James H. Leckman - US grants

Tourette's syndrome (TS) is a chronic neuropsychiatric disorder of childhood onset that is characterized by multiple motor and phonic tics that wax and wane in severity and an array of behavioral problems including some forms of obsessive compulsive disorder (OCO). Once thought to be a rare condition, the prevalence of TS is now estimated to be one case per 1,000 boys and one case for 10,000 girls. Although the etiology of TS remains unknown, the vertical transmission of TS within families follows a pattern consisstent with an autosomal dominant form of inheritance. Neurobiologic and pharmacological data have implciated central monoaminergic and neuropeptidergic systems in the pathophysiology of TS, and the basal ganglia and frontal cortex remain the prime candidates as the neuroanatomical origin for TS related pathology. The long term objective of this project is to identify and localize the neurobiological mechanisms repsonsible for TS. During the first four years of this project, we seek the following objectives: 1. Collect and assay CSF from 200 "drug-free" patients and controls in an effort to identify the neurochemical and neuropeptide systems associated with the expression of TS and related disorders, particularly OCD. Based on preliminary data, we are especially interested in the potential role of dynorphin A and its relationship to central dopaminergic and serotonergic systems in TS and OCD patients. 2. Assessment of the clinical severity of TS and OCD symptoms using valid and reliable rating instruments. These data will be analyzed in an effort to define the clinical correlates of the CSF data. 3. Assessment of first degree family members of the patients using direct interview techniques in order to determine the pattern of familial aggregation of TS and OCD symptoms and to establish the relationship, if any, between the CSF findings and the pattern(s) of familial aggregation. Over the past decade, a critical mass of investigators at Yale have focused on TS and related disorders. This project will benefit from the clinical, genetic and neuropathological studies of TS ongoing at Yale.

This Program Project focuses on Tourette's syndrome (TS) and etiologically related disorders as a model for understanding the interplay of biological and psychological factors during the course of development. TS is a chronic neuropsychiatric disorder of childhood onset that is characterized by multiple motor and phonic tics and an array of behavioral problems including some forms of obsessive compulsive disorder (OCD) that can persist into adulthood and be chronically disabling. Although treatment regimens have been developed that benefit individuals with TS and OCD, many patients do not improve or their improvement is not sustained. Over the past two decades, notable advances, have occurred in our understanding of these conditions, including: (1) that TS and related conditions are much more common than previously recognized, affecting as many as 0.3 - 3% of the population; (2) that the natural history of these disorders is complex and dependent on age- and gender-specific factors; (3) that vulnerability to TS is mediated by both genetic and environmental factors; and (4) that specific brain regions and neurotransmitter and neuromodulator systems localized in the basal ganglia and functionally related structures are likely to provide the neurobiological substrate for TS and 0CD. The long-term objectives of this Program Project are to build on these advances using available clinical, neurobiological, genetic and epidemiological techniques and expertise to identify the causes and determinants of these conditions and to develop techniques for early detection and safe and effective treatment. This work is organized within four project areas: Genetic Factors (1), Neurobiological Substrates (II), Epigenetic and Environmental Factors (III), and Treatment Studies (IV), and will be supported by Administrative, Clinical and Data Analytic Core Resources.

Tourette's syndrome (TS) is a chronic neuropsychiatric disorder of childhood onset that is characterized by multiple motor and phonic tics that wax and wane in severity and an array of behavioral problems including some forms of obsessive compulsive disorder (OCO). Once thought to be a rare condition, the prevalence of TS is now estimated to be one case per 1,000 boys and one case for 10,000 girls. Although the etiology of TS remains unknown, the vertical transmission of TS within families follows a pattern consisstent with an autosomal dominant form of inheritance. Neurobiologic and pharmacological data have implciated central monoaminergic and neuropeptidergic systems in the pathophysiology of TS, and the basal ganglia and frontal cortex remain the prime candidates as the neuroanatomical origin for TS related pathology. The long term objective of this project is to identify and localize the neurobiological mechanisms repsonsible for TS. During the first four years of this project, we seek the following objectives: 1. Collect and assay CSF from 200 "drug-free" patients and controls in an effort to identify the neurochemical and neuropeptide systems associated with the expression of TS and related disorders, particularly OCD. Based on preliminary data, we are especially interested in the potential role of dynorphin A and its relationship to central dopaminergic and serotonergic systems in TS and OCD patients. 2. Assessment of the clinical severity of TS and OCD symptoms using valid and reliable rating instruments. These data will be analyzed in an effort to define the clinical correlates of the CSF data. 3. Assessment of first degree family members of the patients using direct interview techniques in order to determine the pattern of familial aggregation of TS and OCD symptoms and to establish the relationship, if any, between the CSF findings and the pattern(s) of familial aggregation. Over the past decade, a critical mass of investigators at Yale have focused on TS and related disorders. This project will benefit from the clinical, genetic and neuropathological studies of TS ongoing at Yale.

cognition disorders; language disorders; fragile X syndromes; longitudinal human study; behavioral /social science research tag; human subject; ultrasonography; psychological tests; clinical research;

Ziprasidone, a dopamine D2 receptor antagonist, is being evaluated for safety, tolerability, and pharmacokinetics in children with Tourette's syndrome or chronic motor or vocal tic disorder. This was a double blind, placebo-controlled pilot study.

