Regulation of lifespan by neural excitation and REST.

The mechanisms that extend lifespan in humans are poorly understood. Here we show that extended longevity in humans is associated with a distinct transcriptome signature in the cerebral cortex that is characterized by downregulation of genes related to neural excitation and synaptic function. In Caenorhabditis elegans, neural excitation increases with age and inhibition of excitation globally, or in glutamatergic or cholinergic neurons, increases longevity. Furthermore, longevity is dynamically regulated by the excitatory-inhibitory balance of neural circuits. The transcription factor REST is upregulated in humans with extended longevity and represses excitation-related genes. Notably, REST-deficient mice exhibit increased cortical activity and neuronal excitability during ageing. Similarly, loss-of-function mutations in the C. elegans REST orthologue genes spr-3 and spr-4 elevate neural excitation and reduce the lifespan of long-lived daf-2 mutants. In wild-type worms, overexpression of spr-4 suppresses excitation and extends lifespan. REST, SPR-3, SPR-4 and reduced excitation activate the longevity-associated transcription factors FOXO1 and DAF-16 in mammals and worms, respectively. These findings reveal a conserved mechanism of ageing that is mediated by neural circuit activity and regulated by REST.

Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits. Current treatment options for SSADHD remain supportive, but there are ongoing attempts to develop targeted genetic therapies. This study aimed to create consensus guidelines for the diagnosis and management of SSADHD. Thirty relevant statements were initially addressed by a systematic literature review, resulting in different evidence levels of strength according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. The highest level of evidence (level A), based on randomized controlled trials, was unavailable for any of the statements. Based on cohort studies, Level B evidence was available for 12 (40%) of the statements. Thereupon, through a process following the Delphi Method and directed by the Appraisal of Guidelines for Research and Evaluation (AGREE II) criteria, expert opinion was sought, and members of an SSADHD Consensus Group evaluated all the statements. The group consisted of neurologists, epileptologists, neuropsychologists, neurophysiologists, metabolic disease specialists, clinical and biochemical geneticists, and laboratory scientists affiliated with 19 institutions from 11 countries who have clinical experience with SSADHD patients and have studied the disorder. Representatives from parent groups were also included in the Consensus Group. An analysis of the survey's results yielded 25 (83%) strong and 5 (17%) weak agreement strengths. These first-of-their-kind consensus guidelines intend to consolidate and unify the optimal care that can be provided to individuals with SSADHD.

Glymphatic dysfunction coincides with lower GABA levels and sleep disturbances in succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder of γ-aminobutyrate (GABA) catabolism. Cerebral waste clearance along glymphatic perivascular spaces depends on aquaporin 4 (AQP4) water channels, the function of which was shown to be influenced by GABA. Sleep disturbances are associated independently with SSADHD and glymphatic dysfunction. This study aimed to determine whether indices of the hyperGABAergic state characteristic of SSADHD coincide with glymphatic dysfunction and sleep disturbances and to explicate the modulatory effect that GABA may have on the glymphatic system. The study included 42 individuals (21 with SSADHD; 21 healthy controls) who underwent brain MRIs and magnetic resonance spectroscopy (MRS) for assessment of glymphatic dysfunction and cortical GABA, plasma GABA measurements, and circadian clock gene expression. The SSADHD subjects responded to an additional Children's Sleep Habits Questionnaire (CSHQ). Compared with the control group, SSADHD subjects did not differ in sex and age but had a higher severity of enlarged perivascular spaces in the centrum semiovale (p < 0.001), basal ganglia (p = 0.01), and midbrain (p = 0.001), as well as a higher MRS-derived GABA/NAA peak (p < 0.001). Within the SSADHD group, the severity of glymphatic dysfunction was specific for a lower MRS-derived GABA/NAA (p = 0.04) and lower plasma GABA (p = 0.004). Additionally, the degree of their glymphatic dysfunction correlated with the CSHQ-estimated sleep disturbances scores (R = 5.18, p = 0.03). In the control group, EPVS burden did not correlate with age or cerebral and plasma GABA values. The modulatory effect that GABA may exert on the glymphatic system has therapeutic implications for sleep-related disorders and neurodegenerative conditions associated with glymphatic dysfunction.

