Cannabinoid treatments in epilepsy and seizure disorders.

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 controlled clinical trials that led to US Food and Drug Administration approval of CBD for some types of epilepsy. Overall, we seek to evaluate our current understanding of cannabinoids in epilepsy and focus future research on unanswered questions.

Mental Health of Royal Canadian Mounted Police at the Start of the Cadet Training Program.

OBJECTIVE: Serving Royal Canadian Mounted Police (RCMP) have screened positive for one or more mental disorders based on self-reported symptoms with substantial prevalence (i.e., 50.2%). Mental health challenges for military and paramilitary populations have historically been attributed to insufficient recruit screening; however, cadet mental health when starting the Cadet Training Program (CTP) was unknown. Our objective was to estimate RCMP Cadet mental health when starting the CTP and test for sociodemographic differences. METHOD: Cadets starting the CTP completed a survey assessing self-reported mental health symptoms (n = 772, 72.0% male) and a clinical interview (n = 736, 74.4% male) with a clinician or supervised trainee using the Mini-International Neuropsychiatric Interview to assess current and past mental health. RESULTS: The percentage of participants screening positive for one or more current mental disorders based on self-reported symptoms (15.0%) was higher than the diagnostic prevalence for the general population (10.1%); however, based on clinical interviews, participants were less likely to screen positive for any current mental disorder (6.3%) than the general population. Participants were also less likely to screen positive for any past mental disorder based on self-report (3.9%) and clinical interviews (12.5%) than the general population (33.1%). Females were more likely to score higher than males (all ps<.01; Cohen's ds .23 to .32) on several self-report mental disorder symptom measures. CONCLUSIONS: The current results are the first to describe RCMP cadet mental health when starting the CTP. The data evidenced a lower prevalence of anxiety, depressive, and trauma-related mental disorders than the general population based on clinical interviews, contrasting notions that more rigorous mental health screening would reduce the high prevalence of mental disorders among serving RCMP. Instead, protecting RCMP mental health may require ongoing efforts to mitigate operational and organizational stressors.

Mental Disorder Symptoms among Public Safety Personnel in Canada.

BACKGROUND: Canadian public safety personnel (PSP; e.g., correctional workers, dispatchers, firefighters, paramedics, police officers) are exposed to potentially traumatic events as a function of their work. Such exposures contribute to the risk of developing clinically significant symptoms related to mental disorders. The current study was designed to provide estimates of mental disorder symptom frequencies and severities for Canadian PSP. METHODS: An online survey was made available in English or French from September 2016 to January 2017. The survey assessed current symptoms, and participation was solicited from national PSP agencies and advocacy groups. Estimates were derived using well-validated screening measures. RESULTS: There were 5813 participants (32.5% women) who were grouped into 6 categories (i.e., call center operators/dispatchers, correctional workers, firefighters, municipal/provincial police, paramedics, Royal Canadian Mounted Police). Substantial proportions of participants reported current symptoms consistent with 1 (i.e., 15.1%) or more (i.e., 26.7%) mental disorders based on the screening measures. There were significant differences across PSP categories with respect to proportions screening positive based on each measure. INTERPRETATION: The estimated proportion of PSP reporting current symptom clusters consistent with 1 or more mental disorders appears higher than previously published estimates for the general population; however, direct comparisons are impossible because of methodological differences. The available data suggest that Canadian PSP experience substantial and heterogeneous difficulties with mental health and underscore the need for a rigorous epidemiologic study and category-specific solutions.

A longitudinal assessment of the road to mental readiness training among municipal police.

