Faculty Bibliography

Objective: The Child Behavior Checklist-Dysregulation Profile (CBCL-DP), characterized by elevated scores on the "Attention Problems," "Aggressive Behavior," and "Anxious/Depressed" scales in the CBCL, has been associated with later severe psychopathology. In a sample of children with ADHD, this study sought to further explore the clinical characteristics, the response to methylphenidate medication, and the cognitive features of ADHD children with CBCL-DP. Method: The sample consisted of 173 ADHD outpatients (age = 10.9 +/- 2.81) assessed using symptom severity scales, personality questionnaires (Emotionality Activity Sociability [EAS] and Junior Temperament and Character Inventory [JTCI]), and neuropsychological tests. A subsample of 136 participants was reassessed after optimal adjustment of methylphenidate dosage. Results and Conclusion: Variables that were independently associated with CBCL-DP were clinical severity (ADHD Rating Scale [ADHD-RS]), internalized disorders, high emotionality (EAS), and low self-directedness (JTCI). CBCL-DP was associated neither with poorer response to methylphenidate nor with more side effects. There were no differences in cognitive performances between participants with and without CBCL-DP. (J. of Att. Dis. 2012; XX(X) 1-XX).

OBJECTIVE: To compare measures of sensation seeking in a clinical group of cocaine-dependent (CD) patients with and without a history of probable childhood ADHD and in non-cocaine-dependent (NCD) healthy volunteers. METHOD: Patients (n = 75; 42 with and 33 without probable childhood ADHD) and comparisons (n = 84) were assessed with the Diagnostic Interview for Genetic Studies, the Wender Utah Rating Scale for childhood ADHD, and the Zuckerman Seeking Sensation Scale. RESULTS: We found significantly higher prevalence rates of probable childhood ADHD in CD versus NCD (p < .001). The mean total scores of sensation seeking were significantly higher in CD versus NCD participants (p < .001) as well as in CD patients with versus those without a probable history of childhood ADHD (p < .001). CONCLUSION: Our study sets the basis for longitudinal investigation assessing whether the persistence of high level of sensation seeking in adults with childhood ADHD contributes to the transition to cocaine dependence.

Down syndrome (DS) is the most prevalent cause of intellectual disability (ID). Individuals with DS show a variety of cognitive deficits, most notably in hippocampal learning and memory, and display pathological hallmarks of Alzheimer's disease (AD), with neurodegeneration of cholinergic basal forebrain (CBF) neurons. Elucidation of the molecular and cellular underpinnings of neuropathology has been assessed via gene expression analysis in a relevant animal model, termed the Ts65Dn mouse. The Ts65Dn mouse is a segmental trisomy model of DS which mimics DS/AD pathology, notably age-related cognitive dysfunction and degeneration of basal forebrain cholinergic neurons (BFCNs). To determine expression level changes, molecular fingerprinting of Cornu Ammonis 1 (CA1) pyramidal neurons was performed in adult (4-9 month old) Ts65Dn mice, at the initiation of BFCN degeneration. To quantitate transcriptomic changes during this early time period, laser capture microdissection (LCM), terminal continuation (TC) RNA amplification, custom-designed microarray analysis, and subsequent validation of individual transcripts by qPCR and protein analysis via immunoblotting was performed. Results indicate significant alterations within CA1 pyramidal neurons of Ts65Dn mice compared to normal disomic (2N) littermates, notably in the downregulation of neurotrophins and their cognate neurotrophin receptors among other classes of transcripts relevant to neurodegeneration. These results of this single population gene expression analysis at the time of septohippocampal deficits in a trisomic mouse model shed light on a vulnerable circuit that may cause the AD-like pathology invariably seen in DS that could help to identify mechanisms of degeneration, and provide novel gene targets for therapeutic interventions. J. Comp. Neurol., 2014. (c) 2014 Wiley Periodicals, Inc.