Gene replacement therapies for inherited disorders of neurotransmission: Current progress in succinic semialdehyde dehydrogenase deficiency.

Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction. However, practical challenges for gene replacement therapy remain major hurdles for its translation from bench to bedside. We discuss key considerations for the development of gene replacement therapies for IDNT. As an example, we describe our ongoing work on gene replacement therapy for succinic semialdehyde dehydrogenase deficiency, a GABA catabolic disorder.

Sleep Spindle Generation Before and After Epilepsy Surgery: A Source Imaging Study in Children with Drug-Resistant Epilepsy.

INTRODUCTION: Literature lacks studies investigating the cortical generation of sleep spindles in drug-resistant epilepsy (DRE) and how they evolve after resection of the epileptogenic zone (EZ). Here, we examined sleep EEGs of children with focal DRE who became seizure-free after focal epilepsy surgery, and aimed to investigate the changes in the spindle generation before and after the surgery using low-density scalp EEG and electrical source imaging (ESI). METHODS: We analyzed N2-sleep EEGs from 19 children with DRE before and after surgery. We identified slow (8-12 Hz) and fast spindles (13-16 Hz), computed their spectral features and cortical generators through ESI and computed their distance from the EZ and irritative zone (IZ). We performed two-way ANOVA testing the effect of spindle type (slow vs. fast) and surgical phase (pre-surgery vs. post-surgery) on each feature. RESULTS: Power, frequency and cortical activation of slow spindles increased after surgery (p < 0.005), while this was not seen for fast spindles. Before surgery, the cortical generators of slow spindles were closer to the EZ (57.3 vs. 66.2 mm, p = 0.007) and IZ (41.3 vs. 55.5 mm, p = 0.02) than fast spindle generators. CONCLUSIONS: Our data indicate alterations in the EEG slow spindles after resective epilepsy surgery. Fast spindle generation on the contrary did not change after surgery. Although the study is limited by its retrospective nature, lack of healthy controls, and reduced cortical spatial sampling, our findings suggest a spatial relationship between the slow spindles and the epileptogenic generators.

N-acetylcysteine treatment mitigates loss of cortical parvalbumin-positive interneuron and perineuronal net integrity resulting from persistent oxidative stress in a rat TBI model.

Traumatic brain injury (TBI) increases cerebral reactive oxygen species production, which leads to continuing secondary neuronal injury after the initial insult. Cortical parvalbumin-positive interneurons (PVIs; neurons responsible for maintaining cortical inhibitory tone) are particularly vulnerable to oxidative stress and are thus disproportionately affected by TBI. Systemic N-acetylcysteine (NAC) treatment may restore cerebral glutathione equilibrium, thus preventing post-traumatic cortical PVI loss. We therefore tested whether weeks-long post-traumatic NAC treatment mitigates cortical oxidative stress, and whether such treatment preserves PVI counts and related markers of PVI integrity and prevents pathologic electroencephalographic (EEG) changes, 3 and 6 weeks after fluid percussion injury in rats. We find that moderate TBI results in persistent oxidative stress for at least 6 weeks after injury and leads to the loss of PVIs and the perineuronal net (PNN) that surrounds them as well as of per-cell parvalbumin expression. Prolonged post-TBI NAC treatment normalizes the cortical redox state, mitigates PVI and PNN loss, and - in surviving PVIs - increases per-cell parvalbumin expression. NAC treatment also preserves normal spectral EEG measures after TBI. We cautiously conclude that weeks-long NAC treatment after TBI may be a practical and well-tolerated treatment strategy to preserve cortical inhibitory tone post-TBI.

