ARCHIVE

ANNUAL REPORT

July 1, 2003 – June 30, 2004

SACKLER INSTITUTE FOR DEVELOPMENTAL PSYCHOBIOLOGY

AT COLUMBIA UNIVERSITY

This report covers the third year of operation of the Sackler Institute, established at Columbia April 27 th 2001 with a gift from the Sackler Foundation made in December 2000. The Institute is an organization within the College of Physicians and Surgeons and the Department of Psychiatry that brings together federally funded scientists active in research on the developmental origins of vulnerability to psychiatric illness. Our faculty brought in more than 6 million dollars in outside support last year. 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 Dr. Cheryl Corcoran

Sackler Awardees: 2004 Dr. Mark Ansorge and Dr. Jonathan Polan

The research programs of the faculty and the 2003 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 - Highlights

Opening of the new Brain Imaging Laboratory in the New York State Psychiatric Institute under the direction of Bradley Peterson, took place in May of 2004. This suite of rooms centers around a powerful '3 Tesla' scanner, and state-of-the art computer acquisition and analysis equipment dedicated to use for research. An extensive consultation and teaching program is available for prospective users. (please see attachment). Studies underway are described in the Research Program summaries in Part II.

The Sackler Award competition in the spring of 2004 elicited a record number of 9 applications. Because there were so many good applications, and because of an additional $50,000 gift from the Sackler Foundation in February '04, we were able to make 2 awards. One was to Dr. Mark Ansorge, a postdoctoral fellow with Dr. Jay Gingrich in the Sackler Laboratories. His project is titled "Early Life Inhibition of the Serotonin Transporter Alters Emotional Behavior in Adult Mice". He has created an animal model for understanding the vulnerability to depression known to be due to a human genetic polymorphism affecting the serotonin transporter gene that has been mimicked in Dr. Gingrich's lab by a serotonin transporter gene knockout in mice. This knockout effect is unlikely to be due to altered expression in adulthood since inhibition of serotonin transporter in adults by drugs such as Prozac relieves depression in man and mouse. Mark has found that Prozac given to mice during their neonatal and weaning periods reproduces the effect of the gene knockout, increasing depression-like behaviors. This provides, for the first time, direct evidence for an important (and paradoxical) early developmental role for the serotonin transporter and may also help explain the unexpected ill effects of SSRI antidepressant drugs in childhood and adolescence. Planned research includes search for a sensitive period, the central site and the cellular/molecular mechanisms for the effect.

The second Sackler Award was a special award to Dr. Jonathan Polan, the joint Cornell-Columbia Sackler faculty member, for his studies titled: "Developmental Dopaminergic Excess, Developmental Stress and Pathogenesis of Schizophrenia". Dr. Polan has embarked on a faculty mid-career training fellowship in the laboratory of Eric Kandel. Here he is leaving the concepts and techniques of molecular neurobiology in order to complement his expertise in animal models of early behavior development and apply them both to his future research in Developmental Psychobiology.

Sackler faculty who received honors and awards . Dr Fifer's seminal paper, demonstrating for the first time that newborn infants can recognize their own mother's voice, was designated as one of the 5 most important studies in child psychology published since 1950, by the Society for Child Research on Development. Dr. Hofer was appointed to the NIMH Council workgroup on Priority Setting for the Basic Sciences of Mental Health.

At the annual meeting of the American Psychiatric Association in May 2004 an invited review of Developmental Psychobiology was presented in a half day session that drew an audience of several hundred. Sackler faculty were well represented in this summary of recent progress in the field. B.J. Casey (Chair) and Bruce McCandliss represented the Cornell Sackler and Myron Hofer, representing the Columbia Sackler, gave a paper on the Developmental Psychobiology of Early Attachment. A book titled "Developmental Psychobiology" was published in May 2004 by American Psychiatric Publishing Inc. based on the proceedings of the conference.

A joint meeting of members of the Cornell and Columbia Sackler Institute Faculty was held in the Fall of 2003 together with members of the Department of Developmental Psychobiology, in the first of what we plan to be an annual series. A number of short talks were given with time for discussion around the talks and at lunch. Another is planned for November 11, 2004. We have found this is an effective way to spark collaborative projects like the highly productive shared post doctoral research project carried out a year ago by Inge-Marie Eigsti on the attentional deficit in early autism. On the basis of this work, Dr. Eigsti was able to secure a tenure track position at the University of Connecticut , where she moved in July 2004. In the spring of 2005 a joint meeting with faculty of the new Glasgow and Edinburgh Institutes is planned with much

curiosity and anticipation on both sides of the Atlantic .

On May 19 and 20, 2004 Dr. Michael Meaney, a member of our outside Scientific Review Committee, visited our laboratories and met with faculty members and other developmental researchers working in his area of research. Dr. Meaney also gave an informal presentation describing his most recent research on molecular-genetic and methylation-based mechanisms for the shaping of hypothalmic-adrenocortical and anxiety behavior development by variations in specific maternal behavior patterns. This visit generated considerable interest among clinical researchers such as Drs. Weissman and Peterson as well as among the more basic behavioral neuroscientists. These visits are also designed to give us the benefit of outside review of the functioning of the Institute.

We sponsored Sackler Symposia at 2 international conferences: one on Childhood Bipolar Disorder at the Annual Meeting of the International Society for Developmental Psychobiology in November 2003 in New Orleans . There were presentations on the diagnosis, genetics, brain imaging findings and effects of early trauma with an excellent discussion by Susan Sweto of the NIMH. The other was a symposium on Postnatal Neurogenesis at the Winter Conference for Research on Early Development in January of 2004. This was chaired by Dr. Elizabeth Gould and presented the latest findings on how stress and deprivation affect the differentiation of new neurons in several brain regions during a time frame extending into adulthood.

