ARCHIVE

ANNUAL REPORT
July 1, 2002 – June 30, 2003

SACKLER INSTITUTE FOR DEVELOPMENTAL PSYCHOBIOLOGY
AT COLUMBIA UNIVERSITY

Table of Contents

This report covers the second 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. The income from the endowment supports a professorship for the Director of the Institute, and has made a major contribution to the construction of the new Sackler Laboratories at the New York State Psychiatric Institute. In addition, it provides support for new directions in faculty research and funds the annual Sackler Award, a stipend for a postdoctoral fellow/junior faculty worker to facilitate their transition to becoming an independent researcher. Together with an annual contribution to the Director’s Fund by Columbia University, the Institute sponsors conferences and symposia at National and International meetings, makes ‘mini-grants’ to selected Sackler Fellows for their research costs, gives small seed money grants for novel research pilot studies that enable subsequent grant applications for federal support, and provides administrative support for the Institute.

The administrative structure and faculty of the institute over the past year were as follows:

Director, Dr. Myron A. Hofer
Assistant Director, Dr. William P. Fifer
Administrative Assistant, Jennifer Knowles
Chief, Basic Science Division - Dr. Thomas Jessell
Chiefs, Behavioral Neuroscience Division - Drs. Michael Myers and William Fifer
Chief, Clinical Division - Dr. Myrna Weissman
Head, Developmental Neuroimaging Laboratory - Dr. Bradley Peterson
Liason, Cornell - Sackler Institute - Dr. Jonathan Polan
Sackler Awardee: 2003-2004 Dr.Cheryl Corcoran

The research programs of the faculty and the Sackler Awardee are described in the second section of this report along with their publications for the year and their current Federal and other grant support.

Part I Narrative of Events

A ribbon-cutting ceremony for the Sackler Institute Laboratories and dedication of the plaque commemorating the founding of the Sackler Institute took place in late January of 2003. A description of the event is given below at the end of Part I.

[In the past year] several of the Sackler Faculty received honors and awards. Myrna Weissman was elected fellow of the New York Academy of Medicine and was invited to be on the editorial board of the American Journal of Psychiatry. Dr. Jessell received the Mayor’s Award and Dr. Peterson, an Independent Investigator Award from the National Association for Research in Schizophrenia and Depression. Dr. Fifer gave the Presidential address to the International Society for Developmental Psychobiology. Drs. Myron Hofer and Michael Myers were awarded a 5 year renewal of the NIMH Research Fellowship Training Program that provides support for Sackler Fellows (see below). Dr. Daniel Schecter, one of these Sackler Fellows, was awarded a 5 year Research Scientist Development Award from NIMH beginning in July 2003. In addition, he was appointed to the National Child Traumatic Stress Network and the New York City Department of Health Early Childhood Strategic Work Group.

“September 11th : Trauma and Human Bonds” was published by the Analytic Press in early 2003, edited by Susan Coates, director of the Columbia Parent Infant Program (founded with Sackler Award support), Daniel Schecter and Jane Rosenthal of the Columbia Psychoanalytic Institute. This book is the product of the Sackler- funded conference last year and contains chapters by Myron Hofer in addition to Coates and Schecter. The book has been very well reviewed and was described by Dr. Alicia Lieberman of San Francisco General Hospital as making “… a compelling case for the importance of human bonds in the recovery from trauma. “

The Sackler Award Dr. Cheryl Corcoran submitted a progress report for the first year of her research to the Award Committee and after review, a second year of support was awarded. Dr. Corcoran has submitted an application for a 5 year Research Scientist Development Award (K05) from the National Institute for Mental Health to begin funding in April 2004. Her research is aimed at identifying the earliest expressions of prodromal symptoms of schizophrenia.

A webpage for the Columbia Sackler Institute has been established at the internet address <www.sacklerinstitute.org>. In addition to a brief description and history of the Institute and a listing of the faculty, the web page provides links to the personal home pages of individual faculty members. A list of Affiliated Programs at the medical center provides links to the home pages for the Center for Neurobiology and Behavior, The Department of Pediatrics, The Parent Infant Program and others. There is a link to the most recent Annual Report for more details about the kinds of programs and activities supported. We are in the process of completing a Directory of all developmental research being carried out in departments and laboratories at the medical school with e-mail addresses and links to the researchers’ home pages. We intend this Directory to provide a central source of information on current developmental research going on at Columbia and foster cross disciplinary collaborative projects.

An International Scientific Advisory Committee has been formed with the plan that all members will receive the Annual Report each year for their comments and from time to time members of the committee will be invited to Columbia to give a Sackler Institute Lecture and to meet with individuals and groups of faculty members and fellows to give their perspective and advice on the progress of the Institute. Committee members that have accepted are:

Ronald Dahl - University of Pittsburgh
Alison Doupe – University of California at San Francisco
Barry Keverne - Cambridge University, UK
Michael Meaney – McGill University, Montreal
Charles Nelson - University of Minnesota
Herbert Pardes – Columbia University
Michael Rutter - University of London, UK

A joint meeting of the two New York City Sackler Institutes with members of the new Glasgow/Edinburgh Sackler Institute is being planned for the year 2004. Dr. BJ Casey of the Cornell Institute will host this meeting which will serve to introduce us to our Scottish sister institute and help promote international collaborative projects in the future.

Sackler Fellow small grants were awarded to Inge-Marie Eigsti, who is a cross - campus post doctoral research fellow with Bill Fifer and BJ Casey, to support her work on shared attention and autism. A second was awarded to Jeff Muller, a post doctoral fellow with Michael Myers, for his novel animal model research mapping localized changes in brain gene expression in infant rats as a result of certain interactions with their dams. Two other grants were awarded: one to Sanjay Mathews to support his imaging study of adults first identified as depressed in adolescence and another to Adrianna Feder to support her analytic study of sleep and cortisol levels in previously studied prepubertal depressed children.

Sponsored Symposia An invited Sackler Symposium was given at the annual meeting of the International Society for Developmental Psychobiology on October 31, 2002 in new Orleans on the Development of Memory. At the Winter Developmental Conference in Cancun, Mexico, a Sackler Workshop took place on the emerging technology of magnetoencephalography – the first method for studying fetal brain function in utero.

Visiting Scientist Program Three workshops were funded here at Columbia:
Magnus Magnuson – October 23, 2002 – talk on “Discovering Hidden Time Patterns in Behavior.” Jeffrey Cohen – December 2002 – talk on “Automated Recognition of Facial Expressions.” and Mathias Koelliker – January 16, 2003 – talk on “Role of Family Conflicts in the Evolution of the Parent-Infant Relationship.”

The ribbon cutting ceremony for the dedication of the new Sackler Laboratories was held in the atrium of New York State Psychiatric Institute on January 31, 2003. The Dean of the medical school, Dr. Gerald Fischbach, the C.E.O of the New York Presbyterian Hospital, Dr. Herbert Pardes, and the acting chairman of the Department of Psychiatry, Dr. Timothy Walsh spoke briefly, describing the critically important role that the Institute plays in fostering research and teaching at the medical school campus on of developmental processes at all levels, from molecular genetics to epidemiology. Many thanks were given to the Sackler family for their generosity and vision that together have made the Institute possible.

