A N N U A L R E P O R TJuly 1, 2008 – June 30, 2009

SACKLER INSTITUTE FOR DEVELOPMENTAL PSYCHOBIOLOGYAT COLUMBIA UNIVERSITY

Table of Contents

Pages

Introduction 2

Part I Highlights 3

Part II Research Programs 5

1. Basic Science Division 5

2. Behavioral Neuroscience Division 8

3. Clinical Research Division 13

4. Developmental Neuroimaging Laboratories 19

5. Department of Pediatrics-Neonatology 25

6. Sackler Awardees Progress Reports 28

Part III Financial Report enclosure

This report covers the eighth 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. This year, our faculty has more than 10 million dollars of federal and other outside support. The income from the endowment supports a professorship for the Director of the Institute, and in 2002-03 made a major contribution to the construction of the new Sackler Laboratories at the New York State Psychiatric Institute. In addition, the Institutes’ endowment provides support for new directions in faculty research and funds the annual Sackler Awards. These are stipends for postdoctoral fellow/junior faculty members 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 has supported a special project on the early developmental role of serotonin transporter function (see highlights).

The administrative structure and faculty on June 30, 2009 were as follows:

Director, Dr. Myron A. HoferAssistant Director, Dr. William P. FiferAdministrator, Jennifer KnowlesChief, Basic Science Division – Dr. Jay GingrichSackler Scientist - Dr. Christoph KellendonkSackler Scientist – Dr. Mark AnsorgeChiefs, Behavioral Neuroscience Division - Drs. Michael Myers and William FiferSackler Scientists – Drs. Susan Brunelli, Catherine Monk and Frances ChampagneChief, Clinical Division - Dr. Myrna WeissmanSackler Scientist - Dr. Alan BrownHead, Developmental Neuroimaging Laboratory - Dr. Bradley PetersonDepartment of Pediatrics (Neonatology) – Drs. Raymond Stark and Marianne GarlandSackler Awardees: Amar Sahey and Tizziano Collibazzi

The research programs of the faculty and two Sackler Awardees of ’08-‘09 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.

Dr. Hofer plans to retire from the Directorship of the Institute at the end of 2010. A search committee was set up in the Fall of 2009, and candidates for the new director will be considered, drawing on local, national and international sources.

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Part I – Highlights

A major focus of the Institute faculty during the past year has been to prepare a major NIMH Center grant proposal based on the exploratory findings that have emerged from our ‘Sackler Serotonin Project ‘, funded by a gift from the Sackler Foundation in June of 2007. In these studies we have gathered new evidence that serotonin plays an important but seemingly paradoxical role in early development. When increased, either by gene mutation, or pharmacological agents (SSRIs) during infancy in animal model studies, serotonin appears to increase the long term vulnerability of adults to depression - in contrast to the effectiveness of SSRIs when given during adulthood as treatment for depression. The Sackler Serotonin project and the NIMH Conte Center grant proposal that has grown from it, consist of an interlocking set of projects, involving most of the institute faculty with Jay Gingrich as P.I. and Myrna Weissman as Co-P.I. The proposal brings together epidemiology, genetics, clinical longitudinal studies, and brain imaging studies in humans, Rhesus monkeys and mice, together with basic cell /molecular /genetic and neural circuit studies aimed at the fundamental mechanisms underlying the clinical findings. One of the urgent public issues addressed by these studies is whether SSRI treatment of major depressive disorder in women can safely be continued when they become pregnant. The clinical projects focus on two unique cohorts: a 3-generation study of the children of depressed women and a Finnish cohort of 11,000 children exposed in utero to SSRIs from 1996-2010. The infant studies during the first week of life are also unique in combining brain imaging structural studies, with blood flow, neuro-metabolic and neuro-electric functioning measures, as well as high density (128 leads) EEG recordings. The early developmental effects of serotonin were first discovered by Jay Gingrich in his animal model system, and the ongoing and proposed studies of structural brain alterations, tract abnormalities and neural properties at the cell/molecular level are the first of their kind.

During the year, a plan has been formalized by the Sackler family to fund in perpetuity, a biennial Mortimer D. Sackler M.D. Prize for Distinguished Achievement in Developmental Psychobiology, to be awarded by Columbia and by the Cornell Sackler Institutes on alternate years. The $2 million endowment gift will be held by Columbia to fund a $100,000 prize every 2 years. Columbia awarded the first Mortimer D. Sackler Prize in April of 2008, funded by a single gift in December 2007. Thus, the first newly endowed prize will be awarded by the Cornell Institute at the Weill Cornell Medical College in the Fall of 2010. The Prize Committee will consist of representatives from all of the Sackler Institutes, (the others being the Glasgow and Edinburgh Institutes, the McGill Program and most recently, the Sussex Sackler Center), as well as 3 representatives from outside the Sackler Institutes. Nominations are currently being solicited and the procedures for nominating candidates for the Prize will be described on our joint website: www.sacklerinstitute.org.

In June of 2009, the Sackler family asked us to prepare a preliminary proposal to add to the endowment of the Institute over the next 3-5 years to permit the addition of a new faculty position in human genetics and to fund and re-name the long-established annual Winter Developmental Conference to become the Mortimer D. Sackler Conference in Developmental Psychobiology. A human geneticist with expertise in the developmental role of genes is an urgent need for our ongoing and planned clinical studies. The new Mortimer D. Sackler Winter Conference will enable us to fund the travel expenses of a selected senior scientists from abroad and selected younger scientists in training, who would otherwise be unable to attend. The format that makes this multidisciplinary conference unique is one in

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which a small number of scientists are invited to present their work informally on very focused developmental topics, to serve as a workshop for the discussion of novel ideas and directions. A number of collaborations and some new research approaches for the Sackler Institute have emerged from this meeting in the past years, and with this new funding, we will be able to enlarge the range and impact of this annual conference without eroding its informal workshop atmosphere.

Faculty Awards and Press Coverage

The paper by Drs. Peterson and Weissman published in PNAS, received much attention in the press because it described for the first time, MRI and EEG evidence of widespread cortical thinning (of nearly 30%) in the right hemispheres of unaffected relatives in a cohort of 3 generations of the descendents of a group of depressed women.

Jay Gingrich was elected to the scientific advisory board of the National Associates for Research in Anxiety and Depression.

Myron Hofer was chosen for the 2009 Senior Investigator Award by the International Society for Developmental Psychobiology.

Myrna Weissman was chosen to receive the 2009 Thomas William Salmon Medal at the NY Academy of Medicine.

Our two current Sackler Awardees, Dr. Amar Sahay and Dr. Tizio Colibazzi, now in the second years of their award, have heard that they will be awarded 5 year NIMH Career Development grants (K23s). Providing interim support in this transition from postdoctoral trainee to independent researcher has been the main purpose of the Sackler Awards since their inception in 1998. Thus far, we have supported 10 young scientist through this crucial transition in their careers. Progress reports are provided in the appendix for both current awardees: Dr. Sahay’s project explores the cell/molecular mechanisms by which a specific gene (Klf-9), mediates vulnerability of certain individuals to early life stress experience in the development of adult anxiety-like behavior, using a mouse model system. Dr. Collabazzi’s project is a longitudinal brain imaging study, with multiple anatomical measures, of adolescents who are showing early cognitive and behavioral signs of increased risk for developing schizophrenia. These prognostic signs were discovered by a former Sackler awardee, Cheryl Corcoran, and Dr. Colibazzi’s detailed anatomical studies will help delineate the nature of the abnormal developmental trajectories involved in the etiology of schizophrenia.