Background EEG Suppression Ratio for Early Detection of Cerebral Injury in Pediatric Cardiac Arrest.

BACKGROUND: Our objective was to assess the utility of the 1-h suppression ratio (SR) as a biomarker of cerebral injury and neurologic prognosis after cardiac arrest (CA) in the pediatric hospital setting. METHODS: Prospectively, we reviewed data from children presenting after CA and monitored by continuous electroencephalography (cEEG). Patients aged 1 month to 21 years were included. The SR, a quantitative measure of low-voltage cEEG (≤ 3 µV) content, was dichotomized as present or absent if there was > 0% suppression for one continuous hour. A multivariate logistic regression analysis was performed including age, sex, type of CA (i.e., in-hospital or out-of-hospital), and the presence of SR as a predictor of global anoxic cerebral injury as confirmed by magnetic resonance imaging (MRI). RESULTS: We included 84 patients with a median age of 4 years (interquartile range 0.9-13), 64% were male, and 49% (41/84) had in-hospital CA. Cerebral injury was seen in 50% of patients, of whom 65% had global injury. One-hour SR presence, independent of amount, predicted cerebral injury with 81% sensitivity (95% confidence interval (CI) (66-91%) and 98% specificity (95% CI 88-100%). Multivariate logistic regression analyses indicated that SR was a significant predictor of both cerebral injury (ß = 6.28, p < 0.001) and mortality (ß = 3.56, p < 0.001). CONCLUSIONS: The SR a sensitive and specific marker of anoxic brain injury and post-CA mortality in the pediatric population. Once detected in the post-CA setting, the 1-h SR may be a useful threshold finding for deployment of early neuroprotective strategies prior or for prompting diagnostic neuroimaging.

Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants.

To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders.

Preclinical pharmacokinetics and tolerability of a novel meglumine-based parenteral solution of topiramate and topiramate combinations for treatment of status epilepticus.

OBJECTIVE: For an antiseizure medication (ASM) to be effective in status epilepticus (SE), the drug should be administered intravenously (i.v.) to provide quick access to the brain. However, poor aqueous solubility is a major problem in the development of parenteral drug solutions. Given its multiple mechanisms of action, topiramate (TPM) is a promising candidate for the treatment of established or refractory SE, as supported by clinical studies using nasogastric tube TPM administration. However, TPM is not clinically available as a solution for i.v. administration, which hampers its use in the treatment of SE. Here, we describe a novel easy-to-use and easy-to-prepare i.v. TPM formulation using the U.S. Food and Drug Administration (FDA)-approved excipient meglumine. METHODS: During formulation development, we compared the solubility of TPM in bi-distilled water with vs without a range of meglumine concentrations. Furthermore, the solubility of combinations of TPM and levetiracetam and TPM, levetiracetam, and atorvastatin in aqueous meglumine concentrations was determined. Subsequently, the pharmacokinetics and tolerability of meglumine-based solutions of TPM and TPM combinations were evaluated in rats, including animals following fluid percussion injury or pilocarpine-induced SE. RESULTS: The amino sugar meglumine markedly enhances the aqueous solubility of TPM. A comparison with data on dissolving TPM using sulfobutylether-ß-cyclodextrin (Captisol) demonstrates that meglumine is much more effective for dissolving TPM. Furthermore, meglumine can be used to prepare drug cocktails where TPM is co-administered with another ASM for SE treatment. The tolerability studies of the meglumine-based TPM solution and meglumine-based TPM combinations in normal rats and the rat fluid percussion injury and pilocarpine-induced SE models demonstrate excellent tolerability of the novel drug solutions. Preclinical studies on antiseizure efficacy in the SE model are underway. SIGNIFICANCE: In conclusion, the novel meglumine-based solution of TPM presented here may be well suited for clinical development.

The presence and severity of epilepsy coincide with reduced γ-aminobutyrate and cortical excitatory markers in succinic semialdehyde dehydrogenase deficiency.

