Background Activity Research Articles

Positron emission tomography in CUP syndrome

In approximately 2% of all cancers, no primary tumor can be detected and cancer of unknown primary (CUP) syndrome, adiagnosis of exclusion, is made. In CUP syndrome, computed tomography (CT) and/or magnetic resonance imaging (MRI) do not lead to the detection of primary tumors. In the advanced diagnostic workup of CUP syndrome, 18F‑fluordeoxyglucose positron emission tomography/computed tomography (18F‑FDG PET/CT) can be used. In addition, 68Ga-fibroblast activation protein inhibitor (FAPI) PET/CT as anovel, experimental imaging technique may be considered. 18F‑FDG PET/CT is clinically established for the detection of primary tumors of cervical CUP syndrome. High detection rates have also been reported for 18F‑FDG-PET/CT in extracervical CUP syndrome. 68Ga-FAPI PET/CT has not yet been clinically established, but remarkably high detection rates have been shown for 18F‑FDG-negative cervical CUP syndrome due to its low background activity. The benefit of 18F‑FDG PET in CUP syndrome has been documented in several meta-analyses. To date, the evidence for the use of 68Ga-FAPI PET/CT in CUP syndrome is still rudimentary. 18F‑FDG PET should be applied regularly in cervical CUP syndrome and can be individually considered in extracervical CUP syndrome.

Cognition is entangled with metabolism: relevance for resting-state EEG-fMRI.

The brain is a living organ with distinct metabolic constraints. However, these constraints are typically considered as secondary or supportive of information processing which is primarily performed by neurons. The default operational definition of neural information processing is that (1) it is ultimately encoded as a change in individual neuronal firing rate as this correlates with the presentation of a peripheral stimulus, motor action or cognitive task. Two additional assumptions are associated with this default interpretation: (2) that the incessant background firing activity against which changes in activity are measured plays no role in assigning significance to the extrinsically evoked change in neural firing, and (3) that the metabolic energy that sustains this background activity and which correlates with differences in neuronal firing rate is merely a response to an evoked change in neuronal activity. These assumptions underlie the design, implementation, and interpretation of neuroimaging studies, particularly fMRI, which relies on changes in blood oxygen as an indirect measure of neural activity. In this article we reconsider all three of these assumptions in light of recent evidence. We suggest that by combining EEG with fMRI, new experimental work can reconcile emerging controversies in neurovascular coupling and the significance of ongoing, background activity during resting-state paradigms. A new conceptual framework for neuroimaging paradigms is developed to investigate how ongoing neural activity is "entangled" with metabolism. That is, in addition to being recruited to support locally evoked neuronal activity (the traditional hemodynamic response), changes in metabolic support may be independently "invoked" by non-local brain regions, yielding flexible neurovascular coupling dynamics that inform the cognitive context. This framework demonstrates how multimodal neuroimaging is necessary to probe the neurometabolic foundations of cognition, with implications for the study of neuropsychiatric disorders.

Comparison of 68GA-FAPI-04 PET/CT and 18F-FDG PET/CT findings in peritonitis carcinomatosa cases.

This study was conducted to compare the diagnostic accuracy of gallium-68-radiolabeled fibroblast activation protein inhibitor (68Ga-FAPI-04), positron emission tomography/computed tomography (PET/CT), and fluorine-18-fluorodeoxyglucose (18F-FDG) PET/CT based on the peritoneal carcinomatosis (PC) index for detecting peritoneal metastases of various cancer types, and to evaluate the potential benefits of FAPI PET/CT in patients with peritoneal metastases. This retrospective study included 57 patients with peritoneal metastases between November 2020 and December 2021. All patients underwent 68Ga-FAPI-04 PET/CT and 18F-FDG PET/CT scans within 7 days. Among the 57 patients included, 32 (56.1%) were male and the median age was 54 years (22-86 years). In the visual evaluation made from a total of 13 quadrants on the abdominopelvic peritoneal surfaces, positive findings were observed in 111 quadrants in 39 patients by 18F-FDG PET/CT and in 280 quadrants in 57 patients by 68Ga-FAPI-04 PET/CT (P<0.001). The maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR) values of 68Ga-FAPI-04 PET/CT for the PC lesions were significantly higher than the SUVmax and TBR values of 18F-FDG PET/CT in all patients and in all quadrants (SUVmax 6.45 vs 4.1; P<0.001; TBR 14.9 vs 6.8; P<0.001). Gallium-68-FAPI-04 PET/CT showed superior sensitivity compared to 18F-FDG PET/CT in both quantitative and visual evaluations of PC. Considering the low background activity and higher specific activity uptake values, 68Ga-FAPI-04 PET/CT helped improve diagnostic accuracy.