Sponsored Symposia

In January of 2009 we were able to support some of the expenses for two “Sackler Symposia” at the Winter Conference on Issues in Developmental Psychobiology (soon to become the Mortimer D. Sackler conference). The first, on Serotonin and Development was chaired by our assistant director, Bill Fifer, while Mark Ansorge presented his latest findings on how serotonin signaling in infancy modulates adult emotional behavior. One invited guest came from Rome, Italy and presented recent research on the role of hippocampal development in later anxiety and its relationship to serotonin signaling. Another presentation was on the role of brain stem serotonin in breathing defects in an animal model of sudden infant death. The second seminar was chaired by Frances Champagne, a Sackler faculty member, and was centered on the newest findings on epigenetic mechanisms. These novel

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mechanisms that link environmental experience with long term gene activation patterns were reported to mediate transgenerational effects of maternal behavior, paternal age effects on offspring vulnerability to psychiatric illness, and the extinction of conditioned fear in adults.

At the Fall 2008 annual meeting of the International Society for Developmental Psychobiology, the Sackler Institute funded a symposium entitled: “Early Maternal-Fetal/Infant Relationship Contributions to Behavioral, Neural and Physiological Development” and also provided travel support for 10 students from 4 countries to enable them to present posters of their work and attend the meeting.

Part II - RESEARCH PROGRAMS

1. Basic Science Division

Jay Gingrich, Chief – Laboratory of Translational Neurogenetics

The Gingrich 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 R01 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 R01 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 this project has been critical for achieving these 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 prestigious Simons Foundation. 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 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 spermatagonia DNA decreases with increased number of divisions (as would occur over time in older fathers).

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The fourth project my lab is working on 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 manipulate receptor signaling exclusively 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, MS., 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

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, MS, 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.

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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) 4/01/08 to 03/31/13NIH/NIMH $88,426Serotonin 5HT2C Agonist Drugs with 5HT2A/B Antagonist ActivityThis project proposes preclinical evaluation of (-)-trans-PAT as pharmacotherapy for obesity and Neuropsychiatric disorders, and synthesis of PATs with enhanced 5HT2C agonist activity; PATs. With 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 11/30/12NIH/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. 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 InvestigatorOverlap: There is no overlap

NIDA P01 DA12923 (Weinstein) 08/01/07 to 06/30/12NIDA ` $193,953Hallucinogens on 5-HT2A Receptors: Mechanisms and Effects. Five year project to examine the role of 5-HT2A receptors in the mechanism ofhallucinogens 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.

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NIMH (5 RO1-MH076026) (Gingrich) 03/01/06 to 02/28/11NIH/NIMH $206,338Gene - 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 InvestigatorsOverlap: There is no overlap.

MH066171-01A1 (Lieberman) 07/01/04 to 06/30/09NIH/NIMH $50,000 Etiological Pathways to Dopamine-Glutamate DysfunctionConte Center for the Neuroscience of Mental DisordersOur component of this Center uses mice partially deficient in neuregulin-1 as an animal model of schizophrenia. Role on Project: Co-PI Project 6Overlap: There is no overlap.

5 P50 MH062185-08 (Mann) 07/01/05 to 06/30/10NIMH $1,495,657Conte Center for the Neuroscience of Mental Disorders: The Neurobiology of Suicidal Behavior

Project 6- Genetic Modulation Of Serotonin During Development: $107,000Models 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-PIOverlap: There is no overlap.

Sackler Foundation 07/1/05 to 06/30/09$100,000

Serotonin Transporter Research Project - Molecular Genetic MechanismsTo investigate the developmental effects of serotonin transporter dysregulation on brain development.Role on Project: PIOverlap: 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

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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, and have initiated an NIH study on the role of stress in adolescent risk for delivering premature infants vulnerable to neurobehavioral disorders. 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. We have recently developed new methods for assessing brain function through high density EEG to examine neonatal learning abilities. We have also received a $1,200,000 supplement from the National Institute of Deafness and Communicative Disorders to examine sensory function in high risk infants.

Sackler Serotonin Project: Drs. Peterson, Monk, Myers and Fifer are continuing work on the clinical research arm of this project and are part of the larger Conte Grant application for this endeavor. We are investigating the effects of SSRI antidepressant exposure during pregnancy on fetal and infant neurobehavioral development. The joint Sackler Center collaboration with the Glasgow group continues with the pilot study of a large population of women diagnosed with depression who are treated with SSRI’s

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

The major focus of our work over the years has been the experimental analysis of the behavioral, sensorimotor, thermal, metabolic, and neurophysiological interaction patterns that make up the mother-infant relationship. By using an animal model in the laboratory rat, we have been able to study the regulatory processes that form the basis for the origins of attachment, the dynamics of the infant separation response and the long term shaping of development into adulthood.

As a part of my ongoing work on the theoretical foundations of development, Dr. Susan Brunelli and I have been studying a laboratory model of the evolution of development within the attachment system. By selective breeding over generations, we have created two lines of rats which, as infants, showed the most (and in the other line the least) intense levels of their acute vocal response to separation. Major differences between the lines in adult, as well as infant ‘temperament’ (patterns of behavior and physiology) have emerged after 25 generations, and have included significant differences between the lines in their patterns of maternal behavior toward their infants. These novel findings demonstrate how developmental and evolutionary processes are linked in the origins of attachment behaviors within the early mother-infant relationship.

In June, Dr. Hofer was chosen for the 2009 Senior Investigator Award by the International Society for Developmental Psychobiology “In recognition of his many contributions to the field”.

Dr. Michael Myers, Division Chief - Early Nutritional Influences on Vulnerability to Disease

Work in this laboratory continues to focus on relationships between variation in the environment during pregnancy and in the early postnatal period, and the development of disease later in life. Numerous studies have shown that vulnerability for physical and mental

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illnesses can be shaped by events occurring 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 and rapid advances in developmental neuroscience, genetics and molecular epigenetics now make it possible to study the developmental processes that account for enduring changes in risk and resilience to disease.

Our goals are to understand the modulators and mechanisms that underlie long-term effects of factors such as nutrition, preterm birth, stress, drug exposure, and mother/infant behavioral interactions on brain development and, in turn, behavior. Toward those ends, this year’s major effort was the preparation and submission of new grants to support this work. One submission was as section of the NIMH Conte Center proposal in conjunction with other Sackler Institute Faculty (see Highlights).

The second grant submission is a new initiative for this laboratory. During the past year we discovered (based on analyses of extant data sets) that aspects of electrical activity emanating from the human infant brain exhibit unexpected discontinuities in developmental patterns. Specifically, we found that electroencephalographic activity at higher frequencies increases from 24 to 34 weeks post conceptional age (PCA), decreases to about 44 weeks PCA, and increases again through out the first year of life. We have proposed that the early increase and decrease in EEG activity reflects the transition in effects of the neurotransmitter GABA from a depolarizing, neurotrophic agent, to a hyperpolarizing inhibitory neurotransmitter. The RO1 application responded to an NIMH request for grants entitled “Identification and Characterization of Sensitive Periods for Neurodevelopment in Studies

of Mental Illness”. The proposed research addresses the goals of this initiative by focusing on research to characterize a sensitive period during perinatal development of the brain, that is, the period encompassing the shift GABA’s effects. Since the early neurophysiogical effects of GABA are essential for normal maturation of excitatory and inhibitory neural circuits in thalamus, hippocampus, cerebral cortex and other brain regions, disruptions in GABA function during this early period lead to structural and functional changes in the brain that could underlie vulnerabilities to dysfunction in sensory processing, emotion regulation, and cognition. In turn, these dysfunctions are apparent in a wide range of mental disorders including autism, depression, and schizophrenia. Accordingly, the overall goal of our proposal is to collect and analyze data from non-invasive EEG in human infants, non-human primates, and rats to evaluate the developmental course of this fundamental neurophysiologic process. The studies proposed will involve many Sackler scientists including Drs. Myers, Stark, Grieve, Fifer, Garland, and Peterson and represents an exciting new area of research focus for these investigators.

