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A N N U A L R E P O R T July 1, 2007 – June 30, 2008

SACKLER INSTITUTE FOR DEVELOPMENTAL PSYCHOBIOLOGY AT COLUMBIA UNIVERSITY

Table of Contents

Pages

Introduction 2

Part I Highlights 3 - 5

Part II Research Programs 5

1. Basic Science Division 5 - 9

2. Behavioral Neuroscience Division 9 - 13

3. Clinical Research Division 13 - 17

4. Developmental Neuroimaging Laboratories 17 - 23

5. Department of Pediatrics-Neonatology 23 - 24

6. Sackler Awardees 24 - 29

Part III Financial Report enclosure

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This report covers the seventh year of operation of the Sackler Institute, established at Columbia April 27th 2001 with a gift from the Sackler Foundation made in December 2000. The Institute is an organization within the College of Physicians and Surgeons and the Department of Psychiatry that brings together federally funded scientists active in research on the developmental origins of vulnerability to psychiatric illness. Our faculty has more that 7 million dollars in outside support this year. The income from the endowment supports a professorship for the Director of the Institute, and made a major contribution to the construction of the new Sackler Laboratories at the New York State Psychiatric Institute in 2002-2003. In addition, it provides support for new directions in faculty research and funds the annual Sackler Awards, stipends for postdoctoral fellow/junior faculty workers to facilitate their transition to becoming independent researchers. The Institute sponsors conferences and symposia at national and international meetings, awards ‘mini-grants’ to selected Sackler Fellows for their research costs, gives ‘seed money’ grants to faculty for novel research pilot studies that enable subsequent grant applications for federal support, and provides administrative support for the Institute. An additional gift from the Sackler Foundation in June of 2007 is supporting a special project on the early developmental role of serotonin transporter function. The administrative structure and faculty on June 30, 2008 were as follows: Director, Dr. Myron A. Hofer Assistant Director, Dr. William P. Fifer Administrator, Jennifer Knowles Chief, Basic Science Division – Dr. Jay Gingrich Sackler Scientist – Dr. Mark Ansorge Chiefs, Behavioral Neuroscience Division - Drs. Michael Myers and William Fifer Sackler Scientists – Drs. Susan Brunelli and Catherine Monk Chief, Clinical Division - Dr. Myrna Weissman Head, Developmental Neuroimaging Laboratory - Dr. Bradley Peterson Department of Pediatrics (Neonatology) – Drs. Raymond Stark and Marianne Garland New Sackler Institute Scientists appointed: Dr. Alan Brown - Clinical Division, Dr. Frances Champagne - Department of Psychology at Columbia University Morningside Campus, Dr. Christoph Kellendonk - Basic Science Division Sackler Awardees: (2nd Year) – Dr. Amir Levine and an award shared by Drs. Rachel Marsh and Dr. Phil Grieve The research programs of the faculty and the three Sackler Awardees of ’07-‘08 are described in the second section of this report along with their publications for the year and their current Federal and other grant support. A financial report is available separately.

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Part I – Highlights The first Mortimer D. Sackler, M.D. Prize was announced in December of 2007 and presented on April 25th to Avshalom Caspi, PhD for his studies on the interactions of defined early experiences and specific gene variants in determining later vulnerability to a range of psychiatric disorders. The first prize was given in honor of Mortimer D. Sackler’s 90th birthday by his 7 children. The prize of $60,000 is “For distinguished achievement in developmental psychobiology” and plans are in progress for the prize to be endowed in perpetuity. The presentation of the prize will be shared on alternate years with the Cornell Sackler Institute. The recipient will give Grand Rounds at Cornell and Columbia as well as participate in formal workshops at both institutes. The prize committee will include representation from all 5 Sackler Institutes who will be invited to the prize presentation, Grand Rounds and workshops. On May 28th of 2008 Dr. Thomas Jessell, who was chief of our Basic Science Division from 2001-2008, was named by the President of the Norwegian Academy of Science as co-recipient of the first Kavli Prize in Neuroscience. This is a million dollar prize that will be awarded biannually in Nanoscience and Astophysics as well as in Neuroscience. Dr. Jessell was honored for his research that “has revealed the chemical signals behind the differentiation of early progenitor cells into the complex assembly of different types of neurons that make up neuronal circuits”. During the spring of 2008 a new chief of the Basic Science Division was appointed and we expanded our faculty to include three additional Sackler Scientists, bringing new expertise, areas of research and interdepartmental collaborations. Dr. Thomas Jessell stepped down from his position as chief of the Basic Science Division in June, after nearly 10 years in that position, to pursue new responsibilities in the Department of Neuroscience. Dr. Jay Gingrich, head of the Sackler Mouse Genetics and Behavior Laboratory, became the new Chief of the Basic Science Division on June 30, 2008. A new Sackler Scientist, Dr. Christoph Kellendonk will join the Basic Science Division with a joint appointment in Pharmacology and Psychiatry. Dr. Kellendonk has been working in the Eric Kandel lab where he has been studying the genetic/molecular mechanisms that may underlie the development of certain cognitive deficits that are characteristic of schizophrenic patients, using a mouse genetic model. He has found that the deficit in working memory in adult mice caused by (experimentally induced) over-expression of the Dopamine 2 receptor gene is not due to abnormal gene activity in adulthood, as it had been expected, but rather to genetic over-expression during early development, in the pre-or early postnatal periods. This finding opens up a new area in research on the developmental origins of schizophrenia. Dr. Alan Brown, associate professor of clinical psychiatry and epidemiology, has joined the Clinical Research Division. Dr. Brown works closely with Dr. Weissman and brings special expertise in identifying early developmental contributors to the onset of mental illness. He is currently working with a large Finnish population database providing records of extensive prenatal and postnatal developmental risk factors compiled many years ago. Dr. Brown was the first to demonstrate that serologically documental prenatal exposure to viral illnesses such as influenza and inflammatory markers are risk factors of schizophrenia.

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Dr. Frances Champagne, assistant professor of Psychology at Columbia’s downtown campus has joined the Behavioral Neuroscience Division. During her doctoral work in Michael Meaney’s lab at McGill University using mouse models, Dr Champagne discovered a number of early developmental mechanisms involving gestational stress and estrogen-oxytocin receptor interactions regulating the later development of maternal behavior. Last year, at the University of Cambridge, she investigated epigenetic mechanisms for these efforts and for the transmission of maternal behavior patterns across generations. We had a record number of Sackler Award applications this year (13) and were able to fund 2 stipends for 2 years. Tiziano Colibazzi was funded for a project titled “Longitudinal Imaging in Adolescents Prodromal for Schizophrenia”. His proposed research aims to identify the neuroanatomical changes in MRI scans of cortical surface and mantle during adolescence and into early adult development in subjects, 30 of whom are identified as showing prodromal signs of developing schizophrenia and in 30 controls. His mentors will be Drs. Peterson, Lieberman and Cheryl Corcoran (a former Sackler Awardee – ’02-’04). The second awardee, Dr. Amar Sahay proposes to study the role of a particular genetic transcription factor (Klf-9) regulating activity-dependant processes, such as synapse maturation and dendrictic branching, that are hypothesized to mediate the effects of early life stress on anxiety-like behavior in adult mice. His mentor will be Rene Hen, director of the Division of Integrative Neuroscience. The Final Reports of the previous 3 Sackler Awardees are presented in Part II No. 6 of this report. The five divisions of the Sackler Institute are united in a common project – “The Developmental Role of the Serotonin Transporter in Affective Illness and Its Treatment”, that was funded last year by a gift from the Sackler Foundation. Progress reports on this aspect of Sackler faculty activities can be found in each of the Division reports. This project is an interlocking set of human and laboratory animal studies using novel approaches to understanding how and why genetic reduction of serotonin transporter function (acting from conception on) or infant and juvenile pharmacologic inhibition of transporter function in mice with selective serotonin reuptake inhibitors (SSRI) drugs, can increase vulnerability to depression in adulthood, whereas these drugs effectively relieve depression or depression-like behaviors when given to adult humans or mice. The question of the immediate and long term risks to offspring of SSRI’s taken by mothers during pregnancy or taken later by adolescents, and the mechanisms of such effects, are urgent clinical questions and a focus of both animal and human studies in our project. A small grant was awarded to Mark Alter who applied for bridging funds to enable him to complete and prepare for publication, a series of remarkable studies revealing novel epigenetically-mediated developmental processes in genetically identical strains of mice. At the 2007 annual meeting of the International Society for Developmental Psychobiology, the Sackler Institute funded a symposium entitled "Maternal Effects on Offspring Behavioral and Neuroendocrine Development ". The leaders in the field , Drs. Frances Champagne, Columbia University, Karen Parker, Stanford University; Dario Maestripieri, University ofChicago; Kai McCormack and Mar Sanchez,; Emory University and J. Dee Higley, at National Institute on Alcohol Abuse and Alcoholism, presented their latest research. Society members and their students were uniformly impressed, interested

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and interactive during the symposium and in the collaborative discussions that followed. Several of these interactions were made possible by Sackler Institute travel grants for students from Europe, Israel, Mexico, and New Zealand who also presented papers at the meeting. Sponsored Symposia : At the 23rd annual meeting of the Winter Conference in Developmental Psychobiology, we co-sponsored, with the Cornell Sackler, two symposia. This meeting brings together a multi-disciplinary group of outstanding scientists in a warm, friendly and highly interactive forum. The growing reputation of this invited only conference, with the help of a small amount of Sackler Institute funding, enables world experts from disparate fields to share data, ideas and techniques and form long lasting and often unique collaborations. This year's Sackler sponsored symposia were focused on "The Psychobiology of Social Engagement" and on "Understanding the Development of Neural Circuitry".

