Dynamic flexibility and controllability of network communities in juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is the most common syndrome within the idiopathic generalized epilepsy spectrum, manifested by myoclonic and generalized tonic-clonic seizures and spike-and-wave discharges (SWDs) on electroencephalography (EEG). Currently, the pathophysiological concepts addressing SWD generation in JME are still incomplete. In this work, we characterize the temporal and spatial organization of functional networks and their dynamic properties as derived from high-density EEG (hdEEG) recordings and MRI in 40 JME patients (25.4 ± 7.6 years, 25 females). The adopted approach allows for the construction of a precise dynamic model of ictal transformation in JME at the cortical and deep brain nuclei source levels. We implement Louvain algorithm to attribute brain regions with similar topological properties to modules during separate time windows before and during SWD generation. Afterwards, we quantify how modular assignments evolve and steer through different states towards the ictal state by measuring characteristics of flexibility and controllability. We find antagonistic dynamics of flexibility and controllability within network modules as they evolve towards and undergo ictal transformation. Prior to SWD generation, we observe concomitantly increasing flexibility (F(1,39) = 25.3, corrected p < 0.001) and decreasing controllability (F(1,39) = 55.3, p < 0.001) within the fronto-parietal module in γ-band. On a step further, during interictal SWDs as compared to preceding time windows, we notice decreasing flexibility (F(1,39) = 11.9, p < 0.001) and increasing controllability (F(1,39) = 10.1, p < 0.001) within the fronto-temporal module in γ-band. During ictal SWDs as compared to prior time windows, we demonstrate significantly decreasing flexibility (F(1,14) = 31.6; p < 0.001) and increasing controllability (F(1,14) = 44.7, p < 0.001) within the basal ganglia module. Furthermore, we show that flexibility and controllability within the fronto-temporal module of the interictal SWDs relate to seizure frequency and cognitive performance in JME patients. Our results demonstrate that detection of network modules and quantification of their dynamic properties is relevant to track the generation of SWDs. The observed flexibility and controllability dynamics reflect the reorganization of de-/synchronized connections and the ability of evolving network modules to reach a seizure-free state, respectively. These findings may advance the elaboration of network-based biomarkers and more targeted therapeutic neuromodulatory approaches in JME.

Altered grey matter integrity and network vulnerability relate to epilepsy occurrence in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the relevance of compartmentalized grey matter (GM) pathology and network reorganization in multiple sclerosis (MS) patients with concomitant epilepsy. METHODS: From 3-T magnetic resonance imaging scans of 30 MS patients with epilepsy (MSE group; age 41 ± 15 years, 21 females, disease duration 8 ± 6 years, median Expanded Disability Status Scale [EDSS] score 3), 60 MS patients without epilepsy (MS group; age 41 ± 12 years, 35 females, disease duration 6 ± 4 years, EDSS score 2), and 60 healthy subjects (HS group; age 40 ± 13 years, 27 females) the regional volumes of GM lesions and of cortical, subcortical and hippocampal structures were quantified. Network topology and vulnerability were modelled within the graph theoretical framework. Receiver-operating characteristic (ROC) curve analysis was applied to assess the accuracy of GM pathology measures to discriminate between MSE and MS patients. RESULTS: Higher lesion volumes within the hippocampus, mesiotemporal cortex and amygdala were detected in the MSE compared to the MS group (all p < 0.05). The MSE group had lower cortical volumes mainly in temporal and parietal areas compared to the MS and HS groups (all p < 0.05). Lower hippocampal tail and presubiculum volumes were identified in both the MSE and MS groups compared to the HS group (all p < 0.05). Network topology in the MSE group was characterized by higher transitivity and assortativity, and higher vulnerability compared to the MS and HS groups (all p < 0.05). Hippocampal lesion volume yielded the highest accuracy (area under the ROC curve 0.80 [0.67-0.91]) in discriminating between MSE and MS patients. CONCLUSIONS: High lesion load, altered integrity of mesiotemporal GM structures, and network reorganization are associated with a greater propensity for epilepsy occurrence in people with MS.

Molecular Mechanisms of SARS-CoV-2/COVID-19 Pathogenicity on the Central Nervous System: Bridging Experimental Probes to Clinical Evidence and Therapeutic Interventions.