Publications

FiferSahni R, Schulze K, Ohira-Kist K, Kashyap S, Myers M, Fifer W. Interactionsamong peripheral perfusion, cardiac activity, oxygen saturation, thermal profile and body position in growing low birth weight infants. Acta Paediatr. 2009

Ammari A, Schulze K, Ohira-Kist K, Kashyap S, Fifer WP, Myers MM, Sahni R.Effects of body position on thermal, cardiorespiratory and metabolic activity in

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low birth weight infants. Early Hum Dev. 2009 Aug;85(8):497-501.

Fifer WP, Fingers ST, Youngman M, Gomez-Gribben E, Myers MM. Effects ofalcohol and smoking during pregnancy on infant autonomic control. Dev Psychobiol. 2009 Apr;51(3):234-42.

Nomura Y, Halperin JM, Newcorn JH, Davey C, Fifer WP, Savitz DA, Brooks-Gunn J. The risk for impaired learning-related abilities in childhood and educational attainment among adults born near-term. J Pediatr Psychol. 2009 May;34(4):406-18.

Kinsella MT, Monk C. Impact of maternal stress, depression and anxiety onfetal neurobehavioral development. Clin Obstet Gynecol. 2009 Sep;52(3):425-40.

Myers

Schechter DS, Gross A, Willheim E, McCaw J, Turner JB, Myers MM, Zeanah CH,Gleason MM. Is maternal PTSD associated with greater exposure of very youngchildren to violent media? J Trauma Stress. 2009 Nov 18. [Epub ahead of print]PubMed PMID: 19924819.

Duncan JR, Garland M, Myers MM, Fifer WP, Yang M, Kinney HC, Stark RI.Prenatal nicotine-exposure alters fetal autonomic activity and medullaryneurotransmitter receptors: implications for sudden infant death syndrome. J ApplPhysiol. 2009 Nov;107(5):1579-90. Epub 2009 Sep 3. PubMed PMID: 19729586.

Cohen M, Brown DR, Myers MM. Cardiorespiratory measures before and afterfeeding challenge in term infants are related to birth weight. Acta Paediatr.2009 Jul;98(7):1183-8. Epub 2009 Apr 16. PubMed PMID: 19397552.

Sloan RP, Shapiro PA, DeMeersman RE, Bagiella E, Brondolo EN, McKinley PS,Slavov I, Fang Y, Myers MM. The effect of aerobic training and cardiac autonomic regulation in young adults. Am J Public Health. 2009 May;99(5):921-8. Epub 2009Mar 19. PubMed PMID: 19299682.

Myers MM. Sudden infant death syndrome: a Developmental Psychobiologist'sperspective. Dev Psychobiol. 2009 Apr;51(3):213-4. PubMed PMID: 19206137.

Muller JM, Moore H, Myers MM, Shair HN. Dopamine's role in social modulationof infant isolation-induced vocalization: II. Maternally modulated infantseparation responses are regulated by D1- and D2-family dopamine receptors. DevPsychobiol. 2009 Mar;51(2):158-72. PubMed PMID: 19031490.

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 Dec;119(12):2712-20. Epub 2008 Nov 4. PubMed PMID: 18986834;PubMed Central PMCID: PMC2614343.

Schechter DS, Coates SW, Kaminer T, Coots T, Zeanah CH Jr, Davies M,

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Schonfeld IS, Marshall RD, Liebowitz MR, Trabka KA, McCaw JE, Myers MM. Distortedmaternal mental representations and atypical behavior in a clinical sample ofviolence-exposed mothers and their toddlers. J Trauma Dissociation.2008;9(2):123-47. PubMed PMID: 18985165; PubMed Central PMCID: PMC2577290.

Hofer

Hofer, M. A. (2009). Evolutionary Concepts of Anxiety. In D. J. Stein & E. Hollander (Eds.), APPI Textbook of Anxiety Disorders (2nd ed.), (pp. 129-145). American Psychiatric Press.

Hofer, M. A. (2009). Evolution of the infant separation call: rodent ultrasonic vocalization. In S. M. Brudzynski (Ed.), Handbook of Mammalian Vocalization (pp. 29-36). Academic Press

Hofer, M. A. (2009). Developmental Neuroscience. In G. G. Berntson & J. T. Cacioppo (Eds.), Handbook of Neuroscience for the Behavioral Sciences (pp. 12-31, Ch. 2). Wiley & Sons.

Moriceau, S., Hofer, M.A., Sullivan, R.M. Toward a neurobiology of attachment: modeling abusive attachment in infant rats. Child Development, (In press).

Hofer, M. A. New Concepts in the Evolution and Development of Anxiety. In H. B. Simpson, F. Schneir, Y. Neriu & R. Lewis-Fernandez (Eds.), Anxiety Disorders: Theory, Research and Clinical Perspective ,Cambridge University Press, (In Press).

Other Grant Support

R37 HD32774 (Fifer, W.P., PI)                            04/01/06 -03/30/11             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 NICHD                                                             $5, 879“National Children’s Study- Queens Vanguard Center”A cohort study to examine environmental influences on the health and development of children. 

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

U01 HD55155 (Fifer, W.P. & Myers, M.M. Co-PIs) 09/01/06-07/31/11 NICHD $404,362“Prenatal Alcohol in Sudden Infant Death Syndrome and Stillbirth (PASS) Network” A study of effects of prenatal exposures on fetal and infant neurodevelopmental disorders

U01 HD55155-S (Fifer, W.P. & Myers, M.M. Co-PIs) 09/01/09-08/30/11

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NICHD $1,165,393“Prenatal Alcohol in Sudden Infant Death Syndrome and Stillbirth (PASS) Network” An ARRA supplement to study hearing and EEG in a high risk cohort

R01MH077144- (Monk, C.)                                     5/5/2009 – 4/30/2011        NIMH                                                                       $613,635“Biobehavior of Stress in Adolescent Pregnancy: Perinatal Outcomes” The major goal of this grant is to determine the role of stress in adolescents’ high risk for pre term birth.   

T32 MH018264 (Myers, M.M., PI & Hofer, M.A., Co-PI) 07/01/08-06/30/13NIMH $263,000"Research Training in the Psychobiological Sciences" Postdoctoral research training grant for MDs and PhDs in Psychobiology.

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 of our research has been a longitudinal three-generation study of offspring at high and low risk for major depression (MDD) Our first findings from the structural imaging studies were published in PNAS{ Peterson et al, 2009]. We reported remarkably robust association of familial risk for MDD with asymmetries in cortical thickness, with a nearly 30% reduction in thickness observed in the lateral parietal, temporal, and frontal cortices of the right hemisphere of the high risk group. These MRI findings are consistent with our EEG findings that demonstrated reduced activity over the posterior cortices of the right cerebral hemisphere. Both the MRI and EEG findings were present in high risk individuals who never had MDD in their lifetime, suggesting that these abnormalities were not simply a consequence of previously having been depressed or having been treated for depression. Thinning of the cortical mantel and reduced electrophysiological activity in the right hemisphere therefore may constitute related endophenotypes for familial vulnerability to developing MDD. A more precise examination of the relationship between the EEG and MRI findings in the same subject showed that cortical thinning reported in MRI studies likely accounts for the reduced EEG in the right posterior cortex. EEG is a potential non-invasive, cost-effective marker of vulnerability (Bruder et al., submitted 2009).

With funding from the Sackler Seretonin Transporter Project, we have completed DNA collection in 307 subjects to study the influence of genetic polymorphisms or morphology of cortical surfaces in this sample. In preliminary analyses we found that children (G2) and grandchildren (G3) of probands with MDD (high risk) had over a four fold increased occurrence of the “S/S” 5-HTTLPR genotype than the children and grandchildren of probands without MDD {low risk} This is the largest published study of subjects with both imaging and DNA, and none before in a family context. We mapped the influence of genetic variants for BDNF on cortical thickness on an initial 42 individuals from generations 2 and 3 of the 3-generation cohort scanned. We first examined the effects of BDNF because of its previously described effects on cortical thickness and its reported associations with MDD. Our

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preliminary findings suggest that BDNF may significantly influence the magnitude of the group differences in cortical thinning that we have reported in persons at high vs. low familial risk for depression.

