Orrin Devinsky

Szaflarski JP, Devinsky O, Lopez M, Park YD, Zentil PP, Patel AD, et al. Long-term efficacy and safety of cannabidiol in patients with treatment-resistant epilepsies: Four-year results from the expanded access program. Epilepsia. 2023; 64: 619–629. https://doi. org/10. 1111/epi. 17496.In the Results section, 3.1 Patients, it reads “The median age of patients was 13.5 years (range= 0–74.5) in the safety analysis set and 11.8 years (range= 0–74.5) in the efficacy analysis set.” This should have read “The median age of patients was 11.8 years (range= 0–74.5) in the safety analysis set and 11.7 years (range= 0–74.5) in the efficacy analysis set.”

The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS.

Background and ObjectivesMore than 2,900 US children aged younger than 4 years die from unknown causes each year, accounting for more than 219,000 life years lost annually. They are mostly sleep-related and unwitnessed with unremarkable autopsies, limiting our understanding of death mechanisms. We sought to understand potential mechanisms of death by evaluating videos of sudden deaths in toddlers.MethodsIn our registry of 301 sudden unexplained child deaths, a series of 7 consecutively enrolled cases with home video recordings of the child's last sleep period were independently assessed by 8 physicians for video quality, movement, and sound.ResultsFour boys and 3 girls (13–27 months at death) with terminal videos shared similar demographic features to the 293 other registry cases without video recordings. Five video recordings were continuous and 2 were triggered by sound or motion. Two …

Decoding human speech from neural signals is essential for brain–computer interface (BCI) technologies that aim to restore speech in populations with neurological deficits. However, it remains a highly challenging task, compounded by the scarce availability of neural signals with corresponding speech, data complexity and high dimensionality. Here we present a novel deep learning-based neural speech decoding framework that includes an ECoG decoder that translates electrocorticographic (ECoG) signals from the cortex into interpretable speech parameters and a novel differentiable speech synthesizer that maps speech parameters to spectrograms. We have developed a companion speech-to-speech auto-encoder consisting of a speech encoder and the same speech synthesizer to generate reference speech parameters to facilitate the ECoG decoder training. This framework generates natural-sounding …

ObjectiveDravet syndrome is a rare, early childhood-onset epileptic and developmental encephalopathy. Responses to placebo in clinical trials for epilepsy therapies range widely, but factors influencing placebo response remain poorly understood. This study explored placebo response and its effects on safety, efficacy, and quality of life outcomes in patients with Dravet syndrome.MethodsWe performed exploratory post-hoc analyses of pooled data from placebo-treated patients from the GWPCARE 1B and GWPCARE 2 randomized controlled phase III trials, comparing cannabidiol and matched placebo in 2–18 year old Dravet syndrome patients. All patients had ≥4 convulsive seizures during a baseline period of 4 weeks.Results124 Dravet syndrome-treated patients were included in the analysis (2–5 years: n = 35; 6–12 years: n = 52; 13–18 years: n = 37). Convulsive seizures were experienced by all placebo …

Objective Copy number variants (CNVs) contribute to genetic risk and genetic etiology of both rare and common epilepsies. Whereas many studies have explored the role of CNVs in sporadic or severe cases, fewer have been done in familial generalized and focal epilepsies. Methods We analyzed exome sequence data from 267 multiplex families and 859 first‐degree relative pairs with a diagnosis of genetic generalized epilepsies or nonacquired focal epilepsies to predict CNVs. Validation and segregation studies were performed using an orthogonal method when possible. Results We identified CNVs likely to contribute to epilepsy risk or etiology in the probands of 43 of 1116 (3.9%) families, including known recurrent CNVs (16p13.11 deletion, 15q13.3 deletion, 15q11.2 deletion, 16p11.2 duplication, 1q21.1 duplication, and 5‐Mb duplication of 15q11q13). We also identified CNVs affecting monogenic …

Tuberous sclerosis complex (TSC) is a rare genetic disorder caused by mutations in the mTOR pathway genes TSC1 or TSC2. TSC can affect multiple organs including the brain, and most patients (75-90%) present with seizures during early childhood and intractable epilepsy throughout life. mTOR inhibitors, part of the current standard of care, lack the optimal characteristics to fully address patient phenotypes. Here, we report on the application of our all-optical electrophysiology platform for phenotypic screening in a human neuronal model of TSC. We used CRISPR/Cas9-isogenic TSC2-/- iPS cell lines to identify disease-associated changes to neuronal morphology, transcript expression and neuronal excitability. We established a robust multiparametric electrophysiological phenotype which we then validated in TSC patient-derived neurons. We used this phenotype to conduct a screen of ~30,000 small molecule compounds in human iPS cell-derived neurons and identified chemical scaffolds that rescued the functional TSC disease parameters. Confirmed hits may act via different mechanisms than direct mTOR pathway inhibition. This strategy provides molecular starting points for therapeutic development in TSC and a framework for phenotype discovery and drug screening in other neurological disorders.

The idiopathic generalized epilepsies (IGE) make up a fifth of all epilepsies, but <1% of epilepsy research. This skew reflects misperceptions: diagnosis is straightforward, pathophysiology is understood, seizures are easily controlled, epilepsy is outgrown, morbidity and mortality are low, and surgical interventions are impossible. Emerging evidence reveals that patients with IGE may go undiagnosed or misdiagnosed with focal epilepsy if EEG or semiology have asymmetric or focal features. Genetic, electrophysiologic, and neuroimaging studies provide insights into pathophysiology, including overlaps and differences from focal epilepsies. IGE can begin in adulthood and patients have chronic and drug-resistant seizures. Neuromodulatory interventions for drug-resistant IGE are emerging. Rates of psychiatric and other comorbidities, including sudden unexpected death in epilepsy, parallel those in focal epilepsy. IGE …

The cannabidiol (CBD) Expanded Access Program (EAP), initiated in 2014, provided CBD (Epidiolex) to patients with treatment‐resistant epilepsy (TRE). In the final pooled analysis of 892 patients treated through January 2019 (median exposure = 694 days), CBD treatment was associated with a 46%–66% reduction in median monthly total (convulsive plus nonconvulsive) seizure frequency. CBD was well tolerated, and adverse events were consistent with previous findings. We used pooled EAP data to investigate the effectiveness of add‐on CBD therapy for individual convulsive seizure types (clonic, tonic, tonic–clonic, atonic, focal to bilateral tonic–clonic), nonconvulsive seizure types (focal with and without impaired consciousness, absence [typical and atypical], myoclonic, myoclonic absence), and epileptic spasms. CBD treatment was associated with a reduction in the frequency of convulsive seizure types …

ObjectiveDravet syndrome is a rare developmental epilepsy syndrome associated with severe, treatment-resistant seizures. Since seizures and seizure clusters are linked to morbidity, reduced quality of life, and premature mortality, a greater understanding of these outcomes could improve trial designs. This analysis explored seizure types, seizure clusters, and factors affecting seizure cluster variability in Dravet syndrome patients.MethodsPooled post-hoc analyses were performed on data from placebo-treated patients in GWPCARE 1B and GWPCARE 2 randomized controlled phase III trials comparing cannabidiol and placebo in Dravet syndrome patients aged 2–18 years. Multivariate stepwise analysis of covariance of log-transformed convulsive seizure cluster frequency was performed, body weight and body mass index z-scores were calculated, and incidence of adverse events was assessed. Data were …