The coronavirus disease 2019 (COVID-19) pandemic, induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has dramatically impacted the global healthcare systems, constantly challenging both research and clinical practice. Although it was initially believed that the SARS-CoV-2 infection is limited merely to the respiratory system, emerging evidence indicates that COVID-19 affects multiple other systems including the central nervous system (CNS). Furthermore, most of the published clinical studies indicate that the confirmed CNS inflammatory manifestations in COVID-19 patients are meningitis, encephalitis, acute necrotizing encephalopathy, acute transverse myelitis, and acute disseminated encephalomyelitis. In addition, the neuroinflammation along with accelerated neurosenescence and susceptible genetic signatures in COVID-19 patients might prime the CNS to neurodegeneration and precipitate the occurrence of neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. Thus, this review provides a critical evaluation and interpretive analysis of existing published preclinical as well as clinical studies on the key molecular mechanisms modulating neuroinflammation and neurodegeneration induced by the SARS-CoV-2. In addition, the essential age- and gender-dependent impacts of SARS-CoV-2 on the CNS of COVID-19 patients are also discussed.

Cortical Thickness Changes Associated with Photoparoxysmal Response.

Photoparoxysmal response (PPR) is an EEG trait of spike and spike-wave discharges in response to photic stimulation that is closely linked to idiopathic generalized epilepsy (IGE). In our previous studies we showed that PPR is associated with functional alterations in the occipital and frontal cortices. The aim of the present study was to determine structural changes associated with PPR. For this purpose we analysed the cortical thickness as derived from T1 MRI images in PPR-positive-subjects (n = 12; 15.5 ± 8.6 years; 4 males), PPR-positive-IGE-patients (n = 12; 14.9 ± 2.7 years; 4 males) and compared these groups with a group of PPR-negative-healthy-controls (HC, n = 17; 15.3 ± 3.6 years; 6 males). Our results revealed an increase of cortical thickness in the occipital, frontal and parietal cortices bilaterally in PPR-positive-subjects in comparison to HC. Moreover PPR-positive-subjects presented a significant decrease of cortical thickness in the temporal cortex in the same group contrast. IGE patients exhibited lower cortical thickness in the temporal lobe bilaterally and in the right paracentral region in comparison to PPR-positive-subjects. Our study demonstrates structural changes in the occipital lobe, frontoparietal regions and temporal lobe, which also show functional changes associated with PPR. Patients with epilepsy present changes in the temporal lobe and supplementary motor area.

Dissecting the Spectrum of Stroke Risk Factors in an Apparently Healthy Population: Paving the Roadmap to Primary Stroke Prevention.

We aimed to investigate, for the first time, the spectrum of stroke risk factors specific to the population of the Republic of Moldova. The subjects were examined according to a pre-established protocol of risk factor estimation. The study involved 300 subjects, including 60% women and 40% men, with a mean age of 49.9 ± 14.5 years. The most common risk factor was abdominal obesity, identified in 75% of subjects; general obesity was detected in 48%, while 32% of subjects were overweight and 20% were normally weighted. Hypertension was observed in 44%; 8% of those examined had atrial fibrillation, and 9% had diabetes mellitus. Left myocardial hypertrophy on ECG was present in 53% of subjects, and acute ischemic changes in 2%. Laboratory observations detected that glycosylated hemoglobin increased by 7%, and >50% had dyslipidemia. Total cholesterol was significantly elevated by 58%, LDL-cholesterol was increased by 32%, and HDL-cholesterol was decreased by 9%. Homocysteine was increased in 55% and high-sensitivity C-reactive protein in 28% of subjects. These results indicate the presence of modifiable risk factors and the necessity to elaborate on the primary prevention strategies aimed at minimizing the burden of stroke in the population of the Republic of Moldova.

Serum Urate Levels and Ultrasound Characteristics of Carotid Atherosclerosis across Obesity Phenotypes.

