Faculty Bibliography

Purpose: To image and analyze individual RPE melanosomes (M), lipofuscin (LF), and melanolipofuscin (MLF) granules using high-resolution structured illumination microscopy (hrSIM) and confocal multispectral laser scanning microscopy (cmLSM). Methods: Human donor RPE-flatmounts (n=35; normal macular status: 9<51yrs, 9>80yrs; age-related macular degeneration (AMD): 17) were scanned apical to basal through RPE cells at the fovea, perifovea, and near periphery using hrSIM (Zeiss Elyra.S1; ex488 nm; em>510 nm; 100 nm step size) and cmLSM (Zeiss LSM780; ex488 nm; em 490-695 nm; 390 nm step size; 8.9 nm spectral channel width). The hrSIM and lower-resolution cmLSM images were co-registered by linear 3D registration and choice of mutual information as the image match criterion (PMID16545965). This results in a 1:1 mapping between the single channel hrSIM and multichannel cmLSM data. Individual granules were segmented from the hrSIM data by expert-guided 3D level-set segmentation. Via the hrSIM-cmLSM mapping, the spectra of individual granules can be extracted for quantitative analysis. M, LF, MLF granules/cell were also counted using a custom FIJI plugin. Results: HrSIM imaging and segmentation enables clear delineation and identification of M, LF, and MLF granules (Fig. A,B). Individual granules can be tracked in the z-direction, and size, shape, dimensions, and intracellular position can be monitored. Each cell contains several hundred granules. A cushion of M localizes apically, while LF/MLF prefer basolateral accumulation. Software-assisted mapping of corresponding z-sections (hrSIM/cmLSM) for spectral characterization (Fig. C,D) demonstrates spectral variability among granules. Conclusions: With the combination of hrSIM and cmLSM imaging, individual autofluorescent RPE granules can be identified, localized in three-dimensions, and spectrally analyzed. The examination of spectral characteristics and changes related to intracellular and tissue localization, age, and disease status, on an individual granule basis, might reveal LF/MLF metabolism, and help elucidate LF's role in human RPE physiology. Ongoing studies are examining RPE granule properties in aging and AMD

Exposure to trauma is a common event in the lives of children and adolescents living in the United States. Although a minority of youth develop full posttraumatic stress disorder (PTSD) after a traumatic event, those who do tend to have an extended course of symptoms in multiple functional domains and higher rates of psychiatric comorbidities. Pediatric PTSD can play an important role in legal settings, and requires that an expert witness be well versed in advances in clinical and conceptual models of this diagnosis and familiar with current research devoted to the posttraumatic response in youth. This review is designed to be a resource for the forensic evaluator and outlines the current understanding of epidemiological and clinical features of pediatric PTSD, as well as the neurobiological, dimensional, and developmental conceptual models that describe it.

Research on positive emotion disturbance has gained increasing attention, yet it is not clear which specific positive emotions are affected by mood symptoms, particularly during the critical period of adolescence. This is especially pertinent for identifying potential endophenotypic markers associated with mood disorder onset and course. The present study examined self-reported discrete positive and negative emotions in association with clinician-rated manic and depressive mood symptoms in a clinically and demographically diverse group of 401 outpatient adolescents between 11-18 years of age. Results indicated that higher self reported joy and contempt were associated with increased symptoms of mania, after controlling for symptoms of depression. Low levels of joy and high sadness uniquely predicted symptoms of depression, after controlling for symptoms of mania. Results were independent of age, ethnicity, gender and bipolar diagnosis. These findings extend work on specific emotions implicated in mood pathology in adulthood, and provide insights into associations between emotions associated with goal driven behavior with manic and depressive mood symptom severity in adolescence. In particular, joy was the only emotion associated with both depressive and manic symptoms across adolescent psychopathology, highlighting the importance of understanding positive emotion disturbance during adolescent development.

Adolescents are generally characterized as impulsive. However, impulsivity is a multi-dimensional construct that involves multiple component processes. Which of these components contribute to adolescent impulsivity is currently unclear. This study focused on the neural mechanisms underlying individual differences in distinct components of temporal discounting (TD), i.e., the preference for smaller immediate rewards over larger delayed rewards. Participants were 58 adolescents (12-16 years-old) who performed an fMRI TD task with both monetary and snack rewards. Using mixed-effects modeling, we determined participants' average impatience, and further decomposed TD choices into: 1) amount sensitivity (unique contribution of the magnitude of the immediate reward); and 2) delay sensitivity (unique contribution of delay duration). Adolescents' average impatience was positively correlated with frontoparietal and ventral striatal activity during delayed reward choices, and with ventromedial prefrontal cortex activity during immediate reward choices. Adolescents' amount sensitivity was positively associated with ventral striatal and dorsal anterior cingulate cortex activity during immediate reward choices. Delay sensitivity was positively correlated with inferior parietal cortex activity during delayed reward choices. As expected, snacks were discounted more steeply than money, and TD of both reward types was associated with overlapping activation in the inferior parietal cortex. Exploring whether testosterone or estradiol were associated with TD and its neural correlates revealed no significant associations. These findings indicate that distinct components contribute uniquely to TD choice and that individual differences in amount sensitivity are uniquely associated with activation of reward valuation areas, while individual differences in delay sensitivity are uniquely associated with activation of cognitive control areas.