Anti-amphiphysin encephalitis: Expanding the clinical spectrum.

An analysis of the clinical features of autoimmune encephalitis accompanied by anti-amphiphysin antibodies. The data of encephalitis patients with anti-amphiphysin antibodies were retrospectively evaluated, including demographics, neurological and laboratory findings, imaging, treatment, and prognostic predictions. Ten patients aged between 29 and 78 years (median age 52 years) were included. The male: female ratio was 4:6. Limbic encephalitis was found in nine patients while epileptic seizures were present in seven patients. All patients showed anti-amphiphysin antibody positivity in sera while one ninth was positive for CSF antibody. The EEG findings were abnormal, including reductions in background activity, and the presence of diffuse slow waves, sharp waves, and spikes and waves. Five patients showed signs of increased T2 signals in the medial temporal lobe on MRI while PET showed either hyper- or hypo-metabolic changes in several brain regions, including the temporal lobe, hippocampus, basal ganglia, frontal and parietal cortices. Nine of ten patients were treated with immunotherapy, with improvements of varying degrees. There was a significant reduction in seizure frequency, and all patients were seizure-free at last follow-up. Autoimmune encephalitis with anti-amphiphysin antibodies has a variety of clinical manifestations. The most common symptom is limbic encephalitis. Although relief from seizures can be achieved relatively easily, many patients suffer psychiatric, cognitive, and sleep sequelae. The disease was found to be associated with a lower incidence of cancer than has been previously reported for paraneoplastic neurologic syndromes.

Thymosin alpha 1 – Reimagine its broader applications in the immuno-oncology era

Thymosin alpha 1 (Tα1) is a highly conserved 28 amino-acid peptide naturally occurring in the thymus and plays critical roles in T cell maturity and differentiation. Its synthetic form, thymalfasin, has been approved by various regulatory agencies in the treatment of hepatitis B viral infection and as an enhancer of vaccine response in immune-compromised populations. In China, it has also widely utilized in patients with cancer and severe infections, as well as the emergency use during (Severe Acute Respiratory Syndrome)SARS and COVID-19 pandemic as an immune-regulator. Recent studies showed that Tα1 could significantly improve overall survival (OS) in patients with surgically resectable non-small cell lung cancer (NSCLC) and liver cancers in the adjuvant setting. For patients with locally advanced, unresectable NSCLC, Tα1 could significantly reduce chemoradiation-induced lymphopenia, pneumonia, and trending improvement of OS. Preclinical evidence are emerging to demonstrate that Tα1 may augment efficacy of cancer chemotherapy by reversing efferocytosis-induced M2 polarization of macrophages via activation of a TLR7/SHIP1 axis and enhancing anti-tumor immunity by turning "cold-tumors" to "hot-tumors"; a protective role in reducing colitis caused by immune check-point inhibitors (ICIs). Potential enhancement of ICIs' clinical efficacies has also been indicated. ICIs have transformed ways treating patients with cancer but limitations such as relatively low response rates and certain safety issues remains. Given the roles of Tα1 in regulating cellular immunities and exceptional safety profiles demonstrated in decades clinical uses, we believe that it is plausible to explore implications of Tα1 the immune-oncology setting by combining with ICI-based therapeutic strategies. Background Activities of Tα1. Tα1 is a biological response modifier which activates various cells in the immune system [1-3]. Tα1 is therefore expected to have clinical benefits in disorders where immune responses are impaired or ineffective. These disorders include acute and chronic infections, cancers, and vaccine non-responsiveness. In severe sepsis, for example, sepsis-induced immunosuppression is increasingly recognized as the overriding immune dysfunction in these vulnerable patients [4] and there is now agreement that many patients with severe sepsis survive the first critical hours of the syndrome but eventually die later due to patients' immunosuppression which make the system difficulty to fight the primary bacterial infection, decreased resistance to secondary nosocomial infections, and reactivation of viral infections [5]. Tα1 has been shown to restore immune functions and help to reduce mortality in patients with severe sepsis.

