatic DCM in 1 surgical case (2.4%) compared to 9 patients in the non-surgical group (13.2%, P = 0.054) and 7 cases in the matched non-surgical group (17.1%, P = 0.029). We observed non-serious early postoperative complications in 4 patients, which resolved spontaneously or after surgical revision. In 9 patients with progression to DCM, the myelopathy was mild with mJOA scale 15-17. One patient in the non-surgical group and 1 patient in the surgical group who progressed to DCM underwent surgery with a good outcome.ConclusionsProphylactic surgery led to a significant decrease in proportion of ADCC patients with progression to DCM.

24 Mar

Altered Patterns of Dynamic Functional Connectivity Underpin Reduced Expressions of Social-Emotional Reciprocity in Autistic Adults

To identify the neurocognitive mechanisms underpinning the social difficulties that characterize autism, we performed functional magnetic resonance imaging on pairs of autistic and non-autistic adults simultaneously whilst they interacted with one another on the iterated Ultimatum Game (iUG)-an interactive task that emulates the reciprocal characteristic of naturalistic interpersonal exchanges. Two age-matched sets of male-male dyads were investigated: 16 comprised an autistic Responder and a non-autistic Proposer, and 19 comprised non-autistic pairs of Responder and Proposer. Players' round-by-round behavior on the iUG was modeled as reciprocal choices, and dynamic functional connectivity (dFC) was measured to identify the neural mechanisms underpinning reciprocal behaviors. Behavioral expressions of reciprocity were significantly reduced in autistic compared with non-autistic Responders, yet no such differences were observed between the non-autistic Proposers in either set of dyads. Furthermore, we identified latent dFC states with temporal properties associated with reciprocity. Autistic interactants spent less time in brain states characterized by dynamic inter-network integration and segregation among the Default Mode Network and cognitive control networks, suggesting that their reduced expressions of social-emotional reciprocity reflect less efficient reconfigurations among brain networks supporting flexible cognition and behavior.