Members of the Sackler family present were Ilene Sackler Lefcourt, Dr. Kathe Sackler and, Dr. Mortimer D.A. Sackler .A letter of greeting and appreciation from Dr. Mortimer Sackler was read by Ilene Lefcourt, and Dr. Hofer recognized the special contributions to the construction of the laboratories made by Steven Papp and Frank Mucha, administrators of the Psychiatric Institute; Donald Tapert, architect for the planning of the laboratories; Ronald Hellman, the builder; Peter Reynolds, the Psychiatric Institute engineer; and Jennifer Knowles, Susan Rotgard and Christine Fontaneda who planned the reception for the ceremony.

A blue ribbon across the entrance to the laboratory corridor was cut by Ilene Lefcourt with some assistance from the dean in wielding an enormous pair of ceremonial scissors. Upon cutting the ribbon, a plaque was unveiled, commemorating the establishment of the laboratories and listing the members of the Sackler Foundation who made this possible. Finally a tour of the laboratories was conducted by Dr. Michael Myers, Director of the Department of Developmental Psychobiology at New York State Psychiatric Institute as well as Faculty Member in the Sackler Institute.

Part II - RESEARCH PROGRAMS

1. Basic Science Division

Dr. Thomas Jessell – Early Development of the Vertebrate Nervous System

Our work has addressed the mechanisms that control the assembly of neural circuits in the vertebrate central nervous system. These studies have explored the link between neuronal identity and circuitry: how does the early specification of neuronal identity define the position of neurons, the projection pattern of their axons, and the selectivity of their synaptic contacts? We have focused on neurons that form the monosynaptic stretch reflex circuit in the spinal cord, for two reasons. First, this circuit forms early in development, in an activity-independent manner, suggesting that its assembly is genetically encoded. Second, a century of anatomy and physiology, from the pioneering studies of Sherrington and Ramón y Cajal onward, has provided a rigorous cellular and functional framework for interpreting molecular steps in the assembly of sensory-motor connections.

Over the past year we have continued our studies of the roles of signaling factors and transcriptional regulators in the specification of motor neuron identity in the developing spinal cord. We have found that retinoid signaling, mediated by the transcriptional activator function of retinoid receptors, acts in concert with the gene Shh, to pattern the expression of homeodomain and bHLH proteins in ventral progenitor cells, and to specify motor neuron identity. We also revealed that Fibroblast Growth Factors (FGFs) are potent repressors of progenitor homeodomain protein expression, implying that the evasion of FGF signaling and subsequent exposure to retinoid and Shh signals are obligate steps in the emergence of ventral neural pattern. Indeed, joint exposure of neural progenitor cells to retinoids and FGFs is sufficient to induce motor neuron differentiation in an entirely Shh-independent manner. After their initial generation, motor neurons acquire distinct subtype identities that determine their projection patterns and connectivity. In the spinal cord, as in many regions of the CNS, the grouping of neurons into columns links cell body position to axonal trajectory, thus contributing to the establishment of topographic neural maps. In the developing spinal cord columnar sets of motor neurons innervate distinct targets in the periphery. We have found that sequential phases of Hox-c protein expression and activity control the columnar differentiation of spinal motor neurons. Hox expression in neural progenitors is established by graded FGF signaling and translated into a distinct motor neuron Hox pattern. Motor neuron columnar fate then emerges through cell autonomous repressor and activator functions of Hox proteins. Hox proteins also direct the expression of genes that establish motor topographic projections, thus implicating Hox proteins as critical determinants of spinal motor neuron identity and organization.

We have also found that retinoid receptor activation in newly-generated spinal motor neurons has a crucial role in specifying motor neuron columnar subtypes. Blockade of retinoid receptor signaling in brachial motor neurons inhibits lateral motor column differentiation, and converts many of these neurons to thoracic columnar subtypes. Conversely, expression of a constitutively active retinoid receptor derivative impairs the differentiation of thoracic motor neuron columnar subtypes. Thus retinoids also have a regionally restricted role in the post-mitotic specification of motor neuron columnar identity.

Publications
Hippenmeyer, S., Shneider, N.A., Birchmeier, C., Burden, S.J., Jessell, T.M., and Arber, S. (2002). A role for Neuregulin 1 signaling in muscle spindle differentiation. Neuron 36, 1035-1049.
William, C.M., Tanabe, Y. and Jessell, T.M. (2003). Regulation of motor neuron subtype identity by repressor activity of Mnx homeodomain proteins. Development, 130, 1523-1536.
Gunhaga, L., Marklund, M., Campbell, K., Jessell, T.M., and Edlund, T. (2003). Dorsoventral patterning of the prospective telencephalon by hierarchical Wnt and BMP signaling. Nat. Neurosci. 6, 701-707.
Kania, A. and Jessell, T.M. (2003). Topographic motor projections in the limb imposed by LIM homeodomain protein regulation of Ephrin-A: EphA interactions. Neuron, 38, 581-596.
Patel, T.D., Kramer, I., Kucera, J., Niederkofler, V., Jessell, T.M., Arber, S., and Snider, W.D. (2003). Peripheral NT3 signaling is required for ETS protein expression and central patterning of proprioceptive sensory afferents. Neuron, 38 403-416.
Brivanlou, A.H., Gage, F.H., Jaenisch, R., Jessell, T., Melton, D., and Rossant, J. (2003). Setting standards for human embryonic stem cells. Science 300, 913-916.
Novitch, B.G., Wichterle, H., Jessell, T.M., and Sockanathan, S. (2003). A requirement for retinoic acid mediated transcriptional activation in ventral neural patterning and motor neuron specification. Neuron, In Press.

Grant Support

Howard Hughes Medical Institute 9/01/2002 - 8/31/2003 35%
(Jessell)) $496,751 (operating expenses)
Molecular Analysis of Vertebrate Neural Development

Research support from HHMI is focused on the inductive interactions that control neural identity in the spinal cord.

RO1 NS33245 (Jessell) 9/24/2001-8/31/2005 10%
NIH $211,398
Control of Motor Neuron Differentiation
To study the mechanisms by which the diversity of different motor neuron subpopulation are generated.
1P50 MH50733
NIH/NIMH (Kandel,) 9/20/1994 - 8/31/2004 10% $130,727 (Proj 1 Jessell)
Center for Neuroscience Research (Kandel): Genetic Approaches to Neural Plasticity and Learning

Project 1(Jessell): The Development of Neural Circuits for a Simple Reflex Behavior: Genetic Analysis of Motor Neuron Identity. This project aims to define the mechanisms whereby distinct classes of motor neurons and interneurons are generated and assembled into functional motor circuits in the spinal cord.

The G. Harold and Leila Y.
Mathers Charitable Foundation (Kandel) 9/1/2001-8/31/2004 5%
$175,000 (Proj Jessell)
Molecular Approaches to cognition: The Development and Modification of Internal Representations within the Brain.

The aim of this project is to determine how individual genes contribute to the cellular properties essential for the development and maintenance of cognitive maps.

WELLT066790-C-02-Z
The Wellcome Trust 5/01/2002-4/30/2007 10%
$123.115
Functional Genomics of Neuronal Identity

The aim of this project is to define the molecular cascades and gene networks involved in the determination of two defined neuronal cell types – the motor neuron and the olfactory neuron.

RGP0161/2001
Human Frontier Science Program 4/01/2002-3/1/2005 10%
$45,455
Functional Analysis of Genetically Defined Interneurons in the Ventral Spinal Cord
The aim of this project is to develop a genetic basis for neuronal classification in the spinal cord.
Project ALS 1/22/2003 (each year) 5%
$270,025
Regulated Gene Expression in Motor Neurons and Neuron Progenitor Cells.