Police agencies increasingly implement training programs to protect mental health. The Road to Mental Readiness (R2MR) program was designed by the Canadian military to increase mental health resilience. A version of R2MR was adapted for municipal police by the Mental Health Commission of Canada (MHCC). The current research was designed to assess the R2MR program, as adapted and delivered by the MHCC, in a municipal police sample. Participants were 147 Canadian police agency employees (57% women) who received a single R2MR training session. Participants completed pre- and post-training self-report questionnaires, and follow-ups at 6 and 12 months. The questionnaires assessed mental health symptoms, work engagement, resiliency, mental health knowledge, and stigma. Multilevel modeling analyses assessed for within-participant changes over time. The results were consistent with other single session interventions; specifically, there were no significant changes in mental health symptoms, resilience, or work engagement (p > .05). There were small, but significant (p < .05), reductions in stigma at post-training that may facilitate help-seeking among police; relatedly, in open-ended response fields, participants commonly described the training as helpful for changing attitudes and improving communication. More engagement with the material may produce larger, sustained gains, but more published research is critically needed.

Cerebellar zonal patterning relies on Purkinje cell neurotransmission.

Cerebellar circuits are patterned into an array of topographic parasagittal domains called zones. The proper connectivity of zones is critical for motor coordination and motor learning, and in several neurological diseases cerebellar circuits degenerate in zonal patterns. Despite recent advances in understanding zone function, we still have a limited understanding of how zones are formed. Here, we focused our attention on Purkinje cells to gain a better understanding of their specific role in establishing zonal circuits. We used conditional mouse genetics to test the hypothesis that Purkinje cell neurotransmission is essential for refining prefunctional developmental zones into sharp functional zones. Our results show that inhibitory synaptic transmission in Purkinje cells is necessary for the precise patterning of Purkinje cell zones and the topographic targeting of mossy fiber afferents. As expected, blocking Purkinje cell neurotransmission caused ataxia. Using in vivo electrophysiology, we demonstrate that loss of Purkinje cell communication altered the firing rate and pattern of their target cerebellar nuclear neurons. Analysis of Purkinje cell complex spike firing revealed that feedback in the cerebellar nuclei to inferior olive to Purkinje cell loop is obstructed. Loss of Purkinje neurotransmission also caused ectopic zonal expression of tyrosine hydroxylase, which is only expressed in adult Purkinje cells when calcium is dysregulated and if excitability is altered. Our results suggest that Purkinje cell inhibitory neurotransmission establishes the functional circuitry of the cerebellum by patterning the molecular zones, fine-tuning afferent circuitry, and shaping neuronal activity.

Geographical range, heat tolerance and invasion success in aquatic species.

Species with broader geographical ranges are expected to be ecological generalists, while species with higher heat tolerances may be relatively competitive at more extreme and increasing temperatures. Thus, both traits are expected to relate to increased survival during transport to new regions of the globe, and once there, establishment and spread. Here, we explore these expectations using datasets of latitudinal range breadth and heat tolerance in freshwater and marine invertebrates and fishes. After accounting for the latitude and hemisphere of each species' native range, we find that species introduced to freshwater systems have broader geographical ranges in comparison to native species. Moreover, introduced species are more heat tolerant than related native species collected from the same habitats. We further test for differences in range breadth and heat tolerance in relation to invasion success by comparing species that have established geographically restricted versus extensive introduced distributions. We find that geographical range size is positively related to invasion success in freshwater species only. However, heat tolerance is implicated as a trait correlated to widespread occurrence of introduced populations in both freshwater and marine systems. Our results emphasize the importance of formal risk assessments before moving heat tolerant species to novel locations.

Impact of a Novel Biplane User Interface on Ultrasound-Guided Vascular Access Performance: A Prospective, Randomized, Crossover Study.

