Faculty Bibliography

Adult hippocampal neurogenesis (AHN) is crucial for the maintenance of hippocampal function. Several neurodegenerative diseases such as Alzheimer's disease (AD) are accompanied by memory deficits that could be related to alterations in AHN. Here, we took advantage of a conditional mouse model to study the involvement of glycogen synthase kinase-3β (GSK-3β) overexpression (OE) in AHN. By injecting GFP- and PSD95-GFP-expressing retroviruses, we have determined that hippocampal GSK-3β-OE causes dramatic alterations in both dendritic tree morphology and post-synaptic densities in newborn neurons. Alterations in previously damaged neurons were reverted by switching off the transgenic system and also by using a physiological approach (environmental enrichment) to increase hippocampal plasticity. Furthermore, comparative morphometric analysis of granule neurons from patients with AD and from GSK-3β overexpressing mice revealed shared morphological alterations. Taken together, these data indicate that GSK-3β is crucial for hippocampal function, thereby supporting this kinase as a relevant target for the treatment of AD.

PURPOSE: Remelted highly crosslinked polyethylenes (HXLPEs) were introduced in total knee replacement (TKR) starting in 2001 to reduce wear and particle-induced lysis. The purpose of this study was to investigate the damage mechanisms and oxidative stability of remelted HXLPEs used in TKR. METHODS: A total of 186 posteriorly stabilised tibial components were retrieved at consecutive revision operations. Sixty nine components were identified as remelted HXLPE. The conventional inserts were implanted for 3.4 +/- 2.7 years, while the remelted components were implanted 1.4 +/- 1.2 years. Oxidation was assessed using Fourier transform infrared spectroscopy. RESULTS: Remelted HXLPE inserts exhibited lower oxidation indices compared to conventional inserts. We were able to detect slight regional differences within the HXLPE cohort, specifically at the bearing surface. CONCLUSION: Remelted HXLPE was effective at reducing oxidation in comparison to gamma inert sterilised controls. Additional long-term HXLPE retrievals are necessary to ascertain the long term in vivo stability of these materials in TKR.

BACKGROUND: Obesity is associated with poor asthma outcomes; weight loss improves such outcomes. Inaccurate recognition of obesity may impede weight control. PURPOSE: We examined perception of weight by early adolescents with uncontrolled asthma and their caregivers, and tested the relationship between medical visit frequency and accuracy of perceived weight status. METHODS: A total of 373 adolescents and their caregivers reported the adolescent's height/weight and weight perception; caregivers reported healthcare utilization. We measured height/weight. Logistic regression modeled accuracy of weight perception. RESULTS: A total of 43.7 % of the overweight/obese adolescents and caregivers accurately perceived weight status. BMI percentile [odds ratio (OR) = 1.19, confidence interval (CI) = 1.10-1.28] and total medical visits (OR = 1.18, CI = 1.05-1.33) were associated with higher accuracy in caregivers. Total medical visits (OR = 0.84, CI = 0.74-0.96) was associated with lower accuracy in adolescents. CONCLUSIONS: Accurate perception of weight status was poor for overweight adolescents with uncontrolled asthma and their caregivers. Frequent medical visits were associated with improved caregivers' but not adolescents' perceptions.

OBJECTIVE: Attention bias modification training (ABMT) is a promising treatment. Nevertheless, few studies examine its effectiveness in anxious children. This study examined the efficacy of such an ABMT protocol in pediatric anxiety. METHOD: 37 anxious children were randomly assigned to one of two ABMT conditions. In the attention-towards-positive (ATP) condition, children searched 3x3 matrices for a happy face amongst angry faces. In the attention-training-control (ATC) condition, they searched for a bird amongst flowers. Children completed 160 trials in each of four training sessions per week for three weeks at home (1920 total trials). Clinical and attention bias measures were assessed before and after ABMT. RESULTS: Children randomized to ATP showed greater post-training attention bias towards happy faces than children randomized to ATC. ATP also produced significantly greater reductions in clinician-rated diagnostic severity and number of diagnoses, compared to ATC. In the ATP group, 50% of children who completed training did not meet criteria for their principal diagnosis, compared to 8% in the ATC group. CONCLUSION: Training anxious children to focus attention on positive features of their environment may be a promising treatment.

IMPORTANCE: Combat places soldiers at risk for posttraumatic stress disorder (PTSD). The excessive rates of PTSD and other adjustment disorders in soldiers returning home make it imperative to identify risk and resilience factors that could be targeted by novel therapeutic treatments. OBJECTIVE: To investigate the interplay among attention to threat, combat exposure, and other risk factors for PTSD symptoms in soldiers deployed to combat. DESIGN AND SETTING: Longitudinal prospective study of Israeli Defense Force infantry soldiers carried out in 2008 through 2010. Repeated measurements during a 1-year period included baseline and predeployment data collected in training camps and deployment data collected in the combat theater. PARTICIPANTS: Infantry soldiers (1085 men; mean age, 18.8 years). MAIN OUTCOME MEASURES: Postcombat PTSD symptoms. RESULTS Soldiers developed threat vigilance during combat deployment, particularly when they were exposed to high-intensity combat, as indicated by faster response times to targets appearing at the location of threat relative to neutral stimuli (P < .001). Threat-related attention bias also interacted with combat exposure to predict risk for PTSD (P < .05). Bias toward threat at recruitment (P < .001) and bias away from threat just before deployment (P < .05) predicted postcombat PTSD symptoms. Moreover, these threat-related attention associations with PTSD were moderated by genetic and environmental factors, including serotonin transporter (5-HTTLPR) genotype. CONCLUSIONS AND RELEVANCE: Combat exposure interacts with threat-related attention to place soldiers at risk for PTSD, and interactions with other risk factors account for considerable variance in PTSD vulnerability. Understanding these associations informs research on novel attention bias modification techniques and prevention of PTSD.