Small-grants of $1,000 to $5,000 were awarded to purchase research supplies and/or technical support for pilot projects in preparation for grant applications. $5,000 was awarded to Joseph Isler, a postdoctoral fellow with expertise in complex non-linear systems and mathematical modeling allowing him to buy equipment needed for his novel approach to analyzing infant and fetal EEG responses. $2,000 was awarded to Susan Brunelli for supplies and animal care costs to study the role of a progesterone metabolite, allopregnanolone, in an animal model of increased early separation anxiety. $1,000 went to Harry Shair to ascertain the feasibility of studying, in genetically altered mice, a novel potentiation of infant separation responses previously discovered in rats.

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 organization of motor neurons into columns, a prominent feature of central nervous system structure and function. In many regions of the central nervous system the grouping of neurons into columns links cell-body position to axonal trajectory, thus contributing to the establishment of topographic neural maps. This link is prominent in the developing spinal cord, where columnar sets of motor neurons innervate distinct targets in the periphery. We show here 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 fibroblast growth factor signalling 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. Our findings reveal that 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.

In addition, we have been examining the genetic control of locomotor behavior. The sequential stepping of left and right limbs is a fundamental motor behavior that underlies walking movements. This relatively simple locomotor behavior is generated by the rhythmic activity of motor neurons under the control of spinal neural networks known as central pattern generators (CPGs) that comprise multiple interneuron cell types. Little, however, is known about the identity and contribution of defined interneuronal populations to mammalian locomotor behaviors. We have found that a discrete subset of commissural spinal interneurons, whose fate is controlled by the activity of the homeobox gene Dbx1, has a critical role in controlling the left-right alternation of motor neurons innervating hindlimb muscles. Dbx1 mutant mice lacking these ventral interneurons exhibit an increased incidence of cobursting between left and right flexor/extensor motor neurons during drug-induced locomotion. Together, these findings identify Dbx1-dependent interneurons as key components of the spinal locomotor circuits that control stepping movements in mammals.

Sockanathan, S., Perlmann, T. and Jessell, T.M. (2003). Contrasting requirements for retinoid signaling in the specification of motor neuron columnar identity at limb and thoracic levels of the spinal cord. Neuron, 40 97-111.

Dasen, J.S., Liu, J-P., and Jessell, T.M. (2003). Motor neuron columnar fate imposed by sequential phases of Hox-c activity. Nature, 425 926-933.

Thaler, J.P., Lettieri, K., Andrews, S., Cox, C., Jessell, T.M., and Pfaff, S.L. (2004). A post-mitotic role for Isl-class LIM homeodomain proteins in the assignment of visceral spinal motor neuron identity. Neuron 41, 337-350.

Lanuza, G.M., Gosgnach, S., Pierani, A., Jessell, T.M., and Goulding, M. (2004). Genetic identification of spinal interneurons that coordinate left-right locomotor activity. Neuron 42, 375-386.

Marklund, M., Sjödal, M., Beehler, B.C., Jessell, T.M., Edlund, T., and Gunhaga, L. (2004). Retinoic acid signaling specifies intermediate character in the developing telencephalon. Development, 131, 4323-4333.

Miles,G.B., Yohn , D.C. , Wichterle, H., Jessell, T.M., Rafuse, V.F., and Brownstone, R.M. (2004). Functional properties of motoneurons derived from mouse embryonic stem cells. J. Neurosci. In Press.

Gu, C., Yoshida, Y., Livet, J., Reimert, D.V., Mann, D., Merte, J., Henderson , C.E., Jessell, T.M., Kolodkin, A.L., and Ginty, D.D. (2004). Semaphorin 3E and its receptor plexin-D1 control vascular patterning independently of neuropilins. Submitted.

Gareth B. Miles, Damien C. Yohn, Hynek Wichterle, Thomas M. Jessell, Victor F. Rafuse, and Robert M. Brownstone. (2004). Functional Properties of Motoneurons Derived from Mouse Embryonic Stem Cells. J. Neurosci. 24, 7848-7858

Howard Hughes Medical Institute 09/01/2002-08/31/2003 43%

Role: PI $613,992 (operating expenses)

Molecular Analysis of Vertebrate Neural Development

Research support from HHMI is currently focused on experiments to examine the molecular basis of synaptic specificity in the developing spinal cord, with an emphasis on sensory-motor connections and role role of local circuit interneurons in modifying motor output.

R01 NS33245 09/01/1999 – 08/31/2005 10%

NIH $199,252

Role: PI

Control of Motor Neuron Differentiation

The aim of this grant since its inception has been to define the cellular and molecular steps that control motor neuron differentiation in the developing spinal cord.

2P01 CA23767-25

NIH- National Cancer Institute (Axel) 10/1/03 – 11/30/08 10%

Role: Project IV- Jessell $129,655

Proto-oncogenes—Signaling in Development and Neoplasia.

Project title: Cell Interactions in Motor Neuron Differentiation. The main goal of this proposal is to link the transcriptional regulation of sensory neuron identity to key cell surface recognition molecules that control axonal growth and target specificity during the formation of the spinal sensory-motor reflex circuit.

WELLT066790-C-02-Z

The Wellcome Trust 05/01/2002 04/30/2007 10%

Role: Project leader on consortium grant. $293,732

Functional Genomics of Identified Neurons

Project title: Functional genomics of the motor neuron

The aim of this collaborative project (with the Lumsden, DuLac, Kontges and Wernische labs) is to use functional genomic methods to identify novel genetic markers that permit the identification of motor neuron subtypes.