OBJECTIVE: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of γ-aminobutyrate (GABA) catabolism. Despite the resultant hyper-GABAergic environment facilitated by the metabolic defect, individuals with this disorder have a paradoxically high prevalence of epilepsy. We aimed to study the characteristics of epilepsy in SSADHD and its concordance with GABA-related metabolites and neurophysiologic markers of cortical excitation. METHODS: Subjects in an international natural history study of SSADHD underwent clinical assessments, electroencephalography, transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy for GABA/N-acetyl aspartate quantification, and plasma GABA-related metabolite measurements. RESULTS: A total of 61 subjects with SSADHD and 42 healthy controls were included in the study. Epilepsy was present in 49% of the SSADHD cohort. Over time, there was an increase in severity in 33% of the subjects with seizures. The presence of seizures was associated with increasing age (p = .001) and lower levels of GABA (p = .002), γ-hydroxybutyrate (GHB; p = .004), and γ-guanidinobutyrate (GBA; p = .003). Seizure severity was associated with increasing age and lower levels of GABA-related metabolites as well as lower TMS-derived resting motor thresholds (p = .04). The cutoff values with the highest discriminative ability to predict seizures were age > 9.2 years (p = .001), GABA < 2.57 µmol·L-1 (p = .002), GHB < 143.6 µmol·L-1 (p = .004), and GBA < .075 µmol·L-1 (p = .007). A prediction model for seizures in SSADHD was comprised of the additive effect of older age and lower plasma GABA, GHB, and GBA (area under the receiver operating characteristic curve of .798, p = .008). SIGNIFICANCE: Epilepsy is highly prevalent in SSADHD, and its onset and severity correlate with an age-related decline in GABA and GABA-related metabolite levels as well as TMS markers of reduced cortical inhibition. The reduction of GABAergic activity in this otherwise hyper-GABAergic disorder demonstrates a concordance between epileptogenesis and compensatory responses. These findings may furthermore inform the timing of molecular interventions for SSADHD.

Prevalence of suicidality in children and adolescents with depressive disorders with and without epilepsy.

OBJECTIVE: Children with epilepsy (CWE) are at risk for a range of adverse emotional, behavioral, and social outcomes. Approximately one-third of CWE experience depressive disorders, and up to 20% of children and adolescents with epilepsy may experience suicidality, suggesting that epilepsy increases the risk for suicidality among children and adolescents with depressive disorders. Consequently, the goal of the present study is to compare rates of suicidality in children and adolescents diagnosed with depressive disorders with or without co-morbid epilepsy. PARTICIPANTS AND METHODS: A retrospective chart review was conducted for 100 pediatric patients with a history of both seizures and depressive disorders and 100 patients with a history of depressive disorders only. Cases were coded for depression diagnosis, suicidality, suicidal ideation, suicide attempts, psychiatric hospitalizations, and self-injury. The distributions of these variables for the two groups were compared. RESULTS: The age and sex distributions of the two groups were comparable. Patients with co-morbid depressive disorders and epilepsy found a high rate of suicidal ideation (69%) but did not differ from those with depressive disorders without epilepsy on any of the suicidality variables (all p > 0.20), with the exception of self-injury, which was higher in those without epilepsy. CONCLUSIONS: CWE and co-morbid depression are at significant risk for suicidality, including ideation, attempts, and hospitalizations, but at rates that are comparable to those with depressive disorders without seizures. However, patients with co-morbid epilepsy are less likely to engage in other self-injurious behaviors. These findings support the need for careful monitoring of the psychiatric status of children and adolescents with epilepsy.

Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency.

