Cyclooxygenase-2 (COX-2), a source of inflammatory mediators and a multifunctional neuronal modulator, is rapidly induced in select populations of cortical neurons after status epilepticus. The consequences of rapid activity-triggered induction of COX-2 in neurons have been the subject of much study and speculation. To address this issue directly, we created a mouse in which COX-2 is conditionally ablated in selected forebrain neurons. Results following pilocarpine-induced status epilepticus indicate that neuronal COX-2 promotes early neuroprotection and then delayed neurodegeneration of CA1 pyramidal neurons, promotes neurodegeneration of nearby somatostatin interneurons in the CA1 stratum oriens and dentate hilus (which themselves do not express COX-2), intensifies a broad inflammatory reaction involving numerous cytokines and other inflammatory mediators in the hippocampus, and is essential for development of a leaky blood- brain barrier after seizures. These findings point to a profound role of seizure-induced neuronal COX-2 expression in neuropathologies that accompany epileptogenesis.
Cortical compression can be a significant problem in many types of brain injuries, such as brain trauma, localized brain edema, hematoma, focal cerebral ischemia, or brain tumors. Mechanical and cellular alterations can result in global changes in excitation and inhibition on the neuronal network level even in the absence of histologically significant cell injury, often manifesting clinically as seizures. Despite the importance and prevalence of this problem, however, the preciseelectro physiological effects of brain injury have not been well characterized. In this study, the changes in electrophysiology were characterized following sustained cortical compression usinglarge-scale, multi electrode measurement of multiun it activity in primary somatosensory cortexinasensory-evoked, in vivoanimal model. Immediately following the initiation of injury at a distal site, there was a period of suppression of the evoked response in the rat somatosensory cortex, followed by hyper-excitability that was accompanied by an increase in the spatial extent of cortical activation. Paired-pulse tactile stimulation revealed a dramatic shift in the excitatory/inhibitory dynamics, suggesting a longer term hyperexcitability of the cortical circuit following the initial suppression that could be linked to the disruption of one or more inhibitory mechanisms of the thalamocortical circuit. Together, our results showed that the use of a sensory-evoked response provided a robust and repeatable functional marker of the evolution of the consequences of mild injury, serving as an important step toward in vivo quantification of alterations in excitation and inhibition in the cortex in the setting of traumatic brain injury.
Background: Focal hand dystonia may be task specific, as is the case with writer's cramp. In early stages, task specificity can be so specific that it may be mistaken for a psychogenic movement disorder. Methods: We describe 4 patients who showed extreme task specificity in writer's cramp. They initially only had problems writing either a single letter or number. Although they were largely thought to be psychogenic, they progressed to typical writer's cramp. Conclusions: Early recognition of this condition may provide an opportunity for early initiation of treatment.
The social motivation hypothesis posits that aberrant neural response to human faces in autism is attributable to atypical social development and consequently reduced exposure to faces. The specificity of deficits in neural specialization remains unclear, and alternative theories suggest generalized processing difficulties. The current study contrasted neural specialization for social information versus nonsocial information in 36 individuals with autism and 18 typically developing individuals matched for age, race, sex, handedness, and cognitive ability. Event-related potentials elicited by faces, inverted faces, houses, letters, and pseudoletters were recorded. Groups were compared on an electrophysiological marker of neural specialization (N170), as well as behavioral performance on standardized measures of face recognition and word reading/decoding. Consistent with prior results, individuals with autism displayed slowed face processing and decreased sensitivity to face inversion; however, they showed comparable brain responses to letters, which were associated with behavioral performance in both groups. Results suggest that individuals with autism display atypical neural specialization for social information but intact specialization for nonsocial information. Findings concord with the notion of specific dysfunction in social brain systems rather than nonspecific information-processing difficulties in autism.
