Faculty Bibliography

BACKGROUND:SCN2A is a gene that codes for the alpha subunit of voltage-gated, type II sodium channels, and is highly expressed in the brain. Sodium channel disruptions, such as mutations in SCN2A, may play an important role in psychiatric disorders. Recently, de novo SCN2A mutations in autism spectrum disorder (ASD) have been identified. The current study characterizes a de novo splice site mutation in SCN2A that alters mRNA and protein products. CASE PRESENTATION/METHODS:We describe results from clinical and genetic characterizations of a seven-year-old boy with ASD. Psychiatric interview and gold standard autism diagnostic instruments (ADOS and ADI-R) were used to confirm ASD diagnosis, in addition to performing standardized cognitive and adaptive functioning assessments (Leiter-R and Vineland Adaptive Behavior Scale), and sensory reactivity assessments (Sensory Profile and Sensory Processing Scales). Genetic testing by whole exome sequencing revealed four de novo events, including a splice site mutation c.476 + 1G > A in SCN2A, a missense mutation (c.2263G > A) causing a p.V755I change in the TLE1 gene, and two synonymous mutations (c.2943A > G in the BUB1 gene, and c.1254 T > A in C10orf68 gene). The de novo SCN2A splice site mutation produced a stop codon 10 amino acids downstream, possibly resulting in a truncated protein and/or a nonsense-mediated mRNA decay. The participant met new DSM-5 criteria for ASD, presenting with social and communication impairment, repetitive behaviors, and sensory reactivity issues. The participant's adaptive and cognitive skills fell in the low range of functioning. CONCLUSION/CONCLUSIONS:This report indicates that a splice site mutation in SCN2A might be contributing to the risk of ASD. Describing the specific phenotype associated with SCN2A mutations might help to reduce heterogeneity seen in ASD.

INTRODUCTION: An increasing number of clinical and epidemiological studies suggest a possible association between attention-deficit/hyperactivity disorder (ADHD) and obesity/overweight. However, overall evidence is mixed. Given the public health relevance of ADHD and obesity/overweight, understanding whether and to what extent they are associated is paramount to plan intervention and prevention strategies. We describe the protocol of a systematic review and meta-analysis aimed at assessing the prevalence of obesity/overweight in individuals with ADHD versus those without ADHD. METHODS AND ANALYSIS: We will include studies of any design (except case reports or case series) comparing the prevalence of obesity and/or overweight in children or adults with and without ADHD (or hyperkinetic disorder). We will search an extensive number of databases including PubMed, Ovid databases, Web of Knowledge and Thomson-Reuters databases, ERIC and CINAHL. No restrictions of language will be applied. We will also contact experts in the field for possible unpublished or in press data. Primary and additional outcomes will be the prevalence of obesity and overweight, respectively. We will combine ORs using random-effects models in STATA V.12.0. The quality of the study will be assessed primarily using the Newcastle-Ottawa Scale. Subgroup meta-analyses will be conducted according to participants' age (children vs adults) and study setting (clinical vs general population). We will explore the feasibility of conducting meta-regression analyses to assess the moderating effect of age, gender, socioeconomic status, study setting, geographic location of the study (low-income, middle-income countries vs high-income countries), definition of obesity, method to assess ADHD, psychiatric comorbidities and medication status. ETHICS AND DISSEMINATION: No ethical issues are foreseen. The results will be published in a peer-reviewed journal and presented at national and international conferences of psychiatry, psychology, obesity and paediatrics. REGISTRATION: PROSPERO-National Institute of Health Research (NIHR) Prospective Register of Systematic Reviews (CRD42013006410).

Reelin is an extracellular matrix protein that is crucial for neural development and adult brain plasticity. While the Reelin signalling cascade has been reported to be associated with Alzheimer's disease (AD), the role of Reelin in this pathology is not understood. Here we use an in vitro approach to show that Reelin interacts with amyloid-β (Aβ42) soluble species, delays Aβ42 fibril formation and is recruited into amyloid fibrils. Furthermore, Reelin protects against both the neuronal death and dendritic spine loss induced by Aβ42 oligomers. In mice carrying the APP(Swe/Ind) mutation (J20 mice), Reelin overexpression delays amyloid plaque formation and rescues the recognition memory deficits. Our results indicate that by interacting with Aβ42 soluble species, delaying Aβ plaque formation, protecting against neuronal death and dendritic spine loss and preventing AD cognitive deficits, the Reelin pathway deserves consideration as a therapeutic target for the treatment of AD pathogenesis.