Part II - RESEARCH PROGRAMS

1. Basic Science Division

Jay Gingrich, Chief – Laboratory of Translational Neurogenetics Our laboratory is currently pursuing different lines of research related to the genetics of neuropsychiatric disorders. Mice offer an excellent model to understand the developmental contribution of genes to normal brain maturation and thus are employed extensively in our studies. Mice with transiently-reduced transporter function during early life matured into adult mice with numerous abnormalities in depression and anxiety-related behaviors. We are taking a multilevel approach to understand the underlying biology—using techniques of anatomy, electrophysiology, gene expression, and behavioral analyses. We are in the second year of an RO1 grant from NIMH to examine the biological underpinnings of environmental influences on mice with genetically-reduced serotonin transporter (SERT) function. We also received a second RO1 from NIMH on this project, which focuses on investigating the role of developmental serotonin signaling in circuit maturation. Specifically, the second project aims at identifying biological mechanisms that underpin the effects of post-natal SSRI exposure. Lastly, Mark Ansorge, a former Sackler Fellowship Awardee, has received a K99 career development award from NIMH. In 2008, Mark Ansorge has also been promoted to faculty, both at the Sackler Institute as well as at the NYSPI. Prior and ongoing Sackler support through the Serotonin Transporter project has been crucial for achieving these research milestones and obtaining federal funding.

We have two projects directly related to schizophrenia and autism, that have received either NIMH funding or funding from the Simons Foundation. In the first, Neuregulin1 (NRG1) has been identified as a susceptibility gene in schizophrenia. Mice with reduced expression of different NRG1 isoforms exhibit several behavioral abnormalities that are consistent with both positive and negative symptoms of schizophrenia. We have identified that these mice exhibit social deficits, olfactory deficits (as do some schizophrenics). We have found that these mice have underlying deficiencies in the

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targeting of newly generated neurons to the olfactory bulb. Thus, we are working to discover to what degree NRG1 is involved in brain development and to what degree it serves a maintenance function.

The second project (funded by the Simons Foundation) examines the role of aberrant DNA methylation as a possible epigenetic contribution to autism susceptibility. We have developed an animal model of advanced paternal age effects on complex behaviors in the offspring. We are exploring the hypothesis that methylation accuracy of years of replication of spermatagonia DNA decreases with increased number of divisions (as would occur over time in older fathers).

The fourth project examines the role of a major post synaptic receptor for the neurotransmitter serotonin 5HT2A in behavioral control of anxiety-like behaviors and in psychosis-related endophenotypes. We have recently developed the technology to specifically manipulate receptor signaling in specific brain areas. This will allow us to define the minimal circuits that are sufficient to mediate serotonin effects on anxiety and schizophrenia-related behaviors. This work was recently published in the journal, Science. In 2008, Dr. Gingrich was promoted to Associate Professor of Psychiatry at Columbia and was elected to the NARSAD Scientific Advisory Board.

Publications

Salomon L, Lanteri C, Godeheu G, Blanc G, Gingrich JA, Tassin JP (2007): Paradoxical constitutive behavioral sensitization to amphetamine in mice lacking 5-HT(2A) receptors. Psychopharmacology (Berl) 194:11-20.

Ansorge, M., Hen, R, Gingrich, JA (2007): Developmental Origins of Depressive and Anxiety Disorders. 7:8-17 Current Opinions in Pharmacology 7 (1): 8-17.

Kayser V, Elfassi IE, Aubel B, Melfort M, Julius D, Gingrich JA, Hamon M, Bourgoin S. (2007): Mechanical, thermal and formalin-induced nociception is differentially altered in 5-HT1A-/-, 5-HT1B-/-, 5-HT2A-/-, 5-HT3A-/- and 5-HTT-/- knock-out male mice. Pain (3):235-48

Javier González-Maeso, Noelia V. Weisstaub, Mingming Zhou, Alena Lira, Maria Bradley-Moore, Pokman Chan, Lidija Ivic, Yongchao Ge, Qiang Zhou, Stuart C. Sealfon, and Jay A. Gingrich (2007): Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior. Neuron 53: 439-452.

Beique JC, Imad M, Mladenovic L, Gingrich JA, Andrade R (2007): Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex. Proc Natl Acad Sci U S A 104:9870-9875.

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Van Steenwinckel J, Brisorgueil MJ, Fischer J, Verge D, Gingrich JA, Bourgoin S, Hamon M, Bernard R, Conrath M. (2007): Role of spinal serotonin 5-HT2A receptor in 2',3'-dideoxycytidine-induced neuropathic pain in the rat and the mouse. Pain Jul;137(1):66-80.

Ansorge, MA, Morelli, E., Gingrich, JA (2008): Inhibition of serotonin but not norepinephrine reuptake during early development impairs affective and anxiety behaviors in adult mice. J. Neuroscience 28 (1): 199-207.

Gonzalez-Maeso J, Ang R, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez J, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC (2008): Identification of a novel serotonin/glutamate receptor complex implicated in psychosis. Nature 452 (7183)93-97.

Chen YJ, Johnson MA, Lieberman MD, Goodchild RE, Schobel S, Lewandowski N, Rosoklija G, Liu RC, Gingrich JA, Small S, Moore H, Dwork AJ, Talmage DA, Role LW. (2008): Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components. J Neuroscience Jul 2;28 (27):6872-83.

Lu R, Alioua A, Kumar Y, Kundu P, Eghbali M, Weisstaub NV, Gingrich JA, Stefani E, Toro L. (2008): c-Src tyrosine kinase, a critical component for 5-HT2A receptor-mediated contraction in rat aorta. J Physiology Aug15;586 (16):3855-69.

Other Grant Support

NIMH (1R01 MH081193-01A1) (Booth) 04/01/08 to 03/31/13 NIH/NIMH $88,426 Serotonin 5HT2C Agonist Drugs with 5HT2A/B Antagonist Activity This project proposes preclinical evaluation of (-)-trans-PAT as pharmacotherapy for obesity and Neuropsychiatric disorders, and synthesis of PATs with enhanced 5HT2C agonist activity; PATsWith potent 5HT2A/5HT2B antagonism may lead to drugs for psychiatric and cardiovascular diseases. Role on Project: Co-Principal Investigator Overlap: There is no overlap

NIMH (1 R01 MH080116-01) (Gingrich) 12/01/07 to 11/30/12 NIH/NIMH $225,000 Serotonin and the Modulation of Brain Development. Five year project that will increase our understanding of which developmental periods are sensitive to SERT inhibition as well as advancing our understanding of the mechanisms that might explain this phenomenon.

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Role on Project: Principal Investigator Overlap: There is no overlap

Simons Foundation Autism Research Initiative 10/1/07 to 09/30/10 (SFARI) $416,350 Identification of Aberrantly Methylated Genes in Autism: The Role of Advanced Paternal Age. Three year project to identify specific loci that are most prone to aberrant methylation with advancing Age, and are transmitted frequently to affected offspring. Role on Project: Principal Investigator Overlap: There is no overlap

NIDA P01 DA12923 (Weinstein) 08/01/07 to 06/30/12 NIDA $193,953 Hallucinogens on 5-HT2A Receptors: Mechanisms and Effects. Five year project to examine the role of 5-HT2A receptors in the mechanism of hallucinogens such as LSD. Proposes to generate several knock-in mutations of 5-HT2A receptors that selectively p12*.10=erturb different aspects of receptor function (ligand binding, G-protein coupling, desensitization. Role on Project: Co-PI of Project 3. Overlap: There is no overlap.

NIMH (5 RO1-MH076026) (Gingrich) 03/01/06 to 02/28/11 NIH/NIMH $206,338

Gene - Environment Interactions and Vulnerability to Neuropsychiatric Disorders. This study examines the environmental factors that contribute to the worsening or amelioration of the depressive phenotype that have been described in the 5HTT knockout mice. Role on project: Principal Investigators Overlap: There is no overlap.