As participants in the NIMH multi-site study to identify MDD susceptibility genes, the collection of about 1000 sibling pairs with recurrent early onset MDD has been completed and analysis are underway. Biological material and clinical data are being shared through a repository with the scientific community. In September 2009 we completed collection of the next 900.samples . About 2000 samples with recurrent MDD and DNA will be available in 2010 for a Genome-Wide association study. These samples will also be available to follow-up findings from the 3 generation study. As part of the NIH stimulus package we secured a grant to collect new samples to carry out gene expression studies.

Work has been 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 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., 2009). No other candidate genes tested were significant.

In collaboration with Charles Glatt, M.D., Ph.D., from the Cornell/Sackler group, we followed 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 had 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. R. Subaran, Ph.D., a post-doctoral fellow at Columbia, under supervision of Dr. Glatt, genotyped the polyadenylation polymorphism in this sample and showed that it likely explained the biological mechanism for the association with panic disorder (Glatt, et al., in press 2009).

In September 2009, based primarily on the separate studies in the Sackler Serotonin Project, we applied for a Silvio O. Conte Center for Basic and Translational Mental Health Research. Weissman’s contribution will be as co-P.I. of the Center. We will build on the 3 generation study of families at high risk for depression as well as the existing clinically characterized samples of subjects with major depression or anxiety disorders where DNA has been collected. The contribution will be to understand how variation genes and neurocircuitry related to serotonergic tone can modify the risk for major depression.

Alan Brown, M.D., M.P.H. is a new member of the Sackler group. His work is on the relationship between early developmental risk factors and schizophrenia, bipolar disorder, depressive disorders, and autism. Over the past year, he has demonstrated associations between prenatal infectious and nutritional factors and schizophrenia and neuromorphologic anomalies in schizophrenia cases, and has obtained 2 NIH-funded grants to study risk factors for schizophrenia and autism in a Finnish national birth cohort. He has collaborated with other members of the Sackler Center and has colleagues in Finland on development of a study on the relationship between use of selective serotonin reuptake inhibitors during pregnancy and neuropsychiatric outcomes in the offspring in a large sample of pregnant women in Finland, and is co-principle investigator on a project using the Finnish birth cohort in a proposed Conte Center grant application to study this question.

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HonorsWeissman received the 2009 Thomas William Salmon Medal from the New York Academy of Medicine for her research.

Publications

Brown AS, Deicken RF, Vinogradov S, Kremen WS, Poole JH, Penner JD, Kochetkova A, Kern D, Schaefer CA: Prenatal infection and cavum septum pellucidum in adult schizophrenia. Schizophrenia Research 2009: 108: 285-287.

Brown AS, Vinogradov S, Kremen WS, Poole JH, Deicken RF, Penner JD, McKeague IW, Kochetkova A, Kern D, Schaefer CA: Prenatal inflectional and executive dysfunction in adult schizophrenia. American Journal of Psychiatry 2009; 166: 683-690.

Feder A, Alonso A, Tang M, Liriano W, Warner V, Pilowsky D, Barranco E, Wang Y, Verdeli H, Wickramaratne P, Weissman MM: Children of low-income depressed mothers: psychiatric disorders and social adjustment. Depression and Anxiety 2009: 26(6): 513-20. [PMID: 19016460]

Insel BJ, Schaefer CA, McKeague IW, Susser ES, Brown AS: Maternal iron deficiency and the risk of schizophrenia in offspring. Archives of General Psychiatry 2008: 65: 1136-1144.

Logue MW, Durner M, Heiman GA, Hodge SE, Hamilton SP, Knowles JA, Fyer AJ, Weissman MM: A linkage search for joint panic disorder/bipolar genes. American Journal of Medical Genetics B: Neuropsychiatry Genetics 2009: Mar 23. [PMID: 19308964]

Mahon PB, Payne JL, Mackinnon DF, Mondimore FM, Goes FS, Schweizer B, Jancic D; NIMH Genetics Initiative Bipolar Disorder Consortium; BiGS Consortium, Coryell WH, Holmans PA, Shi J, Knowles JA, Scheftner WA, Weissman MM, Levinson DF, DePaulo JR, Zandi PP, Potash JB. Genome-wide linkage and follow-up association study of postpartum mood symptoms. American Journal of Psychiatry 2009: Sep 15. [PMID: 19755578]

Opler MG, Buka SL, Groeger J, McKeague IW, Wei C, Factor-Litvak P, Bresnahan M, Graziano J, Goldstein JM, Seidman LJ, Brown AS, Susser ES: Prenatal exposure to lead, delta aminovulinic acid, and schizophrenia: Further evidence. Environmental Health Perspectives 2008: 116: 1586-1590.

Palmer A, Brown AS, Keegan D, Siska LD, Susser E, Rotrosen J, Butler PD, Prenatal protein deprivation alters dopaminemediated behaviors and dopaminergic and glutamatergic receptor binding. Brain Research 2008: 1237: 62-74.

Peterson BS, Warner V, Bansal R, Zhu H, Hao X, Liu J, Durkin K, Adams PB, Wickramaratne P, Weissman MM. Cortical thinning in persons at increased familial risk for major depression. Proceedings of the National Academy of Science USA 2009: Apr 14:106(15): 6273-8.

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Peterson BS, Weissman MM. Reply to Pomara, et al: Spatially distributed patterns of cortical thinning likely constitute distinct brain-based biomarkers for disease. Proceedings of the National Academy of Science, USA 2009: 106: E83, 2009.

Plodges LM, Weissman MM, Haghighi F, Costa R, Bravo O, Evgrafov O, Knowles JA, Fyer AJ, Hamilton SP: Association and linkage analysis of candidate genes GRP, GRPR, CRHR1, and TACR1 in panic disorder. American Journal of Medical Genetics 2009; Jan 5; 150B (1): 65-73 [PMID: 18452185]

Psychiatric GWAS Consortium Coordinating Committee. Genomewide association studies: History, rationale and prospects for psychiatric disorders. American Journal of Psychiatry 2009: May; 166(5): 540-56.

Strug LJ, Suresh R, Fyer AJ, Talati A, Adams PB, Li W, Hodge SE, Gilliam TC, Weissman MM: Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR). Molecular Psychiatry 2008: Jul 29. [PMID: 18663369]

Verma R, Holmans P, Knowles JA, Grover D, Evgrafov OV, Crowe RR, Scheftner WA, Weissman MM, DePaulo JR Jr, Potash JB, Levinson DF: Linkage disequilibrium mapping of a chromosome 15q25-26 major depression linkage region and sequencing of NTRK3. Biological Psychiatry 2008: Jun 15; 63(12): 1185-9. [PMID: 18367154]

Weissman, MM: Depression. Annals of Epidemiology 2009; 19: 264-267.

Warner V, Wickramaratne P, Weissman MM: The role of fear and anxiety in the familial risk for major depression: A three-generation study. Psychological Medicine 2008: Feb 14: 1-14. [PMID: 18275630]

Warren JW, Howard FM, Cross RK, Good, JL, Weissman MM, Wesselmann U, Langenberg P, Greenberg P, Clauw DJ: Antecedent non-bladder syndromes in a case control study of interstitial cystitis/painful bladder syndrome. Urology 2009: 73: 52-57.

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 2008: 18: 1569-1591.

Other Grant Support

1 R01 MH60912 (Weissman) 07/01/05 – 06/30/10(NIMH) $327, 053Genetics 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.

1 R01 MH36197(Weissman) 01/01/03 – 12/31/09(NIMH) $654, 783 (in submission for continuation)

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Children at High and Low Risk for Depression, The aims of this study are (1) to make 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 the NIDA to examine drug use disorders and smoking in families at high risk for depression using data collected in MH36197.

1 R01 MH082255 (Weissman) 07/01/07 – 06/30/11(NIMH) $500, 546 Parental Remission from Depression, 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 T32 MH16434 07/01/05 – 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.

