Faculty Bibliography

The use of prescription medication to augment cognitive or affective function in healthy persons-or neuroenhancement-is increasing in adult and pediatric populations. In children and adolescents, neuroenhancement appears to be increasing in parallel to the rising rates of attention-deficit disorder diagnoses and stimulant medication prescriptions, and the opportunities for medication diversion. Pediatric neuroenhancement remains a particularly unsettled and value-laden practice, often without appropriate goals or justification. Pediatric neuroenhancement presents its own ethical, social, legal, and developmental issues, including the fiduciary responsibility of physicians caring for children, the special integrity of the doctor-child-parent relationship, the vulnerability of children to various forms of coercion, distributive justice in school settings, and the moral obligation of physicians to prevent misuse of medication. Neurodevelopmental issues include the importance of evolving personal authenticity during childhood and adolescence, the emergence of individual decision-making capacities, and the process of developing autonomy. This Ethics, Law, and Humanities Committee position paper, endorsed by the American Academy of Neurology, Child Neurology Society, and American Neurological Association, focuses on various implications of pediatric neuroenhancement and outlines discussion points in responding to neuroenhancement requests from parents or adolescents. Based on currently available data and the balance of ethics issues reviewed in this position paper, neuroenhancement in legally and developmentally nonautonomous children and adolescents without a diagnosis of a neurologic disorder is not justifiable. In nearly autonomous adolescents, the fiduciary obligation of the physician may be weaker, but the prescription of neuroenhancements is inadvisable because of numerous social, developmental, and professional integrity issues.

BACKGROUND: Evidence-based treatments (EBTs) are not widely available in community mental health settings. In response to the call for implementation of evidence-based treatments in the United States, states and counties have mandated behavioral health reform through policies and other initiatives. Evaluations of the impact of these policies on implementation are rare. A systems transformation about to occur in Philadelphia, Pennsylvania, offers an important opportunity to prospectively study implementation in response to a policy mandate. METHODS/DESIGN: Using a prospective sequential mixed-methods design, with observations at multiple points in time, we will investigate the responses of staff from 30 community mental health clinics to a policy from the Department of Behavioral Health encouraging and incentivizing providers to implement evidence-based treatments to treat youth with mental health problems. Study participants will be 30 executive directors, 30 clinical directors, and 240 therapists. Data will be collected prior to the policy implementation, and then at two and four years following policy implementation. Quantitative data will include measures of intervention implementation and potential moderators of implementation (i.e., organizational- and leader-level variables) and will be collected from executive directors, clinical directors, and therapists. Measures include self-reported therapist fidelity to evidence-based treatment techniques as measured by the Therapist Procedures Checklist-Revised, organizational variables as measured by the Organizational Social Context Measurement System and the Implementation Climate Assessment, leader variables as measured by the Multifactor Leadership Questionnaire, attitudes towards EBTs as measured by the Evidence-Based Practice Attitude Scale, and knowledge of EBTs as measured by the Knowledge of Evidence- Based Services Questionnaire. Qualitative data will include semi-structured interviews with a subset of the sample to assess the implementation experience of high-, average-, and low-performing agencies. Mixed methods will be integrated through comparing and contrasting results from the two methods for each of the primary hypotheses in this study. DISCUSSION: Findings from the proposed research will inform both future policy mandates around implementation and the support required for the success of these policies, with the ultimate goal of improving the quality of treatment provided to youth in the public sector.

Updating memories is critical for adaptive behaviors, but the rules and mechanisms governing that process are still not well defined. During a limited time window, the reactivation of consolidated aversive memories triggers memory lability and induces a plasticity-dependent reconsolidation process in the lateral nucleus of amygdala (LA) [1-5]. However, whether new information is necessary for initiating reconsolidation is not known. Here we show that changing the temporal relationship between the conditioned stimulus (CS) and unconditioned stimulus (US) during reactivation is sufficient to trigger synaptic plasticity and reconsolidation of an aversive memory in the LA. These findings demonstrate that time is a core part of the CS-US association and that new information must be presented during reactivation in order to trigger LA-dependent reconsolidation processes. In sum, this study provides new basic knowledge about the precise rules governing memory reconsolidation of aversive memories that might be used to treat traumatic memories.