MH066171-01A1 (Lieberman) 07/01/04 to 06/30/09 NIH/NIMH $50,000

Etiological Pathways to Dopamine-Glutamate Dysfunction Conte Center for the Neuroscience of Mental Disorders Our component of this Center uses mice partially deficient in neuregulin-1 as an animal model of schizophrenia. Role on Project: Co-PI Project 6 Overlap: There is no overlap.

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5 P50 MH062185-08 (Mann) 07/01/05 to 06/30/10

NIMH $1,495,657 Conte Center for the Neuroscience of Mental Disorders : The Neurobiology of Suicidal Behavior Project 6- Genetic Modulation Of Serotonin During Development: $107,000 Models of Aggression, Impulsivity And Depression (PI: Underwood) Our component of this Center Animal Project (7) examines the development of behavior in SERT and MAOA KO mice to understand the divergent effects of each genotype on behavior. Role on Project: Co-PI Overlap: There is no overlap.

2. Behavioral Neuroscience Division Dr. William Fifer, Assistant Director Sackler Institute - Human Fetal Behavior and Intrauterine Influences on Vulnerability to Psychiatric Illness Our general research program focuses on the effects of the early environment on fetal and infant brain/behavior development. We are funded by NIH to investigate the effects of prenatal risk factors including maternal stress, depression, nicotine, alcohol and poor nutrition on central nervous system development. With Dr. Monk, from the Department of Behavioral Medicine, we continue our studies on the influence of maternal depression and treatment for depression on the developing infant. With Dr. Myers we continue with Phase II of our NIH study on risk for neurodevelopmental disorders in high risk populations in South Africa and the Dakotas. The CJ Foundation provided funds and the renovation was completed for a new Baby Testing Center in Vanderbilt Clinic, which will provide family friendly space be facilities within the Irving Center dedicated to our preterm and full term infant studies.

Serotonin Transporter Project: Drs. Monk and Fifer are continuing the clinical research arm of this antidepressants project. They are investigating the effects of SSRI during pregnancy on fetal and infant neurobehavioral development. The research protocol has now expanded to include joint studies with Brad Peterson which will add state of the art brain imaging techniques. Additionally, as a result of the Joint Sackler Centers Meeting in Edinburgh, IRB approval has been given for a collaborative study of a large population of women diagnosed with depression and on medication during pregnancy in Glasgow.

Dr. Myron Hofer, Sackler Institute Director - Processes of Attachment and the

Regulation of Development

Our research has centered on the role of the parent-infant relationship as the first major environmental influence on postnatal development. Through an experimental analysis of the psychobiological events that enmesh the infant rat and its mother, we have been studying the hidden regulatory processes that are the basis for the early

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origins of attachment, the dynamics of the separation response and the long term shaping of development by that first relationship. Most recently, with Dr. Susan Brunelli, we have been studying an evolutionary model of repeated selection in which two different alternative developmental paths and anxiety phenotypes have been produced.

I am currently working on a book on developmental processes, viewed from an evolutionary perspective. This has led me to attempt to answer, in a new way, questions such as: what is development? How is it related to evolution? And when and how did development evolve? My (not so modest) goal is to find relatively simple principles that can help us organize and think about the many different developmental processes that are being discovered nearly every day at levels from cells to society. Dr. Hofer, gave the 50th Sandor Rado Lecture on June 3rd 2008 at the N.Y. Academy of Medicine. This award is presented annually by The Association for Psychoanalytic Medicine and the Alumni of the Columbia Psychoanalytic Center. His title was “The Emerging Synthesis of Development and Evolution: A new Biology for Psychoanalysis”. Dr. Michael Myers, Division Chief - Early Nutritional Influences on Vulnerability to Disease Work in this laboratory continues to investigate the relationships between suboptimal environments during pregnancy and in the early postnatal period, and the development of vulnerability for disease later in life. Numerous epidemiological studies have shown that cardiovascular disease, diabetes, schizophrenia, and depression are all influenced by nutritional disturbances during these sensitive periods of development. Characterizing such long-term effects of early experiences remains a central focus of researchers in the field of Developmental Psychobiology. However, recent advances in molecular epigenetics make it now possible to study the developmental processes that account for enduring changes in disease vulnerability. This is a major focus of work in our group. In collaboration with Drs. William Fifer and Harry Shair in our department, and Dr. Morris Cohen at Newark Beth Israel Hospital, we investigate these phenomena in both animal models and human infants. Our long-term goals are to understand the modulators and mechanisms underlying long-term effects of variation in nutrition and other experiences. However, in recent years, we also focused efforts on finding more sensitive early markers of these experiences. In this work, we have determined that profiles of gene expression in the placenta provide a novel method for assessing whether an individual animal or human infant has been exposed to caloric deficits or surfeits, or drugs such as fluoxetine or alcohol. This year we completed a study in humans which expanded the potential of this approach by demonstrating that profiles of placental gene expression are predictive of early postnatal “catch-up growth” in low birth weight babies. This data greater strengthens our belief that assessment of gene and protein expression in the placenta afford a new approach for identifying the most vulnerable of infants.

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We have continued our work supported by the Serotonin Transporter Project in collaboration with Dr. Susan Brunelli. In one aspect of these studies we found further evidence that acute administration of an SSRI (fluoxetine) to adolescent rats alters their behavior in tasks that require animals to wait for the delivery of reward. In contrast to our original hypothesis that fluoxetine would increase impulsive behavior, our latest data continue to support an alternate view that SSRIs may not induce intolerance to waiting, rather SSRIs may enhance expression of frustration after making a response that results in a delay to reinforcement. We hypothesize that such an effect of SSRIs, expressed during a period before the drug effectively reduced depressive symptoms, could underlie the negative consequences of SSRI administration during the early phase of treatment.

Publications

Nomura Y, Halperin JM, Newcorn JH, Davey C, Fifer WP, Savitz DA, Brooks-Gunn J. (2008)The risk for impaired learning-related abilities in childhood and educational achievement among adults born near-term. Journal of Pediatric Psychology (in-press). Fifer, W.P., Ten Fingers, S., Youngman, M., Gomez-Gribben, E and Myers, M.M. (2008) Effects of Alcohol and Smoking during Pregnancy on Infant Autonomic Control. Developmental Psychobiology (in Press)

Monk, C., Leight, K., & Fang, Y. The relationship between women’s attachment style and perinatal mood disturbance: Implications for screening & treatment. Archives of Women’s Mental Health, 2008,11(2), 117–29.

Evans, L, Myers, M.M., & Monk, C. Pregnant women’s cortisol is elevated with anxiety and depression but only when comorbid. Archives of Women’s Mental Health, 2008, 11(3), 239–48.

Brunelli, S. A., & Hofer, M. A. (2007). Selective breeding for infant rat separation-induced ultrasonic vocalizations: Developmental precursors of passive and active coping styles. Behavioural Brain Research(182), 193-207.

Hofer, M.A. and Sullivan, R.M. Toward A Neurobiology of Attachment. In Nelson, C.A. and Luciana, M. (Eds.) Handbook of Developmental Cognitive Neuroscience- 2nd Ed., MIT Press, 2008. Polan, H.J. and Hofer, M.A. Psychobiological Origins of Infant Attachment and Its Role in Development. In Cassidy, J. and Shaver, P.R. (Eds), Handbook of Attachment Theory and Research – 2nd Ed., Guilford Press, 2008.

Hofer, M.A. Developmental Neuroscience. In Berntson, G.G. and Cacioppo, J.T. (Eds.) Handbook of Neuroscience for the Behavioral Sciences, John Wiley, (In Press).

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Evans, L.M., Myers, M.M. Monk, C. (2008) Pregnant women's cortisol is elevated with anxiety and depression - but only when comorbid. Arch Womens Ment Health. 11:239-48. Muller, J.M., Moore, H., Myers, M.M., Shair, H.N. (2008) Ventral striatum dopamine D2 receptor activity inhibits rat pups' vocalization response to loss of maternal contact. Behav Neurosci. 122:119-28.

Other Grant Support

R01 HD32774 (Fifer, W.P., PI) 04/01/06 -03/30/11 38%

NICHD $363,300 ”Perinatal Assessment of At-Risk Populations” This is an investigation of underlying mechanisms and early assessment of risk for Sudden Infant Death.

N01 HD503411 (Fifer Co-investigator) 09/30/05 - 09/30/10 5% NICHD $560, 879 “National Children’s Study- Queens Vanguard Center” A cohort study to examine environmental influences on the health and development of children.

P20 MD001631 09/30/05-06/30/10 10% NCMHHD $108, 960 (total) $90,886 (Myers and Fifer Co-investigators)

(subcontract) ”Center for Health Research with Tribes in SD-MT-WY.” Project IV, “Early predictors of Adverse Neurobehavioral Outcomes in Young Children” To help institutions build the infrastructure to support community-based participatory research on health disparities.