GO NIMH Subcontract (Weissman) 2009-2011Stanford U $137,375 Depression Susceptibility Genes and Networks: Expression, eQTL and GWAS Analysis. Work on this subcontract is collection of clinical data through standardized diagnostic assessments from some 650 referred and consented subjects and transmission of collected clinical data to the central site at Stanford University. Templeton Foundation (Weissman) 2010-2012

$500,000 Understanding the Role of Belief in the Resilience of Families at Risk for Depression: Religion, Brain Structure, and Genetics A study linking 3 areas of research: beliefs, brain structure and function, and genetic endowment. The overarching goals of the proposal are (1) to extend original observations about the protective effects of belief and determine the stability of the findings, and (2) to integrate the clinical and religious variables with brain structure and function, and genetic data in order to answer comprehensive questions about vulnerability and resilience to depression

Interstitial Cystitis Association (Weissman) 2009-2010$10,000

A Medical Syndrome involving Interstitial Cystitis linked to Chromosome 13. The goal of this proposal is to fine-map the previously identified genetic region of chromosome 13 in a newly collected sample, using newer fine-mapping genetic techniques in order to more precisely pinpoint the genes involved in this medical syndrome and thereby obtain a better understanding of its mechanisms

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Pending

1P50MH090966-01 (Gingrich) 07/01/10 – 06/30/15(NIH/NIMH) $1,592,063Silvio O. Conte Centers for Basic and Translational Mental Health Research: Serotonergic Modulation Influence on Structure, Function, and BehaviorBrown (co-investigator)Weissman (co-principal investigator)Several lines of evidence indicate that in species from rodents to humans, serotonin acts as a neural growth factor during early phases of brain maturation to influence brain structure, neurophysiology, and ultimately, behavior. Serotonin signaling can be affected by either genetic (5httlpr) or pharmacologic (SSRI, MAOI) variables during early life. We hypothesize that low-expressing 5httlpr variants of the serotonin transporter (SERT) and pharmacologic inhibition of SERT function produce similar effects on brain maturation and ultimately behavior and increase the risk for clinical diagnoses such as affective and anxiety-related disorders.

Brown Active Grant Support

1 R01ES019004-01 (Brown) 09/28/09 – 07/31/11(NIH-NIMH) $840, 697 Prenatal Factors and Risk of Autism in a Finnish National Birth Cohort, The major goal of this project is to examine if environmental factors during pregnancy are related to the likelihood that the offspring will be diagnosed with autism in a large birth cohort in Finland.

1 R01 MH073080 (Brown) 02/16/05 – 01/31/11(NIH-NIMH) $372,990 Prenatal factors and risk of bipolar disorder, The major goals of this project are to investigate the relationship between early developmental insults and risk of adult bipolar affective disorder.

2 K02 MH065422-06 (Brown) 07/01/08 – 06/30/13(NIH-NIMH) $114,390 Epidemiology of prenatal factors in adult psychopathology, This is a renewal of a previous K02 award. The major goal of this project is to extend ongoing research by investigating prenatal nutritional and genetic factors involved in the etiology of schizophrenia, and the examination of the specificity of prenatal factors previously associated with schizophrenia by investigating their relationship to bipolar disorder.

1 R01 069819 (Schaefer) 09/28/05 – 08/31/10(NIMH) $423, 855 Brown (co-investigator) $83, 945 (subcontract)Prenatal Determinants of Schizophrenia (PDS) II, The proposed study aims to investigate the role of pre and perinatal factors in the development of schizophrenia and schizophrenia spectrum disorder (SSD) not previously addressed in a previous study, PDS 1; and to replicate and extend important findings from the prior study.

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1 R01MH082052-01 (Brown) 07/01/08 – 06/30/13(NIH-NIMH) $845, 319 Prenatal Factors and Risk of Schizophrenia in a Finnish National Birth Cohort, The major goal of this project is to examine the relation of early life exposures to the risk of schizophrenia and other schizophrenia spectrum disorders, using serologic methods to document the exposure of interest in a large birth cohort in Finland.

4. Developmental Neuro-imaging Laboratories

Dr. Bradley Peterson, Chief – Normal Brain Development and the Neural Basis of Psychiatric Disorders

Dr. Peterson received additional funding from the Simons Foundation Autism Research Initiative (SFARI) in order to extend the collection phase of the Simons Simplex Collection (SSC) from June 2010 to June 30, 2011. The primary goal of the SSC is to establish a permanent repository of genetic samples from close to 3,000 simplex families, each of which has one child affected with an Autism Spectrum Disorder (ASD), unaffected siblings, and unaffected parents who are living and available. Each genetic sample will have an associated collection of data that provides a precise characterization of the individual (phenotype). Rigorous phenotyping will maximize the value of the resource for a wide variety of future research projects into the causes and mechanisms of autism.

Dr. Peterson also received NIMH funding to use MRI to identify brain-based biomarkers and biological subtypes in persons with Autistic Spectrum Disorders. The funding will allow acquisition of detailed MRI data in 100 children and adults with Autism and 100 healthy comparison subjects, as well as integration with behavioral, cognitive, and genetic data.

The laboratory also received NIH funding for the acquisition of a high density (32 channel) radio frequency (RF) receiver (HDRFR) system for a 3 Tesla (T) magnetic resonance imaging (MRI) and spectroscopy (MRS) scanner. The HDRFR will be interfaced with the existing 3T MRI system, which is a 100% dedicated scanner for research on human subjects and animals, in order to better understand brain structure and function as applies to mental health and to search for new treatments of neuropsychiatric disorders. It will become part of the scanner that is located in the MRI Research Center (MRC) of the Psychiatry Department of Columbia University (CU) and New York State Psychiatric Institute (NYSPI). The 32 channel RF receivers combined with our in-house RF coil design and construction capability, pulse sequence development team, and image processing lab will (1) substantially increase signal to noise ratio (SNR) from human head which will allow construction of higher resolution (sub-millimeter) images, (2) enable much faster imaging which will reduce scan time up to 5-fold. This is the most important benefit of the 32 channel receiver for studies involving psychiatric patients. (3) reduce some of the debilitating artifacts for brain studies, such as those at the base of the skull and in orbitofrontal and mesial temporal cortices, areas of great interest in the study of human neuropsychiatric illness, (4) increase sensitivity of MRS, allowing acquisition of substantially stronger signal in 1H spectroscopy data for vitally important molecules, such as GABA, that have inherently low SNR, and (5) allow high resolution fMRI studies capable of achieving both higher temporal and spatial resolution.

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Under the mentorship of Dr. Bradley Peterson and Dr. Myrna Weissman, Dr. Dubin has been working on a Three Generation Study of High Risk for Familial Major Depression. During this work, Dr. Dubin has used structural MRI volumetric techniques applied to a longitudinal sample of individuals at high and low risk for familial depression. This has led to the identification of a biomarker of frontal white matter volume decrease that is correlated with risk for depression. Dr. Dubin has rigorously characterized the relationship of this biomarker to cognitive variables and mood and anxiety states as well as its relationship to a cortical thinning biomarker previously published by Drs. Peterson and Weissman on the same high risk cohort.

Publications

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, 47: 1233-1251, 2008.

Maia TV, Cooney RE, Peterson BS. The neural bases of Obsessive-Compulsive Disorder in children and adults. Develop & Psychopath,20: 1251-1283, 2008.

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, 27: 1506-1514, 2008.

Colibazzi T, Zhu H, Bansal R, Schultz R, Peterson BS. Latent volumetric structure of the human brain: Exploratory factor analysis and structural equation modeling of gray matter volumes in healthy children and adults. Hum Brain Map, 29:1302-12, 2008.

Grieve PG, Isler JR, Izraelit A, Peterson BS, Fifer WP, Myers MM, Stark RI. EEG functional connectivity in extremely low birth weight (ELBW) infants. Clin Neurophysiol, 119: 2712-2720, 2008.

