Tau Phosphorylation Patterns in the Rat Cerebral Cortex After Traumatic Brain Injury and Sodium Selenate Effects: An Epibios4rx Project 2 Study.

Sodium selenate (SS) activates protein phosphatase 2 (PP2A) and reduces phosphorylated tau (pTAU) and late post-traumatic seizures after lateral fluid percussion injury (LFPI). In EpiBioS4Rx Project 2, a multi-center international study for post-traumatic targets, biomarkers, and treatments, we tested the target relevance and modification by SS of pTAU forms and PP2A and in the LFPI model, at two sites: Einstein and Melbourne. In Experiment 1, adult male rats were assigned to LFPI and sham (both sites) and naïve controls (Einstein). Motor function was monitored by neuroscores. Brains were studied with immunohistochemistry (IHC), Western blots (WBs), or PP2A activity assay, from 2 days to 8 weeks post-operatively. In Experiment 2, LFPI rats received SS for 7 days (SS0.33: 0.33 mg/kg/day; SS1: 1 mg/kg/day, subcutaneously) or vehicle (Veh) post-LFPI and pTAU, PR55 expression, or PP2A activity were studied at 2 days and 1 week (on treatment), or 2 weeks (1 week off treatment). Plasma selenium and SS levels were measured. In Experiment 1 IHC, LFPI rats had higher cortical pTAU-Ser202/Thr205-immunoreactivity (AT8-ir) and pTAU-Ser199/202-ir at 2 days, and pTAU-Thr231-ir (AT180-ir) at 2 days, 2 weeks, and 8 weeks, ipsilaterally to LFPI, than controls. LFPI-2d rats also had higher AT8/total-TAU5-ir in cortical extracts ipsilateral to the lesion (WB). PP2A (PR55-ir) showed time- and region-dependent changes in IHC, but not in WB. PP2A activity was lower in LFPI-1wk than in sham rats. In Experiment 2, SS did not affect neuroscores or cellular AT8-ir, AT180-ir, or PR55-ir in IHC. In WB, total cortical AT8/total-TAU-ir was lower in SS0.33 and SS1 LFPI rats than in Veh rats (2 days, 1 week); total cortical PR55-ir (WB) and PP2A activity were higher in SS1 than Veh rats (2 days). SS dose dependently increased plasma selenium and SS levels. Concordant across-sites data confirm time and pTAU form-specific cortical increases ipsilateral to LFPI. The discordant SS effects may either suggest SS-induced reduction in the numbers of cells with increased pTAU-ir, need for longer treatment, or the involvement of other mechanisms of action.

A Multidimensional Assessment of Activities of Daily Living, Mental Status, Communication, and Social Abilities Among Older Adults in Shenzhen, China: Cross-Sectional Study.

BACKGROUND: China is facing a rapidly expanding aging population. Insights into the health status of older adults are of great significance for health resource allocation and health care provision to this population. OBJECTIVE: With the goal of providing a comprehensive understanding of the health status of older adults and to inform potential interventions, we investigated the level of disability and identified risk factors associated with disability among the older population (aged ≥60 years) living in China. METHODS: A total of 8467 older adults living in the Chinese city of Shenzhen were enrolled in this cross-sectional study. We used a multidimensional ability assessment survey, which assessed their activities of daily living (ADL; including eating, bathing, grooming, dressing, defecation control, urination control, using a toilet unaided, transfer, flat-ground walking, stair activity), mental status (including cognitive function, aggressive behavior, depression symptoms), sensory and communication (including consciousness level, vision, hearing, communication), and social participation (including living, working, time/space orientation, distinguish persons, social communication) abilities. The impact of demographic risk factors on ability levels was analyzed using ordinal logistic regression. The correlations between the four dimensions of ability mentioned above were analyzed using Spearman correlation analysis. RESULTS: A total of 7766 participants were effectively assessed. The participants' average age was 70.64 (SD 8.46) years comprising 56.53% females. The overall ability level was classified as mildly, moderately, and severely impaired for 27.57% (n=2141), 2.83% (n=220), and 4.28% (n=332) of the 7766 participants, respectively. With increasing age, the proportion of impaired participants increased from 17.62% (365/2071) in the age group 60-64 years to 91.3% (253/277) in the age group above 90 years (P<.001), corresponding to an approximate 10% rise for every 5-year age increment. The odds of having more severe overall ability impairment in females was 1.15 times that in males (odds ratio [OR] 1.15, 95% CI 1.04-1.28). Participants who were divorced or widowed had a higher risk of more severe overall ability impairment than those currently married (OR 1.98, 95% CI 1.68-2.33). Participants living with nonrelatives had an increased risk of more severe overall ability impairment than those living alone (OR 2.38, 95% CI 1.46-3.91). Higher education level was a protective factor of overall ability impairment (college degree or above: OR 0.32, 95% CI 0.24-0.42). The four dimensions of ability assessed were significantly correlated; a low score for ADL was significantly correlated with poorer mental status, sensory and communication, and social participation (all P<.001). CONCLUSIONS: The proportion of disability among Chinese older adults increases with age, being female, having lower education levels, being divorced or widowed, and living with nonrelatives. Impairment in ADL ability is significantly correlated with poor mental status, social participation, and sensory and communication abilities. A holistic approach to improving the health of the older population is recommended in China.