AIM: To elucidate the etiological aspects of autism spectrum disorder (ASD) in succinic semialdehyde dehydrogenase deficiency (SSADHD), related to dysregulation of γ-aminobutyric acid (GABA) and the imbalance of excitatory and inhibitory neurotransmission. METHOD: In this prospective, international study, individuals with SSADHD underwent neuropsychological assessments, as well as biochemical, neurophysiological, and neuroimaging evaluations. RESULTS: Of the 29 individuals (17 females) enrolled (median age [IQR] 10 years 5 months [5 years 11 months-18 years 1 month]), 16 were diagnosed with ASD. ASD severity significantly increased with age (r = 0.67, p < 0.001) but was inversely correlated with plasma GABA (r = -0.67, p < 0.001) and γ-hydroxybutyrate levels (r = -0.538, p = 0.004), and resting motor threshold as measured by transcranial magnetic stimulation (r = -0.44, p = 0.03). A discriminative analysis indicated that an age older than 7 years 2 months (p = 0.004) and plasma GABA levels less than 2.47 µM (p = 0.01) are the threshold values beyond which the likelihood of ASD presenting in individuals with SSADHD is increased. INTERPRETATION: ASD is prevalent but not universal in SSADHD, and it can be predicted by lower levels of plasma GABA and GABA-related metabolites. ASD severity in SSADHD increases with age and the loss of cortical inhibition. These findings add insight into the pathophysiology of ASD and may facilitate its early diagnosis and intervention in individuals with SSADHD.

Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish.

Epilepsy is one of the most common neurological disorders. The X-linked gene PCDH19 is associated with sporadic and familial epilepsy in humans, typically with early-onset clustering seizures and intellectual disability in females but not in so-called 'carrier' males, suggesting that mosaic PCDH19 expression is required to produce epilepsy. To characterize the role of loss of PCDH19 function in epilepsy, we generated zebrafish with truncating pcdh19 variants. Evaluating zebrafish larvae for electrophysiological abnormalities, we observed hyperexcitability phenotypes in both mosaic and non-mosaic pcdh19+/- and pcdh19-/- mutant larvae. Thus, we demonstrate that the key feature of epilepsy-network hyperexcitability-can be modeled effectively in zebrafish, even though overt spontaneous seizure-like swim patterns were not observed. Further, zebrafish with non-mosaic pcdh19 mutation displayed reduced numbers of inhibitory interneurons suggesting a potential cellular basis for the observed hyperexcitability. Our findings in both mosaic and non-mosaic pcdh19 mutant zebrafish challenge the prevailing theory that mosaicism governs all PCDH19-related phenotypes and point to interneuron-mediated mechanisms underlying these phenotypes.

Automated detection of absence seizures using a wearable electroencephalographic device: a phase 3 validation study and feasibility of automated behavioral testing.

OBJECTIVE: Our primary goal was to measure the accuracy of fully automated absence seizure detection, using a wearable electroencephalographic (EEG) device. As a secondary goal, we also tested the feasibility of automated behavioral testing triggered by the automated detection. METHODS: We conducted a phase 3 clinical trial (NCT04615442), with a prospective, multicenter, blinded study design. The input was the one-channel EEG recorded with dry electrodes embedded into a wearable headband device connected to a smartphone. The seizure detection algorithm was developed using artificial intelligence (convolutional neural networks). During the study, the predefined algorithm, with predefined cutoff value, analyzed the EEG in real time. The gold standard was derived from expert evaluation of simultaneously recorded full-array video-EEGs. In addition, we evaluated the patients' responsiveness to the automated alarms on the smartphone, and we compared it with the behavioral changes observed in the clinical video-EEGs. RESULTS: We recorded 102 consecutive patients (57 female, median age = 10 years) on suspicion of absence seizures. We recorded 364 absence seizures in 39 patients. Device deficiency was 4.67%, with a total recording time of 309 h. Average sensitivity per patient was 78.83% (95% confidence interval [CI] = 69.56%-88.11%), and median sensitivity was 92.90% (interquartile range [IQR] = 66.7%-100%). The average false detection rate was .53/h (95% CI = .32-.74). Most patients (n = 66, 64.71%) did not have any false alarms. The median F1 score per patient was .823 (IQR = .57-1). For the total recording duration, F1 score was .74. We assessed the feasibility of automated behavioral testing in 36 seizures; it correctly documented nonresponsiveness in 30 absence seizures, and responsiveness in six electrographic seizures. SIGNIFICANCE: Automated detection of absence seizures with a wearable device will improve seizure quantification and will promote assessment of patients in their home environment. Linking automated seizure detection to automated behavioral testing will provide valuable information from wearable devices.