The aim of this proposal is to apply contemporary methods of gene manipulation in the mouse to the study of the origins of ALS and to the design of novel strategies to prevent the death of motor neurons that occurs in ALS and other neurodegenerative disorders.

2. Behavioral Neuroscience Division

Dr. William Fifer - 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 continue to investigate the effects of prenatal risk factors including maternal nicotine and alcohol use during pregnancy, as well as maternal stress and anxiety, on autonomic nervous system development. With Dr. Monk, from the Department of Behavioral Medicine, we continue our studies on the influence of maternal depression and anxiety on fetal and infant development. With Dr. Myers we continue to study early markers of risk for Developmental Disorders and Sudden Infant Death (SIDS) in high-risk populations in Washington Heights and on the Pine Ridge Reservation in South Dakota. We are anticipating funding for an expansion of these studies to other Aberdeen area reservations to study the influences of alcohol and other factors on unexplained fetal demise and early neurobehavioral disorders. A further extension of this work, with the Department of Pediatrics, focuses on the developing nervous system in prematurely born infants and, together with colleagues from the Division of Environmental Health Science at Columbia, assessments of sleep dependent physiology in infants exposed to environmental toxins during pregnancy.

During this past year we have applied for funding to continue our collaborative studies with colleagues from the Sackler Institute at Cornell, B.J.Casey, Inge-Marie, and Bruce McCandliss. These studies involve the use of high density EEG technology to investigate the ontogeny of sensory evoked potentials as well as the emergence of early conditioning capacities in very young infants. We are also evaluating the new magnetoencephalography technology for the study of fetal brain development and exploring funding possibilities for this expensive, but potentially revolutionary approach to the study of early brain development.

Dr. Myron Hofer - Process 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. I and my colleagues have explored how early maternal separation and different patterns of mothering exert long-term effects on vulnerability to disease. Through an experimental analysis of the psychobiological events that enmesh the infant rat and its mother, we are studying the hidden regulatory processes that are the basis for the early origins of attachment, the dynamics of the separation response and the shaping of development by that first relationship. Recent work with Drs. Brunelli and Shair has focused on the infant rats' vocal response to isolation as a model of the first anxiety state. We have explored its neural basis, how it is regulated behaviorally by littermates, dams and predators, and how its developmental course can be altered by continued selection for high and/or low responders. Dr. Polan and I study the developmental origins of the capacity of newborns to recognize, approach and stay close to their own mothers in the hours after birth. Currently I have become interested in the theoretical aspects of development and in concepts that can help bridge the gap between developmental processes at the molecular, cellular and behavioral levels.
Dr. Michael Myers - Early Nutritional Influences on Vulnerability to Disease

For the past several years, there has been renewed interest in the effects of inadequate nutrition during pregnancy, undergrowth of the fetus, and vulnerability to disease later in life. From large epidemiological studies, it appears that cardiovascular disease, diabetes, schizophrenia, and depression all share the common trait of being influenced by disturbances during this critical period of development. While long-term effects of early experiences has been a focus of much research within the field of Developmental Psychobiology, the proximal mechanisms and chain of events that account for enduring changes in disease vulnerability remain largely undiscovered. This has been a ongoing focus of work in my laboratory. This year, in collaboration with Drs. William Fifer and Harry Shair in our department, and Drs. Morris Cohen and David Brown at Newark Beth Israel Hospital, we have continued to investigate these phenomenon in both animal models and human infants. NIH support for these studies now totals nearly $450,000 per year.

These studies focus on effects of variation in nutrient availability in the perinatal period on physiological, biochemical and behavioral characteristics of newborn infants. Indices derived from animal studies are incorporated into human studies, and the underpinnings of correlative findings from human studies are pursued in animal models. The studies will determine if human infants with low birth weights, or rats whose mothers were underfed during pregnancy, express differences in cardiovascular and behavioral responses to feeding and postural challenge. In addition, we are pursuing the hypothesis that alterations in methylation of regulatory regions of certain genes are key to understanding the persistence of changes in gene expression result from variation in nutrition early in life.

Dr. Jonathan Polan –

Dr. Polan is spending the academic year 2003-04 on sabbatical in the laboratory of Dr. Eric Kandel at Columbia University's Center for Neurobiology and Behavior and Howard Hughes Medical Institute. Dr. Polan will learn to use the concepts and techniques of molecular neurobiology so that he can apply them to his research in developmental psychobiology. For his project In the Kandel lab, he has joined a group investigating genetically engineered mouse models of schizophrenia. These animals have selective dysfunctions of the dopamine or glutamate systems limited to the striatum or neocortex, the neurotransmitters and brain regions implicated in schizophrenia. Dr. Polan is helping to further characterize the molecular and behavioral schizophrenia-like phenotypes that have been identified in these animals. Because of growing evidence that schizophrenia is a neurodevelopmental disorder, Dr. Polan is investigating the developmental aspects of these phenotypes by activating a molecular switch that can turn the transgene off and on during specific developmental windows.

Publications
Fifer, W.P., and Myers. M.M. Sudden fetal and infant deaths: shared characteristics and distinctive features. Seminars in Perinatology, 26(1), 89-96, 2002.

Fifer, W.P.: The fetus, the newborn, and mother's voice. In: J. Gomes-Pedro,T.B. Brazelton, J.K. Nugent and J.G. Young (Eds.). The Infant and Family in the Twenty-First Century, London, UK: Taylor & Francis, Inc., 79-86, 2002.

Sahni, R., Saluja, A.S., Kashyap, S., Ohira-Kist, K., Fifer, W.P., Myers., M.M. and Schulze, K. Quality of diet, body position and time after feeding influence behavioral states in low birth weight infants. Pediatric Research, 52(3), 399-404, 2002.

Monk, C., Myers, M.M., Sloan, R.P., Ellman, L. and Fifer, W.P. Effects of women’s stress-elicited physiological activity and chronic anxiety on fetal heart rate. Journal of Development and Behavioral Pediatrics, 24(1), 32-38, 2003.

Grieve, P.G., Emerson, R.G., Fifer, W.P., Isler, J.R., and Stark, R.I. Spatial correlation of the infant and adult electroencephalogram, Clinical Neurophysiology 114(9),1594-608, 2003.

Fifer, W.P. and Moon, C.: Prenatal development. In: A. Slater and G. Bremner (Eds.). An Introduction to Developmental Psychology, Oxford, UK: Blackwell Publishers Ltd., 95-114, 2003.

Brunelli, S. A., Myers, M. M., Asekoff, S. L., & Hofer, M. A. Effects of selective breeding for infant rat ultrasonic vocalization on cardiac responses to isolation. Behav Neurosci 116, 612-23, 2002.

Hofer, M.A. Evolutionary concepts. In: Textbook of Anxiety Disorders, Stein D.J. and Hollander, E. Am. Psychiatric Press Washington, 65-78, 2002.

Hofer, M.A. The Riddle of Development. In David J. Lewkowicz and Robert Lickliter (Eds.) Conceptions of Development, Psychology Press: Philadelphia 2002.
Polan, H.J., Milano, D., Eljuga,L. and Hofer, M.A. Development of rats: maternally-directed orienting behaviors from birth to day 2. Develop. Psychobiol. 40, 81-103, 2002.
Hofer, M.A., An evolutionary perspective on unexplained infant crying. Acta Paediatrica. 91, 491-496, 2002.