Reports an error in "Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: A cross-sectional mega-analysis" by Martine Hoogman, Janita Bralten, Derrek P. Hibar, Maarten Mennes, Marcel P. Zwiers, Lizanne S. J. Schweren, Kimm J. E. van Hulzen, Sarah E. Medland, Elena Shumskaya, Neda Jahanshad, Patrick de Zeeuw, Eszter Szekely, Gustavo Sudre, Thomas Wolfers, Alberdingk M. H. Onnink, Janneke T. Dammers, Jeanette C. Mostert, Yolanda Vives-Gilabert, Gregor Kohls, Eileen Oberwelland, Jochen Seitz, Martin Schulte-Ruther, Sara Ambrosino, Alysa E. Doyle, Marie F. Hovik, Margaretha Dramsdahl, Leanne Tamm, Theo G. M. van Erp, Anders Dale, Andrew Schork, Annette Conzelmann, Kathrin Zierhut, Ramona Baur, Hazel McCarthy, Yuliya N. Yoncheva, Ana Cubillo, Kaylita Chantiluke, Mitul A. Mehta, Yannis Paloyelis, Sarah Hohmann, Sarah Baumeister, Ivanei Bramati, Paulo Mattos, Fernanda Tovar-Moll, Pamela Douglas, Tobias Banaschewski, Daniel Brandeis, Jonna Kuntsi, Philip Asherson, Katya Rubia, Clare Kelly, Adriana Di Martino, Michael P. Milham, Francisco X. Castellanos, Thomas Frodl, Mariam Zentis, Klaus-Peter Lesch, Andreas Reif, Paul Pauli, Terry L. Jernigan, Jan Haavik, Kerstin J. Plessen, Astri J. Lundervold, Kenneth Hugdahl, Larry J. Seidman, Joseph Biederman, Nanda Rommelse, Dirk J. Heslenfeld, Catharina A. Hartman, Pieter J. Hoekstra, Jaap Oosterlaan, Georg von Polier, Kerstin Konrad, Oscar Vilarroya, Josep Antoni Ramos-Quiroga, Joan Carles Soliva, Sarah Durston, Jan K. Buitelaar, Stephen V. Faraone, Philip Shaw, Paul M. Thompson and Barbara Franke (The Lancet Psychiatry, 2017[Apr], Vol 4[4], 310-319). In the original article, there were some errors. Corrections are present in the erratum. (The abstract of the original article appeared in record 2017-14573-025).

This study examined mother- and teacher-rated internalizing behaviors (i.e., anxiety, depression, and somatization symptoms) among young children using longitudinal data from a community sample of 661 Mexican and Dominican families and tested a conceptual model in which parenting (mother's socialization messages and parenting practices) predicted child internalizing problems 12 months later. Children evidenced elevated levels of mother-rated anxiety at both time points. Findings also supported the validity of the proposed parenting model for both Mexican and Dominican families. Although there were different pathways to child anxiety, depression, and somatization among Mexican and Dominican children, socialization messages and authoritarian parenting were positively associated with internalizing symptoms for both groups.

Antidepressant medications are commonly used to treat depression, but only about 30% of patients reach remission with any single first-step antidepressant. If the first-step treatment fails, response and remission rates at subsequent steps are even more limited. The literature on biomarkers for treatment response is largely based on secondary analyses of studies designed to answer primary questions of efficacy, rather than on a planned systematic evaluation of biomarkers for treatment decision. The lack of evidence-based knowledge to guide treatment decisions for patients with depression has lead to the recognition that specially designed studies with the primary objective being to discover biosignatures for optimizing treatment decisions are necessary. Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) is one such discovery study. Stage 1 of EMBARC is a randomized placebo controlled clinical trial of 8 week duration. A wide array of patient characteristics is collected at baseline, including assessments of brain structure, function and connectivity along with electrophysiological, biological, behavioral and clinical features. This paper reports on the data analytic strategy for discovering biosignatures for treatment response based on Stage 1 of EMBARC.

OBJECTIVE: A large proportion of paediatric patients with attention-deficit/hyperactivity disorder (ADHD) have associated sleep problems which not only affect the child's wellbeing but also impact family functioning. Management of sleep problems is consequently an important aspect of overall ADHD management in paediatric patients. Although some drugs are being used off-label for the management of paediatric insomnia, there is scant clinical evidence supporting their use. Our aim was to identify and assess the quality of published studies reporting the safety, tolerability and efficacy of drugs used for treating behavioural insomnia in children with ADHD. METHODS: After an initial screen to determine which drugs were most commonly used, we conducted a systematic review of English-language publications from searches of PubMed, EMBASE, PsycINFO and two trial register databases to February 2017, using keywords 'clonidine', 'melatonin', 'zolpidem', 'eszopiclone', 'L-theanine', 'guanfacine', 'ADHD', 'sleep disorder' and 'children'. For quality assessment of included studies, we used the CONSORT checklist for randomised control trials (RCTs) and the Downs and Black checklist for non-RCTs. RESULTS: Twelve studies were included. Two case series for clonidine, two RCTs and four observational studies for melatonin and one RCT each for zolpidem, eszopiclone, L-theanine and guanfacine. Of the 12 included studies, only one on eszopiclone scored excellent for quality. The quality of the rest of the studies varied from moderate to low. For clonidine, melatonin and L-theanine, improvements in sleep-onset latency and total sleep duration were reported; however, zolpidem, eszopiclone and guanfacine failed to show any improvement when compared with placebo. Clonidine, melatonin, L-theanine, eszopiclone and guanfacine were well tolerated with mild to moderate adverse events; zolpidem was associated with neuropsychiatric adverse effects. CONCLUSION: There is generally poor evidence for prescribing drugs for behavioural insomnia in children with ADHD. Further controlled studies are warranted.