Project ALS 1/21/2001 – 12/20/2004 5%

Role : PI $149,727

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 disorder.

SCRIB51796001

NYS Spinal Injury Research Program 01/01/2004-12/31/2007 5%

Role: PI $100,000

Analysis of ES Cell Derived Motor Neurons .

The aim of these studies is to optimize procedures for introduction of ES cell derived spinal cord neurons into adult spinal cord in normal and injured states.

The G. Harold and Leila Y.

Mathers Charitable Foundation 9/1/2001-8/31/2007 5%

( PI: E. Kandel, M.D.) $175,000

Role : Project leader

Molecular Approaches to cognition: The development and modification of internal representations within the brain.

The overall aim of this project is to determine how individual genes contribute to the cellular properties essential for the development and maintenance of cognitive maps. Studies in the Jessell project will focus on the characterization of neuronal populations that mediate sensory relay information in the dorsal spinal cord.

CU51912001

Dana Foundation 10/01/2003 – 9/30/2006 2%

Role: PIs: Yong Ri Zou and Jessell $50,000

The Functional and Signaling Pathways of the Chemokine Receptor CXCR4 in the Immune and the Central Nervous Systems

The primary goal of this proposed project is to elucidate the conserved physiological function of CXCR4 in the immune and nervous systems.

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 . 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 fiscal year we have received NIH funding for two additional projects. One is to investigate sleep arousal mechanisms in at-risk infants from a database collected as part of the NICHD CHIME (Cooperative Home Infant Monitoring Evaluation network). The second is a phase 1 planning grant as part of an NIAAA/NICHD network to study the effects of alcohol on SIDS, unexplained fetal demise and other neurobehavioral disorders. This network focuses on high risk populations in South Africa and the Dakotas .

O ur 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.

In the last few years I have been interested in what we can learn about development from the results of targeted gene deletion in mice. For example, single gene deletion can have very different effects when present throughout development than when activated in adulthood. In recent papers, Dr. Jay Gingrich's group in the Sackler Laboratories and Sackler Awardee, Mark Ansorge, have discovered paradoxical effects of serotonin transporter inactivation in early development, unexpectedly increasing adult depression-like behaviors. This has implications for the treatment of depressed children, adolescents and pregnant women with the widely used serotonin transporter inhibitor drugs (SSRIs), as well as providing an experimental model for the puzzling human finding of increased vulnerability to depression in patients with abnormalities of the serotonin transporter gene.

I am currently working on a book on early development that I hope will help bridge the conceptual gap that exists between Developmental Psychologists and research at the cellular/molecular level in Developmental Biology.

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

  Work in this laboratory continues to be spurred by the renewed interest in the effects of inadequate nutrition during pregnancy, undergrowth of the fetus, and vulnerability to disease later in life. From large scale epidemiological studies, it has become clear the that cardiovascular disease, diabetes, schizophrenia, and depression can all be influenced by nutritional disturbances, as well as other types of environmental stress during this critical period of development. While long-term effects of early experiences has been a focus of research within the field of Developmental Psychobiology since its inception, the proximal mechanisms and chain of events that account for enduring changes in disease vulnerability remain largely undiscovered. This is the ongoing focus of work in our group. 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 continue to investigate these phenomena in both animal models and human infants. NIH support for these studies now totals over $500,000 per year.

 Our 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. We are also pursuing gene expression studies from placental tissue that will allow us to determine with greater precision which infants experienced suboptimal growth conditions during gestation. We are also investigating the hypothesis that alterations in methylation of regulatory regions of certain genes are key to understanding the persistence of changes in gene expression resulting from variation in nutrition early in life.

Dr. Jonathan Polan –

  I spent the academic year 2003-04 on sabbatical in the laboratory of Dr. Eric Kandel at Columbia University 's Center for Neurobiology and Behavior learning the concepts and techniques of molecular neurobiology in order to apply them to research in developmental psychobiology. In the Kandel lab I joined a group that is creating genetically engineered mouse models of schizophrenia, animals with selective dysfunctions of the dopamine or glutamate systems limited to the striatum or neocortex, the neurotransmitters and brain regions implicated in schizophrenia. Because of strong evidence that schizophrenia is a neurodevelopmental disorder, we focussed on the developmental aspects of these animals' phenotypes using a molecular switch to turn the transgenes off during specific developmental windows. For the academic year 2004-05 this project is being funded by the Sackler Research Award and by a grant from the Lieber Center for Schizophrenia Research.

  We turned off a transgene in a mouse that over expresses the dopamine D2 receptor in the striatum and causes a schizophrenia-like phenotype of impaired working memory. We found that when the transgene is inactivated in adulthood, the phenotype remains, implying that the animal's cognitive impairment results from overexpression of D2 receptors earlier in development. After turning off the transgene throughout all of postnatal life, our preliminary results are that the adult phenotype still persists, suggesting that the excess doapminergic function in the striatum exerts its pathologenic effect on prenatal brain development. In addition, we are beginning to apply stressors early in development to these transgenic animals to model the "double hit" hypothesis of schizophrenia, i.e., the hypothesis that an interaction between both a genetic predisposition and environmental stress is responsible for the full syndrome.

Publications

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.