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¸ 18:1569-1591, 2008.

Gerber AJ, Peterson BS. Applied brain imaging. J Am Acad Child Adolesc Psychiatry, 47:239, 2008

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, 29:13-22, 2009.

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, 66:51-63, 2009.

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

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cognitive functioning that is either nearly normal or markedly impaired. Am J Psychiatry,166:189-195, 2009.

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, 30:883-95, 2009.

Bansal R, Staib LH, Laine AF, Xu D, Liu J, Posecion LF, Peterson BS. Calculation of confidence intervals for transformation parameters in the registration of medical images. Med Image Anal, 13:215-33, 2009.

Xu D, Cui J, Bansal R, Hao X, Liu J, Chen W, Peterson BS. The ellipsoidal area ratio: an alternative anisotropy index for diffusion tensor imaging. Magnet Reson Imaging, 27:311-23, 2009.

Peterson BS, Warner V, Bansal R, Zhu H, Hao X, Liu J, Durkin K, Adams PB, Wickramaratne P, Weissman MM. Cortical thinning in persons at increased familial risk for major depression. PNAS, 106:6273-6278, 2009.

Dong Z, Peterson BS. Spectral Resolution Amelioration by Deconvolution (SPREAD) in MR Spectroscopic Imaging. J Magnet Reson Imaging, 29:1395-1405, 2009.

Chung YA, Jeong J, Kim SH, Chung SK, Sohn HS, Kim EN, Peterson BS. A Tc-99m SPECT study of regional cerebral blood flow in patients with Transient Global Amnesia. Neuroimage, 47:50-55, 2009.

Marsh R, Maia T, Peterson BS. Functional disturbances within frontostriatal circuits across multiple childhood psychopathologies. Am J Psychiatry, 166:664-674, 2009.

Dong Z, Dreher W, Leibfritz D, Peterson BS. The challenges of using MRS to detect neural progenitor cells in vivo. AJNR, 30:1096-1101, 2009.

Bansal R, Staib L, Xu D, Laine AF, Liu J, Peterson BS. Using perturbation theory to reduce noise in diffusion tensor fields. Med Image Anal, 13:580-597, 2009.

Raz A, Packard MG, Alexander GM, Peterson BS. A slice of π: Exploratory neuroimaging of digit encoding and retrieval in a superior memorist. Neurocase, 6:1-12, 2009.

Gozzo Y, Vohr B, Lacadie C, Hampson M, Katz KH, Maller-Kesselman J, Schneider KC, Peterson BS, Rajeevan N, Makuch RW, Constable RT, Ment LR. Alterations in neural connectivity in preterm children at school age. Neuroimage, 48:458-463, 2009.

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, 54:579-588, 2009.

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Peterson BS, Potenza MN, Wang Z, Zhu H, Martin A, Marsh R, Plessen KJ, Yu S. An fMRI study of the effects of psychostimulants on default-mode processing during Stroop task performance in youths with ADHD. Am J Psychiatry, 166:1286-1294, 2009.

Liu F, Garland M, Duan Y, Stark RI, Xu D, Bansal R, Dong Z, Peterson BS, Kangarlu A. Techniques for in utero, longitudinal MRI of fetal brain development in baboons at 3 Tesla. Methods, Apr 7. [Epub ahead of print], 2009.

Bloch MH, Craiglow BG, Landeros-Weisenberger A, Dombrowski PA, Panza KE, Peterson BS, Leckman JF. Predictors of early adult outcome in pediatric-onset Obsessive-Compulsive Disorder. Pediatrics,124:1085-1093, 2009.

Zhu H, Li Y, Ibrahim JG, Shi X, An H, Chen Y, Gao W, Lin W, Rowe DB, Peterson BS. Regression models for identifying noise sources in magnetic resonance images. J Am Stat Assoc, 104:623-637, 2009.

Plessen KJ, Bansal R, Peterson BS. Anatomical imaging evidence for CNS vulnerability and plasticity in persons with Tourette syndrome. J Psychosomat Res, 67:559-573, 2009.

Tau GZ, Peterson BS. Normal development of brain circuits. Neuropsychopharmacology, 2009 Sep 30. [Epub ahead of print].

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.

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.

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.

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.

Colibazzi T, Posner J, Wang Z, Gorman D, Gerber A, Yu S, Zhu H, Kangarlu A, Duan Y, Russell J, Peterson BS. Neural systems subserving valence and arousal during the experience of induced emotions: a functional MRI study of the circumplex model of affect. Emotions, in press.

Mazzone L, Yu S, Blair C, Gunter BC, Marsh R, Peterson BS. An fMRI study of frontostriatal circuits during the inhibition of eye blinking in persons with Tourette syndrome. Am J Psychiatry, in press.

Tobe RH, Bansal R, Xu D, Hao X, Liu J, Sanchez J, Peterson BS. Morphological features of the cerebellum in Tourette syndrome and comorbid Obsessive-Compulsive Disorder. Ann Neurol, in press.

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Other Grant Support

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

Biomarkers for Psychosis in Velocardiofacial Syndrome 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.

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 far reaching 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).

Klingenstein Third Generation Foundation 8/1/08 – 7/31/10(T. Maia, PI, B. Peterson, Co-PI) $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

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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.

NIH/DHHS (V. Rauh, PI) 12/01/08-11/30/13$636,456

Assess the effects of pre- and postnatal exposure to the organophosphorus pesticide, chlorpyrifos (CPF)We will use Magnetic Resonance Imaging (MRI) to define the intermediary neurobiological effects of chlorpyrifos and diazinon exposure on the structure, metabolism, and anatomical connectivity of the brain in a subset of 300 children. CPF and diazinon were selected as models for translational research because they are representative of the class of OP pesticides, well characterized, and well-studied in animals. Furthermore, agricultural and commercial use continues, despite a 2001 residential ban by EPA. Specifically, we propose to: (1) assess the association between prenatal exposure to CPF/diazinon and child neurobehavioral functioning at 8-9 years in the areas of attention deficits, ADHD, depressive symptoms, pervasive developmental problems, and sleep disorders; (2) assess the effects of prenatal exposure to CPF/diazinon on brain structure, metabolism, and anatomical connectivity in a subset of these children; and (3) develop trajectories of neurodevelopment over 8-9 years as a function of CPR and diazinon exposures.

NIH (B. Peterson, PI) 9/30/09 – 9/29/11$2,435,405

Identifying Brain-Based Biomarkers for ASD & their Biological Subtypes

The ultimate goal of this study is to identify brain biomarkers of Autism Spectrum Disorders (ASDs) using multimodal Magnetic Resonance Imaging (MRI). Participants undergo anatomical MRI, functional MRI (fMRI), diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) in a 3 Tesla scanner, as well as clinical measures that examine intelligence, memory, visuospatial processing, procedural memory, declarative memory and executive functioning. We hypothesize that patterns of disturbances will emerge indistinct neural systems that have been shown to be altered in ASD, such amygdala-hippocampal and the fronostriatal systems. Identifying brain biomarkers for ASD will aid in the identification of biological subtypes, the search for vulnerability genes, and the development of personalized, targeted therapies.

Klingenstein Third Generation Foundation. (J. Posner, PI) $30,000

Attention Deficit/Hyperactivity Disorder (ADHD) is a diverse disorder with multiple biological causes and mechanisms. Indeed, no single cognitive or neurobiological deficit can be identified in all children with the disorder. Rather, certain domains of functioning are impaired in some ADHD youth whereas other ADHD youth are better characterized by deficits in other domains.Our study will use neuropsychological and functional magnetic resonance imaging (fMRI) techniques to investigate the heterogeneity of ADHD. To date, most functional neuroimaging studies of ADHD have focused largely on deficits in impulse control, yet numerous behavioral studies suggest that deficits in impulse control apply to only a portion of children suffering

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with the disorder. For other ADHD children, their symptoms seem to emerge not from poor impulse control but instead from abnormal emotional regulation. Our study will examine the heterogeneity of ADHD by attempting to disentangle these two neuropsychological domains – impulse control and emotional regulation - and identify their relationship with ADHD symptoms. Our study will examine in a single population of ADHD youth the hypothesis that two, distinct neural input pathways can each contribute to ADHDsymptoms.