BACKGROUND: Controversy exists regarding the optimal methods of employing ultrasound to enhance vascular access. A novel user interface which dynamically displays transverse (short) and longitudinal (long) planes simultaneously was developed to optimize ultrasound-guided vascular access. This study aimed to assess the impact of this novel biplane axis technology on central venous access performance. METHODS: Eighteen volunteer emergency medicine resident physicians and physician assistants were recruited from a single center to participate in this prospective, randomized crossover study. Following a brief instructional video, participants were randomized to perform ultrasound-guided vascular access using either short-axis or biplane axis approaches first, followed by the opposite technique following a brief washout period. Time to cannulation was the primary outcome measure. Secondary outcome measures included success rate, posterior wall and arterial puncture rates, time to scout, number of attempts, number of needle redirections, participant cannulization and visualization confidence, and interface preference. RESULTS: Short-axis imaged approach was associated with a significantly shorter time to cannulation (34.9 seconds versus 17.6, p is less than 0.001) and time to scout (30 versus 49 seconds, p is equal to 0.008) when compared to biplaneaxis imaging approach. No significant differences were noted when comparing first pass success, number of attempts, number of redirections, and posterior wall and arterial wall puncture. Participants' cannulation/visualization confidence and axis preference both favored the short-axis imaging approach. CONCLUSION: Further studies are needed to assess the clinical value of novel biplane axis ultrasound imaging in the performance of ultrasound-guided procedures.

Joint Vestibular Schwannoma Enlargement Prediction and Segmentation Using a Deep Multi-task Model.

OBJECTIVE: To develop a deep-learning-based multi-task (DMT) model for joint tumor enlargement prediction (TEP) and automatic tumor segmentation (TS) for vestibular schwannoma (VS) patients using their initial diagnostic contrast-enhanced T1-weighted (ceT1) magnetic resonance images (MRIs). METHODS: Initial ceT1 MRIs for VS patients meeting the inclusion/exclusion criteria of this study were retrospectively collected. VSs on the initial MRIs and their first follow-up scans were manually contoured. Tumor volume and enlargement ratio were measured based on expert contours. A DMT model was constructed for jointly TS and TEP. The manually segmented VS volume on the initial scan and the tumor enlargement label (≥20% volumetric growth) were used as the ground truth for training and evaluating the TS and TEP modules, respectively. RESULTS: We performed 5-fold cross-validation with the eligible patients (n = 103). Median segmentation dice coefficient, prediction sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC) were measured and achieved the following values: 84.20%, 0.68, 0.78, 0.72, and 0.77, respectively. The segmentation result is significantly better than the separate TS network (dice coefficient of 83.13%, p = 0.03) and marginally lower than the state-of-the-art segmentation model nnU-Net (dice coefficient of 86.45%, p = 0.16). The TEP performance is significantly better than the single-task prediction model (AUC = 0.60, p = 0.01) and marginally better than a radiomics-based prediction model (AUC = 0.70, p = 0.17). CONCLUSION: The proposed DMT model is of higher learning efficiency and achieves promising performance on TEP and TS. The proposed technology has the potential to improve VS patient management. LEVEL OF EVIDENCE: NA Laryngoscope, 133:2754-2760, 2023.

The Royal Canadian Mounted Police (RCMP) Study: protocol for a prospective investigation of mental health risk and resilience factors. / Étude de la Gendarmerie royale du Canada : protocole d'enquête prospective sur les facteurs de risque et de résilience en matière de santé mentale.

The Royal Canadian Mounted Police (RCMP), like all public safety personnel (PSP), are frequently exposed to potentially psychologically traumatic events that contribute to posttraumatic stress injuries (PTSI). Addressing PTSI is impeded by the limited available research. In this protocol paper, we describe the RCMP Study, part of the concerted efforts by the RCMP to reduce PTSI by improving access to evidence-based assessments, treatments and training as well as participant recruitment and RCMP Study developments to date. The RCMP Study has been designed to (1) develop, deploy and assess the impact of a system for ongoing annual, monthly and daily evidence-based assessments; (2) evaluate associations between demographic variables and PTSI; (3) longitudinally assess individual differences associated with PTSI; (4) augment the RCMP Cadet Training Program with skills to proactively mitigate PTSI; and (5) assess the impact of the augmented training condition (ATC) versus the standard training condition (STC). Participants in the STC (n = 480) and ATC (n = 480) are assessed before and after training and annually for 5 years on their deployment date; they also complete brief monthly and daily surveys. The RCMP Study results are expected to benefit the mental health of all participants, RCMP and PSP by reducing PTSI among all who serve.