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

Hofer, M. A. The Emerging Neurobiology of Attachment and Separation - How Parents Shape Their Infant's Brain and Behavior. In S. W. Coates, Rosenthal, J.L., Schechter, D.S., (Ed.), September 11 - Trauma and Human Bonds (pp. 191-209). Hillsdale , NJ : The Analytic Press 2003

Lira, A., Zhou M., Castanon N., Ansorge M.S., Gordon J.A., Francis J.H., Bradley-Moore M., Lira J., Underwood M.D., Arango V., Kung H.F., Hofer M.A., Hen R., & Gingrich J.A. Altered depression- related behaviors and functional changes in the dorsal raphe nucleus of serotonin tansporter-deficient mice. Biol. Psychiatry (10), 960-971, 2003

Hofer, M. A., Developmental Psychobiology of Early Attachment. In B. J. Casey (Ed.), American Psychiatric Publishing Review of Psychiatry Series (Vol. 23): A.P.A Publishing Co. 2004

Sloan RP. Deriving Heart Period Variability From Blood Pressure Waveforms. Journal of Applied Physiolog, in press, 2003.

Polan, HJ, Emergence of motivation in the newborn's first relationship. Developmental

Psychobiology. In press

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.

"Developmental Dopaminergic Excess, Environmental Stress, and the Pathogenesis of Schizophrenia"

Lieber Center for Schizophrenia Research

Principal Investigator: Jonathan Polan

Amount: $80,000 per year

Duration: 7/1/04 -6/30/06

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 goal has been to understand the patterns, timing and risk for mood and anxiety disorders across generations. We have followed and carefully clinically characterized the samples of patients at risk for these disorders and have followed them from childhood to adulthood. More recently, we have used genetic, neuropsychological, neurophysiologic and neuroimaging studies to better understand the pathophysiology and neural circuitry of these disorders.

The major work includes a three generation study of offspring at high and low risk for depression. The overall aim has been to better understand the long term temporal sequence and familial patterns of psychiatric disorders from childhood to adulthood, in offspring at high and low risk for depression using clinical and psychophysiological assessments, EEG and startle response. The study has had four waves of assessments for over 20 years. A fifth wave is underway and three generations have now been studied. The fourth wave of assessments found high rates of psychiatric disorders, particularly anxiety disorders in the grandchildren with two generations of major depression. Fifty nine percent of these grandchildren (mean age of 12) are already having psychiatric disorders. The effects of the parental depression of the grandchild outcomes differs significantly with grandparent depression status. Among the grandchildren with a depressed grandparent and parent there was over a five fold increase risk of anxiety disorders and over a five fold risk of any disorder. The pattern that we have observed in these grandchildren (the third generation) paralleled what we found in the parents (the second generation) when they were followed from childhood to adulthood and in the grandparents (the first generation) who retrospectively reported their childhood conditions when we first surveyed them as adult. The patterns in high risk children includes an increase in anxiety disorders, mostly phobias, before puberty with a marked rise in depression around puberty, especially in females and a slight increase in substance dependency in late adolescence and young adulthood. The high rates and early onset of mood and anxiety disorders on the grandchildren from two generations of depression suggests that this group as contrasted with the low risk group, could provide promising contrasts in neuroimaging, genetic and other biological studies.

In collaboration with Dr. Bradley Peterson we are now conducting functional and anatomical magnetic imaging studies of these generations and are developing hypothesis about brain endophenotypes using the EEG and startle data. We have now completed about 115 MRIs and this work will be progressing for the next two years. We have also started to analyze the data from our EEG and startle findings. The results of the EEG showed that offspring with both parents having a major depression had the greater alpha asymmetry at the medial sites with relatively less activity over the right central and parietal regions, when compared to the offspring with having one or no parents with depression. Alpha asymmetry is indicative of right parietotemporal hypoactivity, previously reported for depressed adolescents and adults, and heightened anterior to posterior gradient of alpha are present in high risk offspring having parents concordant for major depression.

The results of the startle response found that startle discriminated between low and high risk groups. In the probands' children, the high risk group showed increased startle magnitude throughout the fear-potentiated startle test. In the probands' grandchildren, a gender-specific abnormality was found in the high risk group, with high risk girls, but not boys, exhibiting elevated startle magnitude throughout the procedure. Increased startle reactivity in threatening contexts, previously found in patients with anxiety disorder and in children of parents with an anxiety disorder, may constitute a vulnerability marker for major depression. Both the EEG and the startle could be endophenotypes.

We have been interested in the work of Caspi et al who showed that functional polymorphism in the promoter region of the serotonin transporter gene moderated the effect of life events on developing depression. Caspi's group showed that the effects of the genes were conditional on exposure to an environmental risk. Our findings suggest another point of heterogeneity in depression. The development of depression in a young person may be conditional on both the parent and grandparent having a moderate to severe depression. These effects may be independent of environmental confounders. Whether these generations also carry the functional polymorphism is an interesting unanswered question. We do have data on life events and will be using some Sackler funds to begin planning the collection of blood for DNA and genetic analysis in the three generation study.

We have followed up previous findings on the high familiality of recurrent major depression beginning before the age of 30. As participants in a multi-site study to identify major depression susceptibility gene, the collection of about 1000 sib pairs with recurrent early onset major depression has been completed. Biological material and clinical data is being shared with the scientific community. Data analyses of this study are underway. Some of our findings on the potential differences between prepubertal and adolescent onset depression will be tested as potential different phenotypes.