5. Department of Pediatrics - Neonatology

Dr. Raymond I. Stark: Director of the Perinatal Research Laboratory in the Division of Neonatal Medicine, Department of Pediatrics Columbia University and Children’s Hospital of New York Presbyterian. Co-investigators, Dr. Marianne Garland Associate Clinical Professor of Pediatrics, Dr. Philip Grieve, Assistant Clinical Professor of Biomedical Engineering in Pediatrics, and Dr. Joseph Isler, Associate Research Fellow in Pediatrics.

Sackler Serotonin Transporter Project : Placental Transport, Fetal Metabolism and Brain Imaging Effects of Different SSRI Types in Fetal Baboons

Work in this laboratory continues to investigate markers of the relationship between stressful events during the pre- and postnatal period of infants born prematurely and their subsequent vulnerability to neurobehavioral abnormalities later in life. These infants are at high risk for cognitive, motor and neurobehavioral deficiencies and vulnerability to psychiatric disorders such as schizophrenia, depression and autism. These risks and vulnerabilities have been attributed to exposure to the extra-uterine environmental during sensitive periods in neurodevelopment that normally occur under homeostatic conditions in utero. The most profound effects are seen in the survivors of extreme low birth weight (< 750 grams) and markedly truncated gestation (< 28 weeks post conceptional age). In the past our work involved studies of pregnant non-human primates and focused on fetal physiological development and impact of drug (nicotine, anti-HIV agents, SSRI’s and morphine) exposure during the latter third of gestation. With constraints on primate research in the Columbia Institute of Comparative Medicine and Animal Care, we have turned our efforts to clinical investigation in early postnatal life using comparable methodological strategies. Our long-term goal is to define markers for and understanding of the mechanisms underlying long-term effects of variation in environmental exposure and the physiological and electro-cortical function of infants. This year we completed three studies relevant to our goals:

1. EEG functional connectivity in term age extremely low birth weight infants [ref 6.] We tested the hypothesis that electrocortical functional connectivity (quantified by coherence) of extremely low birth weight (ELBW) infants, measured at term post-menstrual age, has regional differences from that of full term infants. We used data from 128 lead high density EEG studies collected during sleep from 8 ELBW infants with normal head ultrasound exams and 8 typically developing full term infants. Regional spectral power and coherence were calculated. We found no significant regional differences in EEG power between the infant groups; however, compared to term infants, ELBW infants had significantly reduced interhemispheric coherence (in frontal polar and parietal regions) and intrahemispheric coherence (between frontal polar and parieto-occipital regions) at 1-12Hz but increased

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interhemispheric coherence between occipital regions at 24-50Hz. These data led us to conclude that ELBW infants at term post-menstrual age manifest regional differences in EEG functional connectivity as compared to term infants. From these findings we have speculated that the distinctive spatial patterns of electrocortical synchrony found in ELBW infants may presage regional alterations in the structure of the cortex and subsequent neurobehavioral deficits. It is of interest that regions where we observed decreased interhemispheric coherence (parietal and frontal polar cortices) and reduced intrahemispheric coherence (between frontal polar and occipital cortices) in ELBW infants are also the regions that prior magnetic resonance imaging studies of Dr. Peterson found to have reductions in cortical volumes. We believe that future linkage between EEG markers of cortical activity and MRI will yield a structural functional understanding of abnormalities in the brains of these exceptionally high risk infants that can advise neonatologists in NICU care strategies and provide a means for those care givers responsible to designing early interventions to design therapy to ameliorate poor outcome.

2. EEG Functional Connectivity in Infants and Relationship to OutcomeIdentifying markers in the early postnatal period for subsequent adverse

neurodevelopmental outcomes is an important goal of perinatal research. To this end we have used extant EEG and outcome data from the NIH/NICHD Collaborative Home Infant Monitoring Evaluation (CHIME) data set. In term infants, we reported that there are significant positive correlations between EEG interhemispheric coherence, measure at a mean postnatal age of 10 weeks, and Bayley Mental Developmental Index (MDI) assessed at one year of age. In contrast, the group of prematurely born infants had a significant negative correlation between interhemispheric coherence measured at term equivalent age and MDI. These relationships were particularly strong in extremely low birth weight (ELBW). Our findings demonstrate links between early assessments of EEG electrocortical functional connectivity and subsequent neurodevelopmental outcome in both a normal cohort of infants and in a group at very high risk for suboptimal outcome. 

3. EEG discriminators of children with autism spectrum disorders from typical children [ref 1]: We analyzed EEG synchrony between homologous early visual areas in the cortex to test the hypothesis that interhemispheric functional connectivity during visual stimulation is reduced in children with autism compared to controls. Measures of EEG power and coherence within and between two homologous regions of the occipital cortex were measured during long latency flash visual evoked potentials. Measures were compared between two groups of children (5.5-8.5 yrs), one with autism spectrum disorders and the other with typical development. We found that at and below 9 Hz, interhemispheric synchrony was reduced in autistic subjects compared to typical controls by as much as 50%. Above 9 Hz synchrony in autistic children was virtually nonexistent. Interhemispheric synchrony in autistic subjects was decreased in spite of bilateral increased power. Wavelet power showed autistic children had a stronger and more rapid initial response to stimulation, a slower recovery, and more modulation at longer latencies. These results led us to conclude that the sensory cortices of autistic children are hyper-reactive to stimulation with concurrent diminished functional connectivity across hemispheres. We believe that the significance of our findings of hyper-reactivity in early visual cortex may relate to fMRI findings of increased thalamocortical connectivity in autism and low-level perceptual advantages. Simultaneous decreased (absent) interhemispheric synchronization of elemental visual information

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suggests either that power increases cause poor interhemispheric connectivity or that parallel processes related to thalamocortical regulation impact power and coherence independently.

Future directions: We have coalesced our interests with those of other Sackler investigators in an RFA (request for applications) grant proposal to identify and characterize sensitive periods in neurodevelopment relevant to studies of mental illness. Our laboratory is particularly well positioned to focus clinical research on infants in a period of perinatal brain development which covers a major shift in the effects of GABA from a neurotrophin to a neurotransmitter. We speculate that disruptions in this switch in function could lead to structural and functional changes in the brain and in turn these lead to dysfunction in sensory modulation, behavioral modulation, and cognitive function. Our focus in this proposal tests the hypothesis that parameters of EEG activity provide an accurate indication of the time course of the switch in GABA function, and the studies proposed are linked with multiple Sackler collaborators. Dr. Myers, the PI, summarizes the proposal in his report.

Publications

Duncan JR, Garland M, Myers MM, Fifer WP, Yang M, Kinney HC, Stark RI.Prenatal nicotine-exposure alters fetal autonomic activity and medullaryneurotransmitter receptors: implications for sudden infant death syndrome. J ApplPhysiol. 2009 Nov;107(5):1579-90.

Lo SS, Sobol JB, Mallavaram N, Carson M, Chang C, Grieve PG, Emerson RG, StarkRI, Sun LS. Anesthetic-specific electroencephalographic patterns during emergencefrom sevoflurane and isoflurane in infants and children. Paediatr Anaesth. 2009Aug 25. [Epub ahead of print].

Liu F, Garland M, Duan Y, Stark RI, Xu D, Bansal R, Dong Z, Peterson BS,Kangarlu A. Techniques for in utero, longitudinal MRI of fetal brain development in baboons at 3T. Methods. 2009 Apr 7. [Epub ahead of print]

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 Dec;119(12):2712-20.

Isler JR, Grieve PG, Czernochowski D, Stark RI, Friedman D. Cross-frequencyphase coupling of brain rhythms during the orienting response. Brain Res. 2008Sep 26;1232:163-72. 5.