Pinniped electroencephalography: Methodology and findings in California sea lions (Zalophus californianus).

This study was designed to identify abnormalities in the electroencephalograms (EEGs) recorded from stranded California sea lions (Zalophus californianus) with suspected domoic acid (DA) toxicosis. Recordings from animals presenting for non-neurological issues were also obtained to better understand the normal EEG (background activity and transient events) in this species, as, to date, studies have focused on examining natural sleep in pinnipeds. Most animals were sedated for electrode placement and EEG acquisition with some receiving antiepileptic medications or isoflurane during the procedure. A total of 103 recordings were read and scored from 0 (normal) to 3 (severely abnormal). Epileptiform discharges, consisting of spikes, sharp waves, slow waves, and/or spike waves, were present in all EEGs with scores of 1, 2, or 3. The distribution of these events over the scalp varied. While often generalized, others were lateralized over one hemisphere, bifrontal, bioccipital, and/or bitemporal, while some discharges were multifocal. Findings were different between sea lions and occasionally changed within the EEG on a given sea lion. No clinical seizures were observed during the recording but a few sea lions had findings consistent with electroencephalographic seizures. When available, supporting diagnostic results obtained from magnetic resonance imaging (MRI) and/or necropsy/histopathology were described, as well as the status of those sea lions that recovered and were released with satellite tags.

1980년대 중국 아방가르드 미술에서 문자미술의 전개와 특징

This study focuses on word and image in Chinese avant-garde art in the 1980s. It focuses on the works of Gu Wenda, Wu Shanzhuan, and Xu Bing. It investigates the significance of their anti-art practice activities in China's political, social, and cultural background in the 1980s. It examines what their activities mean in the history of modern Chinese art. After the end of the Cultural Revolution, a large number of Western ideas flocked to China in the 1980s with reform and opening, and discussions on humanities were held with unprecedented personnel. After the end of the Cultural Revolution, modern artists in China began to accept modern and contemporary Western art from the post-revolution period, and the 85 New Art Movement took place in the mid-1980s, led by young young artists. Artists who participated in the 85 New Wave, China's first modern art movement, organized and worked as an organization and indirectly encountered Western contemporary art and philosophy through books. Their activities contributed to the expansion of Chinese avant-garde art into the nationwide avant-garde movement. The movement contributed to hosting the Chinese Contemporary Art Exhibition in February 1989. Although the exhibition ended ostensibly in failure, the artists who participated in the planning and exhibition later went abroad to study or defect to promote China's visual culture and modern art. In particular, Gu Wenda, Wu Shanzhuan, and Xu Bing. who participated in the 85 new wave, earlier modified, reconstructed, and studied Chinese characters and calligraphy to build their own art world. The purpose of this study is not to honor or criticize the achievements of the three artists' current progressive works. Instead, by looking at examples of works at the beginning of Chinese avant-garde art in the 1980s, we have the opportunity to think about China's historical background and the role of writing art in China's reality in the 1980s.

PRO-C3 is a predictor of clinical outcomes in distinct cohorts of patients with advanced liver disease