Shair, H.N., Brunelli, S.A., Masmela, J.R., Boone, E. and Hofer, M.A. Social, thermal, and temporal factors in isolation-induced and maternally potentiated ultrasonic vocalizations of rat pups. Dev Psychobiol, 42:206-222, 2003.

Weller, A., Leguisamo, A. C., Towns, L., Ramboz, S., Bagiella, E., Hofer, M., Hen, R., & Brunner, D. Maternal effects in infant and adult phenotypes of 5HT1A and 5HT1B receptor knockout mice. Dev Psychobiol 42, 194-205, 2003

Sibolboro Mezzacappa E, Tu AY, Myers MM. Lactation and weaning effects on physiological and behavioral response to stressors. Physiology and Behavior, 78:1-9, 2003.

McKinley PS, Shapiro PA, Bagiella E, Myers MM, De Meersman RE, Grant I,
Sloan RP. Deriving Heart Period Variability From Blood Pressure Waveforms. Journal of Applied Physiolog, in press, 2003.

Sullivan, R. M., Landers, M., Flemming, J., Young, T., Vaught., C., & Polan, H. J. 2003. Characterizing the function of neonatal rat vibrissae. Somatosensory and Motor Research, 20:1-6.

Grant Support (dollar figures are per year)

“Perinatal Assessment of At-Risk Infants”
Principal Investigator: Fifer, William P.
$398,920 (current year total)
Agency: NICHD Type: R01 (HD 32774) Period: 05/01/99 - 04/30/04
Goals: These studies focus on making cardiorespiratory measurements in groups of human fetuses and newborns who are at risk for developing subsequent neurologic damage and/or Sudden Infant Death Syndrome.

“International Society for Developmental Psychobiology Student Travel Grant”
Principal Investigator: Fifer, W.P.
$27,500.00
Agency: NIMH Type: R13MH (HD58769) Period: 10/01/00-9/30/05

“Environmental Health in a Cohort of Minority Women/Infants”
Co-Investigator William Fifer
$826,189
Agency: NIEHS Type: R01 (ES08977) Period: 04/01/02-03/31/07
Goals: To investigate the impact of pre- and post-natal exposures to air pollutants on fetal growth and early childhood neurobehavioral development.

“Fetal Origins of Disease: Markers, Modulators, Mechanisms”
Principal Investigator: Myers, Michael M.
$312,612
Agency: NIEHS Type: R01 (ES11596) Period: 08/01/01 – 06/31/06
These are animal model and human infant studies that focus on changes in cardiovascular function, glucose regulation, and gene expression associated with variations in early life growth and nutrition.

“Fetal Responses to Hypoxia and Nutrition During Development”
Co-Director & Project IV: Michael Myers
Co-Investigator: William Fifer
$636,715
Agency: NICHD Type: 3P01 (HD013063) Period: 07/01/00 - 06/31/05
This program project conducts basic physiologic and behavioral studies in human premature infants, fetal baboons, and rodent models to investigate responses to and detrimental effects of hypoxia, nutritional variation and nicotine during the perinatal period.

“Hostility Reduction and Autonomic Control of the Heart”
Co-Investigator Michael Myers
$321,058 (10%)
Agency: NHLBI Type: R01 (HL 63872) Period: 07/01/00 - 06/30/05
These studies investigate the effects of cognitive behavioral therapy on psychophysiological reactivity in subjects with high levels of hostility.

"Research Training in the Psychobiological Sciences"
Principal Investigator: Hofer, Myron A. Co-Director: Michael Myers
$250,066
Agency: NIMH Type: T32 (MH018264) Period: 07/01/03 - 06/30/08
Postdoctoral research training grant for MD and PhDs in Psychobiology.

"Maternally-directed orienting behaviors of newborn rats", National Institute of Mental Health, K08-MH 1569-01.
Principal Investigator: Jonathan Polan
Amount and duration: $ 806,555; 5/1/98 - 4/30/03. Effort: 80%

"Microcephaly: Brain formation and behavior", National Institute of Neurological Diseases and Stroke (submitted June, ‘03).
Co-Principal Investigator: Jonathan Polan
Principal Investigator: Elizabeth Ross, M.D.
Amount and duration: $ 914,597; 4/01/04 - 3/30/09. Effort: 20%

"Mouse models of dopamine and glutamate dysfunction", National Institute of Mental Health (submitted October, '03).
Co-Investigator: Jonathan Polan
Principal Investigator: Eric Kandel, M.D.
Duration: 7/01/04 - 6/30/09.

3. Clinical Research Division

Dr. Myrna Weissman - Clinical Epidemiology Studies of Genetic Risk and Biological Markers in the Development of Mood and Anxiety Disorders

Our overall approach is to use epidemiologic methods, to determine patterns, nature, timing of risk for mood and anxiety disorders in children and adults. Over the years we have followed and carefully characterized samples of patients at risk for these disorders as well as carefully selected controls. More recently we have used genetic, neuropsychologic and neuroimaging studies to better understand the etiology and pathophysiology of these disorders in these well characterized samples. Three studies fall into this group:

Offspring at High and Low Risk for Depression
The overall aim has been to understand the long-term, temporal sequence and familial patterns of psychiatric and behavioral problems from childhood to adulthood of offspring at high and low risk for depression using clinical and psychophysiologic assessments, (EEG and startle response). This study has had 4 waves of assessments and 3 generations. In 2003, we were awarded a 5-year NIMH grant in collaboration with Brad Peterson, M.D. and Gerard Bruder, Ph.D. to carry out anatomical and functional MRI studies, integrating the clinical and psychophysiologic data. We are now seeking funds to collect buccal swabs for DNA analysis.

Depressed Children Grown Up
Adriana Feder, M.D. received a NARSAD Young Investigator Award to study 24-hour cortisol secretion patterns in prepubertal children with depression, anxiety, and normal controls, in light of their longitudinal clinical follow-up into young adulthood. Sanjay Mathew was awarded an American Foundation Suicide Fellowship to pilot MRI in a sample of adolescent onset depressives followed into adulthood.

Genetics of Recurrent Early Onset Major Depression (MDD-RE)
MDD-RE is a multi-site study to identify major depression susceptibility genes. It involves the collection of ?1000 multiple-affected sibling pairs over 6 sites with recurrent, early-onset major depression. Biological materials and clinical data will be shared with the scientific community. The sample collection has just been completed. A competitive renewal was submitted to NIMH March 2003.

We have also been interested in how to apply insight from these studies to improving treatment.

Treatment of Depressed Mothers: A STAR*D Ancillary Study
The overall aim of this NIMH ancillary study to the multi-site Sequenced Treatment Alternatives to Relieve Depression study (STAR-D) is to determine the impact of a reduction of maternal depressive symptoms on children’s psychiatric symptoms and social functioning. Eighty eight mother-child pairs have been enrolled into the study so far.

Publications
Bolton P, Bass J, Neugebauer R, Clougherty KF, Verdeli H, Wickramaratne PJ, Ndogoni L, Speelman L, Weissman MM. A clinical trial of group interpersonal psychotherapy for depression in rural Uganda. JAMA In press, 2003.