Altered protein conformation can cause incurable neurodegenerative disorders. Mutations in SERPINI1, the gene encoding neuroserpin, alter protein conformation resulting in cytotoxic aggregation in neuronal endoplasmic reticulum. Aggregates cause oxidative stress impairing function, leading to neuronal death. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare autosomal dominant progressive myoclonic epilepsy. Patients present with seizures and cognitive impairments that progress to dementia and premature death. We developed HEK293T and induced pluripotent stem cell (iPSC) models of FENIB, harboring the patient's pathogenic SERPINI1 variant or stably overexpressing mutant neuroserpin fused to GFP (MUT NS-GFP). FENIB cells form neuroserpin inclusions which increase in size and number. Here, we utilized a personalized adenine base editor (ABE)-mediated approach to efficiently correct the pathogenic variant and to restore neuronal dendritic morphology. ABE-treated MUT NS-GFP cells demonstrated reduced inclusion size and number. Using an inducible MUT NS-GFP neuron system, we identified early prevention of toxic protein expression allowed aggregate clearance, while late prevention halted neuronal impairments. To address several challenges for clinical applications of gene correction, we developed a neuron-specific engineered virus-like particle to optimize neuronal ABE delivery. Preventing mutant protein with altered conformation production improved toxic protein clearance. Our findings provide a targeted strategy and may treat FENIB and potentially other neurodegenerative diseases …

I met Michael Duchowny as a medical student in Boston more than 40 years ago. Time flies. It was 1977, Michael was an epilepsy fellow at Boston Children’s Hospital. Down the block, I sat in a large auditorium, listening to Norman Geschwind lecture in his course on The Neurology of Behavior. It was a ‘sell-out’crowd, the stairs filled with attendees who flooded in from everywhere–linguists from MIT, psychologists from Harvard, speech pathologists from the Boston VA, psychiatrists from McLean, neurophysiologists from Harvard Med, etc. Next to me was a neuropsychology post-doctoral student, Michael’s girlfriend. When I told her of my interest in neurology, she told said “you have to meet Michael”.One never knows where fate leads, but that conversation took me to a one-month elective with Michael at Boston Children’s Hospital. He taught me about EEG interpretation and pediatric epilepsy. For me, neurology was …

Cannabis has been used to treat convulsions and other disorders since ancient times. In the last few decades, preclinical animal studies and clinical investigations have established the role of cannabidiol (CBD) in treating epilepsy and seizures and support potential therapeutic benefits for cannabinoids in other neurological and psychiatric disorders. Here, we comprehensively review the role of cannabinoids in epilepsy. We briefly review the diverse physiological processes mediating the central nervous system response to cannabinoids, including Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol, and terpenes. Next, we characterize the anti- and proconvulsive effects of cannabinoids from animal studies of acute seizures and chronic epileptogenesis. We then review the clinical literature on using cannabinoids to treat epilepsy, including anecdotal evidence and case studies as well as the more recent randomized …

" What's remarkable is that no one would have ever suspected a seizure. Firstly, seizures don't leave a mark, especially in this age group. In an older adult, there might be a tongue bite or something like that to be a clue. But in this population, they don't have teeth that are going to cause that kind of injury, and so there's really no marker, no sequelae that you could see."Each year, several thousand children in the US die from unknown causes, most of the time sleep-related and unwitnessed. Research on sudden unexplained deaths in childhood (SUDCs), aged 1-18 years, is limited with less than 1% of research publications compared with sudden infant deaths. Led by Orrin Devinsky, MD, a recently published study analyzed terminal videos in a consecutive series of sleep-related child deaths from the SUDC Registry and Research Collaborative to document observations and explore mechanisms of death.

ObjectiveEpilepsy patients often report memory deficits despite normal objective testing, suggesting that available measures are insensitive or that non-mnemonic factors are involved. The Visual Paired Comparison Task (VPCT) assesses novelty preference, the tendency to fixate on novel images rather than previously viewed items, requiring recognition memory for the “old” images. As novelty preference is a sensitive measure of hippocampal-dependent memory function, we predicted impaired VPCT performance in epilepsy patients compared to healthy controls.MethodsWe assessed 26 healthy adult controls and 31 epilepsy patients (16 focal-onset, 13 generalized-onset, 2 unknown-onset) with the VPCT using delays of 2 or 30 s between encoding and recognition. Fifteen healthy controls and 17 epilepsy patients (10 focal-onset, 5 generalized-onset, 2 unknown-onset) completed the task at 2-, 5-, and 30-minute …

Interictal epileptiform discharges (IEDs) are ubiquitously expressed in epileptic networks and disrupt cognitive functions. It is unclear whether addressing IED-induced dysfunction could improve epilepsy outcomes as most therapeutics target seizures. We show in a model of progressive hippocampal epilepsy that IEDs produce pathological oscillatory coupling which is associated with prolonged, hypersynchronous neural spiking in synaptically connected cortex and expands the brain territory capable of generating IEDs. A similar relationship between IED-mediated oscillatory coupling and temporal organization of IEDs across brain regions was identified in human subjects with refractory focal epilepsy. Spatiotemporally targeted closed-loop electrical stimulation triggered on hippocampal IED occurrence eliminated the abnormal cortical activity patterns, preventing spread of the epileptic network and ameliorating long-term spatial memory deficits in rodents. These findings suggest that stimulation-based network interventions that normalize interictal dynamics may be an effective treatment of epilepsy and its comorbidities, with a low barrier to clinical translation.

Objective In the placebo‐controlled, double‐blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin‐dependent kinase‐like 5 deficiency disorder (CDD). We report 2‐year safety and clinical outcomes data from the open‐label extension (OLE) phase of Marigold. Methods Patients with CDD who completed the double‐blind phase were eligible to continue in the OLE. Efficacy assessments included MMSF reduction from prerandomization baseline, responder rates, and Clinical Global Impression–Improvement scores, including assessment of seizure intensity and duration (CGI‐CSID). Safety assessments included treatment‐emergent adverse events (TEAEs) and TEAEs leading to discontinuation. Results Of 101 patients who enrolled in Marigold, 88 (87.1%) entered the OLE (median age = 5 years, 79.5% female …

Contextual embeddings, derived from deep language models (DLMs), provide a continuous vectorial representation of language. This embedding space differs fundamentally from the symbolic representations posited by traditional psycholinguistics. We hypothesize that language areas in the human brain, similar to DLMs, rely on a continuous embedding space to represent language. To test this hypothesis, we densely record the neural activity patterns in the inferior frontal gyrus (IFG) of three participants using dense intracranial arrays while they listened to a 30-minute podcast. From these fine-grained spatiotemporal neural recordings, we derive a continuous vectorial representation for each word (i.e., a brain embedding) in each patient. Using stringent zero-shot mapping we demonstrate that brain embeddings in the IFG and the DLM contextual embedding space have common geometric patterns. The common …

Objective This study investigates speech decoding from neural signals captured by intracranial electrodes. Most prior works can only work with electrodes on a 2D grid (i.e., Electrocorticographic or ECoG array) and data from a single patient. We aim to design a deep-learning model architecture that can accommodate both surface (ECoG) and depth (stereotactic EEG or sEEG) electrodes. The architecture should allow training on data from multiple participants with large variability in electrode placements and the trained model should perform well on participants unseen during training. Approach We propose a novel transformer-based model architecture named SwinTW that can work with arbitrarily positioned electrodes, by leveraging their 3D locations on the cortex rather than their positions on a 2D grid. We train both subject-specific models using data from a single participant as well as multi-patient models exploiting data from multiple participants. Main Results The subject-specific models using only low-density 8x8 ECoG data achieved high decoding Pearson Correlation Coefficient with ground truth spectrogram (PCC=0.817), over N=43 participants, outperforming our prior convolutional ResNet model and the 3D Swin transformer model. Incorporating additional strip, depth, and grid electrodes available in each participant (N=39) led to further improvement (PCC=0.838). For participants with only sEEG electrodes (N=9), subject-specific models still enjoy comparable performance with an average PCC=0.798. The multi- subject models achieved high performance on unseen participants, with an average PCC=0.765 in leave-one-out cross …

Many developmental and epileptic encephalopathies (DEEs) result from variants in cation channel genes. Using mRNA transfection, we generated and characterised an induced pluripotent stem cell (iPSC) line from the fibroblasts of a male late-onset DEE patient carrying a heterozygous missense variant (E1211K) in Nav1.2(SCN2A) protein. The iPSC line displays features characteristic of the human iPSCs, colony morphology and expression of pluripotency-associated marker genes, ability to produce derivatives of all three embryonic germ layers, and normal karyotype without SNP array-detectable abnormalities. We anticipate that this iPSC line will aid in the modelling and development of precision therapies for this debilitating condition.