Background & AimsFibroblast activity is a key feature of fibrosis progression and organ function loss, leading to liver-related complications and mortality. The fibrogenesis marker, PRO-C3, has been shown to have prognostic significance in relation to fibrosis progression and as a treatment efficacy marker. We investigated whether PRO-C3 was prognostic for clinical outcome and mortality in two distinct cohorts of compensated cirrhosis. MethodsCohort 1 was a rapid fibrosis progression cohort including 104 patients with HCV and biopsy-proven Ishak fibrosis stage ≥3 without prior clinical events. Cohort 2 was a prospective cohort including 172 patients with compensated cirrhosis of mixed aetiology. Patients were assessed for clinical outcomes. PRO-C3 was assessed in serum at baseline in cohorts 1 and 2, and compared with model for end-stage liver disease and albumin–bilirubin (ALBI) scores. ResultsIn cohort 1, a 2-fold increase in PRO-C3 was associated with 2.7-fold increased hazard of liver-related events (95% CI 1.6–4.6), whereas a one unit increase in ALBI score was associated with a 6.5-fold increased hazard (95% CI 2.9–14.6). In cohort 2, a 2-fold increase in PRO-C3 was associated with a 2.7-fold increased hazard (95% CI 1.8–3.9), whereas a one unit increase in ALBI score was associated with a 6.3-fold increased hazard (95% CI 3.0–13.2). A multivariable Cox regression analysis identified PRO-C3 and ALBI as being independently associated with the hazard of liver-related outcomes. ConclusionsPRO-C3 and ALBI were independent prognostic factors for predicting liver-related clinical outcomes. Understanding the dynamic range of PRO-C3 might enhance its use for both drug development and clinical practice. Impact and ImplicationsWe tested novel proteins of liver scarring (PRO-C3) in two groups of liver patients with advanced disease to see if they could predict clinical events. We found that this marker and an established test called ALBI were both independently associated with future liver-related clinical outcomes.

Intracerebral Correlates of Scalp EEG Ictal Discharges Based on Simultaneous Stereo-EEG Recordings.

It remains unknown to what extent ictal scalp EEG can accurately predict the localization of the intracerebral seizure onset in presurgical evaluation of drug-resistant epilepsies. In this study, we aimed to define homogeneous ictal scalp EEG profiles (based on their first ictal abnormality) and assess their localizing value using simultaneously recorded scalp EEG and stereo-EEG. We retrospectively included consecutive patients with drug-resistant focal epilepsy who had simultaneous stereo-EEG and scalp EEG recordings of at least 1 seizure in the epileptology unit in Nancy, France. We analyzed 1 seizure per patient and used hierarchical cluster analysis to group similar seizure profiles on scalp EEG and then performed a descriptive analysis of their intracerebral correlates. We enrolled 129 patients in this study. The hierarchical cluster analysis showed 6 profiles on scalp EEG first modification. None were specific to a single intracerebral localization. The "normal EEG" and "blurred EEG" clusters (early muscle artifacts) comprised only 5 patients each and corresponded to no preferential intracerebral localization. The "temporal discharge" cluster (n = 46) was characterized by theta or delta discharges on ipsilateral anterior temporal scalp electrodes and corresponded to a preferential mesial temporal intracerebral localization. The "posterior discharge" cluster (n = 42) was characterized by posterior ipsilateral or contralateral rhythmic alpha discharges or slow waves on scalp and corresponded to a preferential temporal localization. However, this profile was the statistically most frequent scalp EEG correlate of occipital and parietal seizures. The "diffuse suppression" cluster (n = 9) was characterized by a bilateral and diffuse background activity suppression on scalp and corresponded to mesial, and particularly insulo-opercular, localization. Finally, the "frontal discharge" cluster (n = 22) was characterized by bilateral frontal rhythmic fast activity or preictal spike on scalp and corresponded to preferential ventrodorsal frontal intracerebral localizations. The hierarchical cluster analysis identified 6 seizure profiles regarding the first abnormality on scalp EEG. None of them were specific of a single intracerebral localization. Nevertheless, the strong relationships between the "temporal," "frontal," "diffuse suppression," and "posterior" profiles and intracerebral discharge localizations may contribute to hierarchize hypotheses derived from ictal scalp EEG analysis regarding intracerebral seizure onset.

Are associations of leisure-time physical activity with mortality attenuated by high levels of chronic ambient fine particulate matter (PM2.5) in older adults? A prospective cohort study