Garland M, Abildskov KM, Kiu TW, Daniel SS, Weldy P, Stark RI. Placentaltransfer and fetal elimination of morphine-3-beta-glucuronide in the pregnantbaboon. Drug Metab Dispos. 2008 Sep;36(9):1859-68

Other Support K25 NS052230-01

8/05 – 7/10

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Title: Spatiotemporal ERP Modeling & Brain DevelopmentRole: Primary SponsorTo develop new quantitative methods for event related potential and link results to computational models that simulate development neural systems.

AHA, #0635077N (C0-I) 7/1/06 – 6/30/10PI: Vadim TenRole: Co-ITitle: The role of complement activation in the development of hypoxic-ischemic brain injury in neonatal mice.To investigate the role of complement activation in amplification of cerebral injury following hypoxic-ischemic insult in neonatal mice.

1R03HD57410-01A1             7/1/08 – 6/30/10              PI: PG GrieveNIH/NICHD                                                Role: Co-IEEG synchrony of preterm infants: Regional disparities and perinatal risksStudy of brain electrical function in extremely premature infants.

1R03HD060671-01                5/1/09  – 4/31/11       PI: PG GrieveNIH/NICHD Role: Co-I                                            EEG Synchrony, perinatal risk and outcome: analysis of CHIME dataStudy of infant brain electrical function using CHIME data.

6. Sackler Awardees- Annual Progress Report—2009

Amar Sahey - Summary of Proposed Research

“Understanding how experience dependent plasticity mechanisms encode vulnerability to anxiety disorders: A role for Klf-9 dependent neural circuit maturation”

Coupled with a genetic predisposition, environmental stress early in life can disrupt maturation of limbiccircuitry and increase the risk of psychiatric disorders. Although a few genes have been identified as mediatorsof vulnerability to early-life stressors, little is known about the precise mechanisms by which these genes exerttheir effects. Here, we propose that experience-dependent plasticity mechanisms moderate the effects of earlylife stress on anxiety behavior by enabling neural circuits to adaptively encode environmental inputs. Web present evidence for Kruppel-like factor 9 (Klf-9) as a novel regulator of activity-dependent neuronal maturation and hypothesize that deficiency in Klf-9-dependent neural circuit maturation is sufficient to confervulnerability to the effects of early-life stress on anxiety-like behavior. The proposed experiments will provide mechanistic insight into the etiology of anxiety disorders and more generally, inform how mutations and environmental insults converge upon neural circuits to alter the trajectory of emotional reactivity.

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Progress Update1. Establishing an Early-life Stress paradigm to test if Klf-9 null mice are more

vulnerable to the effects of early-life stress on anxiety-like behavior (Aim I)

-Developing an early-life stress paradigm in mice has proven difficult. We have piloted several versions of the foot-shock stress protocol (FSS) with little success. We are now testing a corticosterone (CORT) treatment protocol that has been shown to induce anxiety-like and depression-like behaviors in mice inour laboratory. We are currently determining the CORT treatment regimen during the early-postnatal period (P15-P30) for which wild-type mice are only mildly affected. We will then ask whether Klf-9 null are more vulnerable to a stressor during the P15-P30 window using this treatment protocol.

-We have preliminary evidence to suggest that adult Klf-9 null mice are more vulnerable to stress than wild-type littermates. Specifically, adult Klf-9 null mice exhibited increased anxiety-like behavior in the Novelty Suppressed Feeding paradigm following 4 weeks of repeat-handling related stress. These findings have motivated us to examine whether adult Klf-9 null mice are more vulnerable to the effects of CORT treatment on anxiety-like and depression-like behaviors.

2. Generation of teto-Klf-9 mice (Aim III)We have successfully generated an inducible Klf-9 mouse line with which we plan to reversibly silence Klf-9 during the early-postnatal period (P15-P30) when mice are exposed to the stressor. We are currently characterizing this mouse line.Subsequent funding: K23 Career Development Award NIMH

PublicationsCurrently, I have two manuscripts that are under review.

Increasing adult hippocampal neurogenesis is sufficient to enhance pattern separation but not mood Amar Sahay 1,3,4*, Kimberly Scobie 1,3, Colin M. O'Carroll 1,3, Alex Dranovsky1,3,4 and René Hen1,2,3,4*

Krüppel-like factor 9 (Klf-9) is Necessary for Late-phase Neuronal Maturation in the Developing Dentate Gyrus and During Adult Hippocampal NeurogenesisKimberly Scobie 1,3, Benjamin J. Hall5, Scott A. Wilke6, Kristen C. Klemenhagen1,3, Yoshiaki Fujii-Kuriyama7, Anirvan Ghosh6, René Hen1,2,3,4 and Amar Sahay 1,3,4

Tizziano Colibazzi - Progress Update

“Longitudinal Imaging in Adolescents Prodromal for Schizophrenia”

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To date much progress has been made. We have significantly increased recruitment in 2008 and in the first months of 2009. So far, we have enrolled 6 healthy controls and have scanned 21 prodromal cases. Half of the prodromal cases have been scanned more than once (2 of these patients have been scanned 4 times, one patient 5 times and another patient up to 6 times). Two participants in our cohort have converted to psychosis. Most importantly, through salary support, this Sackler Award has been essential in allowing, the PI to continue his efforts in securing federal funding, as evidenced by a competitive score of 148 in a recent K23 A1 submission. Moreover, with this Sackler support, the PI has been able to pilot the application in schizophrenia of techniques for the analyses of white matter surfaces as well as amygdala/hippocampus (data available upon request). This will enable the PI to characterize anatomical structure using several anatomical variables: cortical surface, cortical thickness, white matter surface as well as more traditional gray/white matter volumes. Characterization of multiple aspects of brain anatomy will allow a more refined delineation of normal and abnormal developmental trajectories in our sample. These findings have been presented at ACNP in 2008 and at the International congress of Schizophrenia Research in 2009.

Goals for second year of the Award During the next year of the Award, the PI plans to focus his efforts on increasing healthy control recruitment and on continuing prodromal recruitment and follow up. The second year of the Award will also be devoted to the completion of cross-sectional analyses comparing healthy controls, converters and non-converters. These analyses will be the seed for a future R01 application. In terms of publications, the PI is planning to submit within the next two months a manuscript detailing findings in patients with schizophrenia obtained using these computational techniques. Further, throughout the second year of the Award, the PI plans to complete and submit a manuscript describing surface analysis of the amygdala and hippocampus in the same sample.

Subsequent funding/honors received: Since the original submission of this application, Dr. Colibazzi has received the following two grants which support his prodromal research: NARSAD Young Investigator Award (NARSAD: 7/1/08 – 6/30/10) and the Bodini Fellowship (Italian Academy of Columbia University: 7/1/08 – 6/30/10). Dr. Colibazzi has also recently received word of the funding for his K23 Career Development Award application to NIMH and has been promoted to Assistant Professor of Clinical Neuroscience in Psychiatry (Columbia University/NYSPI).

Relevant publications

Wexler BE, Goldman-Rakic P, Zhu H, Nicholls SS, Fulbright RK, Gore JC, Bell MD, Colibazzi T, Amat J, Bansal R, Peterson BS. Distinctive cognitive deficits and brain abnormalities suggest subgroups of schizophrenia. Am J Psychiatry. 2009;.Feb 166(2): 189-95.

Corcoran C, Kimhy, D, Stanford A, Khan S, Walsh J, Thompson J, Schobel S, Harkavy-Friedman J, Goetz R, Colibazzi T, Cressman V, Malaspina D. Temporal Association of Cannabis Use with Symptoms in Individuals at Clinical High Risk for Psychosis . Schiz Res. 2008 Dec 106 (2-3): 286-93.

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Sackler Institute for Developmental Psychobiologyat Columbia University

FINANCIAL REPORT 2008 - 2009