Mouse models of Kcnq2 dysfunction.

Variants in the Kv7.2 channel subunit encoded by the KCNQ2 gene cause epileptic disorders ranging from a benign form with self-limited epileptic seizures and normal development to severe forms with intractable epileptic seizures and encephalopathy. The biological mechanisms involved in these neurological diseases are still unclear. The disease remains intractable in patients affected by the severe form. Over the past 20 years, KCNQ2 models have been developed to elucidate pathological mechanisms and to identify new therapeutic targets. The diversity of Kcnq2 mouse models has proven invaluable to access neuronal networks and evaluate the associated cognitive deficits. This review summarizes the available models and their contribution to our current understanding of KCNQ2 epileptic disorders.

Ultrasound-induced seizures in a mouse model of KCNQ2-NEO-DEE.

PURPOSE: KCNQ2 neonatal developmental and epileptic encephalopathy (NEO-DEE) is characterized by intractable seizures accompanied by an abnormal neurodevelopment. In a mouse model of NEO-DEE carrying the p.(Thr274Met) variant of Kcnq2, spontaneous generalized seizures occur unexpectedly preventing controlled studies and highlighting the necessity for a customized setup to trigger seizures on demand. We aimed to obtain a stable and objective read-out to control the efficacy of new antiepileptic drugs or to test seizure susceptibility. We developed a protocol to trigger ultrasound-induced seizures (UIS) on demand in this model. METHODS: We tested the ability of our protocol to induce seizures at four developmental stages in the Kcnq2p.(Thr274Met/+) mouse model. We mapped the activated brain regions using c-fos protein labeling 2 h after seizure induction. RESULTS: We show that the UIS have the same phenotypic expression and the same severity as spontaneous generalized seizures (SGS) in the Kcnq2-NEO-DEE mouse model. The developmental period during which mice exhibit SGS corresponds to the period during which Kcnq2p.(Thr274Met/+) mice are the most susceptible to US. C-fos labeling reveals a subset of 6 brain regions activated 2 h after the induction of the seizure. The same regions were identified in the context of seizure induction in other rodent models. CONCLUSION: This study provides a non-invasive and easy to use method to induce seizures in a Kcnq2-NEO-DEE mouse model and documents early neuronal activation in specific brain regions. This method can be used to test the efficacy of new antiepileptic approaches for this intractable form of genetic epilepsy.

Group-level cortical surface parcellation with sulcal pits labeling.

Sulcal pits are the points of maximal depth within the folds of the cortical surface. These shape descriptors give a unique opportunity to access to a rich, fine-scale representation of the geometry and the developmental milestones of the cortical surface. However, using sulcal pits analysis at group level requires new numerical tools to establish inter-subject correspondences. Here, we address this issue by taking advantage of the geometrical information carried by sulcal basins that are the local patches of surfaces surrounding each sulcal pit. Our framework consists in two phases. First, we present a new method to generate a population-specific atlas of this sulcal basins organi- zation as a fold-level parcellation of the cortical surface. Then, we address the labeling of individual sulcal pits and corresponding basins with respect to this atlas. To assess their validity, we applied these methodological advances on two different populations of healthy subjects. The first database of 137 adults allowed us to compare our method to the state-of-the-art and the second database of 209 children, aged between 0 and 18 years, illustrates the adaptability and relevance of our method in the context of pediatric data showing strong variations in cortical volume and folding.

Diffusion MRI: Assessment of the Impact of Acquisition and Preprocessing Methods Using the BrainVISA-Diffuse Toolbox.

Diffusion MR images are prone to severe geometric distortions induced by head movement, eddy-current and inhomogeneity of magnetic susceptibility. Various correction methods have been proposed that depend on the choice of the acquisition settings and potentially provide highly different data quality. However, the impact of this choice has not been evaluated in terms of the ratio between scan time and preprocessed data quality. This study aims at investigating the impact of six well-known preprocessing methods, each associated to specific acquisition settings, on the outcome of diffusion analyses. For this purpose, we developed a comprehensive toolbox called Diffuse which automatically guides the user to the best preprocessing pipeline according to the input data. Using MR images of 20 subjects from the HCP dataset, we compared the six pre-processing pipelines regarding the following criteria: the ability to recover brain's true geometry, the tensor model estimation and derived indices in the white matter, and finally the spatial dispersion of six well known connectivity pathways. As expected the pipeline associated to the longer acquisition fully repeated with reversed phase-encoding (RPE) yielded the higher data quality and was used as a reference to evaluate the other pipelines. In this way, we highlighted several significant aspects of other pre-processing pipelines. Our results first established that eddy-current correction improves the tensor-fitting performance with a localized impact especially in the corpus callosum. Concerning susceptibility distortions, we showed that the use of a field map is not sufficient and involves additional smoothing, yielding to an artificial decrease of tensor-fitting error. Of most importance, our findings demonstrate that, for an equivalent scan time, the acquisition of a b0 volume with RPE ensures a better brain's geometry reconstruction and local improvement of tensor quality, without any smoothing of the image. This was found to be the best scan time/data quality compromise. To conclude, this study highlights and attempts to quantify the strong dependence of diffusion metrics on acquisition settings and preprocessing methods.

Structural graph-based morphometry: A multiscale searchlight framework based on sulcal pits.