Research is limited on how to mitigate posttraumatic stress injuries (PTSIs) among Royal Canadian Mounted Police (RCMP) who are exposed to potentially psychologically traumatic events. The RCMP Study has been designed to develop, deploy and assess the impact of skills taught to proactively mitigate PTSI. RCMP cadets recruited into the study to receive the augmented training are assessed before and after training and annually for 5 years on their deployment date. The RCMP Study results are expected to benefit the mental health of study participants, RCMP and other public safety personnel by mitigating PTSI among all who serve.

On dispose de peu de recherches sur les moyens d'atténuer les blessures de stress post­traumatique chez les membres de la Gendarmerie royale du Canada (GRC) qui sont exposés à des événements potentiellement traumatiques sur le plan psychologique. L'étude de la GRC a été conçue pour mettre au point des compétences permettant d'atténuer de façon proactive les blessures de stress post­traumatique, pour intégrer ces compétences à la formation offerte aux cadets et pour en évaluer les effets. Les cadets de la GRC recrutés dans le cadre de l'étude en vue de suivre une formation renforcée sont évalués avant et après la formation ainsi que chaque année pendant cinq ans à compter de la date de leur déploiement. Les résultats de l'étude de la GRC devraient être bénéfiques pour la santé mentale des participants de l'étude, pour la GRC et pour les autres membres du personnel de la sécurité publique, en contribuant à atténuer les blessures de stress post­traumatique de tous ceux qui sont au service de la population.

Assessing the impact of the Royal Canadian Mounted Police (RCMP) protocol and Emotional Resilience Skills Training (ERST) among diverse public safety personnel.

BACKGROUND: Public safety personnel (PSP; e.g., border services personnel, correctional workers, firefighters, paramedics, police, public safety communicators) are frequently exposed to potentially psychologically traumatic events. Such events contribute to substantial and growing challenges from posttraumatic stress injuries (PTSIs), including but not limited to posttraumatic stress disorder. METHODS: The current protocol paper describes the PSP PTSI Study (i.e., design, measures, materials, hypotheses, planned analyses, expected implications, and limitations), which was originally designed to evaluate an evidence-informed, proactive system of mental health assessment and training among Royal Canadian Mounted Police for delivery among diverse PSP (i.e., firefighters, municipal police, paramedics, public safety communicators). Specifically, the PSP PTSI Study will: (1) adapt, implement, and assess the impact of a system for ongoing (i.e., annual, monthly, daily) evidence-based assessments; (2) evaluate associations between demographic variables and PTSI; (3) longitudinally assess individual differences associated with PTSI; and, (4) assess the impact of providing diverse PSP with a tailored version of the Emotional Resilience Skills Training originally developed for the Royal Canadian Mounted Police in mitigating PTSIs based on the Unified Protocol for the Transdiagnostic Treatment of Emotional Disorders. Participants are assessed pre- and post-training, and then at a follow-up 1-year after training. The assessments include clinical interviews, self-report surveys including brief daily and monthly assessments, and daily biometric data. The current protocol paper also describes participant recruitment and developments to date. DISCUSSION: The PSP PTSI Study is an opportunity to implement, test, and improve a set of evidence-based tools and training as part of an evidence-informed solution to protect PSP mental health. The current protocol paper provides details to inform and support translation of the PSP PTSI Study results as well as informing and supporting replication efforts by other researchers. TRIAL REGISTRATION: Hypotheses Registration: aspredicted.org, #90136. Registered 7 March 2022-Prospectively registered. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05530642. Registered 1 September 2022-Retrospectively registered. The subsequent PSP PTSI Study results are expected to benefit the mental health of all participants and, ultimately, all PSP.