Costello EJ, Pine DS, Hammen C, March JS, Plotsky PM, Weissman MM, Biederman J, Goldsmith HH, Kaufman J, Lewinsohn PM, Hellander M, Hoagwood K, Koretz DS, Nelson CA, Leckman JF. Development and natural history of mood disorders. Biol Psychiatry 52(6):529-542, 2002.

Hamilton SP, Fyer AJ, Durner M, Heiman GA, deLeon AB, Hodge SE, Knowles JA, Weissman MM. Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. Proc Nat Acad Sciences (PNAS) 100(5):2550-2555, 2003.

Hirshfeld RMA, Weissman MM. Risk factors for major depression and bipolar disorder. In Davis L, Charney D, Coyle JT, Nemeroff C (eds) Neuropsychopharmacology : The 5th Generation of Progress. Lippincott, Williams & Wilkes, NY 2002, Chapt 70, pp. 1017-1025.

Hirschfeld RMA, Holzer C, Calabrese JR. , Weissman MM, Reed M, Davies M, Frye MA, Keck P, McElroy S, Lewis L, Tierce J, Wagner KD, Hazard E. Validity of the mood disorder questionnaire: A general population study. Am J Psych 160(1):178-180, 2003.

Hirschfeld RMA, Calabrese JR, Weissman MM, Reed M, Davies MA, Frye MA, Keck PE, Lewis L, McElroy SL, McNully JP, Wagner KD. Screening for bipolar disorder in the community. J Clin Psychiatry 64(1):53-59, 2003.

Levinson DF, Zubenko GS, Crowe RR, DePaulo JR, Scheftner WS, Weissman MM, Holmans P, Zubenko WN, Boutelle S, Murphy-Eberenz K, MacKinnon D, Marta DH, Adams P, Knowles JA, Thomas J, Chellis J. Genetics of Recurrent Early Onset Depression (GenRED): Design and preliminary clinical characteristics of a repository sample for genetic linkage studies. Am J Med Genet (Neuropsychiatr Gen) 119B: 118-130, 2003.

Masia CL, Storch EA, Dent HC, Adams P, Verdeli H, Davies M, Weissman MM. Recall of childhood psychopathology: More than ten years later. J Am Acad Child Adolesc Psychiatry 41(1):6-12, 2003.

Mathew SJ, Coplan JD, Goetz RR, Feder A, Greenwald S, Dahl RE, Ryan ND, Mann JJ, Weissman MM. Differentiating depressed adolescent twenty-four hour cortisol secretion in light of their adult clinical outcome. Neuropsychopharmacology, In press, 2003.

Miller L, Weissman MM. Interpersonal psychotherapy delivered over the telephone for depression: A pilot study. Depress Anxiety, 16(3):114-117, 2002.

Miller M, Weissman MM, Gur M, Greenwald S. Adult religiousness & history of childhood depression:11 Year follow up study. J Nerv Ment Dis 190:86 93, 2002.

Mufson L, Warner V, Wickramaratne P, Weissman MM. Stability of temperament in offspring over a decade. J Am Acad Child Adolesc Psychiatry In press, 2001.

Mufson L, Nomura Y, Warner V: The relationship between parental diagnosis, offspring temperament, and offspring psychopathology over time. Journal of Affective Dis 71:61-69, 2002.

Mufson L, Pollack-Dorta K, Moreau D, Weissman MM: Efficacy of effectiveness: Adaptations of interpersonal psychotherapy for adolescent depression in Hibbs ED, Jensen PS (eds). (Chapt) 2002, Psychological Treatments for Child and Adolescent Disorders: Emprirically-Based Strategies for Clinical Practice, 2nd edition. American Psychological Association.

Mufson L, Pollack-Dorta KE, Moreau D, Weissman MM. Efficacy to effectiveness: Adaptations of interpersonal psychotherapy for adolescent depression. (Chapter) in Hibbs ED, Jensen PS (eds) Psychosocial Treatments for Child and Adolescent Disorders: Empirically-based Strategies for Clinical Practice, 2nd edition. American Psychological Association. In press, 2003.

Olfson M, Weissman MM, Feder AJ, Gameroff MJ, Pilowsky D, Fuentes M. Psychotic symptoms in an urban general medicine practice. Am J Psychiatry 159:1412 1419, 2002.

Pilowsky DJ, Birmaher B, Weissman. Approaches to chronic depression in children and adolescents. (Chapter) In Alpert J, Fava M (eds) Handbook of Chronic Depression In press, 2001.

Verdeli H, Clougherty K, Bolton P, Speelman L, Ndogoni L, Bass J, Neugebauer R, Weissman MM. Adapting Group Interpersonal Psychotherapy (IPT G) for a Developing Country: Experience in Rural Uganda. World Psychiatry. 2:(2)114 120, 2003.

Weissman MM, Jensen P. What research suggests for depressed women with children. J Clin Psychiatry 63(7):641 647, 2002.

Weissman MM, Markowitz JC. Interpersonal psychotherapy for depression. In Gotlib I, Hammen C. (eds.) Handbook of Depression and its Treatment. Guilford Press, NY 2002, Chapt 17, pp. 404-421.

Weissman MM and Sanderson WC. Promises and problems in modern psychotherapy: The need for increased training in evidence-based treatments. In Hager M (ed) Modern Psychiatry: Challenges in Educating Health Professionals to Meet New Needs. Macy Foundation, NY 2002, Chapt (Session) 2, pp. 132-165.

Weissman MM, Weissman J. Breastfeeding and later intelligence. Letter to the Editor (re: Mortensen et al JAMA 287:2365 71, 2002) JAMA 288(7):828, 2002.

Weissman MM, Feder AJ, Pilowsky D, Olfson M, Fuentes M, Blanco C, Lantigua R, Gameroff MJ, Shea S. Depressed mothers coming to primary care: Problems with their children. J Affective Dis In press, 2003.

Weissman MM and Markowitz JC. Future of psychotherapies for mood disorders. World Psychiatry 2(1):9-13, 2003.

Wilson JJ, Pine DS, Cargan A, Goldstein RB, Nunes EV, Weissman MM. Neurological soft signs and disruptive behavior among children of opiate dependent parents. Child Psychiat Hum Developm In press, 2003.

Grant Support (dollar figures are per year)

5 RO1 MH60912-04 (Weissman) 09/30/99 - 08/31/03 10% effort
NIH/NIMH $247,683
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.

2 RO1 MH28274-25A2 (Weissman) 07/08/02 to 06/30/04 20% effort
NIH/NIMH $265,160
Genetic Studies of Depressive Disorders
This is a project to understand the etiology of panic disorder using a broad range of novel and advanced genetic and epidemiologic approaches.

5 P30 MH60570- 04 (Shaffer) 09/24/99 to 05/31/04<1% effort
NIH/NIMH $129,307 (Core Only)
Psychotherapy Core, part of Child Psychiatry Intervention Research Center
Provide consultation to investigators on the technology of psychotherapy research and its testing by
facilitating training in empirically based treatments and identifying opportunities to test out psychotherapies, both in terms of adapting existing therapies to new uses and implementing new therapies.

5 R01 MH63852-02 (Weissman) 07/19/01 to 06/30/06 20% effort
NIMH $890,683
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 an ancillary study to the Sequenced Treatment Alternatives to Relieve Depression study (STAR*D).

2 T32 MH16434-21 (Shaffer) 07/01/00 to 06/30/05 <1% effort
NIH/NIMH $488,000
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.