The prevalence of epilepsy is increased among Alzheimer’s Disease (AD) patients and cognitive impairment is common among people with epilepsy. Epilepsy and AD are linked but the shared pathophysiological changes remain poorly defined. We aim to identify protein differences associated with epilepsy and AD using published proteomics datasets. We observed a highly significant overlap in protein differences in epilepsy and AD: 89%(689/777) of proteins altered in the hippocampus of epilepsy patients were significantly altered in advanced AD. Of the proteins altered in both epilepsy and AD, 340 were altered in the same direction, while 216 proteins were altered in the opposite direction. Synapse and mitochondrial proteins were markedly decreased in epilepsy and AD, suggesting common disease mechanisms. In contrast, ribosome proteins were increased in epilepsy but decreased in AD. Notably, many of …

Cortical regions supporting speech production are commonly established using neuroimaging techniques in both research and clinical settings. However, for neurosurgical purposes, structural function is routinely mapped peri-operatively using direct electrocortical stimulation. While this method is the gold standard for identification of eloquent cortical regions to preserve in neurosurgical patients, there is lack of specificity of the actual underlying cognitive processes being interrupted. To address this, we propose mapping the temporal dynamics of speech arrest across peri-sylvian cortices by quantifying the latency between stimulation and speech deficits. In doing so, we are able to substantiate hypotheses about distinct region-specific functional roles (e.g. planning versus motor execution). In this retrospective observational study, we analysed 20 patients (12 female; age range 14–43) with refractory epilepsy …

Objective New‐onset refractory status epilepticus (NORSE) is a rare but severe clinical syndrome. Despite rigorous evaluation, the underlying cause is unknown in 30%–50% of patients and treatment strategies are largely empirical. The aim of this study was to describe clinical outcomes in a cohort of well‐phenotyped, thoroughly investigated patients who survived the initial phase of cryptogenic NORSE managed in specialist centers. Methods Well‐characterized cases of cryptogenic NORSE were identified through the EPIGEN and Critical Care EEG Monitoring Research Consortia (CCEMRC) during the period 2005–2019. Treating epileptologists reported on post‐NORSE survival rates and sequelae in patients after discharge from hospital. Among survivors >6 months post‐discharge, we report the rates and severity of active epilepsy, global disability, vocational, and global cognitive and mental health …

Objectives Temporal lobe epilepsy (TLE) is commonly associated with mesiotemporal pathology and widespread alterations of grey and white matter structures. Evidence supports a progressive condition although the temporal evolution of TLE is poorly defined. This ENIGMA-Epilepsy study utilized multimodal magnetic resonance imaging (MRI) data to investigate structural alterations in TLE patients across the adult lifespan. We charted both grey and white matter changes and explored the covariance of age-related alterations in both compartments. Methods We studied 769 TLE patients and 885 healthy controls across an age range of 17-73 years, from multiple international sites. To assess potentially non-linear lifespan changes in TLE, we harmonized data and combined median split assessments with cross-sectional sliding window analyses of grey and white matter age-related changes. Covariance analyses examined the coupling of grey and white matter lifespan curves. Results In TLE, age was associated with a robust grey matter thickness/volume decline across a broad cortico-subcortical territory, extending beyond the mesiotemporal disease epicentre. White matter changes were also widespread across multiple tracts with peak effects in temporo-limbic fibers. While changes spanned the adult time window, changes accelerated in cortical thickness, subcortical volume, and fractional anisotropy (all decreased), and mean diffusivity (increased) after age 55 years. Covariance analyses revealed strong limbic associations between white matter tracts and subcortical structures with cortical regions. Conclusions This study highlights the …

Wearable Digital Health Technologies for Epilepsy One third of people with epilepsy have seizures despite medical treatment. The authors examine wearable digital health devices that can detect seizures and how these devices can affect epilepsy care.

The present disclosure relates to the use of cannabidiol (CBD) for the reduction of total convulsive seizure frequency in the treatment of “treatment-resistant epilepsy”(TRE). In particular, the disclosure relates to the use of CBD of treating TRE when the TRE is Dravet syndrome; myoclonic absence seizures or febrile infection related epilepsy syndrome (FIRES). The disclosure further relates to the use of CBD in combination with one or more anti-epileptic drugs (AEDs).

Objective Approximately 50 million people worldwide have epilepsy and 8-17% of the deaths in patients with epilepsy are attributed to sudden unexpected death in epilepsy (SUDEP). The goal of the present work was to establish a biomarker for SUDEP so that preventive treatment can be instituted. Approach Seizure activity in patients with SUDEP and non-SUDEP was analyzed, specifically, the scalp EEG extracted muscle activity (SMA) and the average wavelet phase coherence (WPC) during seizures was computed for two frequency ranges (1-12 Hz, 13-30 Hz) to identify differences between the two groups. Main results Ictal SMA in SUDEP patients showed a statistically higher average WPC value when compared to non-SUDEP patients for both frequency ranges. Area under curve for a cross-validated logistic classifier was 81%. Significance Average WPC of ictal SMA is a candidate biomarker for early detection of SUDEP.

Describing intracortical laminar organization of interictal epileptiform discharges (IED) and high frequency oscillations (HFOs), also known as ripples. Defining the frequency limits of slow and fast ripples. We recorded potential gradients with laminar multielectrode arrays (LME) for current source density (CSD) and multi-unit activity (MUA) analysis of interictal epileptiform discharges IEDs and HFOs in the neocortex and mesial temporal lobe of focal epilepsy patients. IEDs were observed in 20/29, while ripples only in 9/29 patients. Ripples were all detected within the seizure onset zone (SOZ). Compared to hippocampal HFOs, neocortical ripples proved to be longer, lower in frequency and amplitude, and presented non-uniform cycles. A subset of ripples (≈ 50%) co-occurred with IEDs, while IEDs were shown to contain variable high-frequency activity, even below HFO detection threshold. The limit between slow and …

Introduction: Level of activity has a reported association with sudden death, but cardiac causes are presumed by convention. We investigated association between activity level and causes of presumed SCD (pSCD) in the San Francisco POstmortem Systematic InvesTigation of Sudden Cardiac Death (POST SCD) Study. Methods: POST SCD is a prospective cohort study using autopsy, clinical records, and toxicology to adjudicate arrhythmic (potentially rescuable with implantable defibrillator) or non-arrhythmic (e.g., tamponade, overdose) causes among pSCDs (WHO defined) 18-90 years in San Francisco. We included all incident cases from 2/1/11-3/1/14 (n=525) and incident cases approximately every 3rd day from 3/1/14-12/31/21 (n=358). Activity level at time of pSCD was determined by forensic investigator reports. For unwitnessed deaths, activity level was inferred based on time of arrest and location found …

" It's slow across generations. My grandparents may have consumed 20% of the sugar I consumed. If you go back for generations, it was probably because sugar became very cheap around the mid 1800s. Before that, people just didn't use it. It was a luxury." In the literature, its shown that glucose metabolism can be impaired in epilepsy and contribute to altered neuronal membrane potentials that foster a feed-forward cycle in seizure generation. For patients with treatment-resistant epilepsy, there is evidence that modifying brain metabolism with high fat and low carbohydrate diets may result in reduced seizure frequency. Published in Neurology, a recent study assessed molecular mechanisms in brain tissue and plasma from adults with epilepsy after an average of 10 days of modified Atkins diet (MAD) prior to brain surgical resection relative to those on a non-modified, higher carbohydrate diet. Led by Orrin …