BACKGROUND: Existing evidence suggests a close link among high levels of serum urate (SU), obesity and carotid atherosclerosis. The aim of the present study was to evaluate the interrelations between SU levels and carotid atherosclerosis in subjects with different obesity phenotypes. METHODS: In this study, a total of 2076 subjects (mean age 48.1 ± 13.1 years; 1307 women) were recruited: 59 with general obesity, 616 with central obesity, 715 with mixed (general-central) obesity and 686 non-obese. Anthropometric measurements, vascular risk factors, blood biochemistry analysis (including SU levels), and carotid ultrasound were performed. Ultrasound assessment included evaluation of intima-media thickness (IMT) and plaque characteristics, including number, total area and type (vulnerable vs. stable) of plaques. RESULTS: After adjustment for potential confounders, the highest levels of SU were observed in subjects with mixed obesity, followed by subjects with central obesity, general obesity and the non-obese (309.4 ± 82.2 vs. 301.2 ± 73.1 vs. 272.9 ± 61.8 vs. 234.2 ± 59.8 µmol/L, respectively; F = 149.2, post hoc p < 0.001). Similarly, subjects with mixed and central obesity presented higher values of IMT compared to subjects with general obesity and the non-obese (0.68 ± 0.16 vs. 0.67 ± 0.16 vs. 0.62 ± 0.14 vs. 0.57 ± 0.13 mm, respectively; F = 54.2, post hoc p < 0.001). No difference in number, total area and type of plaques among obesity groups were attested (all p > 0.05). Significantly higher IMT values were observed in subjects with increased SU levels compared to subjects with normal SU levels (0.70 ± 0.10 vs. 0.62 ± 0.14 mm, p = 0.02) only within the central obesity group. Increasing levels of SU were associated with a higher frequency of increased IMT only in subjects with central obesity (OR 1.033, 95% CI 1.025-1.041). Similarly, SU levels yielded a satisfactory performance in detecting subjects with increased IMT (AUC 0.65, 95% CI 0.50-0.73, subjects with carotid plaques (0.62, 95% CI 0.55-0.68) and subjects with vulnerable plaque types (0.68, 0.59-0.76) only within the central obesity group. CONCLUSIONS: Among the studied obesity types, the association between SU levels and markers of carotid atherosclerosis was of particular significance in subjects with central obesity.

Extensive cerebellar involvement and cognitive impairment in COVID-19-associated acute necrotizing encephalopathy.

Neurological complications of the newly appeared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are increasingly recognized. Here, we report a case of a young male presenting with a clinical and neuroimaging scenario of an acute necrotizing encephalopathy related to the coronavirus disease 2019 (COVID-19). This case is notable by its distinct pattern of magnetic resonance imaging findings of an extensive involvement of the cerebellum, and emergence of cognitive and behavioral impairment.

Increased migraine-free intervals with multifocal repetitive transcranial magnetic stimulation.

INTRODUCTION: Episodic migraine is a debilitating condition associated with vast impairments of health, daily living, and life quality. Several prophylactic treatments exist, having a moderate ratio of action related to side effects and therapy costs. Repetitive transcranial magnetic stimulation (rTMS) is an evidence based therapy in several neuropsychiatric conditions, showing robust efficacy in alleviating specific symptoms. However, its efficacy in migraine disorders is unequivocal and might be tightly linked to the applied rTMS protocol. We hypothesized that multifocal rTMS paradigm could improve clinical outcomes in patients with episodic migraine by reducing the number of migraine days, frequency and intensity of migraine attacks, and improve the quality of life. METHODS: We conducted an experimental, double-blind, randomized controlled study by applying a multifocal rTMS paradigm. Patients with episodic migraine with or without aura were enrolled in two centers from August 2018, to December 2019, and randomized to receive either real (n = 37) or sham (sham coil stimulation, n = 28) multifocal rTMS for six sessions over two weeks. Patients, physicians, and raters were blinded to the applied protocol. The experimental multifocal rTMS protocol included two components; first, swipe stimulation of 13 trains of 140 pulses/train, 67 Hz, 60% of RMT, and 2s intertrain interval and second, spot burst stimulation of 33 trains of 15 pulses/train, 67 Hz, 85% of RMT, and 8s intertrain interval. Reduction >50% from the baseline in migraine days (as primary outcome) and frequency and intensity of migraine attacks (as key secondary outcomes) over a 12-week period were assessed. To balance the baseline variables between the treatment arms, we applied the propensity score matching through the logistic regression. RESULTS: Among 65 randomized patients, sixty (age 39.7 ± 11.6; 52 females; real rTMS n = 33 and sham rTMS n = 27) completed the trial and five patients dropped out. Over 12 weeks, the responder's rate in the number of migraine days was significantly higher in the real rTMS compared to the sham group (42% vs. 26%, p < 0.05). The mean migraine days per month decreased from 7.6 to 4.3 days in the real rTMS group and from 6.2 to 4.3 days in the sham rTMS group, resulting in a difference with real vs. sham rTMS of -3.2 days (p < 0.05). Similarly, over the 12-week period, the responder's rate in the reduction of migraine attacks frequency was higher in the real rTMS compared to the sham group (42% vs 33%, p < 0.05). No serious adverse events were observed. CONCLUSION: Our pilot study shows compelling evidence in a double placebo-controlled trial that multifocal rTMS is an effective and well-tolerated preventive treatment in patients with episodic migraine.