Single-stage resection of bottom-of-a-sulcus dysplasia involving eloquent cortex using navigated transcranial magnetic stimulation and intraoperative modalities.

BACKGROUND: Focal cortical dysplasia (FCD) is a common etiology of refractory epilepsy, particularly in children. Surgical management is potentially curative, but poses the challenge of distinguishing the border between ictogenic regions of dysplasia and functionally critical brain tissue. Bottom-of-a-sulcus dysplasia (BOSD) amplifies this challenge, due to difficulties in physiologic mapping of the deep tissue. METHODS: We report a one-stage resection of a dysplasia-associated seizure focus abutting and involving the hand and face primary motor cortex. In doing so, we describe our surgical planning integrating neuronavigated transcranial magnetic stimulation (nTMS) for functional motor mapping, combined with intraoperative ultrasonography, intracranial electroencephalography, and magnetic resonance imaging (MRI). A 5-year-old girl with intractable focal epilepsy was referred to our comprehensive epilepsy program. Despite attentive pharmacotherapy, she experienced status epilepticus and up to 70 seizures per day, accompanied by multiple side effects from her antiseizure medication. A right frontal BOSD in close proximity to the hand motor area of the precentral gyrus was identified on MRI. Postoperatively, she is seizure-free for over 1 year with no hand deficit. CONCLUSION: Although technically complex, single-stage resection taking advantage of comprehensive surgical planning with optimized fusion of functional mapping and intraoperative modalities merits consideration given the invasiveness of a two-stage approach for limited added value. Integrated pre-surgical nTMS allowed for mapping of eloquent cortex without invasive electrocortical stimulation.

Neurosurgery for eloquent lesions in children: state-of-the-art rationale and technical implications of perioperative neurophysiology.

OBJECTIVE: In adult patients, an increasing group of neurosurgeons specialize entirely in the treatment of highly eloquent tumors, particularly gliomas. In contrast, extensive perioperative neurophysiological workup for pediatric cases has been limited essentially to epilepsy surgery. METHODS: The authors discuss radio-oncological and general oncological considerations based on the current literature and their personal experience. RESULTS: While several functional mapping modalities facilitate preoperative identification of cortically and subcortically located eloquent areas, not all are suited for children. Direct cortical intraoperative stimulation is impractical in many young patients due to the reduced excitability of the immature cortex. Behavioral requirements also limit the utility of functional MRI and magnetoencephalography in children. In contrast, MRI-derived tractography and navigated transcranial magnetic stimulation are available across ages. Herein, the authors review the oncological rationale of function-guided resection in pediatric gliomas including technical implications such as personalized perioperative neurophysiology, surgical strategies, and limitations. CONCLUSIONS: Taken together, these techniques, despite the limitations of some, facilitate the identification of eloquent areas prior to tumor surgery and radiotherapy as well as during follow-up of residual tumors.

Understanding the Molecular Mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): Towards the Development of SSADH-Targeted Medicine.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic disorder caused by inefficient metabolic breakdown of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA). Pathologic brain accumulation of GABA and γ-hydroxybutyrate (GHB), a neuroactive by-product of GABA catabolism, leads to a multitude of molecular abnormalities beginning in early life, culminating in multifaceted clinical presentations including delayed psychomotor development, intellectual disability, hypotonia, and ataxia. Paradoxically, over half of patients with SSADHD also develop epilepsy and face a significant risk of sudden unexpected death in epilepsy (SUDEP). Here, we review some of the relevant molecular mechanisms through which impaired synaptic inhibition, astrocytic malfunctions and myelin defects might contribute to the complex SSADHD phenotype. We also discuss the gaps in knowledge that need to be addressed for the implementation of successful gene and enzyme replacement SSADHD therapies. We conclude with a description of a novel SSADHD mouse model that enables 'on-demand' SSADH restoration, allowing proof-of-concept studies to fine-tune SSADH restoration in preparation for eventual human trials.