Febrile seizures affect 2%–5% of U.S. children and are considered benign although associated with an increased risk of epilepsy and, rarely, with sudden unexplained death. We compared rates of mortality, neurodevelopmental disorders, and neuropathology in young children with simple and complex febrile seizures to healthy controls. We systematically reviewed studies of 3‐ to 72‐month‐old children with simple or complex febrile seizures ≤30 min. We searched studies with outcome measures on mortality, neurodevelopment, or neuropathology through July 18, 2022. Bias risk was assessed per study design. Each outcome measure was stratified by study design. PROSPERO registration is CRD42022361645. Twenty‐six studies met criteria reporting mortality (11), neurodevelopment (11), and neuropathology (13), including 2665 children with febrile seizures and 1206 seizure‐free controls. Study designs …

CRISPR/Cas9-mediated genome editing in mammalian cells can generate undesired chromosomal alterations, including deleterious on-target large deletions and chromosomal translocations. Currently few approaches effectively prevent these on-target DNA damage. Here we show that the association of engineered phage DNA polymerases with Cas9 protein substantially inhibits the production of undesired on-target chromosomal alterations. Our “CasPlus” editing platform significantly increases the proportion of precise 1- to 3-base-pair insertions at target sites. CasPlus efficiently corrected common mutations in the DMD (del exon 52) and CFTR (F508del) genes by generating precise insertions without an exogenous template with fewer deleterious edits than Cas9 alone. CasPlus offers safer and more efficient targeting strategies optimized for human applications.One-Sentence Summary Engineered phage …

Idiopathic and acquired pedophilia are two different disorders with two different etiologies. However, the differential diagnosis is still very difficult, as the behavioral indicators used to discriminate the two forms of pedophilia are underexplored, and clinicians are still devoid of clear guidelines describing the clinical and neuroscientific investigations suggested to help them with this difficult task. Furthermore, the consequences of misdiagnosis are not known, and a consensus regarding the legal consequences for the two kinds of offenders is still lacking. The present study used the Delphi method to reach a global consensus on the following six topics: behavioral indicators/red flags helpful for differential diagnosis; neurological conditions potentially leading to acquired pedophilia; neuroscientific investigations important for a correct understanding of the case; consequences of misdiagnosis; legal consequences; and …

Klement’s letter makes 3 problematic comments to dispute the evidence Lieberman et al.[1] present that the trademarked Paleo Diet® underestimates the range of foods hence macronutrient proportions pre-industrial humans used to eat. First, Klement argues incorrectly that the Paleo Diet® does not prescribe macronutrient ranges but only mimics Paleolithic diets by excluding foods unavailable to pre-industrial humans including processed foods, grains, legumes, and dairy. We acknowledge that not all paleo dieters adhere to the trademarked Paleo Diet® first published in the 2002 book, The Paleo Diet: Lose

Across the animal kingdom, neural responses in the auditory cortex are suppressed during vocalization, and humans are no exception. A common hypothesis is that suppression increases sensitivity to auditory feedback, enabling the detection of vocalization errors. This hypothesis has been previously confirmed in non-human primates, however a direct link between auditory suppression and sensitivity in human speech monitoring remains elusive. To address this issue, we obtained intracranial electroencephalography (iEEG) recordings from 35 neurosurgical participants during speech production. We first characterized the detailed topography of auditory suppression, which varied across superior temporal gyrus (STG). Next, we performed a delayed auditory feedback (DAF) task to determine whether the suppressed sites were also sensitive to auditory feedback alterations. Indeed, overlapping sites showed enhanced responses to feedback, indicating sensitivity. Importantly, there was a strong correlation between the degree of auditory suppression and feedback sensitivity, suggesting suppression might be a key mechanism that underlies speech monitoring. Further, we found that when participants produced speech with simultaneous auditory feedback, posterior STG was selectively activated if participants were engaged in a DAF paradigm, suggesting that increased attentional load can modulate auditory feedback sensitivity.

Correction Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein — Maastricht University Skip to main navigation Skip to search Skip to main content Maastricht University Home Maastricht University Logo Support & FAQ Home Researchers Publications Activities Press/Media Prizes Organisations Datasets Projects Search by expertise, name or affiliation Correction Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein Elke de Boer, Charlotte W Ockeloen * , Rosalie A Kampen, Juliet E Hampstead, Alexander JM Dingemans, Dmitrijs Rots, Lukas Lütje, Tazeen Ashraf, Rachel Baker, Mouna Barat-Houari, Brad Angle, Nicolas Chatron, Anne-Sophie Denommé-Pichon, Orrin Devinsky, Christèle Dubourg, Frances Elmslie, Houda Zghal Elloumi, Laurence Faivre, Sarah …

Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsies, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking the pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G-protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3-CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAARγ2 and gephyrin puncta. LPI effects at excitatory and inhibitory synapses were eliminated by CBD pre-treatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures …

Objective: We aim to describe the effectiveness of fenfluramine (FFA) on generalized tonic-clonic seizures (GTCS) in patients with rare epilepsy syndromes. Background: Seizure refractoriness and frequent GTCS are hallmarks of developmental and epileptic encephalopathies (DEEs) and are 2 major risk factors for sudden unexpected death in epilepsy (SUDEP). Patients with 1–3 GTCS/year have up to a 16-fold greater risk of SUDEP. An analysis of SUDEP rates in patients with Dravet syndrome (DS) found a 5-fold lower SUDEP mortality rate in FFA-treated patients compared to historical controls. FFA has demonstrated reduced seizure burden in other rare epilepsies. Design/Methods: Studies where FFA was used to manage convulsive seizures associated with rare epilepsy syndromes were included. Initial FFA doses, duration of treatment (exposure) and reduction in GTCS or tonic-clonic seizures (TCS) are reported. Descriptive statistics were used. Results: We included data from 13 studies: 4 …

Deep Language Models (DLMs) provide a novel computational paradigm for understanding the mechanisms of natural language processing in the human brain. Unlike traditional psycholinguistic models, DLMs use layered sequences of continuous numerical vectors to represent words and context, allowing a plethora of emerging applications such as human-like text generation. In this paper we show evidence that the layered hierarchy of DLMs may be used to model the temporal dynamics of language comprehension in the brain by demonstrating a strong correlation between DLM layer depth and the time at which layers are most predictive of the human brain. Our ability to temporally resolve individual layers benefits from our use of electrocorticography (ECoG) data, which has a much higher temporal resolution than noninvasive methods like fMRI. Using ECoG, we record neural activity from participants listening to a 30-minute narrative while also feeding the same narrative to a high-performing DLM (GPT2-XL). We then extract contextual embeddings from the different layers of the DLM and use linear encoding models to predict neural activity. We first focus on the Inferior Frontal Gyrus (IFG, or Broca's area) and then extend our model to track the increasing temporal receptive window along the linguistic processing hierarchy from auditory to syntactic and semantic areas. Our results reveal a connection between human language processing and DLMs, with the DLM's layer-by-layer accumulation of contextual information mirroring the timing of neural activity in high-order language areas.

Effective communication hinges on a mutual understanding of word meaning in different contexts. The embedding space learned by large language models can serve as an explicit model of the shared, context-rich meaning space humans use to communicate their thoughts. We recorded brain activity using electrocorticography during spontaneous, face-to-face conversations in five pairs of epilepsy patients. We demonstrate that the linguistic embedding space can capture the linguistic content of word-by-word neural alignment between speaker and listener. Linguistic content emerged in the speaker’s brain before word articulation, and the same linguistic content rapidly reemerged in the listener’s brain after word articulation. These findings establish a computational framework to study how human brains transmit their thoughts to one another in real-world contexts.