The potential of closed-loop endovascular neurostimulation as a viable therapeutic approach for drug-resistant epilepsy: A critical review.

Over the last few decades, biomedical implants have successfully delivered therapeutic electrical stimulation to reduce the frequency and severity of seizures in people with drug-resistant epilepsy. However, neurostimulation approaches require invasive surgery to implant stimulating electrodes, and surgical, medical, and hardware complications are not uncommon. An endovascular approach provides a potentially safer and less invasive surgical alternative. This article critically evaluates the feasibility of endovascular closed-loop neuromodulation for the treatment of epilepsy. By reviewing literature that reported the impact of direct electrical stimulation to reduce the frequency of epileptic seizures, we identified clinically validated extracranial, cortical, and deep cortical neural targets. We identified veins in close proximity to these targets and evaluated the potential of delivering an endovascular implant to these veins based on their diameter. We then compared the risks and benefits of existing technology to describe a benchmark of clinical safety and efficacy that would need to be achieved for endovascular neuromodulation to provide therapeutic benefit. For the majority of brain regions that have been clinically demonstrated to reduce seizure occurrence in response to delivered electrical stimulation, vessels of appropriate diameter for delivery of an endovascular electrode to these regions could be achieved. This includes delivery to the vagus nerve via the 13.2 ± 0.9 mm diameter internal jugular vein, the motor cortex via the 6.5 ± 1.7 mm diameter superior sagittal sinus, and the cerebellum via the 7.7 ± 1.4 mm diameter sigmoid sinus or 6.2 ± 1.4 mm diameter transverse sinus. Deep cerebral targets can also be accessed with an endovascular approach, with the 1.9 ± 0.5 mm diameter internal cerebral vein and 1.2-mm-diameter thalamostriate vein lying in close proximity to the anterior and centromedian nuclei of the thalamus, respectively. This work identified numerous veins that are in close proximity to conventional stimulation targets that are of a diameter large enough for delivery and deployment of an endovascular electrode array, supporting future work to assess clinical efficacy and chronic safety of an endovascular approach to deliver therapeutic neurostimulation.

Psychiatric and cognitive characteristics of older adults admitted to a Video-EEG monitoring (VEM) unit.