Automated Detection of Vestibular Schwannoma Growth Using a Two-Dimensional U-Net Convolutional Neural Network.

OBJECTIVES/HYPOTHESIS: To determine if an automated vestibular schwannoma (VS) segmentation model has comparable performance to using the greatest linear dimension to detect growth. STUDY DESIGN: Case-control Study. METHODS: Patients were selected from an internal database who had an initial gadolinium-enhanced T1-weighted magnetic resonance imaging scan and a follow-up scan captured at least 5 months later. Two observers manually segmented the VS to compute volumes, and one observer's segmentations were used to train a convolutional neural network model to automatically segment the VS and determine the volume. The results of automatic segmentation were compared to the observer whose measurements were not used in model development to measure agreement. We then examined the sensitivity, specificity, and area under the receiver-operating characteristic curve (AUC) to compare automated volumetric growth detection versus using the greatest linear dimension. Growth detection determined by the external observer's measurements served as the gold standard. RESULTS: A total of 65 patients and 130 scans were studied. The automated method of segmentation demonstrated excellent agreement with the observer whose measurements were not used for model development for the initial scan (interclass correlational coefficient [ICC] = 0.995; 95% confidence interval [CI]: 0.991-0.997) and follow-up scan (ICC = 0.960; 95% CI: 0.935-0.975). The automated method of segmentation demonstrated increased sensitivity (72.2% vs. 63.9%), specificity (79.3% vs. 69.0%), and AUC (0.822 vs. 0.701) compared to using the greatest linear dimension for growth detection. CONCLUSIONS: In detecting VS growth, a convolutional neural network model outperformed using the greatest linear dimension, demonstrating a potential application of artificial intelligence methods to VS surveillance. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E619-E624, 2021.

Prediction of Vestibular Schwannoma Enlargement After Radiosurgery Using Tumor Shape and MRI Texture Features.

OBJECTIVE: Determine if vestibular schwannoma (VS) shape and MRI texture features predict significant enlargement after stereotactic radiosurgery (SRS). STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Fifty-three patients were selected who underwent SRS and had a contrast-enhanced T1 sequence planning MRI scan and a follow-up contrast enhanced T1 MRI available for review. Median follow-up of 6.5 months (interquartile range/IQR, 5.9-7.4). Median pretreatment tumor volume was 1,006 mm3 (IQR, 465-1,794). INTERVENTIONS: Stereotactic radiosurgery. MAIN OUTCOME MEASURES: Texture and shape features from the SRS planning scans were extracted and used to train a linear support vector machine binary classifier to predict post-SRS enlargement >20% of the pretreatment volume. Sensitivity, specificity, area under the receiver-operating-characteristic curve (AUC), and positive likelihood ratio were computed. A stratified analysis based on pretreatment tumor volume greater or less than the median volume was also performed. RESULTS: The model had a sensitivity of 92%, specificity of 65%, AUC of 0.75, and a positive likelihood ratio of 2.6 (95% CI 1.4-5.0) for predicting post-SRS enlargement of >20%. In the larger tumor subgroup, the model had a sensitivity of 87%, specificity of 73%, AUC of 0.76, and a positive likelihood ratio of 3.2 (95% CI 1.2-8.5). In the smaller tumor subgroup, the model had a sensitivity of 95%, specificity of 50%, AUC of 0.65, and a positive likelihood ratio of 1.9 (95% CI 0.8-4.3). CONCLUSIONS: VS shape and texture features may be useful inputs for machine learning models that predict VS enlargement after SRS.

MRI Texture Features are Associated with Vestibular Schwannoma Histology.