5 R01 MH 36197-19 (Weissman) 01/01/03 - 12/31/08 25% effort
NIH/NIMH $635,513 1st Year
Children at High and at Low Risk For Depression
Overall aim of this study is to understand the long term temporal sequence and familial patters of mood and other disorders from childhood to adulthood in offspring at high and low risk for depression. The study now includes three generations. The aims during this project period are (1) to complete data analyses of the 4th wave of assessments; (2) acquire and analyze both anatomical and functional MRI in 214 subjects; (3) conduct data analyses integrating clinical, psychophysiological, and neuroimaging studies.

1 P01 MH60970-01A2(Gilliam) 12/1/02-11/30/06 15% effort
NIH/NIMH $ 978,490 (Year 1)
Molecular Genetic Studies of Fear and Anxiety
This is a program project to study the molecular and genetic basis of amygdala-regulated fear and anxiety in mice and humans. Several fear conditioning paradigms will be studied in both mice and humans, along with selected anxiety

related traits and disorders in humans. Genes that alter fear-conditioning phenotypes in mice will be analyzed for trait-related DNA sequence variation in humans who score at the phenotypic extremes for the matched paradigm. Genes shown to alter other anxiety measurements in mice will be analyzed for trait or disorder-related variation in humans with a variety of anxiety-related temperaments and disorders.

1 P60 MD000206-01(Carrasquillo) 10/01/02-9/30/07 8% effort
NIH/NCMHHD $73,912 (Year 1) Core Only
Columbia Center for the Health of Urban Minorities - Core 7 (Olfson)

The overall aim of the Mental Health Research Core is to facilitate the development and research evaluation of mental health interventions for low income minority populations

Josiah P Macy Foundation 07/01/03-06/30/05
$100,000 (Year 1)
Bridging the Gap Between Research and Clinical Practice in Modern Psychotherapy
The overall goal is to decrease the considerable gap that now exists between the availability of evidence based treatments (EBT), particularly psychotherapy, and training of clinical practitioners, in psychiatry, psychology, and social work, who actually provide psychotherapy to the patients.

4. Developmental Neuro-imaging Laboratories

Dr. Bradley Peterson – Normal Brain Development and the Neural Basis of Psychiatric Disorder

Dr. Peterson’s pediatric imaging laboratory has undergone rapid expansion in the past year, with the hiring of 4 new faculty members and the addition of 4 new postdoctoral fellows and 2 full-time medical students. Major new initiatives include diffusion tensor imaging, which allows tracking of bundles of nerve fibers in the brain, development of virtual reality paradigms for use with functional MRI, neuroimaging studies of autistic individuals, and improvements in the biostatistics of neuroimaging with the addition of a full-time biostatistician. Dr. Peterson was appointed the Director of MRI Research in the Department of Psychiatry, and he will administer activities of the new 3T MRI scanner that has been installed at NYSPI. The scanner is currently being ramped up, and it is expected to begin acquiring research scans in early October of 2003.

In collaboration with Drs. Myrna Weissman and Gerald Bruder of the Sackler Institute, major new funding from NIMH was received to scan a large, 3-generational cohort that has been followed by Dr. Weissman over the past 20 years. Individuals in all 3 generations who are at either high or low risk for major depressive illness are being studied with MRI and with neuropsychological tasks designed to test the integrity of neural systems thought to be dysfunctional in depression. This is the first such neuroimaging study of individuals at high risk for affective illness.

An R01 was submitted to the National Institute of Drug Abuse to study using MRI methodologies 90 infants exposed to drugs of abuse (cocaine and narcotics) during pregnancy and 45 matched control infants unexposed to those agents. These infants will be followed prospectively for 3 years to assess how well MRI measures predict neurodevelopmental outcome in these high-risk infants. Collaborators include Dr. Tove Rosen, a neonatologist in the Department of Pediatrics at Columbia University.

Publications
Lin H, Yeh C-B, Peterson BS, Scahill L, Grantz H, Findley DB, Katsovich L, Okta J,
Lombroso PJ, King RA, Leckman JF, Assessment of symptom exacerbations in a
longitudinal study of children with Tourette syndrome or obsessive-compulsive disorder.
J Am Acad Child Adolesc Psychiatry, 41:1070-1077, 2002.

Peterson BS. Indeterminacy and compromise formation. Implications for a
contemporary, psychoanalytic theory of mind. Int J Psychoanal,83:1017-1035, 2002.

Jeong J, Gore JC, Peterson BS. Detecting determinism in a short sample of stationary
EEG. IEEE Transactions in Biomedical Engineering, 49:1374-1379, 2002.

Peterson BS, Vohr B, Kane M, Whalen DH, Schneider K, Katz K, Zhang H, Makuch R,
Gore J, Ment L. A functional magnetic resonance imaging study of language processing
and its cognitive correlates in prematurely born children. Pediatrics, 110:1153-1162,
2002.

Davidson RJ, Lewis DA, Alloy L, Amaral D, Bush G, Cohen J., Drevets W, Farah M,
Kagan J, McClelland J, Nolen-Hoeksema S, Peterson BS. Neural and behavioral
substrates of mood and mood regulation. Biol Psychiatry, 52:478-502, 2002.

Sowell ER, Thompson PM, Peterson BS, Mattson SN, Welcome SE, Henkenius AL,
Riley EP, Jernigan TL, Toga AW. Mapping cortical gray matter asymmetry patterns
during normal adolescence and the effects of heavy prenatal alcohol exposure.
Neuroimage, 17:1807-19, 2002

Sukhodolsky DG, Scahill L, Zhang H, Peterson BS, King RA, Lombroso P, Katsovich L,
Findley D, Leckman JF. Disruptive behavior in children with Tourette’s syndrome:
association with ADHD comorbidity, tic severity, and functional outcome. J Am Acad
Child Adolesc Psychiatry, 42:98-105, 2003.

Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW.
Mapping cortical change across the human life span: nonlinear age effects on gray
matter. Nature Neurosci, 6:309-315, 2003.

Peterson BS, Thomas P, Kane MJ, Scahill L, Zhang Z, Bronen R, King R, Leckman JF,
Staib L. Basal ganglia volumes in patients with Gilles de la Tourette syndrome. Arch
Gen Psychiatry, 60:415-424, 2003.

Scahill L, Leckman JF, Schultz RT, Katsovich L, Peterson BS. A placebo-controlled trial
of risperidone in Tourette syndrome. Neurology, 60:1130-1135, 2003.

Peterson BS, Anderson AW, Ehrenkranz R, Staib LH, Tageldin M, Colson E, Gore JC,
Duncan CC, Makuch R, Ment LR. Regional brain volumes and their later
neurodevelopmental correlates in term and preterm infants. Pediatrics, 111:938-948,
2003.

Blumberg HP, Leung H-C, Wexler B, Skudlarski P, Lacadie CM, Anand A, Fredericks C,
Harris BC, Charney D, Krystal J, Gore JC, Peterson BS. An fMRI study of bipolar
disorder. State- and trait-related dysfunction in ventral prefrontal cortices. Arch Gen
Psychiatry, 60:601-609, 2003.

Kim KJ, Peterson BS. Cavum septi pellucidi in Tourette’s syndrome. Biol Psychiatry,
54:76-85, 2003.

Blumberg HP, Martin A, Kaufman J, Leung H-C, Skudlarski P, Lacadie C, Fulbright R,
Gore JC, Charney DS, Krystal JH, Peterson BS. Frontostriatal abnormalities in
adolescents with Bipolar Disorder: preliminary observations using functional MRI. Am J
Psychiatry, 160:1345-1347, 2003.