Work is ongoing in a new initiative to understand the genetic basis of fear and anxiety disorders in humans by identifying variants forms of genes that may contribute to pathological anxiety state. The basic idea is that learned innate fear are tractable target for genetic analysis in mice and humans; that there are similarities in fear conditioning circuitry between animal models and humans; that genes involved in the pathway associated with fear in mice may be involve in the development of human anxiety disorders. Candidate genes that are identified from the study of learned and innate fear will be tested in a sample of normal humans with various degrees of fear conditioning, following startle test. These genes may also be related to human anxiety disorders. We are collecting samples of patients with panic disorders, social anxiety disorders, and normal controls. We are also characterizing these samples on dimensions of anxious temperament for candidate gene analyses. This work began this year and represents an NIMH Program Project grant between Eric Kandel, Rene Hen, Conrad Gilliam, Abby Fyer, and Myrna Weissman.

We have used the Sackler funds to encourage young investigators to further develop the data from our clinical sample. Adriana Feder, MD is studying twenty-four-hour cortisol secretion patterns in prepubertal children with depression, anxiety and normal controls in a longitudinal clinical follow up into young adulthood. Her study yielded the largest sample of 24-hour cortisol and growth hormone data in prepubertal children with depression and anxiety (n=124). She has reanalyzed biological data collected in children in light of longitudinal clinical follow-up of subjects as young adults. Preliminary findings indicate that prepubertal children with major depression, as well as children who are at risk for developing major depression by young adulthood, show abnormalities in their 24-hour cycle of cortisol secretion. In particular, they appear to exhibit a phase delay in the rise of cortisol in the early morning hours. This is a normally cortisol-active period preceding awakening. This neuroendocrine abnormality may represent a trait marker for MDD, in this population, thus a potential way of identifying prepubertal children with MDD, or at risk for MDD, in the future. Her findings, if confirmed, may pave the way for developing prevention and early intervention strategies for this population.

Sanjay Mathew , MD partially funded by Sackler has just completed MRS examination study on sample of adolescent onset depressives followed into adulthood and compared to controls. Data are being analyzed.

Two new collaborations were initiated this year between our group and other members of the Sackler Institute. Yoko Nomura, Ph.D. following up some our efforts to identify multitude risk factors for early onset depression working with William P. Fifer, Ph.D. received an NIMH grant to study pathways to psychiatric and medical comorbidity. Exposure to perinatal problems and social adversity in conjunction with maternal depression may explain the increased risk of behavioral, emotional, and medical problems in offspring in their infancy, childhood, and adulthood. Individuals with psychiatric illness such as depression who have a comorbid medical problem have increased functional impairment, more frequent use of health care services, and a higher prevalence of suicidal ideation. Elucidation of the mechanism through which the phenomenon occurs, through examination of problems across the life cycle (birth, infancy, childhood, and adulthood), will help clarify the temporal sequences of the selected comorbid medical illness (allergies, headaches, and heart disease). Exploiting an unparalleled opportunity to utilize the dataset from a community-based longitudinal study (N=1758) that followed parents and their offspring for over 30 years, the proposed study has 5 aims: 1) to investigate direct and indirect (through social adversity) effects of perinatal risk on different problems (emotional/behavioral, medical, and neurological) in infancy and childhood, as well as psychiatric and medical illness in adulthood; 2) elucidate pathways from social adversity and perinatal risk to adult psychiatric and medical illness, mediated through different problems in infancy and childhood; 3) to examine the temporal sequence of psychiatric and medical illness, from childhood to adulthood; 4) to compare the level of social and functional impairment, such as suicidal ideation, hospital use, and personal resources among those with both psychiatric and comorbid medical illness, those with one and neither illness; 5) to examine the role of maternal depression and family support as moderators.

Catherine Monk, Ph.D. a former fellow of the Sackler Institute and a member of Dr. Hofer's group was assisted by Weissman in successfully preparing an NIMH grant on interpersonal psychotherapy for depressed pregnant mothers, to follow the mothers through pregnancy and post partum and to study their infants.

Publications

Blanco C, Clougherty KF, Lipsitz KF, Mufson L, Weissman MM. Interpersonal Psychotherapy. In Gabbard G, Beck J, Holmes J (eds.) Journal of Psychotherapy Integration (Special Series): Integrating between-session homework activities into different psychotherapies. Concise Oxford Textbook of Psychotherapy. Gabbard, GO, Beck J, Holmes JA. In press, 2003.

Charney DS, Reynolds III CF, Lewis L; Lebowitz BD, Sunderland T, Alexopoulos GS, Blazer DG, Katz IR, Meyers BS, Arean PA, Borson S, Brown C, Bruce ML, Callahan CM, Charlson ME, Conwell Y, Cuthbert BN, Devanand DP, Gibson MJ, Gottlieb GL, Krishnan KR, Laden SK, Lyketsos CG, Mulsant BH, Niederehe G, Olin JT, Oslin DW, Pearson J, Persky T, Pollock BG, Raetzman S, Reynolds M, Salzman C, Schulz R, Schwenk TL, Scolnick E, Unützer J, Weissman MM, Young RC. Depression and bipolar support alliance consensus statement on the unmet needs in diagnosis and treatment of mood disorders in late life. Arch Gen Psychiatry 60:664-672, 2003.

Feder A, Goetz RR, Coplan JD, Mathew SJ, Pine DS, Greenwald S, Dahl RE, Ryan ND, Weissman MM. Twenty-four hour cortisol secretion patterns in prepubertal children with anxiety or depressive disorders. Biol Psychiatry 56:198-204, 2004.

Goodwin R, Olfson M, Shea S, Lantigua RA, Carrasquillo O, Gameroff MJ, Weissman MM. Asthma and mental disorders in primary care. Gen Hosp Psychiatry 25(6):479-83, 2003.

Hamilton SP, Slager SL, Baisre de Leon A, Heiman GA, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA. Evidence for genetic linkage between a polymorphism in the Adenosine 2A receptor (ADORA2A) and panic disorder. Neuropsychopharmacology 29:558-565, 2004.

