Publications

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.

24 Feb

Combined genomics and proteomics unveils elusive variants and vast aetiologic heterogeneity in dystonia

Dystonia is a rare-disease trait for which large-scale genomic investigations are still underrepresented. Genetic heterogeneity among patients with unexplained dystonia warrants interrogation of entire genome sequences, but this has not yet been systematically evaluated. To significantly enhance our understanding of the genetic contribution to dystonia, we (re)analyzed 2,874 whole-exome sequencing (WES), 564 whole-genome sequencing (WGS), as well as 80 fibroblast-derived proteomics datasets, representing the output of high-throughput analyses in 1,990 patients and 973 unaffected relatives from 1,877 families. Recruitment and precision-phenotyping procedures were driven by long-term collaborations of international experts with access to overlooked populations. By exploring WES data, we found that continuous scaling of sample sizes resulted in steady gains in the number of associated disease genes without plateauing. On average, every second diagnosis involved a gene not previously implicated in our cohort. Second-line WGS focused on a subcohort of undiagnosed individuals with high likelihood of having monogenic forms of dystonia, comprising large proportions of patients with early onset (81.3%), generalized symptom distribution (50.8%) and/or coexisting features (68.9%). We undertook extensive searches for variants in nuclear and mitochondrial genomes to uncover 38 (ultra)rare diagnostic-grade findings in 37 of 305 index patients (12.1%), many of which had remained undetected due to methodological inferiority of WES or pipeline limitations. 

24 Feb

A new experimental model for studying peripheral nerve regeneration in dual innervated facial reanimation

Background: Donor nerve selection is a crucial factor in determining clinical outcomes of facial reanimation. Although dual innervation approaches using two neurotizers have shown promise, there is a lack of evidence-based comparison in the literature. Furthermore, no animal model of dual reinnervation has yet been published. This study aimed to establish such a model and verify its technical and anatomical feasibility by performing dual-innervated reanimation approaches in Wistar rats.

Methods: Fifteen Wistar rats were divided into four experimental groups and one control group. The sural nerve was exposed and used as a cross-face nerve graft (CFNG), which was then anastomosed to the contralateral buccal branch of the facial nerve through a subcutaneous tunnel on the forehead. The CFNG, the masseteric nerve (MN), and the recipient nerve were coapted in one or two stages. The length and width of the utilized structures were measured under an operating microscope. Return of whisker motion was visually confirmed.

Results: Nine out of the eleven rats that underwent surgery survived the procedure. Whisker motion was observed in all experimental animals, indicating successful reinnervation. The mean duration of the surgical procedures did not differ significantly between the experimental groups, ensuring similar conditions for all groups.

18 Feb

Mapping conservative Fokker–Planck entropy in neural systems

Mapping the flow of information through the networks of the brain remains one of the most important challenges in computational neuroscience. In certain cases, this flow can be approximated by considering just two contributing factors—a predictable drift and a randomized diffusion. We show here that the uncertainty associated with such a drift-diffusion process can be calculated in terms of the entropy associated with the Fokker–Planck equation. This entropic evolution comprises two components: an irreversible entropic spread that always increases over time and a reversible entropic current that can increase or decrease locally within the system. We apply this dynamic entropy decomposition to two-photon imaging data collected in the murine visual cortex.

Our analysis reveals maps of conserved entropic flow emanating from lateral medial, anterolateral, and rostrolateral regions toward the primary visual cortex (V1).

These results highlight the role of V1 as an entropic sink, facilitating the redistribution of information throughout the visual cortex. These findings offer new insights into the hierarchical organization of cortical processing and provide a framework for exploring information dynamics in complex dynamical systems.

14 Feb

MicroRNA Analysis in Meningiomas with Different Degrees of Tissue Stiffness: A Potential Tool for Effective Preoperative Planning

Background and objectives: Meningioma, the most common primary intracranial tumor, presents challenges in surgical treatment because of varying tissue stiffness. This study explores the molecular background of meningioma stiffness, a critical factor in surgical planning and prognosis, focusing on the utility of microRNAs (miRNAs) as diagnostic biomarkers of tissue stiffness.

