Transient microstructural brain anomalies and epileptiform discharges in mice defective for epilepsy and language-related NMDA receptor subunit gene Grin2a

Wiley Periodicals, Inc. © 2018 International League Against Epilepsy Objective: The epilepsy-aphasia spectrum (EAS) is a heterogeneous group of age-dependent childhood disorders characterized by sleep-activated discharges associated with infrequent seizures and language, cognitive, and behavioral deficits. Defects in the GRIN2A gene, encoding a subunit of glutamate-gated N-methyl-d-aspartate (NMDA) receptors, represent the most important cause of EAS identified so far. Neocortical or thalamic lesions were detected in a subset of severe EAS disorders, and more subtle anomalies were reported in patients with so-called “benign” phenotypes. However, whether brain structural alterations exist in the context of GRIN2A defects is unknown. Methods: Magnetic resonance diffusion tensor imaging (MR-DTI) was used to perform longitudinal analysis of the brain at 3 developmental timepoints in living mice genetically knocked out (KO) for Grin2a. In addition, electroencephalography (EEG) was recorded using multisite extracellular electrodes to characterize the neocortical activity in vivo. Results: Microstructural alterations were detected in the neocortex, the corpus callosum, the hippocampus, and the thalamus of Grin2a KO mice. Most MR-DTI alterations were detected at a specific developmental stage when mice were aged 30 days, but not at earlier (15 days) or later (2 months) ages. EEG analysis detected epileptiform discharges in Grin2a KO mice in the third postnatal week. Significance: Grin2a KO mice replicated several anomalies found in patients with EAS disorders. Transient structural alterations detected by MR-DTI recalled the age-dependent course of EAS disorders, which in humans start during childhood and show variable outcome at the onset of adolescence. Together with the epileptiform discharges detected in young Grin2a KO mice, our data suggested the existence of early anomalies in the maturation of the neocortical and thalamocortical systems. Whereas the possible relationship of those anomalies with sleep warrants further investigations, our data suggest that Grin2a KO mice may serve as an animal model to study the neuronal mechanisms of EAS disorders and to design new therapeutic strategies

Matrix signalling and hippocampal neurogenesis

The adult mammalian brain harbours at least two germinal - or neurogenic - niches in which new neurons are born throughout life. These neurogenic niches comprise the subependymal zone which lines the ventricular system, and the subgranular zone in the hippocampal dentate gyrus. Post-natal hippocampal neurogenesis was in fact first identified experimentally in the 1960s. However perhaps due partly to aforementioned institutionalised belief and partly to a lack of accessible experimental tools, the phenomenon of hippocampal neurogenesis was widely recognised by the scientific community only shortly before the millennium. Consequent study has established that adult hippocampal neurogenesis has been conserved through millions of years of evolution in nearly every mammalian species studied to date. Importantly, post-mortem studies and radioisotope carbon dating techniques suggest that it also occurs in humans.A great deal of this research has focused on understanding the inner workings of the cells that undergo the transformation to become new adult-born neurons. By contrast, relatively little is known about the potential regulatory role of the surrounding extracellular microenvironment. This might be useful to know in light of much evidence that the extracellular matrix is a key regulator of developmental neurogenesis.This thesis describes my study of whether extracellular matrix regulates hippocampal neurogenesis

A Neuroimaging Investigation into Hallucination Proneness in a Healthy Population

The experience of hallucinations is one of the symptoms used in the diagnosis of a psychiatric disorders such as schizophrenia. Functional and structural neuroimaging studies consistently link hallucinatory experience with abnormalities in brain areas supporting normal processing such language areas in auditory verbal hallucinations (AVH) and visual sensory areas in visual hallucinations (VH). Hallucinations are not confined to clinical populations, but are also relatively frequent in the general population. Finding that healthy individuals experience hallucinations without distress has led to models proposing that hallucinatory experiences lie on a continuum, which spans healthy and clinical populations. Continuum models (e.g., Baumeister et al., 2017) provide a theoretical framework with testable hypotheses, that predict brain functional activation, morphometrics or microstructural alterations in the healthy hallucinator group from existing data in the clinical group. Healthy hallucinators therefore may be a key resource in informing transdiagnostic research into the neurological cause of hallucinations. The aim of the current study is to test whether hallucination proneness predict a wide range of multi-modal neuroimaging measures in a large, healthy population. The Launay-Slade Hallucination Scale modified by Morrison’s et al. (2000) LSHS(M) scale as well as auditory (LSHS(A)) and visual (LSHS(V)) subscales were used as a regressors in structural (VBM and FreeSurfer based morphometrics), functional (fMRI) and microstructural (DTI diffusivity and tractography) neuroimaging experiments to test whether alterations seen in patients translate into the healthy population. The morphometric analysis of structural data showed a significant positive correlation between brain thickness in the temporal cortex (bilateral transverse temporal gyrus) (TTG) and LSHS(M) scores. Functional activation data shows a significant positive correlation between LSHS(A) scores and activation in irrelevant task activation (audio/visual) in right (inferior frontal gyrus, superior temporal gyrus and middle temporal gyrus). DTI diffusivity analysis showed that reduced mean diffusivity (MD) in the right inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF) and occipital lobe (OL), also reduced axial diffusivity (AD) in the bilateral (SLF) and (OL) were linked to higher LSHS(M) scores. The arcuate fasciculus (AF) analysis showed that reduced diffusivity in the left (MD) and left (AD) were linked to high LSHS(M) scores. It is striking that, for this healthy population, the effects observed are the opposite of what might have been expected (continuum theory) for brain pathology and contrasts with previously published data for schizophrenia patients suffering from hallucinations. Finding consistent results using multiple imaging modalities in overlapping brain areas and for a relatively large population makes methodological differences or sampling effects an unlikely explanation for the results. The continuum hypothesis of hallucination assumes that psychotic symptoms, such as AVH and VH, which are experienced in clinical and non-clinical populations, have a common cause. In neuroimaging terms this means that similar functional, structural, and microstructural parameters would be expected for clinical and non-clinical populations show the same direction of differences. Our data does not fit well with this model. However, the results failed to prove that. Studying hallucinatory experiences in a healthy population is attractive because it avoids confounding effects, ranging from childhood trauma, medication or hospitalization. Our data suggests that studies in healthy individuals may not provide data that easily extrapolates to the causes underlying schizophrenic hallucinations