Objective Visual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1. Methods Enrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12–60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient <70, and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1‐weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and …

We thank Dr. Bleasel for his interest in our study. 1 We, too, were encouraged to find that the incidence of SUDEP may be declining even in the absence of specific interventions. This confirms what many people caring for people with epilepsy suspected—we have many of the tools to reduce epilepsy mortality already at hand. The next steps are to understand the contribution of each of measures that Dr. Bleasel highlights—awareness, clinician and patient behavior change, and access to treatment—to the reduction in SUDEP rates to maximize their impact. We also agree—as do people living with epilepsy and their caregivers, 2, 3 those bereaved by SUDEP, 3 and professional societies 4—that counseling about SUDEP should be part of general epilepsy education regardless of individual risk to help our patients make fully informed decisions.

Objective In vitro data prompted U.S Food and Drug Administration warnings that lamotrigine, a common sodium channel modulating anti‐seizure medication (NaM‐ASM), could increase the risk of sudden death in patients with structural or ischaemic cardiac disease, however, its implications for Sudden Unexpected Death in Epilepsy (SUDEP) are unclear. Methods This retrospective, nested case–control study identified 101 sudden unexpected death in epilepsy (SUDEP) cases and 199 living epilepsy controls from Epilepsy Monitoring Units (EMUs) in Australia and the USA. Differences in proportions of lamotrigine and NaM‐ASM use were compared between cases and controls at the time of admission, and survival analyses from the time of admission up to 16 years were conducted. Multivariable logistic regression and survival analyses compared each ASM subgroup adjusting for SUDEP risk factors. Results …

Neural responses in visual cortex adapt to prolonged and repeated stimuli. While adaptation occurs across the visual cortex, it is unclear how adaptation patterns and computational mechanisms differ across the visual hierarchy. Here we characterize two signatures of neural adaptation in time-varying intracranial electroencephalography (iEEG) data collected while participants viewed naturalistic image categories varying in duration and repetition interval. Ventral- and lateral-occipitotemporal cortex exhibit slower and prolonged adaptation to single stimuli and slower recovery from adaptation to repeated stimuli compared to V1-V3. For category-selective electrodes, recovery from adaptation is slower for preferred than non-preferred stimuli. To model neural adaptation we augment our delayed divisive normalization (DN) model by scaling the input strength as a function of stimulus category, enabling the model to accurately predict neural responses across multiple image categories. The model fits suggest that differences in adaptation patterns arise from slower normalization dynamics in higher visual areas interacting with differences in input strength resulting from category selectivity. Our results reveal systematic differences in temporal adaptation of neural population responses across the human visual hierarchy and show that a single computational model of history-dependent normalization dynamics, fit with area-specific parameters, accounts for these differences.Author summaryNeural responses in visual cortex adapt over time, with reduced responses to prolonged and repeated stimuli. Here, we examine how adaptation patterns differ across …

The present disclosure relates to the use of cannabidiol (CBD) for the treatment of of nocturnal snoring. In particular the CBD appears particularly effective in treating nocturnal snoring in children and young adults with epilepsy The disclosure further relates to the use of CBD in 5 combination with one or more anti-epileptic drugs (AEDs).

The radiation-attenuated Plasmodium falciparum sporozoites (PfSPZ) Vaccine has demonstrated safety and immunogenicity in 5-month-old to 50-year-old Africans in multiple trials. Except for one, each trial has restricted enrollment to either infants and children or adults< 50 years old. This trial was conducted in Equatorial Guinea and assessed the safety, tolerability, and immunogenicity of three direct venous inoculations of 1.8× 10 6 or 2.7× 10 6 PfSPZ, of PfSPZ Vaccine, or normal saline administered at 8-week intervals in a randomized, double-blind, placebo-controlled trial stratified by age (6–11 months and 1–5, 6–10, 11–17, 18–35, and 36–61 years). All doses were successfully administered. In all, 192/207 injections (93%) in those aged 6–61 years were rated as causing no or mild pain. There were no significant differences in solicited adverse events (AEs) between vaccinees and controls in any age group (P …

Objective High‐fat and low‐carbohydrate diets can reduce seizure frequency in some treatment‐resistant epilepsy patients, including the more flexible modified Atkins diet (MAD), which is more palatable, mimicking fasting and inducing high ketone body levels. Low‐carbohydrate diets may shift brain energy production, particularly impacting neuron‐ and astrocyte‐linked metabolism. Methods We evaluated the effect of short‐term MAD on molecular mechanisms in adult epilepsy patients from surgical brain tissue and plasma compared to control participants consuming a nonmodified higher carbohydrate diet (n = 6 MAD, mean age = 43.7 years, range = 21–53, diet for average 10 days; n = 10 control, mean age = 41.9 years, range = 28–64). Results By metabolomics, there were 13 increased metabolites in plasma (n = 15 participants with available specimens), which included 4.10‐fold increased ketone …

Globally, we are witnessing the rise of complex, non-communicable diseases (NCDs) related to changes in our daily environments. Obesity, asthma, cardiovascular disease, and type 2 diabetes are part of a long list of “lifestyle” diseases that were rare throughout human history but are now common. A key idea from anthropology and evolutionary biology—the evolutionary mismatch hypothesis—seeks to explain this phenomenon. It posits that humans evolved in environments that radically differ from the ones experienced by most people today, and thus traits that were advantageous in past environments may now be “mismatched” and disease-causing. This hypothesis is, at its core, a genetic one: it predicts that loci with a history of selection will exhibit “genotype by environment”(GxE) interactions and have differential health effects in ancestral versus modern environments. Here, we discuss how this concept could …

Introduction Previous case-control studies of sudden unexpected death in epilepsy (SUDEP) patients failed to identify ECG features (peri-ictal heart rate, heart rate variability, corrected QT interval, postictal heart rate recovery, and cardiac rhythm) predictive of SUDEP risk. This implied a need to derive novel metrics to assess SUDEP risk from ECG. Methods We applied Single Spectrum Analysis and Independent Component Analysis (SSA-ICA) to remove artifact from ECG recordings. Then cross-frequency phase-phase coupling (PPC) was applied to a 20-s mid-seizure window and a contour of −3 dB coupling strength was determined. The contour centroid polar coordinates, amplitude (alpha) and angle (theta), were calculated. Association of alpha and theta with SUDEP was assessed and a logistic classifier for alpha was constructed. Results Alpha was higher in SUDEP patients, compared to non-SUDEP patients (p < 0.001). Theta showed no significant difference between patient populations. The receiver operating characteristic (ROC) of a logistic classifier for alpha resulted in an area under the ROC curve (AUC) of 94% and correctly classified two test SUDEP patients. Discussion This study develops a novel metric alpha, which highlights non-linear interactions between two rhythms in the ECG, and is predictive of SUDEP risk.

Provided are compositions and methods used for precise template-free correction of BRCA1 mutation in human cells via genome editing. The method involves modifying DNA that includes a BRCA1-5382-InsC mutation by introducing into cells comprising the BRCA1-5382-InsC a Cas enzyme and a guide RNA. A guide RNA that produces improved results relative to other guide RNAs is provided. Also provided are modified stem cells that contain an introduced BRCA1-5382-InsC mutation.