Hamilton SP, Slager SL, Mayo D, Heiman GA, Klein DF, Hodge SE, Fyer AJ, Weissman MM, Knowles JA. Investigation of polymorphisms in the CREM gene in panic disorder. Am J Med Genet 126B: 111-115, 2004.

Hirschfeld RMA, Calabrese JR, Weissman MM, Reed M, Davies MA, Frye MA, Keck PE , Lewis L, McElroy SL, McNulty J, Wagner KD, Holzer C. Using questionnaires to screen for psychiatric disorders: A comment on a study of screening for bipolar disorder in the community. J Clin Psychiatry 65(5): 721-722, 2004.

Holmans P, Zubenko GS, Crowe RR, DePaulo JR, Scheftner WA, Weissman MM, Zubenko WN, Boutelle S, Murphy-Eberenz K, Mackinnon D, McInnis MG, Marta DH, Adams P, Knowles JA, Gladis M, Thomas J, Chellis J, Miller E, Levinson DF. Genomewide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q. Am J Hum Genet 74: 1154-1167, 2004.

Judd F, Weissman MM, Davis J, Hodgins G, Piterman L. Interpersonal counseling in general practice. Aust Fam Physician 33(5): 332-337, 2004.

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 1336-1343, 2003 .

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, 2 nd edition. American Psychological Association. In press, 2003.

Mufson L, Pollack Dorta K, Moreau D, Weissman, MM. Interpersonal Psychotherapy for Depressed Adolescents, 2 nd edition. Guilford Publications, Inc., New York , 2004.

Mufson L, Pollack-Dorta KE, Wickramaratne PJ, Nomura Y, Olfson M, Weissman MM. A randomized effectiveness trial of interpersonal psychotherapy for depressed adolescents. Arch Gen Psychiatry 61:577-584, 2004.

Olfson M, Tobin JN, Cassells A, Weissman MM. Improving the detection of drug abuse, alcohol abuse and depression in community health centers. J Health Care Poor Underserved 14(3):386-402, 2003.

Oquendo MA, Lizardi D, Greenwald S, Weissman MM, Mann JJ. Rates of lifetime suicide attempt relative to rates of lifetime major depression in different ethnic groups in the United States . Acta Psychiatr Scand In press, 2004.

Pilowsky DJ, Birmaher B, Weissman MM. Approaches to chronic depression in children and adolescents. In Alpert J, Fava M (eds) Handbook of Chronic Depression. Marcel Dekker, Inc. NY, 2004, pp. 339-362.

Verdeli H, Ferro T, Wickaramaratne P., Greenwald S, Blanco C, Weissman MM. Treatment of depressed mothers of depressed children: Pilot study of feasibility. Depression & Anxiety , 19(1):51-59, 2004.

Weissman MM. The epidemiology of bipolar disorder. In Goodwin F, Jamison K (eds.), Manic Depressive Illness, Oxford University Press, In press, 2003.

Weissman MM. Phobias in primary care and in young children. (Commentary) In Maj M, Akiskal HS, López-Ibor JJ, Okasha A (eds). WPA Series, Evidence and Experience in Psychiatry. John Wiley & Sons Ltd, 2004, pp. 342-344.

Weissman MM, Warner V, Wickramaratne PJ, Nomura Y, Merikangas KR, Bruder GE, Tenke CE, Grillon C. Offspring at high and low risk for depression: Preliminary findings from a three generation study. In Gorman JM (ed) Fear and Anxiety: The Benefits of Translational Research . American Psychiatric Publishing, Inc., NY 2004, pp. 65-83.

Weissman MM. Epidemiologic Phenotype Hunting: Panic Disorder and Interstitial Cystitis. In Eaton W (ed) Medical and Psychiatric Comorbidity over the Course of Life, APPI, Washington DC, In press 2004.

Weissman MM, Feder AJ, Pilowsky D, Olfson M, Fuentes M, Blanco C, Lantigua R, Gameroff MJ, Shea S. Depressed mothers coming to primary care: Maternal reports of problems with their children. J Affective Dis 78:93-100, 2004.

Weissman MM , Gross R , Fyer AJ, Heiman GA, Gameroff MJ, Hodge SE, Kaufman D, Kaplan SA, Wickramaratne PJ. Interstitial cystitis and panic disorder: A potential genetic syndrome. Arch Gen Psychiatry 6.1:273-279, 2004.

Weissman MM, Wickaramartne PJ, Nomura Y, Warner V, Verdeli H, Pilowsky DJ, Grillon C, Bruder G. Families at high and low risk for depression: A three generation study. Arch Gen Psychiatry, In press, 2004.

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 Dev 34(1): 19-34, 2003.

Wilson JJ, Nunes EV, Greenwald S, Weissman MM. Verbal deficits and disruptive behavior disorders among children of opiate dependent parents. Am J Addict 13:202-22, 2004.

Grant Support (dollar figures are per year)

Myrna M. Weissman, Ph.D.