R13 MH HD58769 (Fifer, W.P., PI) 10/01/00-9/30/10 1% NIMH $15,000 ”International Society for Developmental Psychobiology Student Travel Grant”

CJ Foundation (Fifer, WP and Myers, MM) 07/01/07-06/30/12 5% Research Grant $50,000 “CJ SIDS Center Without Walls “ A multi-center grant to investigate the role of serotonin in Sudden Infant Death Syndrome.

R21 (Fifer and Myers, Co-Invs.) 04/10/07-03/31/09 5% NICHD $200,000 “Autonomic Reactivity during Sleep Position Thermal Stress” To investigate effects of sleep position and thermal stress in low birth weight infants.

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Irving Institute for Clinical & Translational Research 07/01/08 – 06/30/2011 $180,000 “Biobehavioral Assessment of Stress during Pregnancy: Fetal and Newborn Outcomes” Principal Investigator: Monk, C.E. Role: PI

T32 MH018264 (Myers, M.M.) 07/01/08-06/30/13 1.8 (calendar yr)

NIMH $278,884 "Developmental Neuroscience and Behavior" Postdoctoral research training grant for MDs and PhDs in Psychobiology.

U01 HD55155 (Fifer, W.P. & Myers, M.M. Co-PIs) 09/01/06-07/31/11 2.4mo (calendar yr) NICHD $404,362 “Prenatal Alcohol in Sudden Infant Death Syndrome and Stillbirth (PASS) Network” Co-operative Agreement for Physiological Assessment Center

3. Clinical Research Division Dr. Myrna Weissman, Chief – Clinical Epidemiology Studies of Genetic Risk and Biological Markers in the Development of Mood and Anxiety Disorders A major focus includes a longitudinal three-generation study of offspring at high and low risk for depression. In collaboration with Brad Peterson, we have completed 215 functional and anatomical magnetic imaging studies in this sample. The first findings from the structural imaging studies have shown that right hemisphere cortical thinning produces disturbance in arousal, attention and memory for social stimuli, which in turn may increase the risk for developing depressive illness (Peterson, et al., submitted). We are now comparing the MRI and EEG and completing functional imaging analysis. With funding from the Sackler Serotonin Transporter Project, we are collecting DNA to study the influence of genetic polymorphisms or morphology of cortical surfaces in this sample. As of August 2008, we have completed collections on 273 subjects and collection is continuing. We have followed up findings on the high familial transmission of recurrent major depression beginning before the age of 30. As participants in the NIMH multi-site study to identify MDD susceptibility genes, the collection of about 1000 sib pairs with recurrent early onset MDD has been completed and analysis are underway (Holmans, et al., 2007. Levinson, et al, 2007). Biological material and clinical data are being shared through a repository with the scientific community. We are two thirds through collecting the next 900 sib-pairs. About 2,000 samples with recurrent MDD and DNA will be available by December 2009. Work is ongoing to understand the genetic basis of fear and anxiety disorders in humans by searching for associations with variant forms of genes that have been found

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to contribute to pathological anxiety states in mice. Five candidate genes were tested in a sample of patients with panic disorders and/or social anxiety disorder and normal controls. The serotonin transporter gene was significantly associated with panic disorder, with or without social anxiety disorder (Strug, et al., in press). No other candidate genes tested were significant. 660 samples with anxiety and 4,000 normal controls with DNA are available. In addition, 130 multiplex families with panic disorder and about 1,000 of their relatives, clinically characterized and with DNA are available. Dr. Adi Talati received a NARSAD grant to collect structural and functional MRI scans in 45 subjects from the sample. This work is underway. We have initiated a new collaboration with Charles Glatt M.D., Ph.D., from the Cornell/Sackler group, to follow-up our findings in the anxiety study. We reported an association between panic disorder and a series of markers on the serotonin transporter gene. Glatt has been working on characterizing a functional polymorphism that affects the polyadenylation pattern of the serotonin transporter and is in strong linkage disequilibrium with the associated markers reported in the Strug paper. He will genotype the polyadenylation polymorphism in this sample that may explain the biological mechanism for the association with panic disorder. This work is being carried at Columbia (Ryan Subaran, Ph.D.) under the supervision of C. Glatt. As part of the Sackler Serotonin Transporter Project we have begun a new collaboration (Brown, Sourander, Weissman, Gingrich) on childhood neurodevelopment outcomes following maternal exposure to serotonin reuptake inhibitors (SSRI). The safety of the use of SSRI during pregnancy is a question of immediate public health concern. While most studies have not demonstrated teratogenic effects of these agents, and perinatal complications and neonatal outcomes appear to be relatively minor, the long-term effects of these agents on childhood behavioral outcomes have not been studied. Gingrich’s finding using mouse models show that fetal exposure to SSRI’s have potential adverse consequences on brain development and function as the mouse matures. The Finland birth cohort will be examined to determine whether SSRI exposure during pregnancy adversely affects childhood/adolescent behavioral outcomes. There are 60,000 births per year in this cohort, approximately 1% of their pregnant mothers were prescribed SSRI’s during pregnancy from 2000 on while the estimate today is 2%. Hence, over an 11 year period of enrollment (1996-2007), they expect 8000-10,000 mothers who were prescribed SSRI’s. In 2009, the children will be age 2-13. The goal of the present proposal is to establish an international collaboration aimed at investigating the relationship between SSRI exposure during pregnancy and childhood and adolescent neurodevelopmental outcomes, including psychiatric disorders. This will be a necessary prelude for a subsequent grant using record linkages. Dr. Weissman was selected for her work on depression by the American College of Epidemiology as 1 of the 10 epidemiologists in the United States who has had an impact on public policy and public health. Weissman, et al's paper, "Offspring of depressed parents: 20 years later" from the high risk study was selected by McMaster Online Rating of Evidence as the "second most read and clinically relevant psychiatry and mental health journal article."

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Publications

Bruder GE; Tenke CE; Warner V; Weissman MM. Grandchildren at high and low risk for depression differ in EEG measures of regional brain asymmetry. Biol Psychiatry. 2007 Dec 1;62(11):1317-23. (PMID: 17481594) Talati, A., Fyer, A.J., Weissman, M.M. A Comparison between screened NIMH and clinically interviewed control samples on neuroticism and extroversion. Molecular Psychiatry. Mol Psychiatry. 2008 Feb;13(2):122-30. (PMID: 17938631) Talati, A; Wickramaratne, PJ; Pilowsky, DJ; Alpert, JE; Cerda, G; Garber, J; Hughes, CW; King, CA; Malloy, E; Sood, AB; Verdeli, H; Trivedi, MH; Rush, AJ; Weissman, MM. Remission of Maternal Depression and Child Symptoms Among Single Mothers: a STAR*D-Child report. Soc Psychiatry Psychiatr Epidemiol. 2007 Dec;42(12):962-71. (PMID: 17934684) Gunlicks ML; Weissman, MM. Change in Child Psychopathology With Improvement in Parental Depression: A Systematic Review. JAACAP, 47:4, April 2008. (PMID: 18388766) Neria Y, Olfson M, Gameroff M, Wickramaratne P, Pilowsky D, Verdeli H, Gross R, Manetti-Cusa J, Marshall RD, Lantigua R, Shea S, Weissman MM. Trauma exposure and posttraumatic stress disorder among primary care patients with bipolar spectrum disorder. Bipolar Disord. 2008 Jun;10(4):503-10. (PMID: 18452446) Pilowsky DJ, Wickramaratne P, Talati A, Tang M, Hughes CW, Garber J, Malloy E, King C, Cerda G, Sood AB, Alpert JE, Trivedi MH, Fava M, Rush AJ, Wisniewski S, Weissman MM. Children of Depressed Mothers 1 Year After the Initiation of Maternal Treatment: Findings From the STAR*D-Child Study. Am J Psychiatry. 2008, Jun 16. Sept., 2008. (PMID: 18558646) Talati, A., Ponniah, K., Strug, L., Hodge, S., Fyer, A.J., Weissman, M.M. Panic disorder, Social Anxiety disorder, and a possible medical syndrome previously linked to chromosome 13. Biological Psychiatry. 2008 Mar 15;63(6):594-601. (PMID: 17920564)

Other Grant Support

1 R01 MH60912 07/01/05 - 6/30/09. (NIMH) $327,053 Genetics of Early-Onset Major Depression, A six-site cooperative project to collect a large sample of subjects with early-onset MDD obtaining clinical data and genetic samples aiming to map genes giving a susceptibility to MDD. A Minority Researcher Supplement has been received for this grant which allows Eleanor Murphy, Ph.D., to study MDD in African Americans.

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1 P01 MH60970 12/1/02-11/30/07. (NIMH) (Hen) $172,279 Molecular Genetic Studies of Fear and Anxiety, This is a program project to study the molecular and genetic basis of amygdale-regulated fear and anxiety in mice and humans. Weissman directs Core 4, “Clinical Studies of Human Anxiety Disorders” which collects clinical data and genetic samples from subjects who suffer from Panic Disorder and Social Phobia as well as normal controls. Completed. Continuation under discussion.