BackgroundWe refine the clinical spectrum of FOXG1 syndrome and expand genotype–phenotype correlations through evaluation of 122 individuals enrolled in an international patient registry. MethodsThe FOXG1 syndrome online patient registry allows for remote collection of caregiver-reported outcomes. Inclusion required documentation of a (likely) pathogenic variant in FOXG1. Caregivers were administered a questionnaire to evaluate clinical severity of core features of FOXG1 syndrome. Genotype–phenotype correlations were determined using nonparametric analyses. ResultsWe studied 122 registry participants with FOXG1 syndrome, aged < 12 months to 24 years. Caregivers described delayed or absent developmental milestone attainment, seizures (61%), and movement disorders (58%). Participants harbouring a missense variant had a milder phenotype. Compared to individuals with gene deletions …

Introduction Alzheimer's disease (AD) and epilepsy are reciprocally related. Among sporadic AD patients, clinical seizures occur in 10–22% and subclinical epileptiform abnormalities occur in 22–54%. Cognitive deficits, especially short-term memory impairments, occur in most epilepsy patients. Common neurophysiological and molecular mechanisms occur in AD and epilepsy. The choroid plexus undergoes pathological changes in aging, AD, and epilepsy, including decreased CSF turnover, amyloid beta (Aβ), and tau accumulation due to impaired clearance and disrupted CSF amino acid homeostasis. This pathology may contribute to synaptic dysfunction in AD and epilepsy. Methods We evaluated control (n = 8), severe AD (n = 8; A3, B3, C3 neuropathology), and epilepsy autopsy cases (n = 12) using laser capture microdissection (LCM) followed by label-free quantitative mass spectrometry on the choroid plexus adjacent to the hippocampus at the lateral geniculate nucleus level. Results Proteomics identified 2,459 proteins in the choroid plexus. At a 5% false discovery rate (FDR), 616 proteins were differentially expressed in AD vs. control, 1 protein in epilepsy vs. control, and 438 proteins in AD vs. epilepsy. There was more variability in the epilepsy group across syndromes. The top 20 signaling pathways associated with differentially expressed proteins in AD vs. control included cell metabolism pathways; activated fatty acid beta-oxidation (p = 2.00 x 10−7, z = 3.00), and inhibited glycolysis (p = 1.00 x 10−12, z = −3.46). For AD vs. epilepsy, the altered pathways included cell metabolism pathways, activated complement system (p = 5.62 x …

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the …

Objective To comprehensively examine the associations between changes in carbohydrate intake and weight change at four year intervals.Design Prospective cohort study.Setting Nurses’ Health Study (1986-2010), Nurses’ Health Study II (1991-2015), and Health Professionals Follow-Up Study (1986-2014).Participants 136 432 men and women aged 65 years or younger and free of diabetes, cancer, cardiovascular disease, respiratory disease, neurodegenerative disorders, gastric conditions, chronic kidney disease, and systemic lupus erythematosus before baseline.Main outcome measure Weight change within a four year period.Results The final analyses included 46 722 women in the Nurses’ Health Study, 67 186 women in the Nurses’ Health Study II, and 22 524 men in the Health Professionals Follow-up Study. On average, participants gained 1.5 kg (5th to 95th centile −6.8 to 10.0) every four years …

CRISPR/Cas9-mediated genome editing in mammalian cells can generate undesired chromosomal alterations, including deleterious on-target large deletions and chromosomal translocations. Currently few approaches effectively prevent these on-target DNA damage. Here we show that the association of engineered phage DNA polymerases with Cas9 protein substantially inhibits the production of undesired on-target chromosomal alterations. Our “CasPlus” editing platform significantly increases the proportion of precise 1- to 3-base-pair insertions at target sites. CasPlus efficiently corrected common mutations in the DMD (del exon 52) and CFTR (F508del) genes by generating precise insertions without an exogenous template with fewer deleterious edits than Cas9 alone. CasPlus offers safer and more efficient targeting strategies optimized for human applications.One-Sentence Summary Engineered phage …

Background and ObjectivesSYNGAP1 variants are associated with rare developmental and epileptic encephalopathies (DEEs). Although SYNGAP1-related childhood phenotypes are well characterized, the adult phenotype remains ill-defined. We sought to investigate phenotypes and outcomes in adults with SYNGAP1 variants and epilepsy.MethodsPatients 18 years or older with DEE carrying likely pathogenic and pathogenic (LP/P) SYNGAP1 variants were recruited through physicians' practices and patient organization groups. We used standardized questionnaires to evaluate current seizures, medication use, sleep, gastrointestinal symptoms, pain response, gait, social communication disorder and adaptive skills of patients. We also assessed caregiver burden.ResultsFourteen unrelated adult patients (median: 21 years, range: 18–65 years) with SYNGAP1-DEE were identified, 11 with novel and 3 with known …

Objective Cannabidiol (CBD) expanded access program, initiated in 2014, provided add‐on CBD to patients with treatment‐resistant epilepsies (TREs) at 35 US epilepsy centers. Prior publications reported results through December 2016; herein, we present efficacy and safety results through January 2019. Methods Patients received plant‐derived highly purified CBD (Epidiolex®; 100 mg/ml oral solution), increasing from 2 to 10 mg/kg/day to tolerance or maximum 25–50 mg/kg/day dose, depending on the study site. Efficacy endpoints included percentage change from baseline in median monthly convulsive and total seizure frequency and ≥50%, ≥75%, and 100% responder rates across 12‐week visit windows for up to 192 weeks. Adverse events (AEs) were documented at each visit. Results Of 892 patients in the safety analysis set, 322 (36%) withdrew; lack of efficacy (19%) and AEs (7%) were the …

Speech production is a complex human function requiring continuous feedforward commands together with reafferent feedback processing. These processes are carried out by distinct frontal and temporal cortical networks, but the degree and timing of their recruitment and dynamics remain poorly understood. We present a deep learning architecture that translates neural signals recorded directly from the cortex to an interpretable representational space that can reconstruct speech. We leverage learned decoding networks to disentangle feedforward vs. feedback processing. Unlike prevailing models, we find a mixed cortical architecture in which frontal and temporal networks each process both feedforward and feedback information in tandem. We elucidate the timing of feedforward and feedback–related processing by quantifying the derived receptive fields. Our approach provides evidence for a surprisingly mixed …

Objective: To relate imaging and cognitive correlates of subclinical brain injury to incident epilepsy in the Framingham Heart Study (FHS), a community-based cohort. Background: Late life epilepsy is often due to acquired insults such as strokes and clinical dementia, but its cause remains unknown in up to 30% of cases. There is growing evidence that occult cerebrovascular disease contributes to higher incidence of epilepsy with increasing age. Design/Methods: Participants of the Offspring Cohort who attended FHS exam 7 (1998–2001), were at least 45 years old at that time, had neuropsychological evaluation (NP), brain MRI, and no prior history of stroke, dementia or epilepsy were included in the study. Cognitive measures included Visual Reproductions Delayed Recall, Logical Memory Delayed Recall, Similarities, Trail Making BA (TrB-TrA) and the Hooper Visual Organization Test. MRI measures included total cerebral brain volume, cortical grey matter volume (CGMV), white matter …

We thank Tebartz van Elst et al for their comments. They point out that neurologists frequently disregard recommendations for depression treatment made by consulting psychiatrists. They go on to suggest that the reluctance to treat may result from neurologists’ failure to recognize atypical psychiatric syndromes or a tendency to think their patients’ reactions are ‘normal’or expected. We agree that these are important issues. Further, we note that neurologists are sometimes uncomfortable taking on the management of depression. At the same time, some patients are averse to seeing a psychiatrist. Neurologists should be willing to initiate treatment with antidepressants. Educational efforts starting at least as early as residency could be helpful.There are more barriers to the treatment of depression in epilepsy. The time available for neurology encounters is limited. Perhaps use of screening tools to be filled in by patients …

Objective: The present systematic review aimed to provide an overview of training load (TL), along with their responses, monitoring during training sessions in highly trained and elite adult women soccer players.Data source: Electronic databases searches (PubMed, Scopus, Web of Science and Ebsco) for relevant studies published in peer-reviewed journals were conducted, and eligibility criteria were based on the PICOS model in accordance with PRISMA guidelines.Study selection: Studies were considered as follows:(a) highly trained and elite adult (> 18 years) women's soccer players;(b) continuous (minimum1-week duration) TL monitoring in the context of the team routine;(c) TL collected from entire training session. Methodological qualitative assessments and risk of bias criteria were used for judging the studies.Data extraction: A total of 1,163 studies were identified, and 16 were included. The selected studies were fully screened to extract the population characteristics; the number of players; a type of study design; region where the study was performed; the main findings.Data synthesis: Accumulated external TL (ETL) during the pre-season was positively correlated to enhanced adaptations in intermittent exercise capacity. Daily ETL was negatively correlated to next-day self-reported fatigue and muscle soreness. Daily internal TL (ITL) was negatively correlated to postsession sleep duration and sleep efficiency. One study showed that higher accumulated player load and total distance were associated with injury.