5 RO1 MH60912-04 (Weissman) 09/30/99 - 08/31/04 5% effort

NIH/NIMH $247,683 (No cost extension)

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 MH28274-26 (Weissman) 07/08/02 to 06/30/05 10% effort

NIH/NIMH $265,160 (No cost extension)

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 R01 MH63852-04 (Weissman) 07/19/01 to 06/30/06 20% effort

NIMH $776,539

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 P30 MH60570-05 (Shaffer) 09/24/99 to 05/31/05 <1% effort

NIH/NIMH $129,307 (Core Only) (No Cost extension)

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 MH 36197-20 (Weissman) 01/01/03 - 12/31/08 25% effort

NIH/NIMH $620,928

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 4 th 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 MH60970-02(Gilliam) 12/1/02-11/30/06 15% effort

NIH/NIMH $237,374 (Project 4 only)

Molecular Genetic Studies of Fear and Anxiety (Weissman is Director of Project 4 “ Clinical Studies of Human 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 MD000206-02(Carrasquillo) 10/01/02-9/30/07 8% effort

NIH/NCMHHD $75,651 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 5% effort

$100,000

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 Disorders

The MRI Unit that Dr. Peterson directs opened for research studies in February of this year. It is a 3.0 Tesla scanner manufactured by GE. Equipped recently with the new “parallel imaging” capabilities, it is one of the best performing research scanners in the world. Please see the accompanying brochure, sent to all departmental faculty, describing some of the services provided by the Unit, along with our intensive efforts to help new investigators apply MRI methodologies within their ongoing research projects.

Major activities in Dr. Peterson's pediatric imaging laboratory have focused on securing adequate funding for staff and ongoing projects. Two large independent investigator awards (R01's) were received from the NIMH, and a midlevel Career Development Award for Dr. Peterson was submitted. One funded R01 will study 135 newborn infants with MRI to assess brain structure, connectivity, and metabolites in 45 infants exposed prenatally to crack cocaine, 45 to narcotics, and 45 who were never exposed.

The other funded R01 provides support for morphometric analyses of 620 MRI scans previously obtained in children and adults who have Tourette syndrome, OCD, or ADHD, or who are healthy comparison subjects. Brain-based correlates of morphological measures with performance on cognitive tasks, with brain activity on fMRI scans, and genetic variation will be assessed.

Collaboration with Drs. Myrna Weissman of the Sackler Institute has continued in our third funded R01, and we have thus far successfully scanned 125 individuals in 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.

Finally, in collaboration with Dr. Christina Hoven and colleagues in the School of Public Health , we have received funding to study the effects of trauma on the CNS in children and their parents who resided in close proximity to the World Trade Center on 9/11/01. We will be scanning 80 representative children and their parents who were evacuated from the site after the disaster, as well as 80 matched control children and their parents who were not in physical proximity to the trauma.

Publications

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 , 131(1):79-89, 2004 .

Spessot AL, Plessen KJ, Peterson BS. Neuroimaging of developmental psychopathologies: The importance of self-regulatory and neuroplastic processes in adolescence. Ann NY Acad Sci ,1021:86-104, 2004.

Alexander GM, Peterson BS. Testing the prenatal hormone hypothesis of tic-related disorders: gender identity & gender role behavior. Develop Psychopath , 16, 407-420, 2004 .

von Plessen K, Wentzel-Larsen T, Hugdahl K, Feineigle P, Klein J, Staib L, Leckman JF, Bansal R, Peterson BS. Altered interhemispheric connectivity in individuals with Tourette syndrome. Am J Psychiatry , in press.

Marsh R, Alexander GM, Packard MG, Zhu H, Wingard JC, Quackenbush G, Peterson BS. Habit learning in children and adults with Tourette Syndrome: A translational neuroscience approach to a developmental psychopathology. Arch Gen Psychiatry , in press.

Xu D, Mori S, Shen D, Peterson BS, Davatzikos C. Warping diffusion tensor images. IEEE Trans Medical Imaging , in press.

Bansal R Staib LH, Whiteman R, Wang YM, Peterson BS. ROC-based assessments of 3D cortical surface-matching algorithms. Neuroimage , in press.

Posner J, Russell J, Peterson BS. The circumplex model of affect: an integrative approach to affective neuroscience, cognitive development, and psychopathology. Develop Psychopath , in press.

Kim D-J, Yoon S-J, Choi B, Kim T-S, SupWoo Y, Kim W, Myrick H , Peterson BS, Jeong J. Increased fasting plasma ghrelin levels during alcohol abstinence. Alcohol and Alcoholism , in press.

Peterson BS, Panksepp J. The biological basis of childhood neuropsychiatric disorders. In: Panksepp J (Ed.). A Textbook of Biological Psychiatry . New York : John Wiley & Sons, Inc. 2003, pp.393-436

Spessot AL, Peterson BS. Tourette Syndrome: A Multifactorial, Developmental Pychopathology. In press in: Dante Cicchetti & Donald J. Cohen (Eds.) Manual of Developmental Psychopathology . 2 nd edition. New York : John Wiley

Blumberg HP, Kaufman J, Martin A, Charney DS, Krystal JH, Peterson BS S ignificance of adolescent neurodevelopment for the neural circuitry of bipolar disorder. Ann NY Acad Sci, 1021:376-383, 2004 .

Grant Support

•  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

Annual Direct Cost $46,296 Total Direct Cost $92,592 Total Cost $100,000

2002 NIMH Children at High and Low Risk for Depression, MH36197 (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

Initial Annual Cost $635,513 Total Direct Cost $3,258,079

$4,593,000

2004 NIDA MRI of Infants Exposed Prenatally to Drugs of Abuse, DA017820 (B. Peterson, PI)

25% Effort. To define the effects of drugs of abuse on brain structure and metabolite concentrations, as well as the behavioral correlates of those effects, in infants and children who have been exposed to drugs of abuse during fetal development.

4/01/04-3/31/09

Annual Direct Cost $499,938 Total Direct Cost $2,497,828

$3,636,292

2004 NIMH Neuroanatomical MRI Studies of Childhood Disorder, MH068318 (B. Peterson, PI)

30% Effort. To understand normal brain development and the neural basis of childhood neuropsychiatric disorders using anatomical MRI.