Background and purposeAlthough leisure-time physical activity (PA) has established health benefits in older adults, it is equivocal if exercising in environments with high levels of PM2.5 concentrations is equally beneficial for them. To explore the independent and joint associations of ambient PM2.5 and PA with all-cause mortality among adults aged 60 or older and to assess the modifying effect of age (60–74 years vs. 75+ years) on the joint associations. MethodsA prospective cohort study based on the MJ Cohort repeat examinations (2005–2016) and the Taiwan Air Quality Monitoring Network and death registry linkages (2005–2022). We included MJ Cohort participants aged 60 or more at baseline who attended the health check-ups at least twice (n = 21,760). Metabolic equivalent hours per week (MET-h/week) of leisure-time PA were computed. Multivariable adjusted associations were examined using time-varying Cox proportional hazard models. ResultsThere were 3539 all-cause deaths over a mean follow-up of 12.81 (SD = 3.67) years. Ambient PM2.5 and physical inactivity are both independently associated with all-cause mortality. The joint associations of PA and PM2.5 concentrations with all-cause mortality differed in the young-old (60–74 years) and the older-old (75+ years) (P for interaction = 0.01); Higher levels of long-term PM2.5 exposures (≥25 μg/m3) had little influence on the associations between PA and mortality in the young-old (HR = 0.68 (0.56–0.83) and HR = 0.72 (0.59–0.88) for participants with 7.5–<15 and 15+ MET-h/week respectively) but eliminated associations between exposure and outcome in the older-old (HR = 0.91 (0.69–01.21) and HR = 1.02 (0.76–1.38) for participants with 7.5–<15 and 15+ MET-h/week). ConclusionLong-term exposures to higher PM2.5 concentrations may eliminate the beneficial associations of PA with all-cause mortality among adults aged 75 and over.

Rating by detection: an artifact detection protocol for rating EEG quality with average event duration

Objective. Quantitative evaluation protocols are critical for the development of algorithms that remove artifacts from real electroencephalography (EEG) optimally. However, visually inspecting the real EEG to select the top-performing artifact removal pipeline is infeasible while hand-crafted EEG data allow assessing artifact removal configurations only in a simulated environment. This study proposes a novel, principled approach for quantitatively evaluating algorithmically corrected EEG without access to ground truth in real-world conditions. Approach. Our offline evaluation protocol uses a detector to score the presence of artifacts. It computes their average duration, which measures the recovered EEG’s deviation from the modeled background activity with a single score. As we expect the detector to make generalization errors, we employ a generic and configurable Wiener-based artifact removal method to validate the reliability of our detection protocol. Main results. Quantitative experiments extensively compare many Wiener filters and show their consistent rankings agree with their theoretical assumptions and expectations. Significance. The rating-by-detection protocol with the average event duration measure should be of value for EEG practitioners and developers. After removing artifacts from real EEG, the protocol experimentally shows that reliable comparisons between many artifact filtering configurations are possible despite the missing ground-truth neural signals.

Acute effect of antiseizure drugs on background oscillations in Scn1a A1783V Dravet syndrome mouse model.

Dravet syndrome (Dravet) is a rare and severe form of developmental epileptic encephalopathy. Antiseizure medications (ASMs) for Dravet patients include valproic acid (VA) or clobazam (CLB), with or without stiripentol (STP), while sodium channel blockers like carbamazepine (CBZ) or lamotrigine (LTG) are contraindicated. In addition to their effect on epileptic phenotypes, ASMs were shown to modify the properties of background neuronal activity. Nevertheless, little is known about these background properties alterations in Dravet. Here, utilizing Dravet mice (DS, Scn1a A1783V/WT), we tested the acute effect of several ASMs on background electrocorticography (ECoG) activity and frequency of interictal spikes. Compared to wild-type mice, background ECoG activity in DS mice had lower power and reduced phase coherence, which was not corrected by any of the tested ASMs. However, acute administration of Dravet-recommended drugs, VA, CLB, or a combination of CLB + STP, caused, in most mice, a reduction in the frequency of interictal spikes, alongside an increase in the relative contribution of the beta frequency band. Conversely, CBZ and LTG increased the frequency of interictal spikes, with no effect on background spectral properties. Moreover, we uncovered a correlation between the reduction in interictal spike frequency, the drug-induced effect on the power of background activity, and a spectral shift toward higher frequency bands. Together, these data provide a comprehensive analysis of the effect of selected ASMs on the properties of background neuronal oscillations, and highlight a possible correlation between their effect on epilepsy and background activity.

A multi-label CNN model for the automatic detection and segmentation of gliomas using [18F]FET PET imaging.