2 R01 MH36197 01/01/03 – 12/31/08 (NIMH) $654,783. Children at High and Low Risk For Depression, The aims of this study are (1) to complete data analyses of the 4th wave clinical and psychophysiologic assessments; (2) to acquire and analyze both anatomical and functional MRI in 214 subjects (118 second and 96 third generation) of this cohort; and (3) to conduct data analysis integrating findings of the clinical, psychophysiologic and neuroimaging studies. A supplement is provided by NIDA to examine drug use disorders and smoking in families at high risk for depression using data collected in MH36197.

1 R01 MH082255 07/01/07-06/30/11 (NIMH) $500,546 Parental Remission from Depression and Child Psychopathology, This study will independently study 100 depressed parents undergoing treatment and 200 of their children to replicate and refine previous findings that successful treatment of a depressed parent leads to improvement in their children. These findings, if replicated in this proposed study, will provide new strategies for helping symptomatic children of depressed parents.

1 R01 MH63852 07/19/01 – 06/30/08 (NIMH) $526,225. Completed. Children of Depressed Mothers: A Star*D Ancillary Study The overall aim is to study the impact of a reduction of maternal depressive symptoms on children’s psychiatric symptoms and social functioning as and ancillary study to the Squenced Treatment Alternatives to Relieve Depression Study (STAR*D).

5 P30 MH60570 09/21/04 – 05/31/09. (NIMH) (Shaffer) $240,000. ACISR for Pediatric Psychiatry Disorders. Director of the Principal Research Core. ACISR consists of four cores that work with another to 1) promote and develop efficacy studies that work with another to 1) promote and develop efficacy studies where the evidence-based support for interventions remains substantially deficient and where “export” into the field would be premature. 2) study transportability and effectiveness of interventions or methods of evaluation for which there is substantial evidence-based support, to real-world children and adolescents. 4) Work with basic scientists to investigate whether state of the art imaging and genotyping methods can be used to identify the mediators of treatment response. 5) Train new intervention researchers;

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and 6) take a scientific and advocacy leadership role in promoting and disseminating intervention research.

2 T32 MH16434 07/01/05 to 06/30/10 (NIMH) (Shaffer) $442, 108. No funds Research Training in Child Psychiatry. The Child Psychiatry Research Training Program trains postdoctoral psychiatrists, psychologists, and others to become independent investigators in the field of child and adolescent psychopathology. The grant supports ten M.D. and/or Ph.D. trainees for up to three years,

4. Developmental Neuro-imaging Laboratories Dr. Bradley Peterson, Chief – Normal Brain Development and the Neural Basis of Psychiatric Disorders

Dr. Peterson received additional NIH funding through an administrative supplemental in collaboration with Dr. Xu to develop and disseminate to the MRI research community an integrated software package for processing and analyzing Diffusion Tensor Imaging (DTI) data. In addition to the inclusion of some DTI tools that we have implemented based on well-established algorithms from other’s work, this software package will also include several unique tools and algorithms that we have developed in house through our own research. We have demonstrated through published papers that a number of our key tools and algorithms offer improved performance over previously available methods. This software package will allow investigators and clinicians free access to our research tools within an integrated, user-friendly format, thereby facilitating image analysis and clinical research. In addition, our software package will also provide tools for unified analyses using DTI in conjunction with structural (sMRI) data. He also received funding from the Tourette Syndrome Association to define the thalamus, measure thalamic volumes, and conduct extensive analyses of the thalamic surface in the anatomical MRIs of 165 TS, 60 OCD, 60 ADHD and 165 healthy control subjects; conduct surface analyses of the basal ganglia nuclei that have already been manually defined in these same subjects; compare local volumes at the surfaces of the thalamus and basal ganglia nuclei across diagnostic groups, and correlate those local volumes with measures of symptom severity and measures of neuropsychological functioning In collaboration with Dr Tiago Maia, Dr. Peterson received funding from the Klingenstein Third Generation Foundation to study the pathogenesis of Attention-Deficit/Hyperactivity Disorder (ADHD) which involves anatomical and functional disturbances in cortico-basal ganglia-thalamo-cortical circuits (or simply “cortico-BG circuits”) and develop a new technique (“model-based fMRI”) that allows the seamless integration of computational models with fMRI has recently been developed.

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Dr. Peterson was appointed Chairman of the Division of Child Psychiatry upon the retirement of Dr. David Shaffer in June of 2008.

Publications Dong Z, Peterson BS. The rapid and automatic combination of proton MRSI data acquired using multi-channel coils without water suppression. Magnet Reson Imaging, 25:1148- 1154. 2007. Peterson BS, Choi H, Hao X, Amat J, Zhu H, Whiteman R, Liu J, Xu D, Bansal R. Morphologic features of the amygdala and hippocampus in children and adults with Tourette syndrome. Arch Gen Psychiatry, 64:1281-1291, 2007. Raz A, Lamar M, Buhle JT, Kane MJ, Peterson BS. Selective biasing of a specific bistable-figure percept involves fMRI signal changes in frontostriatal circuits: a step toward unlocking the neural correlates of top-down control and self-regulation. Am J Clin Hypnosis, 50:137-156, 2007 Bansal R, Staib LH, Plessen KJ, Xu D, Royal J, Peterson BS. Voxel-wise comparisons of the morphologies of diffusion tensors across groups of experimental subjects. Psychiatry Research: Neuroimaging, 156:225-45, 2007. Stern EA, Blair C, Peterson BS. Inhibitory deficits in Tourette’s syndrome. Develop Psychobiol, 50:9-18, 2008. Amat JA, Whiteman R, Bansal R, Davies M, Haggerty R, Peterson BS. The cognitive correlates of amygdala and hippocampus volumes in healthy adults. Brain Cognit, 66:105-114, 2008. Liu F, Garland M, Duan Y, Stark RI, Xu D, Dong Z, Bansal R, Peterson BS, Kangarlu A. Study of the development of fetal baboon brain using Magnetic Resonance Imaging at 3 Tesla. Neuroimage, 40:148-159, 2008. Wang Z, Peterson BS. Constrained least absolute deviation neural networks. IEEE Trans Neural Net, 19:273-283, 2008. Gerber AJ, Peterson BS. What is an image? J Am Acad Child Adolesc Psychiatry, 47:245-248, 2008 Xu D, Bansal R, Plessen K, Peterson BS. Seamless warping of diffusion tensor fields. IEEE

Trans Med Imaging, 27:285-299, 2008. Bansal R, Staib LH, Xu D, Laine AF, Royal J, Peterson BS. Using perturbation theory to compute the morphological similarity of diffusion tensors. IEEE Trans Med Imaging, 27:589-607, 2008. Bansal, Gerber AJ, Peterson BS. Brain morphometry using anatomical magnetic resonance imaging. J Am Acad Child Adolesc Psychiatry, 47:619-621, 2008

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Sowell ER, Kan E, Yoshii J, Thompson PM, Bansal R, Xu D, Toga AW, Peterson BS. Thinning of gray matter in the sensorimotor cortices of children with Tourette syndrome. Nat Neurosci, 11:637-639, 2008. Bansal R, Gerber AJ, Peterson BS. Brain morphometry using anatomical magnetic resonance imaging. J Am Acad Child Adolesc Psychiatry, 47:619-621, 2008. Royal J, Peterson BS. The risks and benefits of searching for lesions in MRI research scans. Journal for Law, Medicine, and Ethics, 36:305-314, 2008.

Gerber AJ, Posner J, Gorman D, Colibazzi T, Yu S, Wang Z, Kangarlu A, Zhu H, Russell J, Peterson BS. An affective circumplex model of neural systems subserving valence, arousal, & cognitive overlay during the appraisal of emotional faces. Neuropsychologia, 46:2129-2139, 2008.

Wang Z, Peterson BS. Partner-matching for the automated identification of reproducible ICA components from fMRI datasets: Algorithm and validation. Hum Brain Map,29:875- 893, 2008. Zhu H, Zhang H, Ibrahim JG, Peterson BS. Statistical analysis of diffusion tensors in diffusion-weighted magnetic resonance imaging data. J Am Stat Assoc, in press. Colibazzi T, Zhu H, Bansal R, Schultz R, Peterson BS. Factor analyses and structural equation modeling of cortical and subcortical gray matter volumes in children and adults. Hum Brain Map, in press. Zhu H, Gu M, Peterson BS. Maximum likelihood from spatial random effects models via the stochastic approximation expectation maximization algorithm. Statistics and Computing, in press. Posner J, Russell J, Gerber A, Colibazzi T, Gorman D, Yu S, Wang Z, Kangarlu A, Zu H, Peterson BS. The neurophysiological bases of emotion: an fMRI study of the affective circumplex using emotion-denoting words. Hum Brain Mapping, in press. Zhu H, Li Y, Tang N, Bansal R, Hao X, Weissman MM, Peterson BS. Statistical modeling of brain morphological measures within family pedigrees. Statistica Sinica¸ in press. Raz A, Zhu H, Yu S, Bansal R, Wang Z, Alexander GM, Royal J, Peterson BS. Neural substrates of self-regulatory control in children and adults with Tourette Syndrome. Can J Psychiatry, in press.