Impairment in social functioning is one of the core features of Autism Spectrum Disorder (ASD). However, the basic neural circuits underlying social behavior and cognition and how they are affected in ASD is still being understood. One of the main circuits that modulates social behavior is the mesolimbic circuit. Specifically, previous studies have shown that activating dopaminergic projections from the Ventral Tegmental Area (VTA) to the Nucleus Accumbens (NAc) of the ventral striatum is enough to increase social behavior in mice. In this work, we use a mouse model of autism, knockout for the Cntnap2 gene, which presents the core ASD symptoms, including social behavior alterations. Previous studies in our laboratory have shown an impaired dopamine release in NAc during social behavior in this model, which is likely due to alterations in the VTA-NAc circuit. Therefore, we characterized this circuit to test its role …

Objective This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome. Methods This multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2–18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6‐week baseline period were randomized to placebo, fenfluramine .2 mg/kg/day, or fenfluramine .7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration–maintenance period in patients …

Background and ObjectivesMood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts.MethodsThe data were derived from the Human Epilepsy Project study. A total of 347 consecutive adults aged 18–60 years with newly diagnosed focal epilepsy were enrolled within 4 months of starting treatment. The types of mood and anxiety disorders were identified with the Mini International Neuropsychiatric Interview, whereas suicidal ideation (lifetime, current, active, and passive) and suicidal attempts (lifetime and current) were established with the Columbia Suicidality …

Noncommunicable diseases (NCDs) are on the rise worldwide. Obesity, cardiovascular disease, and type 2 diabetes are among a long list of “lifestyle” diseases that were rare throughout human history but are now common. The evolutionary mismatch hypothesis posits that humans evolved in environments that radically differ from those we currently experience; consequently, traits that were once advantageous may now be “mismatched” and disease causing. At the genetic level, this hypothesis predicts that loci with a history of selection will exhibit “genotype by environment” (GxE) interactions, with different health effects in “ancestral” versus “modern” environments. To identify such loci, we advocate for combining genomic tools in partnership with subsistence-level groups experiencing rapid lifestyle change. In these populations, comparisons of individuals falling on opposite extremes of the “matched” to “mismatched” spectrum are uniquely possible. More broadly, the work we propose will inform our understanding of environmental and genetic risk factors for NCDs across diverse ancestries and cultures.

Objective Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. Methods We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug‐resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis and ≥2‐year postsurgical follow‐up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. Results Nine centers from 3 continents contributed 206 …

Epilepsy has a high prevalence and can severely impair quality of life and increase the risk of premature death. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in drug-resistant epilepsy and most often results from respiratory and cardiac impairments due to brainstem dysfunction. Epileptic activity can spread widely, influencing neuronal activity in regions outside the epileptic network. The brainstem controls cardiorespiratory activity and arousal and reciprocally connects to cortical, diencephalic, and spinal cord areas. Epileptic activity can propagate trans-synaptically or via spreading depression (SD) to alter brainstem functions and cause cardiorespiratory dysfunction. The mechanisms by which seizures propagate to or otherwise impair brainstem function and trigger the cascading effects that cause SUDEP are poorly understood. We review insights from mouse models combined with new techniques to understand the pathophysiology of epilepsy and SUDEP. These techniques include in vivo, ex vivo, invasive and non-invasive methods in anesthetized and awake mice. Optogenetics combined with electrophysiological and optical manipulation and recording methods offer unique opportunities to study neuronal mechanisms under normal conditions, during and after non-fatal seizures, and in SUDEP. These combined approaches can advance our understanding of brainstem pathophysiology associated with seizures and SUDEP and may suggest strategies to prevent SUDEP.

Background and ObjectivesThe relationship between COVID-19 and epilepsy is uncertain. We studied the potential association between COVID-19 and seizures or epilepsy in the 6 months after infection.MethodsWe applied validated methods to an electronic health records network (TriNetX Analytics) of 81 million people. We closely matched people with COVID-19 infections to those with influenza. In each cohort, we measured the incidence and hazard ratios (HRs) of seizures and epilepsy. We stratified data by age and by whether the person was hospitalized during the acute infection. We then explored time-varying HRs to assess temporal patterns of seizure or epilepsy diagnoses.ResultsWe analyzed 860,934 electronic health records. After matching, this yielded 2 cohorts each of 152,754 patients. COVID-19 was associated with an increased risk of seizures and epilepsy compared with influenza. The incidence …

ObjectiveThe association between postictal electroencephalogram (EEG) suppression (PES), autonomic dysfunction, and Sudden Unexpected Death in Epilepsy (SUDEP) remains poorly understood. We compared PES on simultaneous intracranial and scalp-EEG and evaluated the association of PES with postictal heart rate variability (HRV) and SUDEP outcome.MethodsConvulsive seizures were analyzed in patients with drug-resistant epilepsy at 5 centers. Intracranial PES was quantified using the Hilbert transform. HRV was quantified using root mean square of successive differences of interbeat intervals, low-frequency to high-frequency power ratio, and RR-intervals.ResultsThere were 64 seizures from 63 patients without SUDEP and 11 seizures from 6 SUDEP patients. PES occurred in 99% and 87% of seizures on intracranial-EEG and scalp-EEG, respectively. Mean PES duration in intracranial and scalp …

" One of the opportunities is that we can use that tissue to look at changes in the brain or blood and compare them under a variety of different interventions, from medications that might help reduce seizures to drugs that might affect the mTOR pathway in people with tuberous sclerosis or cortical dysplasia." The modified Atkins diet (MAD), mainly introduced in the early 2000s, is a less restrictive change to the traditional ketogenic diet. Along with the medium chain triglyceride diet, and low glycemic index treatment, it is 1 of 3 alternative diets to treat patients with epilepsy. MAD differs from ketogenic diets in that there is no fluid or calorie restriction or limitation, as well as no restrictions on proteins. Although fats are strongly encouraged, they are not weighted and measured, and most patients will consume plenty of dairy and oils. Previous research has shown that high-fat and low-carbohydrate diets can reduce seizure …

Cross-frequency coupling (CFC) between theta and high-frequency oscillations (HFOs) is predominant during active wakefulness, REM sleep and behavioral and learning tasks in rodent hippocampus. Evidence suggests that these state-dependent CFCs are linked to spatial navigation and memory consolidation processes. CFC studies currently include only the cortical and subcortical structures. To our knowledge, the study of nucleus tractus solitarius (NTS)-cortical structure CFC is still lacking. Here we investigate CFC in simultaneous local field potential recordings from hippocampal CA1 and the NTS during behavioral states in freely moving rats. We found a significant increase in theta (6–8 Hz)-HFO (120–160 Hz) coupling both within the hippocampus and between NTS theta and hippocampal HFOs during REM sleep. Also, the hippocampal HFOs were modulated by different but consistent phases of …

Despite the approval of ~20 additional antiseizure medications (ASMs) since the 1980s, one‐third of epilepsy patients experience seizures despite therapy. Drug‐resistant epilepsy (DRE) is associated with cognitive and psychiatric comorbidities, socioeconomic impairment, injuries, and a 9.3–13.4 times higher mortality rate than in seizure‐free patients. Improved seizure control can reduce morbidity and mortality. Two new ASMs were launched in the United States in 2020: cenobamate for focal epilepsy in adults and fenfluramine for Dravet syndrome (DS). They offer markedly improved efficacy. Cenobamate achieved 21% seizure freedom with the highest dose and decreased tonic–clonic seizures by 93% during maintenance treatment in a randomized clinical trial (RCT). In long‐term, open‐label studies, 10%–36% of patients were seizure‐free for a median duration of ~30–45 months. Fenfluramine treatment in …

