Faculty Bibliography

OBJECTIVES: To illustrate how our knowledge about normal patterns of experience-induced plasticity can provide insights into the mechanisms of neurorehabilitation; to provide an overview of the practice-effects literature in order to simplify and amalgamate a large number of heterogeneous findings and identify typical patterns of practice effects and their determining factors; and to concentrate on the impact of practice on higher cognitive functions, such as working memory, and present some preliminary but promising behavioral data that show how practice on a complex cognitive task can benefit cognitive functioning more generally. DATA SOURCES: We performed a systematic search for peer-reviewed journal articles using computerized databases (PubMed, ISI Web of Science, PsycINFO). DATA SELECTION: Neuroimaging studies using functional magnetic resonance imaging (fMRI) or positron-emission tomography (PET) to examine functional activation changes as a result of practice on sensory, motor, or cognitive tasks in normal (healthy) populations were included in the review. Further studies were identified that examined the effects of rehabilitative training on functional activations in clinical populations using fMRI or PET. DATA EXTRACTION: Important characteristics of the selected studies were summarized in a systematic manner so to enable the extraction of specific factors impacting on the pattern of practice effects observed. DATA SYNTHESIS: We identified a number of factors that impact on the patterns of practice effects observed and discuss how the insights gained from the study of healthy populations can by applied to rehabilitation of cognitive deficits in clinical populations. CONCLUSIONS: Progress in our understanding of neurorehabilitative plasticity will be enabled by neuroimaging examinations of cognitive rehabilitation training grounded in a knowledge of normal (healthy) patterns of brain activation and practice-induced plasticity

RATIONALE: Genotype at the 5' promoter region (5-HTTLPR) of the serotonin transporter has been implicated in moderating the effects of acute tryptophan depletion on neurocognitive functioning. Acute tryptophan depletion has been associated with the processing of fear-relevant cues, such as emotional expressions, but the effect of genotype at the 5-HTTLPR has not been assessed. OBJECTIVE: The present study investigated the effects of acute tryptophan depletion on the recognition of standardized facial expressions of emotions in healthy volunteers classified as ll homozygotes or s carriers. MATERIALS AND METHODS: A double-blind between-groups design was used with volunteers randomly selected to ingest capsules containing an amino acid mixture specifically lacking tryptophan, or placebo capsules containing lactose. 5 h after capsule ingestion, subjects were required to identify anger, disgust, fear, happiness, sadness, and surprise expressions that progressed from neutral to each full emotional expression in 5% steps. RESULTS: Tryptophan depletion significantly impaired the recognition of fearful facial expressions in s carriers but not ll homozygotes. This impairment was specific to fear expressions. No significant differences in the recognition of other expressions were found. Free tryptophan levels were correlated with fear recognition in s carriers but not ll homozygotes. CONCLUSIONS: The effects of acute tryptophan depletion on the processing of emotional expressions varies as a function of genotype at the 5-HTTLPR. Depletion impairs the recognition of fear in s carriers but not ll homozygotes. This finding reinforces the importance of considering genotype when assessing the behavioral effects of pharmacologic modulation.

OBJECTIVE: The serotonin transporter gene (SLC6A4) is a strong autism candidate gene because of its association with anxiety, aggression and attention, and the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in treating certain behavioral symptoms. In families with individuals with autism, several reports of biased transmission of both alleles (short, long) at the serotonin transporter gene promotor polymorphism (5-HTTLPR) locus of SLC6A4 now exist. The heterogeneity in these reports may be due to clinical heterogeneity. The authors hypothesized that 5-HTTLPR genotypes would be related to variation in specific symptoms in children with autism. METHOD: The authors explored whether variants of two functional polymorphisms of SLC6A4 (5-HTTLPR, intron 2 variable number tandem repeat [2 VNTR]) were related to behavioral characteristics measured by the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. Subjects (N=73, age 3-19 years old) met diagnostic criteria for autistic disorder based on both measures. RESULTS: Evidence of genotype-phenotype interactions on the Autism Diagnostic Interview-Revised was found with the 5-HTTLPR short group of HTTLPR (S/L or S/S genotypes) being rated as more severe on the subdomain 'failure to use nonverbal communication to regulate social interaction,' and the long group (L/L genotype) being more severe on the subdomain 'stereotyped and repetitive motor mannerisms' and on an aggression measure. In contrast, on the Autism Diagnostic Observation Schedule, the long group was associated with greater severity on directed facial expressions and unusual sensory interests. There were no significant relationships between the intron 2 VNTR genotypes and subdomains or domains of symptoms on the Autism Diagnostic Interview-Revised or the Autism Diagnostic Observation Schedule. CONCLUSIONS: These findings provide initial support for genotype-specific phenotypes for 5-HTTLPR in autism based on ratings from the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule

Attention-deficit/hyperactivity disorder (ADHD) affects a large number of children. For decades, the stimulants have been the mainstay of pharmacological treatment for ADHD. Dexmethylphenidate (d-MPH), the d-isomer of the traditional racemic mixtures of d,l-threo-(R,R)-MPH, was recently introduced as another potential option in the stimulant class of medications. This paper reviews and summarizes the available research literature on d-MPH regarding pharmacodynamic, pharmacokinetic, chemical structure, receptor binding, toxicology, and clinical perspectives. d-MPH potentially may offer some advantages in the realms of absorption and duration of action compared with its racemic counterpart. The differences in pharmacokinetics and clinical implications of the immediate-release and extended-release forms of d-MPH are also compared and contrasted

A systematic review of published and unpublished data on the use of long-acting medications in ADHD and hyperkinetic disorder is reported, giving effect sizes and numbers-to-treat for extended-release stimulant preparations and atomoxetine (ATX). A panel of experts from several European countries used the review to make recommendations about the use of these drugs in practice, and conclusions are reported: (1) Long-acting preparations should be available and used; (2) They should not replace short-acting drugs (which will be the initial treatment for many children for reasons of cost and flexibility of dosing). Individual clinical choice is needed. (3) Both ATX and extended-release preparations of stimulants should be available. The choice will depend upon the circumstances, and detailed recommendations are made

In the CNS, there are widespread and diverse interactions between growth factors and estrogen. Here we examine the interactions of estrogen and brain-derived neurotrophic factor (BDNF), two molecules that have historically been studied separately, despite the fact that they seem to share common targets, effects, and mechanisms of action. The demonstration of an estrogen-sensitive response element on the BDNF gene provided an impetus to explore a direct relationship between estrogen and BDNF, and predicted that the effects of estrogen, at least in part, might be due to the induction of BDNF. This hypothesis is discussed with respect to the hippocampus, where substantial evidence has accumulated in favor of it, but alternate hypotheses are also raised. It is suggested that some of the interactions between estrogen and BDNF, as well as the controversies and implications associated with their respective actions, may be best appreciated in light of the ability of BDNF to induce neuropeptide Y (NPY) synthesis in hippocampal neurons. Taken together, this tri-molecular cascade, estrogen-BDNF-NPY, may be important in understanding the hormonal regulation of hippocampal function. It may also be relevant to other regions of the CNS where estrogen is known to exert profound effects, such as amygdala and hypothalamus; and may provide greater insight into neurological disorders and psychiatric illness, including Alzheimer's disease, depression and epilepsy

In this article, the authors introduce a latent difference score (LDS) approach to analyzing longitudinal data in trauma research. The LDS approach accounts for internal sources of change in an outcome variable, including the influence of prior status on subsequent levels of that variable and the tendency for individuals to experience natural change (e.g., a natural decrease in posttraumatic stress disorder [PTSD] symptoms over time). Under traditional model assumptions, the LDSs are maximally reliable and therefore less likely to introduce biases into model testing. The authors illustrate the method using a sample of children who experienced significant burns or other injuries to examine potential influences (i.e., age of child-adolescent at time of trauma and ongoing family strains) on PTSD symptom severity over time

In the standard model of pavlovian fear learning, sensory input from neutral and aversive stimuli converge in the lateral nucleus of the amygdala (LA), in which alterations in synaptic transmission encode the association. During fear expression, the LA is thought to engage the central nucleus of the amygdala (CE), which serves as the principal output nucleus for the expression of conditioned fear responses. In the present study, we reexamined the roles of LA and CE. Specifically, we asked whether CE, like LA, might also be involved in fear learning and memory consolidation. Using functional inactivation methods, we first show that CE is involved not only in the expression but also the acquisition of fear conditioning. Next, we show that inhibition of protein synthesis in CE after training impairs fear memory consolidation. These findings indicate that CE is not only involved in fear expression but, like LA, is also involved in the learning and consolidation of pavlovian fear conditioning