Studying the topography of the cortex has proved valuable in order to characterize populations of subjects. In particular, the recent interest towards the deepest parts of the cortical sulci - the so-called sulcal pits - has opened new avenues in that regard. In this paper, we introduce the first fully automatic brain morphometry method based on the study of the spatial organization of sulcal pits - Structural Graph-Based Morphometry (SGBM). Our framework uses attributed graphs to model local patterns of sulcal pits, and further relies on three original contributions. First, a graph kernel is defined to provide a new similarity measure between pit-graphs, with few parameters that can be efficiently estimated from the data. Secondly, we present the first searchlight scheme dedicated to brain morphometry, yielding dense information maps covering the full cortical surface. Finally, a multi-scale inference strategy is designed to jointly analyze the searchlight information maps obtained at different spatial scales. We demonstrate the effectiveness of our framework by studying gender differences and cortical asymmetries: we show that SGBM can both localize informative regions and estimate their spatial scales, while providing results which are consistent with the literature. Thanks to the modular design of our kernel and the vast array of available kernel methods, SGBM can easily be extended to include a more detailed description of the sulcal patterns and solve different statistical problems. Therefore, we suggest that our SGBM framework should be useful for both reaching a better understanding of the normal brain and defining imaging biomarkers in clinical settings.

Enzymatic degradation of organophosphorus insecticides decreases toxicity in planarians and enhances survival.

Organophosphorus insecticides (OPs) are toxic compounds used for agricultural purposes and responsible for severe types of contamination worldwide. OPs may also induce chronic deleterious effects and developmental disruption. Finding remediation strategies is a major concern to diminish their impact on environment and human health. Enzymes have emerged as a promising eco-friendly route for decontaminating OPs. The enzyme SsoPox from the archaea Sulfolobus solfataricus has been particularly studied, considering both its tremendous stability and phosphotriesterase activity. However, the toxicity of the degradation products generated through enzyme hydrolysis has been poorly investigated. To address both neurotoxicity and developmental perturbation, freshwater planarians from Platyhelminthes were considered to evaluate the impact of OP and degradation product exposure. Planarians have a large proportion of stem cells that give them an unconventional capacity for regeneration. OPs were found to be highly toxic to planarians and enzyme decontamination drastically enhanced survival rate. Although not completely innocuous, the degradation products were found to be less toxic than insecticides and reduced poisoning effects by increasing NOEC values by up to eight-fold. SsoPox also limited detrimental consequences on planarian mobility and enabled them to recover a non-exposed type regeneration process suggesting that enzymatic decontamination is a promising alternative to bioremediation.

Localized Misfolding Within Broca's Area as a Distinctive Feature of Autistic Disorder.

BACKGROUND: Recent neuroimaging studies suggest that autism spectrum disorder results from abnormalities in the cortical folding pattern. Usual morphometric measurements have failed to provide reliable neuroanatomic markers. Here, we propose that sulcal pits, which are the deepest points in each fold, are suitable candidates to uncover this atypical cortical folding. METHODS: Sulcal pits were extracted from a magnetic resonance imaging database of 102 children (1.5-10 years old) distributed in three groups: children with autistic disorder (n = 59), typically developing children (n = 22), and children with pervasive developmental disorder not otherwise specified (n = 21). The geometrical properties of sulcal pits were compared between these three groups. RESULTS: Fold-level analyses revealed a reduced pit depth in the left ascending ramus of the Sylvian fissure in children with autistic disorder only. The depth of this central fold of Broca's area was correlated with the social communication impairments that are characteristic of the pathology. CONCLUSIONS: Our findings support an atypical gyrogenesis of this specific fold in autistic disorder that could be used for differential diagnosis. Sulcal pits constitute valuable markers of the cortical folding dynamics and could help for the early detection of atypical brain maturation.

Non-motor fluctuations in Parkinson's disease: prevalence, characteristics and management in a large cohort of parkinsonian outpatients.

OBJECTIVE: To describe demographic and clinical characteristics in a group of Parkinson's disease (PD) patients with non-motor fluctuations (NMF) and to evaluate the management of medications proposed to treat NMF. METHODS: Three hundred and three PD patients (mean age, 66 ± 10.3 years; mean disease duration, 10.1 ± 6.5 years) were enrolled. Each patient was interviewed in a non-directed fashion about the main NMF manifestations, i.e. dysautonomic, mental, and sensory symptoms. Both groups of patients with and without NMF were compared. Dysautonomia, motor fluctuations, age, disease duration, and LEDD were included in a multiple regression to determine which were predictive of NMF. RESULTS: NMF were found in 57 (19%) patients, mean age 65 ± 10.1 years, mean age at onset of PD 53.7 ± 10.9 years, mean disease duration 12.5 ± 6.9 years. NMF occurred on average 9.8 ± 7.7 years after the onset of PD. Fifty patients (86%) with NMF had also MF and 10 (21%) had PDD. Twenty-five (44%) patients suffered from sensory, 28 (49%) from autonomic and 25 (44%) from neuropsychiatric symptoms. Both disease and L-Dopa treatment durations, and LEDD were significantly higher in NMF patient's group. Motor fluctuations (p = 0.0016) and presence of dysautonomia (p = 0.007) were found to be two independent predictors of NMF. CONCLUSION: The development of new instruments to assess NMF is crucial for optimized management of advanced PD.