Faculty Bibliography

PURPOSE: The aims of this article are twofold: (a) to offer a set of recommended measures that can be used for evaluating the efficacy of interventions that target spoken language acquisition as part of treatment research studies or for use in applied settings and (b) to propose and define a common terminology for describing levels of spoken language ability in the expressive modality and to set benchmarks for determining a child's language level in order to establish a framework for comparing outcomes across intervention studies. METHOD: The National Institute on Deafness and Other Communication Disorders assembled a group of researchers with interests and experience in the study of language development and disorders in young children with autism spectrum disorders. The group worked for 18 months through a series of conference calls and correspondence, culminating in a meeting held in December 2007 to achieve consensus on these aims. RESULTS: The authors recommend moving away from using the term functional speech, replacing it with a developmental framework. Rather, they recommend multiple sources of information to define language phases, including natural language samples, parent report, and standardized measures. They also provide guidelines and objective criteria for defining children's spoken language expression in three major phases that correspond to developmental levels between 12 and 48 months of age

RATIONALE: Research in rodents and non-human primates implicates the noradrenergic system and hypothalamic-pituitary-adrenal axis in stress, anxiety, and attention to threat. Few studies examine how these two neurochemical systems interact to influence anxiety and attention in humans. OBJECTIVE: The objective of this paper is to examine the effects of exogenous yohimbine and hydrocortisone, as well as their combination (Y + H), on panic symptoms and attention to social threat cues. METHODS: Thirty-two healthy adults underwent a pharmacological challenge in which they were blindly randomized to either yohimbine, hydrocortisone, Y + H, or placebo. Thirty minutes after drug infusion, attention to threat was measured using the dot probe task, a visual attention task that presents angry, happy, and neutral faces and measures the degree of attention allocated towards or away from the emotional faces. Panic and autonomic measures were assessed before and 30 min after drug infusion. RESULTS: There was a significant increase in panic symptoms in the yohimbine and Y + H groups, but not in the hydrocortisone or placebo groups. Yohimbine resulted in a greater increase in panic symptoms than Y + H. On the dot probe task, the placebo group exhibited an attention bias to angry faces, whereas this bias was absent after yohimbine. When collapsing across groups, increased panic symptoms was associated with less attention to angry faces. CONCLUSIONS: Exogenous hydrocortisone may attenuate noradrenergic-induced panic symptoms. The inverse relationship between panic symptoms and attention to angry faces extends prior research demonstrating attention modulation by stressful conditions

Some forms of epigenetic abnormalities transmitted to offspring are manifested in differences in disease incidence that depend on parent-of-origin. To explore whether such phenomena might operate in schizophrenia spectrum disorders, we estimated the relative incidence of these conditions in relation to parent-of-origin by considering the two grandfathers' countries of birth. In a prospective cohort of 88,829 offspring, born in Jerusalem in 1964-76 we identified 637 cases through Israel's psychiatric registry. Relative risks (RR) were estimated for paternal and maternal grandfathers' countries of birth using proportional hazards methods, controlling for parents' ages, low social class and duration of marriage. After adjusting for multiple observations, we found no significant differences between descendants of maternal or paternal grandfathers born in Iraq, Iran, Turkey, Syria, Yemen, Morocco, Algeria, Tunisia, Libya/Egypt, Poland, USSR, Czechoslovakia, Germany or the USA. Those with paternal grandfathers from Romania (RR=1.9, 95% CI=1.3-2.8) or Hungary (1.6, 1.0-2.6) showed an increased incidence; however, those with maternal grandfathers from these countries experienced reduced incidence (RR=0.5, 0.3-0.8 and 0.4, 0.2-0.8). In post-hoc analyses we found that results were similar whether the comparison groups were restricted to descendants of other Europeans or included those from Western Asia and North Africa; and effects of paternal grandfathers from Romania/Hungary were more pronounced in females, while effects of maternal grandfathers from these countries were similar in males and females. These post-hoc 'hypothesis-generating' findings lead one to question whether some families with ancestors in Romania or Hungary might carry a variant or mutation at a parentally imprinted locus that is altering susceptibility to schizophrenia. Such a locus, if it exists, might involve the X chromosome