BACKGROUND: Deficits in facial emotion processing, reported in attention-deficit/hyperactivity disorder (ADHD), have been linked to both early perceptual and later attentional components of event-related potentials (ERPs). However, the neural underpinnings of vocal emotion processing deficits in ADHD have yet to be characterised. Here, we report the first ERP study of vocal affective prosody processing in ADHD. METHODS: Event-related potentials of 6-11-year-old children with ADHD (n = 25) and typically developing controls (n = 25) were recorded as they completed a task measuring recognition of vocal prosodic stimuli (angry, happy and neutral). Audiometric assessments were conducted to screen for hearing impairments. RESULTS: Children with ADHD were less accurate than controls at recognising vocal anger. Relative to controls, they displayed enhanced N100 and attenuated P300 components to vocal anger. The P300 effect was reduced, but remained significant, after controlling for N100 effects by rebaselining. Only the N100 effect was significant when children with ADHD and comorbid conduct disorder (n = 10) were excluded. CONCLUSION: This study provides the first evidence linking ADHD to atypical neural activity during the early perceptual stages of vocal anger processing. These effects may reflect preattentive hyper-vigilance to vocal anger in ADHD.

The entorhinal cortex (EC) is one of the first brain areas to display neuropathology in Alzheimer's disease. A mouse model which simulates amyloid-beta (Abeta) neuropathology, the Tg2576 mouse, was used to address these early changes. Here, we show EC abnormalities occur in 2- to 4-month-old Tg2576 mice, an age before Abeta deposition and where previous studies suggest that there are few behavioral impairments. First we show, using a sandwich enzyme-linked immunosorbent assay, that soluble human Abeta40 and Abeta42 are detectable in the EC of 2-month-old Tg2576 mice before Abeta deposition. We then demonstrate that 2- to 4-month-old Tg2576 mice are impaired at object placement, an EC-dependent cognitive task. Next, we show that defects in neuronal nuclear antigen expression and myelin uptake occur in the superficial layers of the EC in 2- to 4-month-old Tg2576 mice. In slices from Tg2576 mice that contained the EC, there were repetitive field potentials evoked by a single stimulus to the underlying white matter, and a greater response to reduced extracellular magnesium ([Mg2+]o), suggesting increased excitability. However, deep layer neurons in Tg2576 mice had longer latencies to antidromic activation than wild type mice. The results show changes in the EC at early ages and suggest that altered excitability occurs before extensive plaque pathology.

Down syndrome (DS) is caused by the triplication of human chromosome 21 (HSA21) and is the most common genetic cause of intellectual disability, with individuals having deficits in cognitive function including hippocampal learning and memory and neurodegeneration of cholinergic basal forebrain neurons, a pathological hallmark of Alzheimer's disease (AD). To date, the molecular underpinnings driving this pathology have not been elucidated. The Ts65Dn mouse is a segmental trisomy model of DS and like DS/AD pathology, displays age-related cognitive dysfunction and basal forebrain cholinergic neuron (BFCN) degeneration. To determine molecular and cellular changes important for elucidating mechanisms of neurodegeneration in DS/AD pathology, expression profiling studies were performed. Molecular fingerprinting of homogeneous populations of Cornu Ammonis 1 (CA1) pyramidal neurons was performed via laser capture microdissection followed by Terminal Continuation RNA amplification combined with custom-designed microarray analysis and subsequent validation of individual transcripts by qPCR and protein analysis via immunoblotting. Significant alterations were observed within CA1 pyramidal neurons of aged Ts65Dn mice compared to normal disomic (2N) littermates, notably in excitatory and inhibitory neurotransmission receptor families and neurotrophins, including brain-derived neurotrophic factor as well as several cognate neurotrophin receptors. Examining gene and protein expression levels after the onset of BFCN degeneration elucidated transcriptional and translational changes in neurons within a vulnerable circuit that may cause the AD-like pathology seen in DS as these individuals age, and provide rational targets for therapeutic interventions.