Wang Y, Peterson BS, Staib LH. 3D brain surface matching by geodesics and
geometry, Computer Vision and Image Understanding (Academic Press), 89:252-271,
2003.

Peterson BS. Conceptual, methodological, and statistical challenges in brain imaging
studies of developmentally based psychopathologies. Develop Psychopath, 15:811-832,
2003.

Jeong J, Han S, Jin S-H, Kim D-J, Kim SY, Peterson BS. The effect of alpha
entrainment stimulation on nonlinear dynamics of the EEG. Clin Neurophysiol, in press.

Blumberg HP, Kaufman J, Martin A, Whiteman R, Gore JC, Charney DS, Krystal JH,
Peterson BS. Amygdala and hippocampus volumes in adolescents and adults with
Bipolar Disorder. Arch Gen Psychiatry, in press.

Chae J-H, Jeong J, Peterson BS, Kim D-J, Bahk W-M, Jun T, Kim S-Y, Kim K-S.
Dimensional complexity of the EEG in patients with Post-Traumatic Stress Disorder.
Psychiatry Res:Neuroimaging, in press.

Peterson BS. Brain imaging studies of the anatomical and functional consequences of
preterm birth for human brain development. Ann NY Acad Sci, in press.

Potenza MN, Leung, H-C, Blumberg HP, Peterson BS, Fulbright RK, Lacadie CM, Gore
JC. An fMRI Stroop study of pathological gamblers. Am J Psychiatry, in press.

Peterson BS, Panksepp J. The biological basis of childhood neuropsychiatric disorders.
In press in: Panksepp J (Ed.). A Textbook of Biological Psychiatry. New York: John
Wiley & Sons, Inc.

Gerard E, Peterson BS. Developmental processes and brain imaging studies in Tourette syndrome. J Psychosomat Res, 55:13-22, 2003.

Bodner SM, Peterson BS. The PANDAS syndrome in children and adults. Expert
Opinion on Investigational Drugs, in press.

Peterson BS. Brain imaging modalities and methodologies in the study of childhood
neuropsychiatric disorders. Trends in Evidence-Based Neuropsychiatry, in press.

Grant Support- (dollar amounts are per year)

1999 NIMH RO1 MH59139R01 FMRI of Impulse Control in Childhood Disorders (B. Peterson, PI)
30% Concurrent Effort. To study the neural basis of impulse control and its dysfunction in childhood neuropsychiatric disorders.
7/1/99-6/30/04 $602,529

2001 Tourette Syndrome Association Neuroimaging Studies of the Amygdala and Hippocampus in TS (B. Peterson, PI) To test the hypothesis that the volumes of amygdala and hippocampus are reduced in individuals who have Tourette syndrome
10% Effort.
7/1/01-6/30/02 $75,000

2002 National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Award. MRI in unaffected children at high and low risk for depression (B. Peterson, PI) To identify the neural correlates of trait familial vulnerabilities to major depression in a sample of children who are unaffected by the illness but who are at high risk for developing it. (5% effort)
9/15/02-9/14/04 $50,000

2002 NIMH R01 Children at High and Low Risk for Depression, R01 MH36197-15 (M. Weissman. & B Peterson, Co-PI’s)
20% Effort. To identify the brain-based correlates of children and adults at high or low risk for depressive illness using anatomical and functional MRI.
1/1/03-12/31/08 $635,513

5. Sackler Awardee

Dr. Cheryl Corcoran
Report Year 1
The funding that I have received from the Sackler Institute is for a protocol that involves the identification of adolescents and young adults who are showing symptoms consistent with an increased risk for psychosis, specifically 40-50% within 1-2 years. The goal of this study is to test the stress-vulnerability model of psychosis onset in schizophrenia. This study is a longitudinal study of life events, cortisol levels, and emerging positive symptoms and cognitive deficits in prodromal or clinically at risk individuals. The study takes place in the Center of Prevention and Evaluation (COPE), which is the prodromal research clinic at NYSPI. The research aims of this clinic are unique for a prodromal clinic as it focuses on the effects of potential environmental exposures, particularly psychosocial stress, and their interaction with the prodromal state in explaining psychosis onset.

Final IRB approval was given for the study in March 2003, with the delay being attributable to debates and concerns about the risks of labeling and treatment in minors who are identified as being at risk but who do not yet have (and may never have) a serious mental disorder such as schizophrenia. A certificate of confidentiality was also required and then obtained for the study. In the ensuing months, we have received a number of referrals and there are currently two patients who are actively engaged in the protocol. Prodromal patients have been recruited from NYSPI, including the Schizophrenia Research Unit (SRU) and the Child Psychiatry clinics, and there is now greater outreach to schools with concomitant education for school officials. Now that the autumn has arrived, clinicians have returned from vacation, and school has begun, we have commenced a very active recruitment process, with distribution of brochures, liaison with schools, and contact with potential referrals, both here at Columbia/NYSPI and in the community. It is anticipated that recruitment for this study will not be difficult and should be assured in a dense metropolitan area at a research institute that has such impressive supports for child psychiatry, including the Intervention Research Center.

The project has important support from among others, Dr. Walsh, Dr. Malaspina, Dr. Shaffer, Dr. Erlenmeyer-Kimling, Dr. Kestenbaum, Dr. Mufson, and Helle Thorning. The COPE prodromal research clinic is integrated seamlessly into schizophrenia research at PI, as well as into clinical research on adolescents within the department of child psychiatry, as the COPE clinic has the full backing of the Division of Child Psychiatry. In fact, I presented on prodromal research at the Grand Rounds for Child Psychiatry on June 11, 2003. Further, Dr. Clarice Kestenbaum, previously the director of training for child psychiatry and the president of the American Academy of Child and Adolescent Psychiatry, has donated 2 hours of her time each week as a clinical consultant for the treatment of children. We also have two research fellows (a psychologist and psychiatrist) who work in the clinic, as well as a full-time social worker and a social work student.

I have collected cross-sectional data on prodromal patients at the RAP Clinic at Hillside Hospital, in collaboration with Barbara Cornblatt. These data, presented below, support the rationale for longitudinal study in a prodromal population. In sum, these data show that emerging positive symptoms are related in prodromal patients to both life event exposure and to cortisol secretion in response to a laboratory stressor. Prodromal patients did not have an excess of life events as compared with normal controls, which suggests that the symptoms are not causing the life events. Further, HPA activity in response to a stressor was correlated with “impaired tolerance to normal stress”, which characterized almost half of all prodromal patients and none of the controls.
Since April of 2003, I have been awarded a full scholarship to the Patient Oriented Research Program at the Mailman School of Public Health, which is specifically designed for young investigators, and I will receive a master’s in biostatistics as a result of this program. The material that I learn will be of tremendous help in analyzing the data that result from the current protocol.
Again, I wish to reiterate that I am very grateful to the Sacklers for their funding during this period of transition between the conclusion of my research fellowship and the onset of federal funding for a mentored clinical research award. Please contact me with any comments or questions.