Clinical and Radiological Deterioration in a Case of Creutzfeldt-Jakob Disease following SARS-CoV-2 Infection: Hints to Accelerated Age-Dependent Neurodegeneration.

Systemic inflammation and the host immune responses associated with certain viral infections may accelerate the rate of neurodegeneration in patients with Creutzfeldt-Jakob disease (CJD), a rare, transmissible neurodegenerative disease. However, the effects of the newly emerged SARS-CoV-2 infection on the pathogenesis of CJD are unknown. In this study, we describe the case of an elderly female patient with sporadic CJD that exhibited clinical deterioration with the emergence of seizures and radiological neurodegenerative progression following an infection with SARS-CoV-2 and severe COVID-19. Despite efforts to control the progression of the disease, a dismal outcome ensued. This report further evidences the age-dependent neurological effects of SARS-CoV-2 infection and proposes a vulnerability to CJD and increased CJD progression following COVID-19.

Enhancing and accelerating stroke treatment in Eastern European region: Methods and achievement of the ESO EAST program.

INTRODUCTION: Despite the availability of prevention and therapies of stroke, their implementation in clinical practice, even of low-cost ones, remains poor. In 2015, the European Stroke Organisation (ESO) initiated the ESO Enhancing and Accelerating Stroke Treatment (EAST) program, which aims to improve stroke care quality, primarily in Eastern Europe. Here, we describe its methods and milestones. PATIENTS AND METHODS: The ESO EAST program is using an implementation strategy based on a 'detecting-understanding-reducing disparities' conceptual framework: stroke care quality is first measured (after developing a platform for data collection), gaps are identified in the current service delivery, and ultimately feedback is provided to participating hospitals, followed by the application of interventions to reduce disparities. The ESO EAST program is carried out by establishing a stroke quality registry, stroke management infrastructure, and creating education and training opportunities for healthcare professionals. RESULTS: Program management and leadership infrastructure has been established in 19 countries (Country Representatives in 22 countries, National Steering Committee in 19 countries). A software platform for data collection and analysis: Registry of Stroke Care Quality was developed, and launched in 2016, and has been used to collect data from over 90,000 patients from >750 hospitals and 56 countries between September 2016 and May 2019. Training in thrombolysis, nursing and research skills has been initiated. DISCUSSION: ESO EAST is the first pan-Eastern European (and beyond) multifaceted quality improvement intervention putting evidence-informed policies into practice. Continuous monitoring of stroke care quality allows hospital-to-hospital and country-to-country benchmarking and identification of the gaps and needs in health care.

Breakdown of Thalamo-Cortical Connectivity Precedes Spike Generation in Focal Epilepsies.

Electroencephalography (EEG) spikes and focal epileptic seizures are generated in circumscribed cerebral networks that have been insufficiently described. For precise time and spatial domain network characterization, we applied in patients with focal epilepsy dense array 256-channel EEG recordings with causal connectivity estimation by using time-resolved partial directed coherence and 3T-magnetic resonance imaging-derived cortical and thalamus integrity reconstruction. Before spike generation, significant theta and alpha bands driven information flows alterations were noted from both temporal and frontal lobes to the thalamus and from the thalamus to the frontal lobe. Medial dorsal and ventral anterior nuclei of the thalamus were delimited as possible pacemakers. Markedly reduced thalamic volumes and impaired cortical integrity in widespread areas predicted the altered information flows. Our data reveal distinct patterns of connectivity involving the thalamus and frontal cortex that are both directly and causally involved in spike generation. These structures might play an essential role in epileptogenesis and could be targeted in future therapeutic approaches.