Methods: Patients with meningiomas treated surgically at the University Hospital Brno were included in this study. Total RNA, isolated from tumor tissue samples, underwent quality control and small RNA sequencing to analyze miRNA expression. Differentially expressed miRNAs were identified, and their association with tumor stiffness was assessed.

Results: This study identified specific miRNAs differentially expressed in meningiomas with different stiffness levels. Key miRNAs, such as miR-31-5p and miR-34b-5p, showed significant upregulation in stiffer meningiomas. These findings were validated using reverse transcription-quantitative polymerase chain reaction, revealing a potential link between miRNA expression and tumor consistency. The expression of miR-31-5p was most notably associated with the stiffness of the tumor tissue (sensitivity = 71% and specificity = 83%).

14 Feb

Maternal depression during the perinatal period and its relationship with emotion regulation in young adulthood: An fMRI study in a prenatal birth cohort

Background: Maternal perinatal mental health is essential for optimal brain development and mental health of the offspring. We evaluated whether maternal depression during the perinatal period and early life of the offspring might be selectively associated with altered brain function during emotion regulation and whether those may further correlate with physiological responses and the typical use of emotion regulation strategies.

Methods: Participants included 163 young adults (49% female, 28-30 years) from the ELSPAC prenatal birth cohort who took part in its neuroimaging follow-up and had complete mental health data from the perinatal period and early life. Maternal depressive symptoms were measured mid-pregnancy, 2 weeks, 6 months, and 18 months after birth. Regulation of negative affect was studied using functional magnetic resonance imaging, concurrent skin conductance response (SCR) and heart rate variability (HRV), and assessment of typical emotion regulation strategy.

Results: Maternal depression 2 weeks after birth interacted with sex and showed a relationship with greater brain response during emotion regulation in a right frontal cluster in women. Moreover, this brain response mediated the relationship between greater maternal depression 2 weeks after birth and greater suppression of emotions in young adult women (ab = 0.11, SE = 0.05, 95% CI [0.016; 0.226]). 

4 Feb

Mitochondrial DNA variants and their impact on epigenetic and biological aging in young adulthood

The pace of biological aging varies between people independently of chronological age and mitochondria dysfunction is a key hallmark of biological aging. We hypothesized that higher functional impact (FI) score of mitochondrial DNA (mtDNA) variants might contribute to premature aging and tested the relationships between a novel FI score of mtDNA variants and epigenetic and biological aging in young adulthood.

A total of 81 participants from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) prenatal birth cohort had good quality genetic data as well as blood-based markers to estimate biological aging in the late 20. A subset of these participants (n = 69) also had epigenetic data to estimate epigenetic aging in the early 20s using Horvath's epigenetic clock.

The novel FI score was calculated based on 7 potentially pathogenic mtDNA variants. Greater FI score of mtDNA variants was associated with older epigenetic age in the early 20s and older biological age in the late 20s. These medium to large effects were independent of sex, current BMI, cigarette smoking, cannabis, and alcohol use. These findings suggest that elevated FI score of mtDNA variants might contribute to premature aging in young adulthood.

4 Feb

Robust acute myeloid leukemia engraftment in humanized scaffolds using injectable biomaterials and intravenous xenotransplantation

Keywords: AML; T‐cell; collagen; mouse model; ossicles; patient‐derived xenografts.

4 Feb

The role of the somatosensory cortex in self-paced movement impairment in Parkinson's disease

Objective: The aim of this work was to study the differences at the whole-brain level between self-paced and cued movement processing in Parkinson's disease (PD).

Methods: High density electroencephalogram (HD-EEG) was recorded during the performance of self-paced movements (Bereitschaftspotential - BP) and visually cued movements (VMT) in PD patients (n = 38) and in a group of healthy controls (HC, n = 23). Oscillatory changes in the alpha, beta, and gamma frequencies were evaluated and correlated to the clinical scales- MDS-UPDRS and Freezing of Gait Questionnaire (FOGQ).

Results: The main difference in the alpha range was an activation in the basal ganglia area during VMT performance as compared to BP performance; this activation was present only in HC. The most important finding was observed in the high beta range: a higher activation of the right postcentral area during BP performance in PD subjects as compared to HC, correlating to the severity of FOG. Moreover, PD patients had lower gamma activation of the right frontal areas.