Preliminary Data: 1) Recent life events are associated with positive symptoms in prodromal patients 27 prodromal patients were evaluated for prodromal symptoms (SOPS) and psychosocial stress (Life Event Checklist, Perceived Stress Scale, modified Early Trauma Inventory). Parents were also interviewed to confirm early trauma and life events. 12 normal controls were also assessed for life events, early trauma, perceived stress, and prodromal symptoms. The prodromal sample (18 boys, 9 girls) was 15.2 +/- 2.6 years old. On the Scale of Prodromal Symptoms (SOPS), positive symptom ratings were 9.4 +/- 4.7 (range 0 to 17) and negative symptoms, 12.5 +/- 4.7.The normal controls (6 boys, 6 girls) were ages 16.0 +/- 2.8 year. Their SOPS ratings were positive symptoms 2.2 +/- 1.3 and negative symptoms 3.00 +/- 2.1. Both prodromal and normal adolescents were 2/3 white, 1/3 nonwhite. For item D4 “impaired tolerance to normal stress”, 44% of prodromal patients were scored as having some impairment, whereas none of the normal controls were noted to have impaired tolerance to normal stress. In prodromal patients, positive symptoms were correlated with recent life events. In the prodromal sample, positive symptoms were associated with more recent life events at a trend level (r = .36, p = .07, n = 27). This is consistent with life events playing a role in the exacerbation of positive symptoms and possibly conversion to psychosis. Exposure to and perception of stress was not different in this prodromal sample from normal controls. Mean number of life events in the last 12 months was 7.2 +/- 4.4 for prodromal patients and 8.6 +/-5.4 for controls. Numbers of adverse childhood events were 2.9 +/- 1.8 for prodromal patients and 2.3 +/-1.4 for controls. This suggests that life events do not result from prodromal symptoms. There was concurrent validity of current stress scales for prodromal patients: Current perceived stress was correlated with the number of recent life events (r = .44, p = .03, n = 24) in prodromal patients. The correlation for perceived stress and total events was .50 in normal controls though not significant (p = .12) in this small sample. No correlations were found between psychosocial measures and cognitive variables in prodromal patients, including the WCST, the WMS, and the CPT.

2) Stress-reactivity (cortisol) is also associated with positive symptoms in prodromal patients. 17 subjects were assessed for baseline and stress-reactive salivary cortisol levels. The stressor was the Continuous Performance Test (CPT). Saliva was sampled at the time of arrival at the clinic at 11 am (Sample #1), a half hour later at 11:30 am, when subjects were more acclimated to the research setting (Sample #2), and one hour later, at 12:30 pm, after intervening testing, including the CPT (Sample #3). The structure of this assessment was designed in collaboration with Barbara Cornblatt and Wolfgang Maier, and was meant to assess baseline cortisol levels (average of samples #1 and #2) as well as stress-reactive cortisol levels (difference between samples #3 and #2), with the CPT as the stressor. Previously, we reported that mean differences between samples #3 and #2 were negligible, and had concluded that the CPT was not an appropriate stressor. However, further review of other studies showed that normally, salivary cortisol levels should decline within this time period. A stressor then could lead either to an increase in cortisol over this hour or to an attenuation of the expected decline. In fact, in this sample, positive symptoms, as measured by the SIPS/SOPS, were positively correlated with stress-reactive cortisol levels (#3 - #2) (Pearson r = .64, p = .03, n = 11), even using nonparametric methods (Spearman’s rho = .69, p = .018, n = 11). 3) Stress-reactivity is associated with impaired tolerance to normal stress in prodromal patients. Stress-reactive cortisol levels (#3-#2) (high > 0; low < 0 ) were also associated with an item on the SOPS, “impaired tolerance to normal stress” (none or present) in a 2 X 2 cross-tabulation (Fisher exact test = 7.00 p < .001), though were unrelated to psychosocial stress (early trauma, life events or perceived stress), sex, age, or negative symptoms.

PUBLISHED ARTICLES (2002-2003)

(1) Malaspina D, Corcoran CM, Fahim C, Berman A, Harkavy-Friedman J, Yale S, Goetz D, Goetz R, Harlap S and Gorman J: Paternal Age and Sporadic Schizophrenia: Evidence for De Novo Mutations. American Journal of Medical Genetics. 2002 Apr 8;114(3):299-303.
(2) Malaspina D, Coleman E, Goetz R, Harkavy-Friedman J, Corcoran C, Amador X, Yale S, Gorman J: “Odor Identification, Eye Tracking and Deficit Syndrome Schizophrenia”. Biological Psychiatry. 2002 May 15;51(10):809-15.
(3) Malaspina D, Simon N, Corcoran C, Mujica-Parodi L, Goetz R, Gorman J: Using Figure Ground Perception to Examine the Unitary and Heterogeneity Models for Psychopathology in Schizophrenia. Schizophrenia Research. 2003 Feb 1;59 (2-3):297-9.

ARTICLES IN PRESS
(1) Malaspina D and Corcoran C: Head Injury as a Risk Factor for Schizophrenia. The Economics of Neuroscience (TEN). In press.
(2) *Corcoran C, Walker E, Huot R, Mittal V, Tessner K, Kestler L: The Stress Cascade and Schizophrenia: Etiology and Onset. Schizophrenia Bulletin. In press.
(3) *Corcoran C, Davidson L, Sills-Shahar R, Nickou C, Malaspina D, Miller T, McGlashan T: A Qualitative Research Study of the Evolution of Symptoms in Individuals Identified as Prodromal to Psychosis. Psychiatric Quarterly. In press.

ARTICLES IN SUBMISSION
(1) *Corcoran C, Coleman E, Seckinger RA, Whitaker A, Fried J, Malaspina D: Olfactory Deficits in Childhood Psychoses and their Associations with Symptoms and Cognition. Under review at the Journal of Child and Adolescent Psychiatry.
(2) Malaspina D, Corcoran C, Herscher L: Prodromal Interventions for Schizophrenia Vulnerability: the Risks of Being “At Risk”. Submitted to Psychosomatics.

ARTICLES IN PREPARATION
(1) *Corcoran C, Malaspina D: Leitman D, Goetz R, Yale S, Morphometry, Symptoms, Cognition and the HPA axis in Schizophrenia.
(2) *Corcoran C, Malaspina D, Goetz R: Neuropsychological Deficits and Traumatic Brain Injury in Schizophrenia.
(3) *Corcoran C, Davidson L, McGlashan T, Sills-Shahar R, Nickou C, Miller T, Goetz R: Help-seeking, Family Burden, and Stigma in Early Schizophrenia.
(4) *Corcoran C, Harkavy-Friedman J, Malaspina D: Traumatic Brain Injury and Suicide Risk in Members of Multiplex Schizophrenia and Bipolar Pedigrees.
(5) *Corcoran C, Davidson L, Lyle J, Sills-Shahar R, Nickou C, Malaspina D, Miller T, McGlashan T: Perspectives on Care by Family Members of First-Episode Psychosis Patients.

BOOK CHAPTERS (2002)
(1)*Corcoran C, McAllister T, Malaspina D: “Psychotic Disorders” in Neuropsychiatry of Traumatic Brain Injury, 2nd edition. Editors: Jonathan Silver, Stuart Yudofsky, and Thomas McAllister. Published by American Psychiatric Press, Washington, D.C.
(2) Malaspina D, Corcoran CM, and Hamilton S: “Genetics and Epidemiology of Selected Neuropsychiatric Disorders”, American Psychiatric Press Textbook of Neuropsychiatry, 4th edition. Editors: RE Hales and S Yudofsky. American Psychiatric Press, Washington, D.C.

Part III Financial Report

(see attached)

11/30/2003