Studies of resting state fMRI have shown that BOLD signals giving rise to temporal correlation across voxels (or regions) are dominated by low frequency fluctuations in the range of approx. 0.01 - 0.1 Hz. These low-frequency fluctuations have been further divided into multiple distinct frequency bands (slow-5 and -4) based on earlier neurophysiological studies, though low sampling frequency of fMRI (~0.5 Hz) has substantially limited the exploration of other known frequency bands of neurophysiological origins(slow 3, -2 and -1). In this study, we use resting state fMRI data acquired from 21 healthy subjects at higher sampling frequency of 1.5 Hz to assess the presence of resting state functional connectivity (RSFC) across multiple frequency bands: slow-5 to slow-1. The effect of different frequency bands on spatial extent and connectivity strength for known resting state networks (RSNs) was also evaluated. RSNs were derived using independent component analysis and seed based correlation. Commonly known RSNs such as the default mode, the fronto-parietal, the dorsal attention and the visual networks were consistently observed at multiple frequency bands. Significant inter-hemispheric connectivity was observed between a seed and its contralateral brain region across all frequency bands, though overall spatial extent of seed based correlation maps decreased in slow-2 and slow-1 frequency bands. These results suggest that functional integration between brain regions at 'rest' occurs over multiple frequency bands and RSFC is a multi-band phenomenon. These results also suggest further investigation of BOLD signal in multiple frequency bands and related cognitive processes.

This study examined parents' perceptions/awareness and internalization of public courtesy stigma (affiliate stigma) about their children's inattentive and hyperactive/impulsive symptoms, and associations between parental affiliate stigma, parental negativity expressed toward the child, and child social functioning. Participants were families of 63 children (ages 6-10; 42 boys) with attention-deficit/hyperactivity disorder, assessed in a cross-sectional design. After statistical control of children's severity of inattentive and hyperactive/impulsive symptoms (as reported by parents and teachers), parents' self-reports of greater affiliate stigma were associated with more observed negative parenting. The associations between high parental affiliate stigma and children's poorer adult informant-rated social skills and greater observed aggression were partially mediated by increased parental negativity. As well, the positive association between children's adult informant-rated aggressive behavior and parental negativity was partially mediated by parents' increased affiliate stigma. Parental affiliate stigma about their children's inattentive and hyperactive/impulsive symptoms may have negative ramifications for parent-child interactions and children's social functioning. Clinical implications for parent training interventions are discussed.

After children enter the child welfare system, subsequent out-of-home placement decisions and their impact on children's well-being are complex and under-researched. This study examined two placement decision-making models: a multidisciplinary team approach, and a decision support algorithm using a standardized assessment. Based on 3,911 placement records in the Illinois child welfare system over 4 years, concordant (agreement) and discordant (disagreement) decisions between the two models were compared. Concordant decisions consistently predicted improvement in children's well-being regardless of placement type. Discordant decisions showed greater variability. In general, placing children in settings less restrictive than the algorithm suggested ("under-placing") was associated with less severe baseline functioning but also less improvement over time than placing children according to the algorithm. "Over-placing" children in settings more restrictive than the algorithm recommended was associated with more severe baseline functioning but fewer significant results in rate of improvement than predicted by concordant decisions. The importance of placement decision-making on policy, restrictiveness of placement, and delivery of treatments and services in child welfare are discussed.

Facial emotion-recognition difficulties have been reported in school-aged children with behavior problems; little is known, however, about either this association in preschool children or with regard to vocal emotion recognition. The current study explored the association between facial and vocal emotion recognition and behavior problems in a sample of 3 to 6-year-old children. A sample of 57 children enriched for risk of behavior problems (41 were recruited from the general population while 16 had been referred for behavior problems to local clinics) were each presented with a series of vocal and facial stimuli expressing different emotions (i.e., angry, happy, and sad) of low and high intensity. Parents rated children's externalizing and internalizing behavior problems. Vocal and facial emotion recognition accuracy was negatively correlated with externalizing but not internalizing behavior problems independent of emotion type. The effects with the externalizing domain were independently associated with hyperactivity rather than conduct problems. The results highlight the importance of using vocal as well as facial stimuli when studying the relationship between emotion-recognition and behavior problems. Future studies should test the hypothesis that difficulties in responding to adult instructions and commands seen in children with attention deficit/hyperactivity disorder (ADHD) may be due to deficits in the processing of vocal emotions.