The development and exacerbation of many psychiatric and neurologic conditions are associated with dysregulation of the hypothalamic pituitary adrenal (HPA) axis as measured by aberrant levels of cortisol secretion. Here we report on the relationship between the amplitude of diurnal cortisol secretion, measured across 3 typical days in 18 healthy individuals, and blood oxygen level dependant (BOLD) response in limbic fear/stress circuits, elicited by in-scanner presentation of emotionally negative stimuli, specifically, images of the World Trade Center (WTC) attack. Results indicate that subjects who secrete a greater amplitude of cortisol diurnally demonstrate less brain activation in limbic regions, including the amygdala and hippocampus/parahippocampus, and hypothalamus during exposure to traumatic WTC-related images. Such initial findings can begin to link our understanding, in humans, of the relationship between the diurnal amplitude of a hormone integral to the stress response, and those neuroanatomical regions that are implicated as both modulating and being modulated by that response

The dopamine transporter locus (DAT1) has been studied as a risk factor for attention-deficit/hyperactivity disorder (ADHD) and in pharmacogenetic studies of stimulant response. Several prospective studies have reported an association between the homozygous 9 repeat allele of the DAT1 3' untranslated region (UTR) variable number tandem repeat (VNTR) (DAT1 3') and decreased efficacy of methylphenidate (MPH). We hypothesized that children with the 9/9 genotype would display higher rates of specific stimulant side effects. Data on adverse events and DAT1 3' genotypes were combined from two, double-blind, placebo-controlled, crossover studies of MPH conducted in child psychiatric outpatient clinics in Montreal and Washington, D.C. There were 177 participants, 5-16 years old (mean age = 8.99, standard deviation [SD] = 2), with ADHD. Parents completed the Stimulant Side Effect Scale (SERS) after a week of placebo and a week of MPH treatment. Principal components analysis of the SERS resulted in three factors: Emotionality, Somatic Complaints, and Over-focused. Children with the 9/9 genotype displayed higher scores on the Emotionality factor during placebo than children with the 9/10 and the 10/10 genotype, and their Emotionality scores increased further during MPH treatment (F[2,151] = 3.24, p < 0.05). Children with the 10/10 genotype displayed a significant increase in Somatic Complaint factor scores during MPH treatment relative to the other genotype groups (F[2,150] = 3.4, p < 0.05). These data provide suggestive evidence that DAT1 variants are differentially associated with specific stimulant side effects. Children with the 9/10 genotype displayed less severe stimulant side-effect ratings than either of the homozygous groups, who each displayed increased susceptibility to different types of adverse events. Preliminary evidence suggests that pharmacogenetic analysis using DAT1 variants shows promise for identifying individuals at increased or decreased risk for poor tolerability

BACKGROUND: Recent functional MRI (fMRI) studies have demonstrated that there is an intrinsically organized default mode network (DMN) in the resting brain, primarily made up of the posterior cingulate cortex (PCC) and the medial prefrontal cortex (MPFC). Several previous studies have found that the DMN is minimally disturbed during different resting-state conditions with limited cognitive demand. However, this conclusion was drawn from the visual inspection of the functional connectivity patterns within the DMN and no statistical comparison was performed. METHODOLOGY/PRINCIPAL FINDINGS: Four resting-state fMRI sessions were acquired: 1) eyes-closed (EC) (used to generate the DMN mask); 2) EC; 3) eyes-open with no fixation (EO); and 4) eyes-open with a fixation (EO-F). The 2-4 sessions were counterbalanced across participants (n = 20, 10 males). We examined the statistical differences in both functional connectivity and regional amplitude of low frequency fluctuation (ALFF) within the DMN among the 2-4 resting-state conditions (i.e., EC, EO, and EO-F). Although the connectivity patterns of the DMN were visually similar across these three different conditions, we observed significantly higher functional connectivity and ALFF in both the EO and the EO-F conditions as compared to the EC condition. In addition, the first and second resting EC conditions showed significant differences within the DMN, suggesting an order effect on the DMN activity. CONCLUSIONS/SIGNIFICANCE: Our findings of the higher DMN connectivity and regional spontaneous activities in the resting state with the eyes open suggest that the participants might have more non-specific or non-goal-directed visual information gathering and evaluation, and mind wandering or daydreaming during the resting state with the eyes open as compared to that with the eyes closed, thus providing insights into the understanding of unconstrained mental activity within the DMN. Our results also suggest that it should be cautious when choosing the type of a resting condition and designating the order of the resting condition in multiple scanning sessions in experimental design.