Conclusion: A simplification of motor circuits and a hyperactivation of the right somatosensory cortex were observed in PD subjects.

Significance: Future studies should be focused on this area to confirm or disprove its role in FOG.

4 Feb

Safety and efficacy of nipocalimab in adults with generalised myasthenia gravis (Vivacity-MG3): a phase 3, randomised, double-blind, placebo-controlled study

Background: Given burdensome side-effects and long latency for efficacy with conventional agents, there is a continued need for generalised myasthenia gravis treatments that are safe and provide consistently sustained, long-term disease control. Nipocalimab, a neonatal Fc receptor blocker, was associated with dose-dependent reductions in total IgG and anti-acetylcholine receptor (AChR) antibodies and clinically meaningful improvements in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale in patients with generalised myasthenia gravis in a phase 2 study. We aimed to assess the safety and efficacy of nipocalimab in a phase 3 study.

Methods: Vivacity-MG3 was a phase 3, randomised, double-blind, placebo-controlled, phase 3 study conducted at 81 outpatient centres with expertise in myasthenia gravis in 17 countries in Asia-Pacific, Europe, and North America. Adults (aged ≥18 years) with generalised myasthenia gravis inadequately controlled with standard-of-care therapy (MG-ADL score ≥6) were randomly assigned (1:1) to either nipocalimab (30 mg/kg loading dose then 15 mg/kg every 2 weeks for maintenance dosing) or placebo infusions every 2 weeks, added to standard-of-care therapy in both groups, for 24 weeks. Randomisation was stratified by antibody status, day 1 MG-ADL total score, and region. The sponsor, investigators, clinical raters, and participants were masked to treatment assignment. 

4 Feb

Breaking boundaries: role of the brain barriers in metastatic process

Keywords: Blood-cerebrospinal fluid barrier; Blood-spinal cord barrier; Blood–brain barrier; Brain Metastasis; Cancer.

4 Feb

The Intrinsic Neuronal Activation of the CXCR4 Signaling Axis Is Associated with a Pro-Regenerative State in Cervical Primary Sensory Neurons Conditioned by a Sciatic Nerve Lesion

CXCL12 and CXCR4 proteins and mRNAs were monitored in the dorsal root ganglia (DRGs) of lumbar (L4-L5) and cervical (C7-C8) spinal segments of naïve rats, rats subjected to sham operation, and those undergoing unilateral complete sciatic nerve transection (CSNT) on post-operation day 7 (POD7). Immunohistochemical, Western blot, and RT-PCR analyses revealed bilaterally increased levels of CXCR4 protein and mRNA in both lumbar and cervical DRG neurons after CSNT. Similarly, CXCL12 protein levels increased, and CXCL12 mRNA was upregulated primarily in lumbar DRGs ipsilateral to the nerve lesion. Intrathecal application of the CXCR4 inhibitor AMD3100 following CSNT reduced CXCL12 and CXCR4 protein levels in cervical DRG neurons, as well as the length of afferent axons regenerated distal to the ulnar nerve crush. Furthermore, treatment with the CXCR4 inhibitor decreased levels of activated Signal Transducer and Activator of Transcription 3 (STAT3), a critical transforming factor in the neuronal regeneration program. Administration of IL-6 increased CXCR4 levels, whereas the JAK2-dependent STAT3 phosphorylation inhibitor (AG490) conversely decreased CXCR4 levels. This indicates a link between the CXCL12/CXCR4 signaling axis and IL-6-induced activation of STAT3 in the sciatic nerve injury-induced pro-regenerative state of cervical DRG neurons.