Chung YA, Jaeseung Jeong, Kim SH, Chung SK, Hyung Sun Sohn, Euy Neyng Kim, Peterson BS. A Tc-99m SPECT study of regional cerebral blood flow in patients with Transient Global Amnesia. Neuroimage, in press.

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Raz A, Packard MG, Alexander GM, Peterson BS. A slice of : Exploratory neuroimaging of digit encoding and retrieval in a superior memorist. Neuro Case Report, in press. Wexler BE, Zhu H, Nicholls SS, Fulbright RK, Gore JC, Bell MD, Colibazzi T, Amat J, Bansal R, Peterson BS. Differences in brain structure in persons with Schizophrenia and with cognitive functioning that is either nearly normal or markedly impaired. Am J Psychiatry, in press. Bansal R, Staib LH, Xu D, Laine AF, Royal J, Peterson BS. Calculation of confidence intervals for transformation parameters in the registration of medical images. Medical Image Analysis, in press. Kim I, Lee W, Sohn H, Hong H, Chae J-H, Peterson BS, Hong S, Jeong J. Linear and nonlinear analysis of the EEG in adolescents with Attention-Deficit/Hyperactivity Disorder during a cognitive task. Clin Neurophys, in press. Duan Y, Peterson BS, Liu R, Brown TR, Ibrahim TS, Kangarlu A. Computational and experimental optimization of a double-tuned 1H/31P four-ring birdcage head coil for MRS at 3T. J Magnet Reson Imaging, in press. Yuan Y, Zhu H, Ibrahim JG, Lin W, Peterson BS. A note on the validity of statistical bootstrapping for estimating the uncertainty of tensor parameters in diffusion tensor images. IEEE TMI, in press. Duan Y, Kangarlu A, Ibrahim T, Peterson BS, Liu F. Assessment of a PML boundary condition for simulating an MRI radio frequency coil. Int J Ant Propagation, in press. Marsh R, Gerber AJ, Steinglass JE, O’Leary KG, Walsh BT, Peterson BS. Deficient activity in the neural systems that mediate self-regulator control in Bulemia Nervosa Arch Gen Psychiatry in press. Marsh R, Gerber AJ, Peterson BS. Neuroimaging studies of normal brain development and their relevance for understanding childhood neuropsychiatric disorders. J Am Acad Child Adolesc Psychiatry, in press.

Maia TV, Cooney RE, Peterson BS. The neural bases of Obsessive-Compulsive Disorder I n children and adults. Develop & Psychopath, in press.

Xu D, Cui J, Bansal R, Hao X, Liu J, Peterson BS. The Ellipsoidal Area Ratio (SAR): an alternative anisotropy index for diffusion tensor imaging. Magnet Reson Imaging, in press.

Other Grant Support

NIMH (W. Kates, PI) 7/1/2007 - 6/30/2011 $738,465

Biomarkers for Psychosis in Velocardiofacial Syndrome

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This application requests funding to continue our longitudinal study of risk factors for psychosis in velocardiofacial syndrome (VCFS), a relatively common disorder caused by a microdeletion on chromosome 22q11.2. Up to 30% of individuals with VCFS develop schizophrenia (SZ) or bipolar disorder (BPD) as they enter adulthood, making this a significant public health concern for both families and society. Since we began this project in February of 2001, we have identified several factors that are associated with the deterioration of psychiatric function in adolescents with this disorder. However, the youth in our sample are just reaching the age at which they are most vulnerable to the onset of psychosis. Accordingly, it is critical that we continue follow this cohort in order to identify the neuroanatomic and neuropsychological factors that are associated with, and may be predictive of, the onset of psychosis.

NIBIB (B. Peterson, PI) 10/1/07 – 9/30/08 $80,825

Statistical Software for Correcting for Multiple Comparisons of Hypothesis In this supplement, we propose to enhance our statistical tool for detecting statistically significant associations between brain measures and clinical and genetic measures across brain surfaces. Our enhanced tool will enable researchers in the neuroimaging community to apply seamlessly our methods (which are based on a heteroskedastic linear model and wild bootstrap) for computing corrected p-value for associations by controlling for multiple comparisons across all points on brain surfaces. To enable easy use of our invaluable tool, we will develop a sophisticated and intuitive Graphical User Interface (GUI) and provide a user’s manual complete with details on the functionality of our tool as well as a short tutorial for typical tasks that can be performed using our methods. Using our tool, researchers therefore will be able to identify and implicate local brain regions in various neuropsychiatric disorders. In addition, we will extend our software tool to enable researchers to analyze functional Magnetic Resonance Imaging (fMRI) datasets using our advanced statistical methods.

NARSAD (A. Gerber, PI) 7/1/07 – 6/30/09 $60,000 MRI of Brain Changes during Psychotherapy for Panic Disorder In this study, we propose to perform MRI scans on subjects before and after treatment in connection with a new NIMH-funded randomized controlled trial (RCT) comparing three psychotherapies for PD, each lasting 19 to 24 sessions: (1) Cognitive Behavioral Therapy (CBT), (2) Applied Relaxation Therapy (ART), and (3) Panic-Focused

Psychodynamic Psychotherapy (PFPP).4, 5

We will also scan a fourth group of matched controls without PD and not undergoing psychotherapy during the same time interval. We aim to demonstrate pre-treatment brain abnormalities in PD patients as compared with the matched controls. Additionally, we will explore brain changes in response to each of the three psychotherapies, as compared with each other and the controls.

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Matheson Foundation (A. Gerber, PI) 7/1/07 – 6/30/09 $50,000 MRI of Brain Changes in Psychoanalysis and Neurology of Creative Learning Although psychoanalysis has long been considered an important treatment modality and contributor to psychiatric knowledge, little is known about its effect on the brain. We believe that patients in psychoanalysis undergo a specific type of learning which produces greater self-regulation of affective states and behavior, greater creativity and a wareness of internal mental states, and altered processes of representing the interaction between self and others. This study therefore has the potential not only to validate psychoanalysis as a treatment but to explore the neurology of creative emotional learning. McGue Millhiser Family Trust (B. Peterson, PI) 11/1/07 – 10/31/10 $409,500 An MRI study of the Neural Basis of Stuttering This imaging study aims to identify the neural systems that cause and modulate the symptoms of stuttering. Based on our prior imaging studies of the repetitive behaviors seen in other childhood-onset disorders, we predict that the basal ganglia and motor cortices will be hypoplastic (i.e., evidence a failure to grow properly) in children who stutter, and that anatomical hypertrophy (i.e., a relative overgrowth) and greater functional activity in the frontal cortex will be detected in the stutterers, reflecting the role of the frontal cortex in helping to attenuate the symptoms of stuttering. Failure of this compensatory response of the frontal cortex will produce more severe and more sustained stuttering across time. We will detect these effects using anatomical Magnetic Resonance Imaging (MRI), Diffusion Tensor Imaging (DTI), MR Spectroscopy (MRS), and functional MRI (fMRI) in 25 children with stuttering and 25 matched controls, 6-12 years of age. This study will have farreaching consequences for our understanding of the pathophysiology of stuttering, and it will position us to extend the work through future funding applications to the National Institute of Health (NIH). Tourette Syndrome Association (B. Peterson, PI) 7/1/08 – 6/30/09 $75,000 Surface Morphological Features of the Thalamus and Basal Ganglia in Tourette Syndrome The aims of the study are to define the thalamus, measure thalamic volumes, and conduct extensive analyses of the thalamic surface in the anatomical MRIs of 165 TS, 60 OCD, 60 ADHD and 165 healthy control subjects; conduct surface analyses of the basal ganglia nuclei that have already been manually defined in these same subjects; compare local volumes at the surfaces of the thalamus and basal ganglia nuclei across diagnostic groups, and correlate those local volumes with measures of symptom severity and measures of neuropsychological functioning NIH (D. Xu, PI, B-Peterson, Co-PI) 7/1/08 – 6/30/09 $100,000 An Integrated Software Package for the Processing and Analysis of Diffusion Tensor Images

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We aim to develop and disseminate to the MRI research community an integrated software package for processing and analyzing Diffusion Tensor Imaging (DTI) data. In addition to the inclusion of some DTI tools that we have implemented based on well- established algorithms from other’s work, this software package will also include several unique tools and algorithms that we have developed in house through our own research. We have demonstrated through published papers that a number of our key tools and algorithms offer improved performance over previously available methods. This software package will allow investigators and clinicians free access to our research tools within an integrated, user-friendly format, thereby facilitating image analysis and clinical research. In addition, our software package will also provide tools for unified analyses using DTI in conjunction with structural (sMRI) data Klingenstein Third Generation Foundation (T. Maia, PI, B-Peterson, Co-PI) 8/1/08 – 7/31/10 $60,000 Integrated neurocomputational modeling and functional neuroimaging of Tourette syndrome The pathogenesis of Attention-Deficit/Hyperactivity Disorder (ADHD) involves anatomical and functional disturbances in cortico-basal ganglia-thalamo-cortical circuits (or simply “cortico-BG circuits”). Detailed computational models have demonstrated recently how the neuroanatomical, neurophysiological, and neurochemical characteristics of these circuits support attention, cognitive control, and working memory the core neurocognitive processes impaired in ADHD. In a different line of research, a new technique (“model-based fMRI”) that allows the seamless integration of computational models with fMRI has recently been developed.