The aim of this study was to develop a convolutional neural network (CNN) for the automatic detection and segmentation of gliomas using [18F]fluoroethyl-L-tyrosine ([18F]FET) PET. Ninety-three patients (84 in-house/7 external) who underwent a 20-40-min static [18F]FET PET scan were retrospectively included. Lesions and background regions were defined by two nuclear medicine physicians using the MIM software, such that delineations by one expert reader served as ground truth for training and testing the CNN model, while delineations by the second expert reader were used to evaluate inter-reader agreement. A multi-label CNN was developed to segment the lesion and background region while a single-label CNN was implemented for a lesion-only segmentation. Lesion detectability was evaluated by classifying [18F]FET PET scans as negative when no tumor was segmented and vice versa, while segmentation performance was assessed using the dice similarity coefficient (DSC) and segmented tumor volume. The quantitative accuracy was evaluated using the maximal and mean tumor to mean background uptake ratio (TBRmax/TBRmean). CNN models were trained and tested by a threefold cross-validation (CV) using the in-house data, while the external data was used for an independent evaluation to assess the generalizability of the two CNN models. Based on the threefold CV, the multi-label CNN model achieved 88.9% sensitivity and 96.5% precision for discriminating between positive and negative [18F]FET PET scans compared to a 35.3% sensitivity and 83.1% precision obtained with the single-label CNN model. In addition, the multi-label CNN allowed an accurate estimation of the maximal/mean lesion and mean background uptake, resulting in an accurate TBRmax/TBRmean estimation compared to a semi-automatic approach. In terms of lesion segmentation, the multi-label CNN model (DSC = 74.6 ± 23.1%) demonstrated equal performance as the single-label CNN model (DSC = 73.7 ± 23.2%) with tumor volumes estimated by the single-label and multi-label model (22.9 ± 23.6ml and 23.1 ± 24.3ml, respectively) closely approximating the tumor volumes estimated by the expert reader (24.1 ± 24.4ml). DSCs of both CNN models were in line with the DSCs by the second expert reader compared with the lesion segmentations by the first expert reader, while detection and segmentation performance of both CNN models as determined with the in-house data were confirmed by the independent evaluation using external data. The proposed multi-label CNN model detected positive [18F]FET PET scans with high sensitivity and precision. Once detected, an accurate tumor segmentation and estimation of background activity was achieved resulting in an automatic and accurate TBRmax/TBRmean estimation, such that user interaction and potential inter-reader variability can be minimized.

Alterations in the properties of the glutamatergic system of the rat hippocampus in a lithium-pilocarpine model of temporal lobe epilepsy

Status epilepticus (SE) triggers many pathological changes in the nervous system that are not yet fully understood and may lead to the development of epilepsy. In this work, we studied the effects of SE on the properties of excitatory glutamatergic transmission in the hippocampus in a rat model of lithium-pilocarpine temporal lobe epilepsy. Studies were performed 1 day (acute phase of the model), 3 and 7 days (latent phase), and 30 to 80 days (chronic phase) after SE. Using real-time PCR, we found that in the latent phase there is a decrease in gene expression of GluA1 and GluA2 AMPA receptor subunits, which may also be accompanied by an increased proportion of calcium-permeable AMPA receptors, which play an essential role in the pathogenesis of many CNS diseases. In acute brain slices we found a decrease in the efficiency of excitatory synaptic neurotransmission in all phases of the model when recording field responses in the CA1 region of the hippocampus in response to stimulation of Schaffer collaterals by electric currents of different intensities. However, in the chronic phase we found an increase in the frequency of spontaneous excitatory postsynaptic potentials, indicating an increased background activity of the glutamatergic system in epilepsy. This is also supported by a decrease in the threshold of hind limb extension in the test of maximal electroshock seizure in rats with temporal lobe epilepsy compared to control animals. The results obtained indicate the presence of a number of functional alterations in the glutamatergic system related to epilepsy. These findings can be used to develop antiepileptogenic therapy.

WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk.