OBJECTIVE: To compare the clinical, psychiatric, and cognitive characteristics of older with younger patients presenting to a video-EEG monitoring (VEM) unit. METHOD: This was a retrospective case-control study involving patients admitted for VEM over a two-year period (from April 2018 to April 2020) at two comprehensive epilepsy units. Patients were categorized into an older (≥60 years) and a younger (<60 years) group. Younger patients were individually matched to older adults to form a matched younger group. Diagnosis was determined by a consensus opinion of epileptologists, neurologists, and neuropsychiatrists. The main diagnostic categories were epilepsy, psychogenic nonepileptic seizures (PNES), and 'other' diagnosis (non-diagnostic and other nonepileptic diagnoses). Clinical psychiatric diagnoses were obtained from neuropsychiatric reports. Objective cognitive function was measured with the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG). Subjective cognitive function was assessed using the Quality of Life in Epilepsy Inventory-89 (QOLIE-89) cognitive subscales. RESULTS: Five-hundred and thirty three patients (71 older, 462 younger) aged 16-91 years were admitted to the VEM unit during the study period. There was a diagnosis of focal epilepsy in 55% of the older group and 48% of the younger group, generalized epilepsy in 3% of the older group and 10% of the younger group, and 'other' in 32% of the older group and 19% of the younger group. Ten percent (2 males and 5 females) of the older group were diagnosed with PNES compared to 22% of the younger group (p = 0.016). A depressive disorder was diagnosed in 34% of the older group and 24% of the younger group (p = 0.20). An anxiety disorder was diagnosed in 15% of the older group and 25% of the younger group (p = 0.15). Mild neurocognitive disorder was more common in the older group (34%) compared to the matched younger group (34% vs 3%, p < 0.001). The older group had lower mean NUCOG scores compared to the matched younger group (79.49 vs 87.73, p = <0.001). There was no evidence for a relationship between mean NUCOG score and overall subjective cognitive difficulties for the older group (r = 0.03, p = 0.83). Among older adults, those diagnosed with PNES had more experiences of childhood trauma. Measures of dissociation, depression, or general anxiety did not differ between PNES and non-PNES diagnoses in the older group. CONCLUSION: Psychiatric comorbidities are common among older adults admitted for VEM. The psychological impact of epilepsy and risk factors for PNES seen in younger patients are also applicable in the older group. The older group demonstrated more cognitive impairments than the younger group, although these were usually unrecognized by individuals. Older adults admitted to VEM will benefit from psychiatric and neuropsychological input to ensure a comprehensive care approach to evaluation and management.

Folic acid dose, valproate, and fetal malformations.

OBJECTIVE: To determine whether there is a relationship between folic acid dose and the degree of protection against valproate-associated and other antiepileptic drug (AED)-associated fetal structural malformations in women with AED-treated epilepsy. METHODS: Statistical analysis of data from the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy involving 2104 folic acid-treated pregnancies in women with epilepsy. RESULTS: Multiple variable logistic regression failed to demonstrate any statistically significant effect of folic acid dosage in reducing overall fetal malformation rates in women taking folic acid either before and during pregnancy (P = 0.640) or during early pregnancy only (P = 0.801), and in reducing spina bifida occurrence rates (P = 0.409). CONCLUSIONS: In the present state of knowledge, it would seem misguided to hope that a folic acid dose of 5 mg/day taken before and during pregnancy would protect against the occurrence of valproate-associated and other AED-associated fetal structural malformations. Future studies are required to determine whether high-dose periconceptional folate use may decrease the risk of other valproate-associated adverse fetal outcomes, including impaired post-natal neurobehavioral development.

Gut Microbiota and Epilepsy: A Systematic Review on Their Relationship and Possible Therapeutics.

Dysbiosis of gut microbiota may lead to a range of diseases including neurological disorders. Thus, it is hypothesized that regulation of the intestinal microbiota may prevent or treat epilepsy. The purpose of this systematic review is to evaluate the evidence investigating the relationship between gut microbiota and epilepsy and possible interventions. A systematic review of the literature was done on four databases (PubMed, Scopus, EMBASE, and Web of Science). Study selection was restricted to original research articles while following the PRISMA guidelines. Six studies were selected. These studies cohesively support the interaction between gut microbiota and epileptic seizures. Gut microbiota analysis identified increases in Firmicutes, Proteobacteria, Verrucomicrobia, and Fusobacteria with decreases in Bacteroidetes and Actinobacteria in epileptic patients. Ketogenic diet, probiotics, and fecal microbiota transplantation (FMT) improved the dysbiosis of the gut microbiota and seizure activity. However, the studies either had a small sample size, lack of subject variability, or short study or follow-up period, which may question their reliability. Nevertheless, these limited studies conclusively suggest that gut microbiota diversity and dysbiosis may be involved in the pathology of epilepsy. Future studies providing more reliable and in depth insight into the gut microbial community will spark promising alternative therapies to current epilepsy treatment.

Vitamin D status in an Australian patient population: a large retrospective case series focusing on factors associated with variations in serum 25(OH)D.