Prior research assessing the relationship between autism spectrum disorder (ASD) symptom severity and sleep problems has considered the association in a unidirectional manner; researchers have primarily focused on how sleep difficulties affect ASD symptom presentation. Specifically, extant research literature on this topic indicates that sleep problems exacerbate ASD symptom severity. The present study provides an investigation of this topic in a bidirectional manner. Primary results corroborated the compounding effect of sleep problems on ASD symptom severity. Furthermore, the results of a multinomial linear regression provided preliminary evidence that increased ASD symptom severity may predict an increased likelihood of the presence of sleep problems. As such, the authors conclude that the relationship between ASD symptom severity and sleep problems should be considered bidirectionally in future research. Implications for a relationship in each direction are discussed. (C) 2013 Elsevier Ltd. All rights reserved.

"Cruising" infants can only walk using external support to augment their balance. We examined cruisers' understanding of support for upright locomotion under four conditions: cruising over a wooden handrail at chest height, a large gap in the handrail, a wobbly unstable handrail, and an ill positioned low handrail. Infants distinguished among the support properties of the handrails with differential attempts to cruise and handrail-specific forms of haptic exploration and gait modifications. They consistently attempted the wood handrail, rarely attempted the gap, and occasionally attempted the low and wobbly handrails. On the wood and gap handrails, attempt rates matched the probability of cruising successfully; but on the low and wobbly handrails, attempt rates under- and over-estimated the probability of success, respectively. Haptic exploration was most frequent and varied on the wobbly handrail, and gait modifications-including previously undocumented "knee cruising"-were most frequent and effective on the low handrail. Results are discussed in terms of developmental changes in the meaning of support.

The ascendancy of functional neuroimaging has facilitated the addition of network-based approaches to the neuropsychologist's toolbox for evaluating the sequelae of brain insult. In particular, intrinsic functional connectivity (iFC) mapping of resting state fMRI (R-fMRI) data constitutes an ideal approach to measuring macro-scale networks in the human brain. Beyond the value of iFC mapping for charting how the functional topography of the brain is altered by insult and injury, iFC analyses can provide insights into experience-dependent plasticity at the macro level of large-scale functional networks. Such insights are foundational to the design of training and remediation interventions that will best facilitate recovery of function. In this review, we consider what is currently known about the origin and function of iFC in the brain, and how this knowledge is informative in neuropsychological settings. We then summarize studies that have examined experience-driven plasticity of iFC in healthy control participants, and frame these findings in terms of a schema that may aid in the interpretation of results and the generation of hypotheses for rehabilitative studies. Finally, we outline some caveats to the R-fMRI approach, as well as some current developments that are likely to bolster the utility of the iFC paradigm for neuropsychology.

BACKGROUND: Cogmed Working Memory Training (CWMT) has received considerable attention as a promising intervention for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children. At the same time, methodological weaknesses in previous clinical trials call into question reported efficacy of CWMT. In particular, lack of equivalence in key aspects of CWMT (i.e., contingent reinforcement, time-on-task with computer training, parent-child interactions, supportive coaching) between CWMT and placebo versions of CWMT used in previous trials may account for the beneficial outcomes favoring CWMT. METHODS: Eighty-five 7- to 11-year old school-age children with ADHD (66 male; 78%) were randomized to either standard CWMT (CWMT Active) or a well-controlled CWMT placebo condition (CWMT Placebo) and evaluated before and 3 weeks after treatment. Dependent measures included parent and teacher ratings of ADHD symptoms; objective measures of attention, activity level, and impulsivity; and psychometric indices of working memory and academic achievement (Clinical trial title: Combined cognitive remediation and behavioral intervention for the treatment of Attention-Deficit/Hyperactivity Disorder; http://clinicaltrials.gov/ct2/show/NCT01137318). RESULTS: CWMT Active participants demonstrated significantly greater improvements in verbal and nonverbal working memory storage, but evidenced no discernible gains in working memory storage plus processing/manipulation. In addition, no treatment group differences were observed for any other outcome measures. CONCLUSIONS: When a more rigorous comparison condition is utilized, CWMT demonstrates effects on certain aspects of working memory in children with ADHD; however, CWMT does not appear to foster treatment generalization to other domains of functioning. As such, CWMT should not be considered a viable treatment for children with ADHD.