Abstract The relationship between specific genes and particular diseases in neuropsychiatry is unclear, and newer studies focus on shared domains of neurobiological and cognitive pathology across different disorders. This paper reviews the evidence for an association between schizophrenia and frontotemporal dementia, including symptom similarity, familial co-morbidity, and neuroanatomical changes. Genetic as well as epigenetic findings from both schizophrenia and frontotemporal dementia are also discussed. As a result, we introduce the hypothesis of a shared susceptibility for certain subgroups of schizophrenia and frontotemporal dementia. This common causation may involve the same gene(s) at different stages of life: early in schizophrenia and late in frontotemporal dementia. Additionally, we provide a rationale for future research that should emphasize both genetic and cognitive parallels between certain forms of schizophrenia and frontotemporal dementia in a synergistic, coordinated way, placing both in the context of aberrant lateralization patterns.

Attention Bias Modification Treatment (ABMT), an emerging treatment for anxiety disorders, is thought to modify underlying, stable patterns of attention. Therefore, ABMT research should take into account the impact of attention bias stability on attention training response, especially in pediatric populations. ABMT research typically relies on the dot-probe task, where individuals detect a probe following an emotional-neutral stimulus pair. The current research presents two dot-probe experiments relevant to ABMT and attention-bias stability. In Experiment 1, anxious youth receiving 8-weeks of cognitive-behavioral therapy (CBT) were randomly assigned to ABMT that trains attention towards happy faces (n=18) or placebo (n=18). Two additional comparison groups, anxious youth receiving only CBT (n=17) and healthy comparison youth (n=16), were studied. Active attention training towards happy faces did not augment clinician-rated response to CBT; however, individuals receiving training exhibited reductions on self-report measures of anxiety earlier than individuals receiving CBT only. In Experiment 2, healthy youth (n=12) completed a dot-probe task twice while undergoing functional magnetic resonance imaging. Intra-class correlation demonstrated stability of neural activation in response to attention bias in the ventrolateral prefrontal cortex and amygdala. Together, these two studies investigate the ways in which attention-bias stability may impact future work on ABMT.

It is notoriously difficult to name odours. Without the benefit of non-olfactory information, even common household smells elude our ability to name them. The neuroscientific basis for this olfactory language 'deficit' is poorly understood, and even basic models to explain how odour inputs gain access to transmodal representations required for naming have not been put forward. This study used patients with primary progressive aphasia, a clinical dementia syndrome characterized by primary deficits in language, to investigate the interactions between olfactory inputs and lexical access by assessing behavioural performance of olfactory knowledge and its relationship to brain atrophy. We specifically hypothesized that the temporal pole would play a key role in linking odour object representations to transmodal networks, given its anatomical proximity to olfactory and visual object processing areas. Behaviourally, patients with primary progressive aphasia with non-semantic subtypes were severely impaired on an odour naming task, in comparison with an age-matched control group. However, with the availability of picture cues or word cues, odour matching performance approached control levels, demonstrating an inability to retrieve but not to recognize the name and nature of the odorant. The magnitude of cortical thinning in the temporal pole was found to correlate with reductions in odour familiarity and odour matching to visual cues, whereas the inferior frontal gyrus correlated with both odour naming and matching. Volumetric changes in the mediodorsal thalamus correlated with the proportion of categorical mismatch errors, indicating a possible role of this region in error-signal monitoring to optimize recognition of associations linked to the odour. A complementary analysis of patients with the semantic subtype of primary progressive aphasia, which is associated with marked temporopolar atrophy, revealed much more pronounced impairments of odour naming and matching. In identifying the critical role of the temporal pole and inferior frontal gyrus in transmodal linking and verbalization of olfactory objects, our findings provide a new neurobiological foundation for understanding why even common odours are hard to name.

BACKGROUND: Overweight and obese adolescents commonly underestimate their weight status, considering themselves to be at a healthy weight or underweight. These adolescents are more likely to be male, older, and Latino, black, or Native American. Associations with acculturation have not been previously assessed. The goal of this study was to identify the prevalence of underestimation of weight status in Californian adolescents and to identify factors associated with this underestimation, in particular examining relationships with race/ethnicity and acculturation. METHODS: Secondary data analysis of the 2005 Adolescent California Health Interview Survey. RESULTS: A total of 36.6% of overweight and obese Californian adolescents underestimated their weight status. Adolescents not born in the United States had increased odds of underestimating their weight status compared to those born in the United States [adjusted odds ratio (aOR)=1.94, 95% confidence interval (CI) 1.08, 3.49; p=0.03]. No significant associations with race/ethnicity were found. An age-sex interaction was observed with older adolescent males having increased odds compared to younger females. CONCLUSIONS: Identification of individuals at increased odds of underestimating their weight status may be important in developing and targeting appropriate counseling and interventions to ameliorate long-term health risks of excess weight.