OBJECTIVES: To investigate whether sex, age, medical specialty and seasonal variations in serum concentration of 25-hydroxy vitamin D (25(OH)D) are evident among an Australian patient population. DESIGN: Retrospective study analysing the results of serum 25(OH)D lab tests and vitamin D supplementation from Royal Melbourne Hospital (RMH) between 2014 and 2017. SETTING: Tertiary healthcare centre in Victoria, Australia. PARTICIPANTS: 30 023 patients (inpatient and outpatient) who had their serum 25(OH)D levels measured at RMH between 2014 and 2017. MAIN OUTCOME MEASURES: Serum 25(OH)D levels stratified according to patients' sex, age and medical specialty admitted to, as well as the season and year (2014 to 2017) 25(OH)D level was measured. RESULTS: Mean serum 25(OH)D level of study population was 69.9 nmol/L (95% CI 69.5 to 70.2). Only 40.2% patients in this cohort were sufficient in vitamin D (>75 nmol/L). On average, 25(OH)D levels in male patients were 6.1 units (95% CI 5.4 to 6.9) lower than in females. Linear regression analysis found that 25(OH)D levels increased by 0.16 unit (95% CI 0.14 to 0.18) for every year increase in age. One-way analysis of variance showed patients from neurology had the highest average 25(OH)D level, 76.8 nmol/L (95% CI 74.2 to 79.3) compared with other medical specialties. Mean 25(OH)D level during winter, 64.9 nmol/L (95% CI 64.2 to 65.6) was significantly lower compared with other seasons despite supplementation. Average 25(OH)D level measured in 2014, 71.5 nmol/L (95 CI% 70.8 to 72.2) was significantly higher than levels measured in 2016-2017. CONCLUSIONS: There is a sex, age, medical specialty, seasonal and yearly variation in vitamin D status in an Australian patient population. The association between low vitamin D status and winter despite supplementation suggests other interventions are required to boost serum 25(OH)D levels.

Glutamate weighted imaging contrast in gliomas with 7 Tesla magnetic resonance imaging.

INTRODUCTION: Diffuse gliomas are incurable malignancies, which undergo inevitable progression and are associated with seizure in 50-90% of cases. Glutamate has the potential to be an important glioma biomarker of survival and local epileptogenicity if it can be accurately quantified noninvasively. METHODS: We applied the glutamate-weighted imaging method GluCEST (glutamate chemical exchange saturation transfer) and single voxel MRS (magnetic resonance spectroscopy) at 7 Telsa (7 T) to patients with gliomas. GluCEST contrast and MRS metabolite concentrations were quantified within the tumour region and peritumoural rim. Clinical variables of tumour aggressiveness (prior adjuvant therapy and previous radiological progression) and epilepsy (any prior seizures, seizure in last month and drug refractory epilepsy) were correlated with respective glutamate concentrations. Images were separated into post-hoc determined patterns and clinical variables were compared across patterns. RESULTS: Ten adult patients with a histo-molecular (n = 9) or radiological (n = 1) diagnosis of grade II-III diffuse glioma were recruited, 40.3 +/- 12.3 years. Increased tumour GluCEST contrast was associated with prior adjuvant therapy (p = .001), and increased peritumoural GluCEST contrast was associated with both recent seizures (p = .038) and drug refractory epilepsy (p = .029). We distinguished two unique GluCEST contrast patterns with distinct clinical and radiological features. MRS glutamate correlated with GluCEST contrast within the peritumoural voxel (R = 0.89, p = .003) and a positive trend existed in the tumour voxel (R = 0.65, p = .113). CONCLUSION: This study supports the role of glutamate in diffuse glioma biology. It further implicates elevated peritumoural glutamate in epileptogenesis and altered tumour glutamate homeostasis in glioma aggressiveness. Given the ability to non-invasively visualise and quantify glutamate, our findings raise the prospect of 7 T GluCEST selecting patients for individualised therapies directed at the glutamate pathway. Larger studies with prospective follow-up are required.

Supranutritional Sodium Selenate Supplementation Delivers Selenium to the Central Nervous System: Results from a Randomized Controlled Pilot Trial in Alzheimer's Disease.