7/01/04-6/30/09

Annual Direct Cost $499,999 Total Direct Cost $2,499,995

$4,000,427

2004 NIMH WTC Impact, Familial Transmission and Child PTSD, MH070424 (C. Hoven, PI)

We will use MRI to study the effects of trauma on the CNS in children and their parents who resided in close proximity to the World Trade Center on 9/11/01. We will be scanning 80 representative children and their parents who were evacuated from the site after the disaster, as well as 80 matched control children and their parents who were not in physical proximity to the trauma.

Role: Director of the MRI research component of the project.

4/04/04-4/03/05

Annual Direct Cost $426,563 Total Direct Cost $426,563

$ 601,611

5. Sackler Awardee

Dr. Cheryl Corcoran

The funding that I received from the Sackler Institute was for a study of stress and symptoms in adolescents and young adults who have enhanced clinical risk for psychosis and schizophrenia. In the first year of the grant, preliminary analysis was done of cross-sectional data collected in collaboration with Barbara Cornblatt at her RAP prodromal research clinic. These data showed that emerging positive symptoms were related in prodromal patients to both life event exposure and to cortisol secretion in response to a laboratory stressor. Of note, prodromal patients were not found to have an excess of life events as compared with normal controls, which suggests that the symptoms were not causing the life events. Further, HPA activity in response to a stressor was correlated with endorsement by patients of “impaired tolerance to normal stress”, which characterized nearly half of all prodromal patients and none of the controls.

These pilot data supported the rationale for a longitudinal study of stress and symptoms in a prodromal sample, with the aim of testing the stress-diathesis hypothesis of psychosis onset in schizophrenia. These data analyses were therefore crucial to obtaining funding as from NIMH for a K23 award, entitled “Schizophrenia risk to onset: Neurobiology and prevention”, which began in April of 2004. It entails a prospective cohort study of prodromal patients that employs clinical methodologies that probe HPA axis function, prodromal symptoms and psychosocial stress exposure. The main hypothesis is that baseline stress-reactivity (stress reactive cortisol and impaired tolerance to normal stress) and intervening life events will increase risk for psychosis in prodromal patients. The training plan for this K23 award involves increased expertise in 1) prodromal research and neuropsychology; 2) adolescent cognitive and social development; 3) data analysis in longitudinal studies and 4) assessment of stress and the HPA axis in schizophrenia.

More generally, the Sackler Award was also instrumental simply in launching a prodromal research clinic here at NYSPI and Columbia , the Center of Prevention and Evaluation (COPE). Since the last report, in the past year, the COPE clinic has recruited an additional 18 patients who are all actively engaged in the protocol. Recruitment is ongoing, with distribution of brochures, liaison with schools, and contact with potential referrals, both here at Columbia/NYSPI and in the community.

Therefore, in addition to providing data for examination of the stress-vulnerability hypothesis of schizophrenia, the COPE prodromal research clinic is now the site for collaborative pilot studies that evaluate other aspects of risk and pathophysiology, including electrophysiology (Bruder and Foxe), structural and functional imaging (Small), cannabis exposure (Kleber), and family and social factors (Thorning). Each of these pilot studies are being done with the expectation of generating preliminary data for R01 applications.

Further, COPE has also become a vital resource for other young investigators who are interested in early schizophrenia and the unfolding of pathophysiological processes, including two schizophrenia research fellows (neuropsychology), two adult psychiatry residents (phenomenology and imaging), a child psychiatry resident (social functioning during the prodrome). There is now also a collaboration with basic scientists, specifically Holly Moore and her fellows, to study the prodrome in an animal model of schizophrenia.

In sum, the Sackler Award has been absolutely instrumental in providing bridge funds for me as an investigator between my research fellowship and initiation of a K23 award in the spring of 2004. The Sackler funding enabled me to collect pilot data that were instrumental in receiving a training award. Further, I believe the generosity of the Sacklers has led to the launching of a research clinic that is a tremendous resource now for other young investigators and which is the site for the initiation of several important collaborations that will shed light on the development of schizophrenia, in the trajectory from latent to manifest illness. I am immensely grateful for the opportunity afforded to me by the Sackler Award to initiate research in such an exciting area and to work toward becoming an independent investigator with expertise in prodromal research, uniquely regarding potential triggers and intervening variables in psychosis risk.

PUBLISHED ARTICLES (2003)

•  * Corcoran C, Walker E, Huot R, Mittal V, Tessner K, Kestler L: The Stress Cascade and Schizophrenia: Etiology and Onset. Schizophrenia Bulletin. 2003. Vol. 29 (4): 671- 692.

•  * 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. 2003 Winter;74(4):313-32.

ARTICLES IN PRESS (2004)

•  Corcoran C, Malaspina D, Herscher L: Prodromal Interventions for Schizophrenia Vulnerability: the Risks of Being “At Risk”, Schizophrenia Research.

ARTICLES IN SUBMISSION (2004)

(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. Submitted to Biological Psychiatry

BOOK CHAPTERS (2004)

•  Stanford AD, Corcoran C , Malaspina D (in press). Schizophrenia, In:
Merritt's Neurology, ed. Rowland, LP. Lippincott, Williams & Wilkins,
Philadelphia , PA.

•  Malaspina D , Corcoran C , Goudsmit N (in press). Role of Olfaction in Social Function, In: Olfaction and the Brain: Window to the Mind, ed. Brewer W, Castle D, Pantelis C. Cambridge University Press.

Part III Financial Report

3/12/2005

SklrAnnualRpt.2004