PURPOSE: The UNC-Utah NA-MIC DTI framework represents a coherent, open source, atlas fiber tract based DTI analysis framework that addresses the lack of a standardized fiber tract based DTI analysis workflow in the field. Most steps utilize graphical user interfaces (GUI) to simplify interaction and provide an extensive DTI analysis framework for non-technical researchers/investigators. DATA: We illustrate the use of our framework on a 54 directional DWI neuroimaging study contrasting 15 Smokers and 14 Controls. METHODS: At the heart of the framework is a set of tools anchored around the multi-purpose image analysis platform 3D-Slicer. Several workflow steps are handled via external modules called from Slicer in order to provide an integrated approach. Our workflow starts with conversion from DICOM, followed by thorough automatic and interactive quality control (QC), which is a must for a good DTI study. Our framework is centered around a DTI atlas that is either provided as a template or computed directly as an unbiased average atlas from the study data via deformable atlas building. Fiber tracts are defined via interactive tractography and clustering on that atlas. DTI fiber profiles are extracted automatically using the atlas mapping information. These tract parameter profiles are then analyzed using our statistics toolbox (FADTTS). The statistical results are then mapped back on to the fiber bundles and visualized with 3D Slicer. RESULTS: This framework provides a coherent set of tools for DTI quality control and analysis. CONCLUSIONS: This framework will provide the field with a uniform process for DTI quality control and analysis.

Diffusion Tensor Imaging (DTI) is currently the state of the art method for characterizing microscopic tissue structure in the white matter in normal or diseased brain in vivo. DTI is estimated from a series of Diffusion Weighted Imaging (DWI) volumes. DWIs suffer from a number of artifacts which mandate stringent Quality Control (QC) schemes to eliminate lower quality images for optimal tensor estimation. Conventionally, QC procedures exclude artifact-affected DWIs from subsequent computations leading to a cleaned, reduced set of DWIs, called DWI-QC. Often, a rejection threshold is heuristically/empirically chosen above which the entire DWI-QC data is rendered unacceptable and thus no DTI is computed. In this work, we have devised a more sophisticated, Monte-Carlo simulation based method for the assessment of resulting tensor properties. This allows for a consistent, error-based threshold definition in order to reject/accept the DWI-QC data. Specifically, we propose the estimation of two error metrics related to directional distribution bias of Fractional Anisotropy (FA) and the Principal Direction (PD). The bias is modeled from the DWI-QC gradient information and a Rician noise model incorporating the loss of signal due to the DWI exclusions. Our simulations further show that the estimated bias can be substantially different with respect to magnitude and directional distribution depending on the degree of spatial clustering of the excluded DWIs. Thus, determination of diffusion properties with minimal error requires an evenly distributed sampling of the gradient directions before and after QC.

OBJECTIVE: To determine long-term effects on substance use and substance use disorder (SUD), up to 8 years after childhood enrollment, of the randomly assigned 14-month treatments in the multisite Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (MTA; n = 436); to test whether medication at follow-up, cumulative psychostimulant treatment over time, or both relate to substance use/SUD; and to compare substance use/SUD in the ADHD sample to the non-ADHD childhood classmate comparison group (n = 261). METHOD: Mixed-effects regression models with planned contrasts were used for all tests except the important cumulative stimulant treatment question, for which propensity score matching analysis was used. RESULTS: The originally randomized treatment groups did not differ significantly on substance use/SUD by the 8-year follow-up or earlier (mean age = 17 years). Neither medication at follow-up (mostly stimulants) nor cumulative stimulant treatment was associated with adolescent substance use/SUD. Substance use at all time points, including use of two or more substances and SUD, were each greater in the ADHD than in the non-ADHD samples, regardless of sex. CONCLUSIONS: Medication for ADHD did not protect from, or contribute to, visible risk of substance use or SUD by adolescence, whether analyzed as randomized treatment assignment in childhood, as medication at follow-up, or as cumulative stimulant treatment over an 8-year follow-up from childhood. These results suggest the need to identify alternative or adjunctive adolescent-focused approaches to substance abuse prevention and treatment for boys and girls with ADHD, especially given their increased risk for use and abuse of multiple substances that is not improved with stimulant medication. Clinical trial registration information-Multimodal Treatment Study of Children With Attention Deficit and Hyperactivity Disorder (MTA); http://clinical trials.gov/; NCT00000388.