Insufficient supply of selenium to antioxidant enzymes in the brain may contribute to Alzheimer's disease (AD) pathophysiology; therefore, oral supplementation may potentially slow neurodegeneration. We examined selenium and selenoproteins in serum and cerebrospinal fluid (CSF) from a dual-dose 24-week randomized controlled trial of sodium selenate in AD patients, to assess tolerability, and efficacy of selenate in modulating selenium concentration in the central nervous system (CNS). A pilot study of 40 AD cases was randomized to placebo, nutritional (0.32 mg sodium selenate, 3 times daily), or supranutritional (10 mg, 3 times daily) groups. We measured total selenium, selenoproteins, and inorganic selenium levels, in serum and CSF, and compared against cognitive outcomes. Supranutritional selenium supplementation was well tolerated and yielded a significant (p < 0.001) but variable (95% CI = 13.4-24.8 µg/L) increase in CSF selenium, distributed across selenoproteins and inorganic species. Reclassifying subjects as either responsive or non-responsive based on elevation in CSF selenium concentrations revealed that responsive group did not deteriorate in Mini-Mental Status Examination (MMSE) as non-responsive group (p = 0.03). Pooled analysis of all samples revealed that CSF selenium could predict change in MMSE performance (Spearman's rho = 0.403; p = 0.023). High-dose sodium selenate supplementation is well tolerated and can modulate CNS selenium concentration, although individual variation in selenium metabolism must be considered to optimize potential benefits in AD. The Vel002 study is listed on the Australian and New Zealand Clinical Trials Registry ( http://www.anzctr.org.au /), ID: ACTRN12611001200976.

Feasibility of identifying the ideal locations for motor intention decoding using unimodal and multimodal classification at 7T-fMRI.

Invasive Brain-Computer Interfaces (BCIs) require surgeries with high health-risks. The risk-to-benefit ratio of the procedure could potentially be improved by pre-surgically identifying the ideal locations for mental strategy classification. We recorded high-spatiotemporal resolution blood-oxygenation-level-dependent (BOLD) signals using functional MRI at 7 Tesla in eleven healthy participants during two motor imagery tasks. BCI diagnostic task isolated the intent to imagine movements, while BCI simulation task simulated the neural states that may be yielded in a real-life BCI-operation scenario. Imagination of movements were classified from the BOLD signals in sub-regions of activation within a single or multiple dorsal motor network regions. Then, the participant's decoding performance during the BCI simulation task was predicted from the BCI diagnostic task. The results revealed that drawing information from multiple regions compared to a single region increased the classification accuracy of imagined movements. Importantly, systematic unimodal and multimodal classification revealed the ideal combination of regions that yielded the best classification accuracy at the individual-level. Lastly, a given participant's decoding performance achieved during the BCI simulation task could be predicted from the BCI diagnostic task. These results show the feasibility of 7T-fMRI with unimodal and multimodal classification being utilized for identifying ideal sites for mental strategy classification.

CaV 3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons.

OBJECTIVE: Genetic alterations have been identified in the CACNA1H gene, encoding the CaV 3.2 T-type calcium channel in patients with absence epilepsy, yet the precise mechanisms relating to seizure propagation and spike-wave-discharge (SWD) pacemaking remain unknown. Neurons of the thalamic reticular nucleus (TRN) express high levels of CaV 3.2 calcium channels, and we investigated whether a gain-of-function mutation in the Cacna1h gene in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) contributes to seizure propagation and pacemaking in the TRN. METHODS: Pathophysiological contributions of CaV 3.2 calcium channels to burst firing and absence seizures were assessed in vitro using acute brain slice electrophysiology and quantitative real-time polymerase chain reaction (PCR) and in vivo using free-moving electrocorticography recordings. RESULTS: TRN neurons from GAERS display sustained oscillatory burst-firing that is both age- and frequency-dependent, occurring only in the frequencies overlapping with GAERS SWDs and correlating with the expression of a CaV 3.2 mutation-sensitive splice variant. In vivo knock-down of CaV 3.2 using direct thalamic injection of lipid nanoparticles containing CaV 3.2 dicer small interfering (Dsi) RNA normalized TRN burst-firing, and in free-moving GAERS significantly shortened seizures. SIGNIFICANCE: This supports a role for TRN CaV 3.2 T-type channels in propagating thalamocortical network seizures and setting the pacemaking frequency of SWDs.

The N-Methyl d-Aspartate Glutamate Receptor Antagonist Ketamine Disrupts the Functional State of the Corticothalamic Pathway.