Dysregulation of the fear system is at the core of many psychiatric disorders. Much progress has been made in uncovering the neural basis of fear learning through studies in which associative emotional memories are formed by pairing an initially neutral stimulus (conditioned stimulus, CS; e.g., a tone) to an unconditioned stimulus (US; e.g., a shock). Despite recent advances, the question of how to persistently weaken aversive CS-US associations, or dampen traumatic memories in pathological cases, remains a major dilemma. Two paradigms (blockade of reconsolidation and extinction) have been used in the laboratory to reduce acquired fear. Unfortunately, their clinical efficacy is limited: Reconsolidation blockade typically requires potentially toxic drugs, and extinction is not permanent. Here, we describe a behavioral design in which a fear memory in rats is destabilized and reinterpreted as safe by presenting an isolated retrieval trial before an extinction session. This procedure permanently attenuates the fear memory without the use of drugs

The authors examined a new assessment of behavioral regulation and contributions to achievement and teacher-rated classroom functioning in a sample (N = 343) of kindergarteners from 2 geographical sites in the United States. Behavioral regulation was measured with the Head-Toes-Knees-Shoulders (HTKS) task, a structured observation requiring children to perform the opposite of a dominant response to 4 different oral commands. Results revealed considerable variability in HTKS scores. Evidence for construct validity was found in positive correlations with parent ratings of attentional focusing and inhibitory control and teacher ratings of classroom behavioral regulation. Hierarchical linear modeling indicated that higher levels of behavioral regulation in the fall predicted stronger levels of achievement in the spring and better teacher-rated classroom self-regulation (all ps < .01) but not interpersonal skills. Evidence for domain specificity emerged, in which gains in behavioral regulation predicted gains in mathematics but not in language and literacy over the kindergarten year (p < .01) after site, child gender, and other background variables were controlled. Discussion focuses on the importance of behavioral regulation for successful adjustment to the demands of kindergarten

With increased public awareness of the early signs and recent American Academy of Pediatrics recommendations that all 18- and 24-month-olds be screened for autism spectrum disorders, there is an increasing need for diagnostic assessment of very young children. However, unique challenges exist in applying current diagnostic guidelines for autism spectrum disorders to children under the age of 2 years. In this article, we address challenges related to early detection, diagnosis, and treatment of autism spectrum disorders in this age group. We provide a comprehensive review of findings from recent studies on the early development of children with autism spectrum disorders, summarizing current knowledge on early signs of autism spectrum disorders, the screening properties of early detection tools, and current best practice for diagnostic assessment of autism spectrum disorders before 2 years of age. We also outline principles of effective intervention for children under the age of 2 with suspected/confirmed autism spectrum disorders. It is hoped that ongoing studies will provide an even stronger foundation for evidence-based diagnostic and intervention approaches for this critically important age group

The aim of this study is to standardize Autism Diagnostic Observation Schedule (ADOS) scores within a large sample to approximate an autism severity metric. Using a dataset of 1,415 individuals aged 2-16 years with autism spectrum disorders (ASD) or nonspectrum diagnoses, a subset of 1,807 assessments from 1,118 individuals with ASD were divided into narrow age and language cells. Within each cell, severity scores were based on percentiles of raw totals corresponding to each ADOS diagnostic classification. Calibrated severity scores had more uniform distributions across developmental groups and were less influenced by participant demographics than raw totals. This metric should be useful in comparing assessments across modules and time, and identifying trajectories of autism severity for clinical, genetic, and neurobiological research