5. Department of Pediatrics - Neonatology

Dr. Raymond Stark and Dr. Marianne Garland - Sackler Serotonin Transporter Project : Placental Transport, Fetal Metabolism and Brain Imaging Effects of Different SSRI Types in Fetal Baboons Our progress over the past year has been constrained by an unexpectedly low rate of pregnancy in the baboon colony. With substantial effort we have overcome this issue with changes in the location of non-breeding males, revising the structure of the colony, and persistence. With recent success of breeding, two pregnant animals have been assigned to the chronic SSRI administration group. These animals will be chronically exposed to Fluoxetine through pregnancy and the development of the fetal brain will be evaluated longitudinally with sequential MRI scans. Scanning will use our recently published methodology for MRI study of the fetal brain in the pregnant female baboon and the normative data that were acquired in collaboration with Dr. Bradley Petersen. The fetal brains are then collected in late pregnancy, at a gestational age that the fetal baboon brain is structurally equivalent in developmentl to that of human fetus at term gestation. These brains are examined for histological changes in 5HT transporter and receptor distribution and synaptic density. These histopathological studies of the fetal brain are done in collaboration with Dr. Victoria Arango.

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In the initial work on the promoter region of the baboon serotonin transporter, sequencing suggests that the baboon has the same polymorphism as in the macaque monkey. The macaque polymorphism is believed to have a similar function to the polymorphism in the human population. Our goal over the next 6 months with the funds made available from the Sackler Serotonin Transporter Project will be to complete the longitudinal baboon studies of chronic SSRI exposure in pregnancy and compare the metabolism of SSRI agents in the fetal and adult liver tissue from the baboon. This research will have direct clinical relevance for the selection of agents in clinical trials and in an NIH proposal beyond the current R21 Grant Award entitled ““Pharmacokinetics of SSRI’s in Pregnancy”.

Publications

Garland M, Abildskov KM, Kiu TW, Daniel SS, Weldy P, Stark RI. Placental transfer and fetal elimination of morphine-3-beta-glucuronide in the pregnant baboon. Drug Metab Dispos. 2008 Sep;36(9):1859-68. Epub 2008 Jun 19. Liu F, Garland M, Duan Y, Stark RI, Xu D, Dong Z, Bansal R, Peterson BS, Kangarlu A. Study of the development of fetal baboon brain using magnetic resonance imaging at 3 Tesla. Neuroimage. 2008 Mar 1;40(1):148-59. Epub 2007 Nov 28. Grieve PG, Isler JR, Izraelit A, Peterson BS, Fifer WP, Myers MM, Stark RI. EEG functional connectivity in term age extremely low birth weight infants. Clin Neurophysiol. 2008 Nov 3. [Epub ahead of print] Isler JR, Grieve PG, Czernochowski D, Stark RI, Friedman D. Cross-frequency phase coupling of brain rhythms during the orienting response. Brain Res. 2008 Sep 26;1232:163-72. Epub 2008 Jul 16.

Other Support

NIMH 7/01/07-6/30/08 $125,000 “Pharmacokinetics of SSRI’s in Pregnancy”

6. Sackler Awardees- Annual Progress Report—2008

Amir Levine Molecular Analysis of the ‘Gateway’ Hypothesis

We received an R01 based on data that I collected during the two years on the Sackler and this past year I obtained further evidence to support the preliminary results presented in the proposal. Nicotine enhances cocaine induced fosB expression after prolonged (7-day) but not acute (24 hour) nicotine treatment. By contrast, 7-day cocaine

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treatment does not enhance nicotine induced fosB expression. Behaviorally, nicotine increases sensitization to cocaine. 1. Extension of the findings with cocaine to other drugs of abuse Similar to the effect on cocaine, nicotine pretreatment increases methamphetamine induced fosB: To determine if nicotine can serve as a gateway drug that can enhance transcription responses to other drugs of abuse than cocaine, I examined methamphetamine. Cocaine acts through dopamine, norepinephrine and serotonin transporter inhibition but does not increase release of these monoamines, whereas methamphetamine causes massive release of monoamines in the brain. Thus, I examined whether nicotine also affects fosB expression in response to methamphetamine. I find that, as with cocaine, fosB expression in mice pre-exposed to nicotine and then treated with methamphetamine is increased. There is a 2-fold difference in fosB expression in response to methamphetamine alone compared with methamphetamine in animals pretreated with nicotine. In a behavioral sensitization paradigm for methamphetamine, I find that similar to the effect on cocaine, nicotine enhances methamphetamine induced sensitization. 2. A possible molecular mechanism for the priming effect of nicotine Nicotine induces global and promoter specific histone acetylation in the striatum: To understand the role of nicotine as a gateway drug, I next examined the effects of nicotine on histone acetylation in the striatum. Using immunoblotting with antibodies against acetylated histone H4 and H3, I found that nicotine acetylates histones globally in the striatum. I then focused specifically on the promoter of the fosB gene, where I previously showed that cocaine enhances histone H4 aceytlation. Using immunoprecipitation assays, I found that nicotine also increases Histone H4 acetylation at the fosB promoter, as does cocaine. With histone H3 acetylation, I found, similar to the findings of Eric Nestler, no significant increase in histone H3 acetylation after an acute cocaine treatment alone. However, after chronic nicotine treatment I found a 3-fold increase in Histone H3 aceytlation. Even though by itself acute cocaine does not alter Histone H3 acetylation, with prior exposure to nicotine acute cocaine injection becomes associated with an even greater increase in histone H3 aceytlation than nicotine treatment alone. Acetylation of histone H3 is known to be closely related to transcription. The finding of nicotine as a global acetylator may explain why nicotine, a gateway drug, has other roles in the brain. For example, nicotine enhances learning and memory, ameliorates neurodegenerative disorders, and decreases the risk of relapse to depression and psychosis, all processes in which chromatin modulation is known to be an important mediator. 3. Electrophysiological measurement of the priming effects of nicotine (a) Nicotine enhances the reduction in long-term synaptic potentiation (LTP) in the core of the nucleus accumbens in response to cocaine, enhances LTP increase in the basolateral amygdala, and does not influence cocaine induced LTP in the ventral tegmental area: Previous electrophysiological studies have shown that altered excitatory synaptic transmission in certain brain regions may play an important role in mediating the development of drug addiction. In collaboration with Yan-You Huang I compared LTP, induced by a high-frequency stimulation, in several brain regions in mice treated with cocaine only and in mice pre-treated with nicotine and then cocaine. In the core of the nucleus accumbens, cocaine causes a reduction in LTP and

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nicotine priming dramatically enhances this depression. Similarly, we found that cocaine exposure increases LTP in a specific pathway in the basolateral amygdala and pretreatment with nicotine enhances the increase of LTP induced by cocaine. In the ventral tegmental area, cocaine exposure facilitates LTP induced by high frequency stimulation, but pretreatment with nicotine followed by cocaine does not produce more facilitation of LTP in this region, indicating that LTP may already be saturated by either nicotine or cocaine alone. (b) SAHA, a potent histone deacetylase Inhibitor acts similarly to nicotine in enhancing the changes in LTP in the nucleus accumbens core following cocaine treatment: We have shown in the past in C57BL6/J mice that similar to nicotine, mice that were pre-treated with SAHA prior to cocaine administration show a marked increase in fosB expression compared with cocaine alone. We next examined if the similarity between the affect of pretreatment with nicotine and SAHA on fosB expression also shares similar functional affects on LTP. I therefore administered SAHA 25mg/kg i.p. 2 hrs prior to cocaine 30mg/kg administration. I find that similarly to nicotine pretreatment, SAHA followed by cocaine induced a greater reduction in LTP in the core of the nucleus accumbens than cocaine alone suggesting that the mechanism of action that is responsible for the greater reduction of LTP after nicotine and cocaine is an increase in histone acetyaltion in the striatum. Similar to nicotine, SAHA alone did not cause a depression in LTP by and even had a similar trend as nicotine alone of a slight elevation of LTF (which was not significant). 4. Chronic nicotine acts much like SAHA in reducing HDAC activity in the striatum: Using a colorimetric reaction that detects the activity of histone deacetylases by measuring deacetylation of acetylated lysine side chains, I examined HDAC activity of isolated nuclear fraction of mouse striatum. I found that in the nuclear potion of striata of mice that were treated with chronic nicotine 10 g/ml for one to two weeks there was 30%reduction in histone deacetylase activity. Thus after nicotine treatment HDAC activity in the striatum is reduced leading to increase in histone acetyaltion.