Contemporary models of obsessive-compulsive disorder emphasize the importance of harm avoidance (HA) and related dysfunctional beliefs as motivators of obsessive-compulsive (OC) symptoms. Recently, there has been a resurgence of interest in Janet's (1908) concept of incompleteness (INC) as another potentially important motivator. Contemporary investigators define INC as the sense that one's actions, intentions, or experiences have not been properly achieved. Janet defined INC more broadly to include alexithymia, depersonalization, derealization, and impaired psychological mindedness. We conducted two studies to address four issues: (a) the clinical correlates of INC; (b) whether INC and HA are distinguishable constructs; (c) whether INC predicts OC symptoms after controlling for HA; and (d) the relative merits of broad versus narrow conceptualizations of INC. Study 1 was a meta-analysis of the clinical correlates of narrowly defined INC (16 studies, N=5,940). INC was correlated with all types of OC symptoms, and was more strongly correlated with OC symptoms than with general distress. Study 2 (N=534 nonclinical participants) showed that (a) INC and HA were strongly correlated but factor analytically distinguishable; (b) INC statistically predicted all types of OC symptoms even after controlling for HA; and (c) narrow INC was most strongly correlated with OC symptoms whereas broad INC was most strongly correlated with general distress. Although the findings are limited by being correlational in nature, they support the hypothesis that INC, especially in its narrow form, is a motivator of OC symptoms.

Spike-wave discharges (SWDs) are thalamocortical oscillations that are often considered to be the EEG correlate of absence seizures. Genetic absence epilepsy rats of Strasbourg (GAERS) and Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) exhibit SWDs and are considered to be genetic animal models of absence epilepsy. However, it has been reported that other rat strains have SWDs, suggesting that SWDs may vary in their prevalence, but all rats have a predisposition for them. This is important because many of these rat strains are used to study temporal lobe epilepsy (TLE), where it is assumed that there is no seizure-like activity in controls. In the course of other studies using the Sprague-Dawley rat, a common rat strain for animal models of TLE, we found that approximately 19% of 2- to 3-month-old naive female Sprague-Dawley rats exhibited SWDs spontaneously during periods of behavioral arrest, which continued for months. Males exhibited SWDs only after 3months of age, consistent with previous reports (Buzsaki et al., 1990). Housing in atypical lighting during early life appeared to facilitate the incidence of SWDs. Spike-wave discharges were often accompanied by behaviors similar to stage 1-2 limbic seizures. Therefore, additional analyses were made to address the similarity. We observed that the frequency of SWDs was similar to that of hippocampal theta rhythm during exploration for a given animal, typically 7-8Hz. Therefore, activity in the frequency of theta rhythm that occurs during frozen behavior may not reflect seizures necessarily. Hippocampal recordings exhibited high frequency oscillations (>250Hz) during SWDs, suggesting that neuronal activity in the hippocampus occurs during SWDs, i.e., it is not a passive structure. The data also suggest that high frequency oscillations, if rhythmic, may reflect SWDs. We also confirmed that SWDs were present in a common animal model of TLE, the pilocarpine model, using female Sprague-Dawley rats. Therefore, damage and associated changes to thalamic, hippocampal, and cortical neurons do not prevent SWDs, at least in this animal model. The results suggest that it is possible that SWDs occur in rodent models of TLE and that investigators mistakenly assume that they are stage 1-2 limbic seizures. We discuss the implications of the results and ways to avoid the potential problems associated with SWDs in animal models of TLE.