WWOX is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy (WWOX-DEE), also known as WOREE (WWOX-related epileptic encephalopathy). We analyzed the epileptology and imaging features of WWOX-DEE, and investigated genotype-phenotype correlations, particularly with regard to survival. We studied 13 patients from 12 families with WWOX-DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms, and disease outcome were collected. Electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) data were analyzed. Pathogenic WWOX variants from our cohort and the literature were coded as either null or missense, allowing individuals to be classified into one of three genotype classes: (1) null/null, (2) null/missense, (3) missense/missense. Differences in survival outcome were estimated using the Kaplan-Meier method. All patients experienced multiple seizure types (median onset=5 weeks, range=1day-10months), the most frequent being focal (85%), epileptic spasms (77%), and tonic seizures (69%). Ictal EEG recordings in six of 13 patients showed tonic (n= 5), myoclonic (n= 2), epileptic spasms (n= 2), focal (n= 1), and migrating focal (n= 1) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo-occipital regions. Eleven of 13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippocampal, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout WWOX and comprised both missense and null changes including five copy number variants (four deletions, one duplication). Survival analyses showed that patients with two null variants are at higher mortality risk (p-value=.0085, log-rank test). Biallelic WWOX pathogenic variants cause an early infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type; patients with biallelic null WWOX pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.

Post-ictal Rhythmic Thalamic Activity of the Centromedian Nucleus.

Deep brain stimulation of the centromedian nucleus of the thalamus (CMN) to treat drug-resistant epilepsy has been of interest for decades. However, little is known about the electrophysiological activity of the CMN during seizures. We describe a novel CMN EEG finding associated with seizure: post-ictal rhythmic thalamic activity. Five patients with drug-resistant epilepsy of unknown etiology with focal onset seizures underwent stereoelectroencephalography monitoring as part of evaluation for potential resective surgery or neuromodulation. Two patients had previously undergone complete corpus callosotomy and vagus nerve stimulation. A standardized plan for implantation included targets in the bilateral CMN. Each patient had frontal onset seizures, and two patients had additional insular, parietal, or mesial temporal onset seizures. Contacts of CMN were involved synchronously or rapidly after onset in most recorded seizures, particularly those with frontal onset. Focal onset hemiclonic and bilateral tonic-clonic seizures spread to involve cortical contacts with high-amplitude rhythmic spiking followed by abrupt offset with diffuse voltage attenuation. A post-ictal rhythmic 1.5 to 2.5 Hz delta frequency pattern, post-ictal rhythmic thalamic activity, emerged in CMN contacts amid the suppression of background activity in cortical contacts. In the two patients with corpus callosotomy, unilateral seizure spread and ipsilateral post-ictal rhythmic thalamic activity were observed. We observed post-ictal rhythmic thalamic activity in five patients with stereoelectroencephalography monitoring of the CMN with convulsive seizures. This rhythm appears late in ictal evolution and may signal an important role of the CMN in seizure termination. Furthermore, this rhythm may help identify CMN involvement in the epileptic network.

Relationship Between Epileptic Activity and Developmental Outcome in KCNQ2-Related Epilepsy

BackgroundWe aim to describe a cohort of patients with KCNQ2-related epilepsy and evaluate the relationship between epileptic activity and developmental outcome. This topic is relevant for the selection of clinical end points in future clinical trials, since cessation of seizures may or may not be the most important outcome. MethodsThis retrospective cohort study of children with self-limited (familial) neonatal epilepsy and developmental and epileptic encephalopathy due to pathogenic variants in KCNQ2 was conducted between 2019 and 2021. We collected clinical, therapeutic, and genetic information. Available electroencephalographic recordings were reviewed by a neurophysiologist. Gross motor function was determined using the Gross Motor Function Classification System (GMFCS). The Vineland Adaptive Behavior Composite standard score (ABC SS) was used to measure adaptive functioning. ResultsAmong 44 children (mean age 8.1 ± 4.0 years, 45.5% were male), 15 of 44 had S(F)NE, and 29 of 44 had DEE. Delayed seizure freedom was more frequent in DEE than in S(F)NE (P = 0.025), but no correlation was observed between age at seizure freedom and developmental outcome in patients with DEE. Multifocal interictal epileptiform abnormalities at epilepsy onset were more frequent in DEE than in S(F)NE (P = 0.014), and were associated with higher GMFCS (P = 0.027) and lower ABC SS (P = 0.048) in patients with DEE. Disorganized background activity at follow-up was more frequent in DEE than in S(F)NE (P = 0.001), and was associated with higher GMFCS levels (P = 0.009) and lower ABC SS (P = 0.005) in patients with DEE. ConclusionsThis study shows a partial correlation between epileptic activity and developmental outcome in KCNQ2-related epilepsy.