The non-competitive N-methyl d-aspartate glutamate receptor (NMDAR) antagonist ketamine elicits a brain state resembling high-risk states for developing psychosis and early stages of schizophrenia characterized by sensory and cognitive deficits and aberrant ongoing gamma (30-80 Hz) oscillations in cortical and subcortical structures, including the thalamus. The underlying mechanisms are unknown. The goal of the present study was to determine whether a ketamine-induced psychotic-relevant state disturbs the functional state of the corticothalamic (CT) pathway. Multisite field recordings were performed in the somatosensory CT system of the sedated rat. Baseline activity was challenged by activation of vibrissa-related prethalamic inputs. The sensory-evoked thalamic response was characterized by a short-latency (∼4 ms) prethalamic-mediated negative sharp potential and a longer latency (∼10 ms) CT-mediated negative potential. Following a single subcutaneous injection of ketamine (2.5 mg/kg), spontaneously occurring and sensory-evoked thalamic gamma oscillations increased and decreased in power, respectively. The power of the sensory-related gamma oscillations was positively correlated with both the amplitude and the area under the curve of the corresponding CT potential but not with the prethalamic potential. The present results show that the layer VI CT pathway significantly contributes in thalamic gamma oscillations, and they support the hypothesis that reduced NMDAR activation disturbs the functional state of CT and corticocortical networks.

Peritumoural glutamate correlates with post-operative seizures in supratentorial gliomas.

To examine the impact of glutamate on post-operative seizures and survival in a cohort of patients with grade II to IV supratentorial glioma. A retrospective analysis was performed on 216 patients who underwent surgery for supratentorial gliomas. Primary explanatory variables were peritumoural and/or tumoural glutamate concentrations, glutamate transporter expression (EAAT2 and SXC). Univariate and multivariate survival analysis was performed with primary outcomes of time to first post-operative seizure and overall survival. Subgroup analysis was performed in patients with de novo glioblastomas who received adjuvant chemoradiotherapy. 47 (21.8 %), 34 (15.8 %) and 135 (62.5 %) WHO grade II, III and IV gliomas respectively were followed for a median of 15.8 months. Following multivariate analysis, there was a non-significant association between higher peritumoural glutamate concentrations and time to first post-operative seizure (HR 2.07, CI 0.98-4.37, p = 0.06). In subgroup analysis of 81 glioblastoma patients who received adjunct chemoradiotherapy, peritumoural glutamate concentration was significantly associated with time to first post-operative seizure (HR 3.10, CI 1.20-7.97, p = 0.02). In both the overall cohort and subgroup analysis no glutamate cycle biomarkers were predictive of overall survival. Increased concentrations of peritumoural glutamate were significantly associated with shorter periods of post-operative seizure freedom in patients with de novo glioblastomas treated with adjuvant chemoradiotherapy. No glutamate cycle biomarkers were predictive of overall survival. These results suggest that therapies targeting glutamate may be beneficial in tumour associated epilepsy.

Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy.

PURPOSE: The association between autism spectrum disorders (ASDs) and prenatal anticonvulsant exposure is increasingly investigated, but comprehensive, blinded assessment using a validated instrument for autism within a well-characterized prospective cohort has not been conducted. Thus, existing studies may represent an underestimate of the true risk. Herein we present a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status. METHODS: Participants were 105 Australian children aged 6-8 years who were recruited via the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS). RESULTS: Eleven children (10.5%) had elevated CARS scores. Two were exposed to valproate monotherapy (2/26; 7.7%), two to carbamazepine monotherapy (2/34; 5.9%), and seven to valproate in polytherapy (7/15; 46.7%). Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal intelligence quotient (IQ), and socioeconomic status. First trimester folic acid supplementation and marijuana use were also significant predictors of CARS scores. SIGNIFICANCE: Using direct assessment of children in our prospective study, we found an elevated rate of autism traits across the sample. The most important determinant of association with autistic traits was higher doses of sodium valproate exposure. The use of valproate in women who may become pregnant is now generally avoided; however, there are insufficient data regarding the risk of ASD with low-dose valproate. If this risk is no greater than with other antiepileptic drugs (AED)s, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child.

The challenge and promise of anti-epileptic therapy development in animal models.