OBJECTIVES/HYPOTHESIS: To determine if commonly used radiomics features have an association with histological findings in vestibular schwannomas (VS). STUDY DESIGN: Retrospective case-series. METHODS: Patients were selected from an internal database of those who had a gadolinium-enhanced T1-weighted MRI scan captured prior to surgical resection of VS. Texture features from the presurgical magnetic resonance image (MRI) were extracted, and pathologists examined the resected tumors to assess for the presence of mucin, lymphocytes, necrosis, and hemosiderin and used a validated computational tool to determine cellularity. Sensitivity, specificity, and positive likelihood ratios were also computed for selected features using the Youden index to determine the optimal cut-off value. RESULTS: A total of 45 patients were included. We found significant associations between multiple MRI texture features and the presence of mucin, lymphocytes, hemosiderin, and cellularity. No significant associations between MRI texture features and necrosis were identified. We were able to identify significant positive likelihood ratios using Youden index cut-off values for mucin (2.3; 95% CI 1.2-4.3), hemosiderin (1.5; 95% CI 1.04-2.1), lymphocytes (3.8; 95% CI 1.2-11.7), and necrosis (1.5; 95% CI 1.1-2.2). CONCLUSIONS: MRI texture features are associated with underlying histology in VS. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E2000-E2006, 2021.

Transcription Factor Pit-1 Affects Transcriptional Timing in the Dual-Promoter Human Prolactin Gene.

Gene transcription occurs in short bursts interspersed with silent periods, and these kinetics can be altered by promoter structure. The effect of alternate promoter architecture on transcription bursting is not known. We studied the human prolactin (hPRL) gene that contains 2 promoters, a pituitary-specific promoter that requires the transcription factor Pit-1 and displays dramatic transcriptional bursting activity and an alternate upstream promoter that is active in nonpituitary tissues. We studied large hPRL genomic fragments with luciferase reporters, and used bacterial artificial chromosome recombineering to manipulate critical promoter regions. Stochastic switch mathematical modelling of single-cell time-lapse luminescence image data revealed that the Pit-1-dependent promoter showed longer, higher-amplitude transcriptional bursts. Knockdown studies confirmed that the presence of Pit-1 stabilized and prolonged periods of active transcription. Pit-1 therefore plays an active role in establishing the timing of transcription cycles, in addition to its cell-specific functions.

Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo.

Plant-derived cannabinoids (phytocannabinoids) are compounds with emerging therapeutic potential. Early studies suggested that cannabidiol (CBD) has anticonvulsant properties in animal models and reduced seizure frequency in limited human trials. Here, we examine the antiepileptiform and antiseizure potential of CBD using in vitro electrophysiology and an in vivo animal seizure model, respectively. CBD (0.01-100 muM) effects were assessed in vitro using the Mg(2+)-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings. In the Mg(2+)-free model, CBD decreased epileptiform local field potential (LFP) burst amplitude [in CA1 and dentate gyrus (DG) regions] and burst duration (in all regions) and increased burst frequency (in all regions). In the 4-AP model, CBD decreased LFP burst amplitude (in CA1 only at 100 muM CBD), burst duration (in CA3 and DG), and burst frequency (in all regions). CBD (1, 10, and 100 mg/kg) effects were also examined in vivo using the pentylenetetrazole model of generalized seizures. CBD (100 mg/kg) exerted clear anticonvulsant effects with significant decreases in incidence of severe seizures and mortality compared with vehicle-treated animals. Finally, CBD acted with only low affinity at cannabinoid CB(1) receptors and displayed no agonist activity in [(35)S]guanosine 5'-O-(3-thio)triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB(1) receptor-independent manner, to inhibit epileptiform activity in vitro and seizure severity in vivo. Thus, we demonstrate the potential of CBD as a novel antiepileptic drug in the unmet clinical need associated with generalized seizures.

Δ9-Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats.