A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental anomalies and epilepsy.

PURPOSE: Neurodevelopmental disabilities are common and genetically heterogeneous. We identified a homozygous variant in the gene encoding UFM1-specific peptidase 2 (UFSP2), which participates in the UFMylation pathway of protein modification. UFSP2 variants are implicated in autosomal dominant skeletal dysplasias, but not neurodevelopmental disorders. Homozygosity for the variant occurred in eight children from four South Asian families with neurodevelopmental delay and epilepsy. We describe the clinical consequences of this variant and its effect on UFMylation. METHODS: Exome sequencing was used to detect potentially pathogenic variants and identify shared regions of homozygosity. Immunoblotting assessed protein expression and post-translational modifications in patient-derived fibroblasts. RESULTS: The variant (c.344T>A; p.V115E) is rare and alters a conserved residue in UFSP2. Immunoblotting in patient-derived fibroblasts revealed reduced UFSP2 abundance and increased abundance of UFMylated targets, indicating the variant may impair de-UFMylation rather than UFMylation. Reconstituting patient-derived fibroblasts with wild-type UFSP2 reduced UFMylation marks. Analysis of UFSP2's structure indicated that variants observed in skeletal disorders localize to the catalytic domain, whereas V115 resides in an N-terminal domain possibly involved in substrate binding. CONCLUSION: Different UFSP2 variants cause markedly different diseases, with homozygosity for V115E causing a severe syndrome of neurodevelopmental disability and epilepsy.

Drug-Responsive Inhomogeneous Cortical Modulation by Direct Current Stimulation.

OBJECTIVE: Cathodal direct current stimulation (cDCS) induces long-term depression (LTD)-like reduction of cortical excitability (DCS-LTD), which has been tested in the treatment of epilepsy with modest effects. In part, this may be due to variable cortical neuron orientation relative to the electric field. We tested, in vivo and in vitro, whether DCS-LTD occurs throughout the cortical thickness, and if not, then whether drug-DCS pairing can enhance the uniformity of the cortical response and the cDCS antiepileptic effect. METHODS: cDCS-mediated changes in cortical excitability were measured in vitro in mouse motor cortex (M1) and in human postoperative neocortex, in vivo in mouse somatosensory cortex (S1), and in a mouse kainic acid (KA)-seizure model. Contributions of N-methyl-D-aspartate-type glutamate receptors (NMDARs) to cDCS-mediated plasticity were tested with application of NMDAR blockers (memantine/D-AP5). RESULTS: cDCS reliably induced DCS-LTD in superficial cortical layers, and a long-term potentiation (LTP)-like enhancement (DCS-LTP) was recorded in deep cortical layers. Immunostaining confirmed layer-specific increase of phospho-S6 ribosomal protein in mouse M1. Similar nonuniform cDCS aftereffects on cortical excitability were also found in human neocortex in vitro and in S1 of alert mice in vivo. Application of memantine/D-AP5 either produced a more uniform DCS-LTD throughout the cortical thickness or at least abolished DCS-LTP. Moreover, a combination of memantine and cDCS suppressed KA-induced seizures. INTERPRETATION: cDCS aftereffects are not uniform throughout cortical layers, which may explain the incomplete cDCS clinical efficacy. NMDAR antagonists may augment cDCS efficacy in epilepsy and other disorders where regional depression of cortical excitability is desirable. ANN NEUROL 2020;88:489-502.

Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy.

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer's disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term 'cistauosis', appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer's disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.