29 Jan

Pre-implantation Scalp EEG Can Predict VNS Efficacy in Children

Introduction. Vagal nerve stimulation (VNS) is a therapeutical option for the treatment of drug-resistant epileptic patients. The response to VNS varies from patient to patient and is difficult to predict. The proposed study is based on our previous work, identifying relative mean power in pre-implantation EEG as a reliable marker for VNS efficacy prediction in adult patients. Our study has two main tasks. Firstly, to confirm the utility of relative mean power as a feature correlating with VNS efficacy in children. The second is to validate the applicability of our prediction classifier, Pre-X-Stim, in the pediatric population. Material and Methods. We identified a group of children with drug-resistant epilepsy. We included only children in whom EEG contained photic stimulation (Task 1) or was recorded based on the defined acquisition protocol used for development Pre-X-Stim (Task 2). Relative mean powers were calculated. VNS responders and non-responders were compared based on relative mean powers' values. In the next step, we evaluate the utility of our classifier, Pre-X-Stim, in the children population. Results: We identified 57 children treated with VNS - 17 patients were recruited for the Task 1 and 7 patients for the Task 2. When focusing on relative mean powers in EEG spectra, we observed statistically significant differences in theta range. The Pre-X-Stim algorithm was able to predict VNS efficacy correctly in 6 out of 7 patients (the accuracy 83.3%, the sensitivity 75%, the specificity 100%). Conclusions. Based on our results, it seems that children and adults share a similar pattern of EEG relative mean power changes. These changes can be used for pre-implantation prediction of VNS efficacy.

29 Jan

Revealing connectivity patterns of deep brain stimulation efficacy in Parkinson's disease

Keywords: Connectivity patterns; Deep brain stimulation; EEG; Functional connectivity; Parkinson’s disease; Subthalamic nucleus.

29 Jan

A roadmap toward promoting and improving brain health in Europe and closing the awareness and funding gap

Background and purpose: The global burden of neurological diseases exceeds 43.1%, imposing a significant burden on patients, caregivers and society. This paper presents a roadmap to reduce this burden and improve brain health (BH) in Europe.

Methods: The roadmap is based on the European Academy of Neurology's (EAN) five-pillar BH strategy: advancing a global BH approach (P1), supporting policymaking (P2), fostering research (P3), promoting education (P4), and raising awareness of prevention and treatment (P5). It reviews current efforts, collaborations and future directions aligned with the WHO Intersectoral Global Action Plan (iGAP) for Neurological Disorders and suggests future initiatives and call for action.

Results: P1: Support WHO-iGAP through defined action points, international collaborations, in particular, the WHO BH Unit, and the EAN Brain Health Mission. P2: Collaborate with 48 national neurological societies to promote National Brain Plans (NBPs), addressing local needs, and improving access to care. P3: Advocate for more research funding; identify determinants of BH; develop preventive measures. P4: Provide educational opportunities for neurologists, public education programs, and advocacy training, including tools to educate the public. P5: Spearhead global awareness campaigns, organize public educational activities, and train BH advocates to contribute toward sustainable and long-term public health campaigns and policy engagement.

29 Jan

Exploring medical error taxonomies and human factors in simulation-based healthcare education

This study aims to provide an updated overview of medical error taxonomies by building on a robust review conducted in 2011. It seeks to identify the key characteristics of the most suitable taxonomy for use in high-fidelity simulation-based postgraduate courses in Critical Care. While many taxonomies are available, none seem to be explicitly designed for the unique context of healthcare simulation-based education, in which errors are regarded as essential learning opportunities. Rather than creating a new classification system, this study proposes integrating existing taxonomies to enhance their applicability in simulation training. Through data from surveys of participants and tutors in postgraduate simulation-based courses, this study provides an exploratory analysis of whether a generic or domain-specific taxonomy is more suitable for healthcare education. While a generic classification may cover a broad spectrum of errors, a domain-specific approach could be more relatable and practical for healthcare professionals in a given domain, potentially improving error-reporting rates. Seven strong links were identified in the reviewed classification systems. These correlations allowed the authors to propose various simulation training strategies to address the errors identified in both the classification systems. This approach focuses on error management and fostering a safety culture, aiming to reduce communication-related errors by introducing the principles of Crisis Resource Management, effective communication methods, and overall teamwork improvement. 

29 Jan

The Blood-Cerebrospinal Fluid Barrier as a Potential Entry Site for the SARS-CoV-2 Virus

Keywords: COVID‐19; SARS‐CoV‐2; blood‐cerebrospinal fluid barrier; choroid plexus; neuroinvasion.