PURPOSE: We assessed the anticonvulsant potential of the phytocannabinoid Δ9-tetrahydrocannabivarin (Δ9-THCV) by investigating its effects in an in vitro piriform cortex (PC) brain slice model of epileptiform activity, on cannabinoid CB1 receptor radioligand-binding assays and in a generalized seizure model in rats. METHODS: Δ9-THCV was applied before (10 µm Δ9-THCV) or during (10-50 µm Δ9-THCV) epileptiform activity induced by Mg²(+) -free extracellular media in adult rat PC slices and measured using multielectrode array (MEA) extracellular electrophysiologic techniques. The actions of Δ9-THCV on CB1 receptors were examined using [³H]SR141716A competition binding and [³5S]GTPγS assays in rat cortical membranes. Effects of Δ9-HCV (0.025-2.5 mg/kg) on pentylenetetrazole (PTZ)-induced seizures in adult rats were also assessed. RESULTS: After induction of stable spontaneous epileptiform activity, acute Δ9 -THCV application (≥ 20 µm) significantly reduced burst complex incidence and the amplitude and frequency of paroxysmal depolarizing shifts (PDSs). Furthermore, slices pretreated with 10 µm Δ9-THCV prior to induction of epileptiform activity exhibited significantly reduced burst complex incidence and PDS peak amplitude. In radioligand-binding experiments, Δ9-THCV acted as a CB1 receptor ligand, displacing 0.5 nm [³H]SR141716A with a Ki∼290 nm, but exerted no agonist stimulation of [³5S]GTPγS binding. In PTZ-induced seizures in vivo, 0.25 mg/kg Δ9-THCV significantly reduced seizure incidence. DISCUSSION: These data demonstrate that Δ9-THCV exerts antiepileptiform and anticonvulsant properties, actions that are consistent with a CB1 receptor-mediated mechanism and suggest possible therapeutic application in the treatment of pathophysiologic hyperexcitability states.

Anticonvulsive Properties of Cannabidiol in a Model of Generalized Seizure Are Transient Receptor Potential Vanilloid 1 Dependent.

Introduction: Highly purified cannabidiol (CBD) (approved as Epidiolex® in the United States) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials. CBD possesses affinity for many target classes with functional effects relevant to the pathophysiology of many disease types, including epilepsy. Although the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, transient receptor potential vanilloid 1 (TRPV1) represents a plausible target because (1) CBD activates and then desensitizes TRPV1, (2) TRPV1 is overexpressed in models of temporal lobe epilepsy and patients with epilepsy, (3) and TRPV1 modulates neuronal excitability. Methods: To investigate a potential role of TRPV1 in the anticonvulsive effects of CBD, the effect of CBD on seizure threshold was assessed using a mouse maximal electroshock threshold model of generalized seizure in TRPV1 knockout and wildtype mice. The dose dependence of the CBD effect was determined and compared with that of the positive comparator diazepam and vehicle. Results: At 50 and 100 mg/kg, CBD significantly (p<0.0001) increased seizure threshold in wildtype mice compared with TRPV1 knockout and vehicle controls. This effect was observed only at 100 mg/kg in TRPV1 knockout mice compared with knockout vehicle mice, in which gene deletion partially attenuated the CBD-increased seizure threshold. The effect of high-dose CBD in wildtype mice was nevertheless significantly different from vehicle-treated TRPV1 knockout mice (p<0.0001). Bioanalysis confirmed that genotype-specific differential brain exposure to CBD was not responsible for the observed effect on seizure threshold. Conclusion: These data strongly implicate TRPV1 in the potential mechanisms of action for the anticonvulsive effects of CBD. The partial inhibition of the anticonvulsive effect of high-dose CBD in TRPV1 knockout mice may indicate the involvement of targets other than TRPV1. Further characterization of TRPV1 in the anticonvulsive effect of CBD in validated models of seizure is warranted, as is pharmacological investigation of the molecular interaction between CBD and TRPV1.

Comparing Cochlear Duct Lengths Between CT and MR Images Using an Otological Surgical Planning Software.