We appreciate the constructive comments by Dr. Giannouli in response to our article on the underestimation of sudden unexpected death in epilepsy (SUDEP).[1] We fully agree that patients with epilepsy, parents of children with epilepsy, and caretakers of disabled adults with epilepsy should be educated about the risk factors for SUDEP. We also support the dire need for more systematic surveillance of SUDEP through collaborative efforts of medical examiners, coroners, and neurologists. Unfortunately, the medical examiner systems in the United States, and many other countries, are woefully understaffed to accomplish the systematic review of cases that we were able to accomplish with the support of NIH funding. It is essential that all victims of sudden death be evaluated for a history of seizures by interviewing family members and others, and reviewing medical records. Sadly, many victims of SUDEP come from …

Objective: To determine the utility of using smartphone videos in diagnosing infantile spasms (IS), specifically the impact of brief IS education and clinical history on accuracy of diagnosis and comfort treating without EEG.Background: Infantile spasms (IS) are one of the most concerning seizure types globally. Delayed diagnosis and treatment of IS can significantly impact outcomes. There is an ongoing need to expedite diagnosis, especially in low-resource settings with limited access to electroencephalogram (EEG). The use of smartphone video to aid in diagnosing epileptic seizures has yielded promising results in adult populations but has not been evaluated in IS. If video diagnosis is highly accurate, this could be employed in settings where EEG is not readily available to prompt earlier empiric treatment of IS.Design/Methods: Home videos of episodes concerning for IS were solicited in children 3–24 months in …

High-frequency phase-locked oscillations have been hypothesized to facilitate integration ('binding') of information encoded across widespread cortical areas. Ripples (∼ 100ms long∼ 90Hz oscillations) co-occur broadly in multiple states and locations, but have only been associated with memory replay. We tested whether cortico-cortical co-ripples subserve a general role in binding by recording intracranial EEG during reading. Co-rippling strongly increased to words versus consonant-strings in visual, wordform and semantic areas when letters are binding into words, and words to meaning. Similarly, co-ripples increased prior to correct responses between executive, response, wordform and semantic sites when word meanings are binding to instructions and response. These effects dissociated from non-oscillatory activation and memory reinstatement. Co-ripples were phase-locked at zero-lag, even at long distances, supporting a general role in cognitive binding.

Objective Effective surgical treatment of drug‐resistant epilepsy depends on accurate localization of the epileptogenic zone (EZ). High‐frequency oscillations (HFOs) are potential biomarkers of the EZ. Previous research has shown that HFOs often occur within submillimeter areas of brain tissue and that the coarse spatial sampling of clinical intracranial electrode arrays may limit the accurate capture of HFO activity. In this study, we sought to characterize microscale HFO activity captured on thin, flexible microelectrocorticographic (μECoG) arrays, which provide high spatial resolution over large cortical surface areas. Methods We used novel liquid crystal polymer thin‐film μECoG arrays (.76–1.72‐mm intercontact spacing) to capture HFOs in eight intraoperative recordings from seven patients with epilepsy. We identified ripple (80–250 Hz) and fast ripple (250–600 Hz) HFOs using a common energy thresholding …

The ability of Large Language Models (LLM) to perform remarkably well on various language processing tasks provides a computational modeling framework for studying the neural basis of human language. Recent studies show that the hidden states of the transformer layers of LLM, called contextual embeddings, can predict brain responses through linear encoding models. In this paper, we analyze the neural responses of 8 subjects while they listened to the same 30 minute podcast episode. We use a shared response model to compute the shared information space across subjects and show that LLM-based encoding models achieve significantly better performance in predicting the shared information features than the original brain responses. We also show that we can use this shared space to denoise the individual brain responses by projecting back to the neural space and this process achieves a mean 38% improvement in encoding performance across the subjects. A detailed inspection of this improvement in different brain areas reveals that the improvements are the most prominent in brain areas specialized for language comprehension, specifically in superior temporal gyrus (STG) and inferior frontal gyrus (IFG). Our analysis also shows that the shared space calculated from a group of subjects is generalizable to a new subject. This suggests that the LLM model can be used as a shared linguistic model for how information is shared across brains.

Humans effortlessly use the continuous acoustics of speech to communicate rich linguistic meaning during everyday conversations. In this study, we leverage 100 hours (half a million words) of spontaneous open-ended conversations and concurrent high-quality neural activity recorded using electrocorticography (ECoG) to decipher the neural basis of real-world speech production and comprehension. Employing a deep multimodal speech-to-text model named Whisper, we develop encoding models capable of accurately predicting neural responses to both acoustic and semantic aspects of speech. Our encoding models achieved high accuracy in predicting neural responses in hundreds of thousands of words across many hours of left-out recordings. We uncover a distributed cortical hierarchy for speech and language processing, with sensory and motor regions encoding acoustic features of speech and higher-level language areas encoding syntactic and semantic information. Many electrodes including those in both perceptual and motor areas display mixed selectivity for both speech and linguistic features. Notably, our encoding model reveals a temporal progression from language-to-speech encoding before word onset during speech production and from speech-to-language encoding following word articulation during speech comprehension. This study offers a comprehensive account of the unfolding neural responses during fully natural, unbounded daily conversations. By leveraging a multimodal deep speech recognition model, we highlight the power of deep learning for unraveling the neural mechanisms of language processing in real …

Although the etiology of major depressive disorder remains poorly understood, reduced gamma oscillations is an emerging biomarker. Olfactory bulbectomy, an established model of depression that reduces limbic gamma oscillations, suffers from non-specific effects of structural damage. Here, we show that transient functional suppression of olfactory bulb neurons or their piriform cortex efferents decreased gamma oscillation power in limbic areas and induced depression-like behaviors in rodents. Enhancing transmission of gamma oscillations from olfactory bulb to limbic structures by closed-loop electrical neuromodulation alleviated these behaviors. By contrast, silencing gamma transmission by anti-phase closed-loop stimulation strengthened depression-like behaviors in naive animals. These induced behaviors were neutralized by ketamine treatment that restored limbic gamma power. Taken together, our …

Neuronal oscillations at about 10 Hz, called alpha oscillations, are often thought to arise from synchronous activity across occipital cortex, reflecting general cognitive states such as arousal and alertness. However, there is also evidence that modulation of alpha oscillations in visual cortex can be spatially specific. Here, we used intracranial electrodes in human patients to measure alpha oscillations in response to visual stimuli whose location varied systematically across the visual field. We separated the alpha oscillatory power from broadband power changes. The variation in alpha oscillatory power with stimulus position was then fit by a population receptive field (pRF) model. We find that the alpha pRFs have similar center locations to pRFs estimated from broadband power (70–180 Hz), but are several times larger. The results demonstrate that alpha suppression in human visual cortex can be precisely tuned. Finally, we show how the pattern of alpha responses can explain several features of exogenous visual attention.Significance StatementThe alpha oscillation is the largest electrical signal generated by the human brain. An important question in systems neuroscience is the degree to which this oscillation reflects system-wide states and behaviors such as arousal, alertness, and attention, versus much more specific functions in the routing and processing of information. We examined alpha oscillations at high spatial precision in human patients with intracranial electrodes implanted over visual cortex. We discovered a surprisingly high spatial specificity of visually driven alpha oscillations, which we quantified with receptive field models. We …

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype–phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal …

The new guideline by the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) on sudden unexpected death in epilepsy (SUDEP) is a landmark.[1] The communication between medical professionals and patients about SUDEP risk remains unacceptably low. Tragically, family members often first learn about SUDEP after their loved one's death. Every patient and parent deserves to know the risks of epilepsy. For the first time, the AAN and AES recommend that neurologists inform them about SUDEP, the most common cause of epilepsy-related death.[1]Generalized tonic-clonic seizures increase SUDEP risk; the greater their frequency, the greater the risk.[2, 3] Minimizing seizures through specialized medical care and strategies to reduce breakthrough seizures can reduce risk.[2, 3] Since SUDEP happens more often in sleep,[2] nighttime supervision or monitoring may help and should …