Perinatal stroke and overlapping clinical presentation with HIE; studying practical diagnostic and management challenges through observational analysis of a single tertiary centre stroke patients

Background: While therapeutic hypothermia is accepted as a standard of care for improving neurological outcome for HIE patients, evidence of its benefits for neonatal stroke is lacking. Neurological presentations of HIE and neonatal stroke can be difficult to distinguish and indeed neonatal stroke can coexist with HIE. Our observational analysis of a single centre cohort of stroke infants with MRI diagnosis highlights the practical challenges for distinguishing between the two groups and reaching an early definitive diagnosis to inform appropriate treatment. Methods: A retrospective cohort study of term neonates &gt;37 weeks gestation born between May 2011 and April 2020 born at a specialised NICU network in the East of England with a principal diagnosis of neonatal stroke were obtained from Badgernet data. Results: 81% of infants (13/16) had sentinel events around delivery. 50% (8/16) of infants were therapeutically cooled. Of the 8 cooled infants only 3 (37%) of cooled infants fulfilled both Toby A and B criteria. Infants who received therapeutic hypothermia were more likely to present with early onset seizures (5/8) than infants who were not cooled (1/8) (p=0.019) . 6 of the 8 non-cooled infants compared to 2of the 8 cooled infants (p=0.03) had a higher seizure burden requiring escalation of antiepileptic medication to second line or need for maintenance treatment. Conclusion: Infants with neonatal stroke who present with early seizures are more likely to receive therapeutic hypothermia despite failure to fulfil both Toby A and B criteria. Early suspicion to inform management can be obtained more effectively from CFM while cranial ultrasound findings are generally non-specific. A normal CFM background, unilateral abnormal background and unilateral seizure activity are highly suggestive of neonatal stroke.

Interference Suppression in EEG Dipole Source Localization through Reduced-Rank Beamforming

In this paper, we propose new neural activity indices for the solution of the inverse problem of localizing sources of cortical activity from electroencephalography (EEG) measurements. Such indices are based on reduced-rank beamformers, specifically the generalized sidelobe canceler (GSC), and with the purpose of suppressing the contribution of interfering sources and noise. Here, the GSC is modified with an adaptive blocking matrix (ABM) to optimally estimate and later suppress unwanted brain sources. With respect to the rank-reduction, this is achieved through the cross-spectral metrics (CSM) as they give a sense of the affinity of the beamformers’ eigenstructure to the orthogonal subspace of noise an interference. Based on that, two different neural indices are proposed for the assessment of brain activation. Our realistic simulations show that a more consistent source localization is achieved through the proposed indices in comparison to the use of the traditional full-rank approach, specifically for brain sources embedded in high background activity that originates at the brain cortex and thalamus. We also prove the applicability of our methods on the localization of sources on the visual cortex produced by steady-state visual-evoked potentials.

Alterations in the Properties of the Rat Hippocampus Glutamatergic System in the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy

Status epilepticus (SE) triggers many not yet fully understood pathological changes in the nervous system that can lead to the development of epilepsy. In this work, we studied the effects of SE on the properties of excitatory glutamatergic transmission in the hippocampus in the lithium-pilocarpine model of temporal lobe epilepsy in rats. The studies were performed 1 day (acute phase), 3 and 7 days (latent phase), and 30 to 80 days (chronic phase) after SE. According to RT-qPCR data, expression of the genes coding for the AMPA receptor subunits GluA1 and GluA2 was downregulated in the latent phase, which may lead to the increased proportion of calcium-permeable AMPA receptors that play an essential role in the pathogenesis of many CNS diseases. The efficiency of excitatory synaptic neurotransmission in acute brain slices was decreased in all phases of the model, as determined by recording field responses in the CA1 region of the hippocampus in response to the stimulation of Schaffer collaterals by electric current of different strengths. However, the frequency of spontaneous excitatory postsynaptic potentials increased in the chronic phase, indicating an increased background activity of the glutamatergic system in epilepsy. This was also evidenced by a decrease in the threshold current causing hindlimb extension in the maximal electroshock seizure threshold test in rats with temporal lobe epilepsy compared to the control animals. The results suggest a series of functional changes in the properties of glutamatergic system associated with the epilepsy development and can be used to develop the antiepileptogenic therapy.