This study used eye-tracking to examine how 20-month-old toddlers with autism spectrum disorder (ASD) (n = 28), typical development (TD) (n = 34), and non-autistic developmental delays (DD) (n = 16) monitored the activities occurring in a context of an adult-child play interaction. Toddlers with ASD, in comparison to control groups, showed less attention to the activities of others and focused more on background objects (e.g., toys). In addition, while all groups spent the same time overall looking at people, toddlers with ASD looked less at people's heads and more at their bodies. In ASD, these patterns were associated with cognitive deficits and greater autism severity. These results suggest that the monitoring of the social activities of others is disrupted early in the developmental progression of autism, limiting future avenues for observational learning.
by
Saori Hata;
Sayaka Fujishige;
Yoichi Araki;
Miyako Taniguchi;
Katsuya Urakami;
Elaine Peskind;
Hiroyasu Akatsu;
Masahiko Araseki;
Kazuo Yamamoto;
Ralph N. Martins;
Masahiro Maeda;
Masaki Nishimura;
Allan Levey;
Kathryn A. Chung;
Thomas Montine;
James Leverenz;
Anne Fagan;
Alison Goate;
Randall Bateman;
David M. Holtzman;
Tohru Yamamoto;
Tadashi Nakaya;
Sam Gandy;
Toshiharu Suzuki
Objective: The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by γ-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor γ-secretase reaction product (Aβ42) to that of the major reaction product (Aβ40). Although no PS1 mutations are present, altered Aβ42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Aβ42 as amyloid. Methods: Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP α-secretases and γ-secretases, yielding a fragment that we have named p3-Alc α because of the parallel genesis of p3-Alc α peptides and the p3 fragment of APP. As with Aβ, both major and minor p3-Alc α s are generated. We studied the alternative processing of p3-Alc α in various clinical populations. Results: We previously reported that changes in the Aβ42/40 ratio showed covariance in a linear relationship with the levels of p3-Alc α [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alc α in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alc α variant, p3-Alc α 38, was elevated (p < 0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts. Interpretation: These results suggest that some SAD may involve alternative processing of multiple γ-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve γ-secretase dysfunction.
by
Stephan J. Sanders;
A. Gulhan Ercan-Sencicek;
Vanessa Hus;
Rui Luo;
Michael T. Murtha;
Daniel Moreno-De-Luca;
Su H. Chu;
Michael P. Moreau;
Abha R. Gupta;
Susanne A. Thomson;
Christopher E. Mason;
Kaya Bilguvar;
Patricia B. S. Celestino-Soper;
Murim Choi;
Emily L. Crawford;
Lea Davis;
Nicole R. Davis Wright;
Rahul M. Dhodapkar;
Donna M Martin;
Christa Martin
We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10 -7 ). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.
This third chapter discusses the evidence for the rehabilitation of the most common movement disorders of the upper extremity. The authors also present a framework, building on the computation, anatomy, and physiology (CAP) model, for incorporating some of the principles discussed in the 2 previous chapters by Frey et al and Sathian et al in the practice of rehabilitation and for discussing potentially helpful interventions based on emergent neuroscience principles.
In this chapter, the authors use the computation, anatomy, and physiology (CAP) principles to consider the impact of common clinical problems on action. They focus on 3 major syndromes: paresis, apraxia, and ataxia. They also review mechanisms that could account for spontaneous recovery, using what is known about the best-studied clinical dysfunction—paresis—and also ataxia. Together, this and the previous chapter lay the groundwork for the third chapter in this series, which reviews the relevant rehabilitative interventions.
Experimental evidence strongly indicates a significant role for inflammatory and immune mediators in initiation of seizures and epileptogenesis. Here we will summarize data supporting the involvement of IL-1β, TNF-α and toll-like receptor 4 in seizure generation and the process of epileptogenesis. The physiological homeostasis and control over brain immune response depends on the integrity of the blood-brain barrier, transforming growth factor (TGF)-β signaling and leukocyte migration. To what extent targeting the immune system is successful in preventing epileptogenesis, and which signaling pathway should be beleaguered is still under intensive research.