It has long been recognized that human beings exposed to severe stress may develop psychological symptoms. With recent terrorist acts around the world including the New York City World Trade Center September 11, 2001 atrocity, there has been a growing interest in the specific impact of terrorist acts on the victims and witnesses. One area that has received less study is the specific impact on children. This paper reviews some of the general effects of traumatic stress on children and the history of the research in this area including a specific discussion of post-traumatic stress disorder in children. This is followed by a review of how children might react to the trauma of a terrorist attack differentiating between three different subgroups of children (preschool age children, school-age children, and adolescents). Then there is a review of what a comprehensive evaluation of childhood victims of terrorism should entail. Finally, treatment modalities that have been shown to be effective are reviewed.

OBJECTIVE: Generalized anxiety disorder (GAD) typically begins during adolescence and can persist into adulthood. The pathophysiological mechanisms underlying this disorder remain unclear. Recent evidence from resting state functional magnetic resonance imaging (R-fMRI) studies in adults suggests disruptions in amygdala-based circuitry; the present study examines this issue in adolescents with GAD. METHOD: Resting state fMRI scans were obtained from 15 adolescents with GAD and 20 adolescents without anxiety who were group matched on age, sex, scanner, and intelligence. Functional connectivity of the centromedial, basolateral, and superficial amygdala subdivisions was compared between groups. We also assessed the relationship between amygdala network dysfunction and anxiety severity. RESULTS: Adolescents with GAD exhibited disruptions in amygdala-based intrinsic functional connectivity networks that included regions in medial prefrontal cortex, insula, and cerebellum. Positive correlations between anxiety severity scores and amygdala functional connectivity with insula and superior temporal gyrus were also observed within the GAD group. There was some evidence of greater overlap (less differentiation of connectivity patterns) of the right basolateral and centromedial amygdala networks in the adolescents with, relative to those without, GAD. CONCLUSIONS: These findings suggest that adolescents with GAD manifest alterations in amygdala circuits involved in emotion processing, similar to findings in adults. In addition, disruptions were observed in amygdala-based networks involved in fear processing and the coding of interoceptive states.

With increased interest in the early diagnosis and treatment of children with autism spectrum disorders (ASD), more attention has been called to the motor skills of very young children with ASD. This study describes the gross and fine motor skills of a cross-sectional group of 162 children with ASD between the ages of 12 and 36 months, as well as a subset of 58 children followed longitudinally. Gross motor and fine motor age equivalent scores were obtained for all children. A 'motor difference' variable was calculated for each child's gross and fine motor skills by taking the absolute difference of the children's age equivalent motor score and their respective chronological age. In Study 1 (the cross-sectional analysis), ANCOVA (co-varied for nonverbal problem solving) revealed significant group differences in the gross motor and fine motor age difference variables. Post-hoc analysis revealed that gross motor and fine motor differences became significantly greater with each 6-month period of chronological age. In Study 2, 58 children were measured twice, an average of 12 months apart. Results indicate that the gross motor and fine motor difference scores significantly increased between the first and second measurements. The importance of addressing motor development in early intervention treatments is discussed

OBJECTIVE:  We examined resting state functional connectivity in the brain between key emotion regulation regions in bipolar I disorder to delineate differences in coupling from healthy subjects. METHODS:  Euthymic subjects with bipolar I disorder (n = 20) and matched healthy subjects (n = 20) participated in a resting state functional magnetic resonance imaging scan. Low-frequency fluctuations in blood oxygen level-dependent (BOLD) signal were correlated in the six connections between four anatomically defined nodes: left and right amygdala and left and right ventrolateral prefrontal cortex (vlPFC). Seed-to-voxel connectivity results were probed for commonly coupled regions. Following this, an identified region was included in a mediation analysis to determine the potential of mediation. RESULTS:  The bipolar I disorder group exhibited significant hyperconnectivity between right amygdala and right vlPFC relative to healthy subjects. The connectivity between these regions in the bipolar I disorder group was partially mediated by activity in the anterior cingulate cortex (ACC). CONCLUSIONS:  Greater coupling between right amygdala and right vlPFC and their partial mediation by the ACC were found in bipolar I disorder subjects in remission and in the absence of a psychological task. These findings have implications for a trait-related and clinically important imaging biomarker.