Significance

The gateway hypothesis posits an important sequence of events in the development of addiction. I have begun to elucidate a molecular mechanism by which one experience, exposure to nicotine, may register in the brain to influence future events (use of cocaine or other drugs). I have shown that pretreatment with nicotine enhances cocaine and induced fosB expression as well as behavioral sensitization to cocaine. This past year I extended the findings to another drug, methamphetamine, and conducted electrophysiological studies. The latter enabled me to examine another functional modality (electrophysiological changes) that is directly related to synaptic plasticity of the priming effect of nicotine. Finally, I have made substantial progress in delineating a molecular mechanism for the priming effect of nicotine, global acetylation showing that nicotine reduces histone deacetylase activity in the striatum. A better understanding of the molecular pathways of these priming effects may have therapeutic as well as public health significance.

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Publications

Huang YY, Kandel ER, Levine A. Chronic nicotine exposure induces a long-lasting and pathway-specific facilitation of LTP in the amygdala. Learn Mem. 2008 Aug 6;15(8):603-10

Other Support

5R01DA024001-01 9/30/07-8/31/12 $2.6 million "A molecular analysis of the Gateway hypothesis in mice", Role: I am a principle investigator on this grant together with Eric Kandel and Denise Kandel.

Rachel Marsh Self-Regulatory Control and Habit Learning in Adolescents with Bulimia Nervosa The Sackler award has enabled me to begin developing my skills in functional neuroimaging, translational cognitive neuroscience methods and clinical assessment. These skills are necessary for my investigatation of self-regulatory control processes and habit learning in childhood psychopathologies, specifically in Bulimia Nervosa (BN). With help from an RA whose time is supported by my Sackler award, I have spent the past year forging relationships with many psychiatrists, psychologists, clinical social workers and school counselors in the tri-state area in an effort to recruit adolescent BN patients. We have posted flyers in multiple locations, sent letters to pediatricians, psychiatrists, psychologists and social workers, and have visted private schools to talk to students about eating disorders. To date, I have scanned and acquired neuropsychological data from 15 adolescent patients with BN and 15 healthy control subjects. I plan to enroll 5 more patients and 5 more control subjects in the next few months. FMRI data from the BN and control adolescents have been pre-processed and analyses are currently underway in preparation for two invited talks that I am giving this fall:

1.) ‘Frontostriatal Control Systems in Bulimia Nervosa,’ in a plenary session entitled, ‘Emotion and Self-Regulation’ at the next Eating Disorders Research Society Meeting, Sept. 26, 2008 in Montreal.

2.) ‘The Role of Frontostriatal Circuits in Eating Disorders,’ in a symposium at the next AACAP meeting, Nov. 1, 2008 in Chicago

I will also be presenting my fMRI findings from this dataset in a poster at the next ACNP meeting, Dec. 2008, in Arizona. During the past year, I have finished acquiring both imaging and neuropsychological data from 40 adult women with and without BN. My fRMI findings from this study are currently in press in the Archives of Genral Psychiatry (title and abstract below).

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Deficient Activity in the Neural Systems that Mediate Self-Regulatory Control in Bulimia Nervosa

Disturbances in neural systems that mediate voluntary self-regulatory processes may contribute to Bulimia Nervosa (BN) by releasing feeding behaviors from regulatory control. We are studying the functional activity in neural circuits that subserve self-regulatory control in women with BN. We compared fMRI BOLD response in patients with BN to normal controls during performance of the Simon Spatial Incompatibility task. We studied forty women including 20 patients with BN and 20 healthy control participants. We used general linear modeling of Simon-related activations to compare groups on their patterns of brain activation associated with the successful and unsuccessful engagement of self-regulatory control. Patients with BN responded more impulsively and made more errors on the Simon task than did healthy controls, and patients with the most severe symptoms made the most errors. During correct responding on incongruent trials, patients failed to activate frontostriatal circuits to the same degree as healthy controls, including in their left inferolateral prefrontal cortex (BA 45), bilateral inferior frontal gyrus (BA 44), lenticular and caudate nuclei, and the anterior cingulate cortex (ACC, BA 24/32). Patients activated the dorsal ACC (BA 32) more when making errors than when responding correctly. In contrast, healthy participants activated the ACC more during correct than during incorrect responses, and they activated the striatum more when responding incorrectly, likely reflecting an automatic response tendency that, in the absence of concomitant ACC activity, produced incorrect responses. In Conclusion, our data showed self-regulatory processes are impaired in women with BN, likely because of their failure to engage frontostriatal circuits appropriately. These findings enhance our understanding of the pathogenesis of BN by pointing to functional abnormalities within a neural system that subserves self-regulatory control, which may contribute to binge-eating and other impulsive behaviors in women with BN. In addition, anatomical data from all my BN and control subjects (adolescents and adults) are currently being prepared for analyses in our Brain Imaging Laboratory. I expect to have a completely pre-processed dataset (40 patients and 40 controls) ready for voxel-based morphometric analyses by the end of the year. The goal of this VBM study is to investigate how the trajectory of anatomical brain development diverges from normal in individuals with BN. My review paper currently in press in the Journal of the American Academy of Child and Adolescent Psychiatry explains how understanding normal developmental trajectories in the brain may improve insight into abnormal patterns of development in various childhood psychiatric disorders. Phil Grieve Novel Measurements of Event Related EEG Spatiotemporal Dynamics with Application to Early Diagnosis of Autism We are measuring the spatiotemporal EEG response to sensory stimuli (visual and auditory) in autistic spectrum disorder (ASD) children (3-6 yrs); young siblings (0-3 yrs) of ASD children and matched low-risk/typically developing (TD) controls. Our goals are to elucidate the early functional manifestations of brain abnormalities in autism and

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autism spectrum disorders, in order to improve methods for the diagnosis of autism in early infancy. My collaborators are at Harvard University/Massachusetts General Hospital (MGH) where the subjects are recruited and EEG data is collected under the leadership of Dr. Martha Herbert and at the Columbia University Dept of Pediatrics where Dr. Joseph Isler, with special expertise in EEG spatiotemporal data processing, is collaborating with me in the processing of EEG data under funding from his NIH career development award. Our group has been awarded grants from the Department of Defense (DoD), Cure Autism Now and another private source to fund the purchase of a 128-lead high density EEG system and to fund EEG collection and processing. EEG data collected at Harvard are transferred to and processed at Columbia using Dr. Grieve and Isler’s computers and custom software. The project data archive now contains EEG data from 18 autistic, 4 autistic spectrum, and 19 typically developing children including 5 siblings of autistic. Collection of new subject data continues at the rate of several subjects per week. Both Dr.s Grieve and Isler will continue collaborating with Harvard colleagues in the post-Sackler award period with funding from DoD (Grieve) and NIH (Isler). Initial results have found that autistics show a diminished ability to integrate complex information that may relate to altered functional connectivity. EEG “coherence”, a novel computer-based technique developed in our laboratory, measures electrocortical synchrony of oscillatory brain rhythms across neural networks. This coherence is hypothesized to function as a mechanism for functional connectivity, binding of neural activity and integration of cognitive processes. We hypothesized that there would be greater coherence differences between autistic children and controls in a complex visual input condition when compared to the differences seen in a simple or minimal visual input condition. Resting EEG was obtained for 3 conditions presented for 5 minutes each: 1) complex visual stimulus: a movie, 2) simple visual stimulus: flashes of light in a visual evoked potential (VEP) paradigm, and 3) no visual stimulus: eyes closed/lights out in 5 children (4.4-9.8yrs): 2 autistic, 2 autistic spectrum (ASD) and 1 typically developing control. Autistics showed broadly increased low frequency (delta/theta) coherence in the “movie” condition compared to control. Coherence differences for VEP and EC/LO were far less significant. ASD children showed the same effect but to a lesser degree. Interhemispheric higher frequency (alpha) coherence was somewhat decreased in the “movie” condition when compared to VEP and EC/LO condition in preliminary data. Our data suggest that autistic children show coherence abnormalities that are not static but dynamic and produced by exposure to complex visual stimuli in motion. This abnormality appears to be proportionate to the severity of the autism. Whether motion or complexity is the critical factor in producing these coherence differences remains to be determined. These results were presented at the International Meeting for Autism Research, Poster presentation #137.27, London, May 2008.