Translation of successful target and compound validation studies into clinically effective therapies is a major challenge, with potential for costly clinical trial failures. This situation holds true for the epilepsies-complex diseases with different causes and symptoms. Although the availability of predictive animal models has led to the development of effective antiseizure therapies that are routinely used in clinical practice, showing that translation can be successful, several important unmet therapeutic needs still exist. Available treatments do not fully control seizures in a third of patients with epilepsy, and produce substantial side-effects. No treatment can prevent the development of epilepsy in at-risk patients or cure patients with epilepsy. And no specific treatment for epilepsy-associated comorbidities exists. To meet these demands, a redesign of translational approaches is urgently needed.

Effects of aberrant gamma frequency oscillations on prepulse inhibition.

Emerging literature implicates abnormalities in gamma frequency oscillations in the pathophysiology of schizophrenia, with hypofunction of N-methyl-D-aspartate (NMDA) receptors implicated as a key factor. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating, which is disrupted in schizophrenia. We studied relationships between ongoing and sensory-evoked gamma oscillations and PPI using pharmacological interventions designed to increase gamma oscillations (ketamine, MK-801); reduce gamma oscillations (LY379268); or disrupt PPI (amphetamine). We predicted that elevating ongoing gamma power would lead to increased 'neural noise' in cortical circuits, dampened sensory-evoked gamma responses and disrupted behaviour. Wistar rats were implanted with EEG recording electrodes. They received ketamine (5 mg/kg), MK-801 (0.16 mg/kg), amphetamine (0.5 mg/kg), LY379268 (3 mg/kg) or vehicle and underwent PPI sessions with concurrent EEG recording. Ketamine and MK-801 increased the power of ongoing gamma oscillations and caused time-matched disruptions of PPI, while amphetamine marginally affected ongoing gamma power. In contrast, LY379268 reduced ongoing gamma power, but had no effect on PPI. The sensory gamma response evoked by the prepulse was reduced following treatment with all psychotomimetics, associating with disruptions in PPI. This was most noticeable following treatment with NMDA receptor antagonists. We found that ketamine and MK-801 increase ongoing gamma power and reduce evoked gamma power, both of which are related to disruptions in sensorimotor gating. This appears to be due to antagonism of NMDA receptors, since amphetamine and LY379268 differentially impacted these outcomes and possess different neuropharmacological substrates. Aberrant gamma frequency oscillations caused by NMDA receptor hypofunction may mediate the sensory processing deficits observed in schizophrenia.

HCN channelopathy and cardiac electrophysiologic dysfunction in genetic and acquired rat epilepsy models.

OBJECTIVE: Evidence from animal and human studies indicates that epilepsy can affect cardiac function, although the molecular basis of this remains poorly understood. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels generate pacemaker activity and modulate cellular excitability in the brain and heart, with altered expression and function associated with epilepsy and cardiomyopathies. Whether HCN expression is altered in the heart in association with epilepsy has not been investigated previously. We studied cardiac electrophysiologic properties and HCN channel subunit expression in rat models of genetic generalized epilepsy (Genetic Absence Epilepsy Rats from Strasbourg, GAERS) and acquired temporal lobe epilepsy (post-status epilepticus SE). We hypothesized that the development of epilepsy is associated with altered cardiac electrophysiologic function and altered cardiac HCN channel expression. METHODS: Electrocardiography studies were recorded in vivo in rats and in vitro in isolated hearts. Cardiac HCN channel messenger RNA (mRNA) and protein expression were measured using quantitative PCR and Western blotting respectively. RESULTS: Cardiac electrophysiology was significantly altered in adult GAERS, with slower heart rate, shorter QRS duration, longer QTc interval, and greater standard deviation of RR intervals compared to control rats. In the post-SE model, we observed similar interictal changes in several of these parameters, and we also observed consistent and striking bradycardia associated with the onset of ictal activity. Molecular analysis demonstrated significant reductions in cardiac HCN2 mRNA and protein expression in both models, providing a molecular correlate of these electrophysiologic abnormalities. SIGNIFICANCE: These results demonstrate that ion channelopathies and cardiac dysfunction can develop as a secondary consequence of chronic epilepsy, which may have relevance for the pathophysiology of cardiac dysfunction in patients with epilepsy.