OBJECTIVE: We sought to examine the intra- and interobserver variability in measuring the cochlear duct length (CDL) from magnetic resonance imaging (MRI) images versus computed tomography (CT) images using an otological surgical planning software that uses measurements of the basal turn diameter and cochlear width to estimate the CDL. PATIENTS: Twenty-one adult cochlear implant patients with preoperative MRI and CT images. INTERVENTION: Three fellowship-trained neurotologists served as the raters in the study. One rater measured the CDL using preoperative CT scans to serve as the benchmark. Two of the raters measured the CDL on preoperative MRI scans. One rater also remeasured the scans using MRI images after a period of 1 week to assess intraobserver variability. MAIN OUTCOME MEASURE: Intraclass correlational coefficients were calculated to assess for intra- and interobserver agreement. RESULTS: The mean CDL measured from the CT scans was 32.7 ±â€Š2.0 mm (range 29.4 - 37.6 mm). The mean difference between the raters when measuring the CDL using MRI scans was -0.15 ±â€Š2.1 mm (range -3.2 to 4.3 mm). The intraclass correlational coefficients for inter-rater reliability of CDL determination using MRI scans was judged as fair to excellent (0.68; 95% CI 0.41-0.84). The intrarater reliability of CDL determination using MRI scans was judged at fair to excellent (0.73; 95% CI 0.491-0.866). CONCLUSION: We demonstrate that a validated otological surgical planning software for estimating the CDL preoperatively had comparable performance using MRI scans versus the gold-standard CT scans.

Dynamic NF-κB and E2F interactions control the priority and timing of inflammatory signalling and cell proliferation.

Dynamic cellular systems reprogram gene expression to ensure appropriate cellular fate responses to specific extracellular cues. Here we demonstrate that the dynamics of Nuclear Factor kappa B (NF-κB) signalling and the cell cycle are prioritised differently depending on the timing of an inflammatory signal. Using iterative experimental and computational analyses, we show physical and functional interactions between NF-κB and the E2 Factor 1 (E2F-1) and E2 Factor 4 (E2F-4) cell cycle regulators. These interactions modulate the NF-κB response. In S-phase, the NF-κB response was delayed or repressed, while cell cycle progression was unimpeded. By contrast, activation of NF-κB at the G1/S boundary resulted in a longer cell cycle and more synchronous initial NF-κB responses between cells. These data identify new mechanisms by which the cellular response to stress is differentially controlled at different stages of the cell cycle.

Voltage-gated sodium (NaV) channel blockade by plant cannabinoids does not confer anticonvulsant effects per se.

Cannabidiol (CBD) is a non-psychoactive, well-tolerated, anticonvulsant plant cannabinoid, although its mechanism(s) of seizure suppression remains unknown. Here, we investigate the effect of CBD and the structurally similar cannabinoid, cannabigerol (CBG), on voltage-gated Na(+) (NaV) channels, a common anti-epileptic drug target. CBG's anticonvulsant potential was also assessed in vivo. CBD effects on NaV channels were investigated using patch-clamp recordings from rat CA1 hippocampal neurons in brain slices, human SH-SY5Y (neuroblastoma) cells and mouse cortical neurons in culture. CBG effects were also assessed in SH-SY5Y cells and mouse cortical neurons. CBD and CBG effects on veratridine-stimulated human recombinant NaV1.1, 1.2 or 1.5 channels were assessed using a membrane potential-sensitive fluorescent dye high-throughput assay. The effect of CBG on pentyleneterazole-induced (PTZ) seizures was assessed in rat. CBD (10µM) blocked NaV currents in SH-SY5Y cells, mouse cortical neurons and recombinant cell lines, and affected spike parameters in rat CA1 neurons; CBD also significantly decreased membrane resistance. CBG blocked NaV to a similar degree to CBD in both SH-SY5Y and mouse recordings, but had no effect (50-200mg/kg) on PTZ-induced seizures in rat. CBD and CBG are NaV channel blockers at micromolar concentrations in human and murine neurons and recombinant cells. In contrast to previous reports investigating CBD, CBG had no effect upon PTZ-induced seizures in rat, indicating that NaV blockade per se does not correlate with anticonvulsant effects.