DESCRIPTION (Adapted from applicant's abstract): This program project focuses on the pathogenesis of Tourette's syndrome (TS) and obsessive-compulsive disorder (OCD) as models for understanding the interplay of genetic, neurobiological, and psychological factors during the course of CNS development. TS, OCD, and related conditions are prevalent disorders affecting as many as 0.3-3% of the population. They are frequently chronic and associated with marked impairment and disability. Although clinical care has improved over the past decade, a significant number of patients fail to respond adequately or experience intolerable side effects. The etiology of these disorders is unknown. Compelling evidence suggests that the vulnerability to develop TS and OCD is mediated by both genetic and environmental factors, and that neural systems located in the basal ganglia and functionally related brain structures are involved in their pathogenesis. Based on explicit models of pathogenesis for TS and OCD and building on work accomplished over the past six years, an array of clinical, neuropsychological, genetic, neuroimaging, epidemiological, neurobiological, and treatment studies are proposed. Translational and integrative studies of perinatal and immunological risk factors are of particular significance. If confirmed as being causally related to TS and OCD, they may lead to clinical and public health interventions, as well as the development of valid animal models. A multidisciplinary team of investigators has joined forces to test specific hypotheses through the integration and translation of basic and clinical neuroscience research. All subjects will be studied using identical clinical, neuropsychological, genetic, and neurobiological techniques. These studies are divided into seven projects and are supported by three cores.

DESCRIPTION (provided by applicant): Tic disorders, obsessive-compulsive disorder (OCD), and related conditions are prevalent disorders affecting as many as 0.3-3 percent of the pediatric population. They are chronic, relapsing disorders that can be associated with marked impairment and disability. Although clinical care has improved over the past decade, a significant number of patients fail to respond adequately or experience intolerable side effects. The etiologies of these disorders are unknown. It has been hypothesized that susceptible individuals develop symptoms of these disorders as a result of post-infectious autoimmune processes. Infections with group A beta hemolytic streptococci (GABHS) are thought to initiate these processes. Swedo, Leonard and colleagues (1998) have proposed that this subgroup of tic disorder patients, identified by the acronym PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) follows a unique clinical course. Although this hypothesis is strengthened by: (1) the presence of potentially crossreactive antineuronal antibodies in the sera of a minority of patients with tic disorders and/or OCD; (2) enlarged basal ganglia in PANDAS cases; and (3) the finding that plasma exchange and intravenous immunoglobulin treatment are effective in reducing symptoms in PANDAS cases, this conceptualization remains controversial. The aim of this revised study is to validate the diagnostic concept of PANDAS by performing a prospective longitudinal study. Further cross-sectional studies cannot resolve this issue. The use of a prospective longitudinal design should permit a close examination of the timing of symptom relapses relative to GABHS exposure. Other specific aims focus on longitudinal fluctuations of psychosocial stress, anti-neuronal antibody levels and basal ganglia volumes in an effort to understand the pathobiology of PANDAS. If specific factors are associated with acute relapse, then the nature of these factors should provide insight into the immunologic mechanisms involved. This knowledge may provide a basis for the rational design of therapeutic and preventative interventions. More generally, the knowledge gained should advance our models of disease pathogenesis and clarify the interaction between psychosocial stress and psychoneuroimmunological mechanisms. These insights may be relevant to our understanding of other diseases including AIDS.

[unreadable] DESCRIPTION (provided by applicant): This application is aimed at preparing physicians for independent careers in the investigation and treatment of childhood psychiatric disorders. Such programs are urgently needed. This need is based on the large number of children affected, the considerable costs to society associated with their care, the limited effectiveness of available treatment and prevention programs, the small number of physician-scientists active in the field, and the potential for significant scientific advances in the foreseeable future. This grant will make it possible for the faculty of the Yale Child Study Center, working with the American Academy of Child and Adolescent Psychiatry (AACAP) and academic leaders across the country, to refine, evaluate and disseminate model research education programs that extend from the first year of medical school through postdoctoral research training and the submission of a Career Development Award. Participants will.be encouraged to pursue advanced degrees. For Yale Medical Students, this award will support research seminars and medical student research thesis projects. This initiative builds on Yale's long-standing requirement that medical students complete a research thesis project in order to graduate. This fellowship program was initially funded by the Klingenstein Third Generation (KTG) Foundation in 2001. Based on the success of the fellowship program at Yale, the KTG Foundation funded five additional sites across the country in 2004 (Harvard, Johns Hopkins, Mt. Sinai, Stanford, and UC Davis). For postdoctoral participants entering the Integrated Child and Adult Psychiatry Research Pathway at Yale, this award will permit us to fund intensive periods of research training prior to their entering our recently renewed interdisciplinary T32 Institutional Research Training Program. A similar program is underway at the University of Colorado. There are currently nine participants between these two sister programs, with another four expected to enter in July 2006. Funds are also requested to support the national independent evaluation of both the KGT Foundation Medical Student Fellowship (at six sites) and the Integrated Research Pathway Program (at two sites). [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This application is for a Senior Scientist Award (K05) from NIMH. Since the 1980s, my colleagues and I at the Child Study Center at Yale have made significant contributions to an improved understanding of the pathogenesis and treatment of Tourette's syndrome and early-onset obsessive-compulsive disorder. The requested K05 Award would make it possible for me to maintain my focus on academic pursuits and thereby further advance my research and educational activities. I have two goals for the period of this Senior Scientist Award. First, I intend to continue to explore the utility of prospective longitudinal studies to add to our knowledge about the determinants of course and outcome of TS and early-onset OCD using state-of-the- art methods for clinical assessment (symptom severity, level of psychosocial stress), genomics, immunobiology, neuroendocrinology of stress response, and in vivo neuroimaging. This will involve working with investigators and trainees across a range of disciplines, completing funded grants, analyzing existing data sets and preparing new grant applications as well as competitive renewals. Second, during this next phase of my career, I plan to refine a model curriculum, based in part on the American Board of Internal Medicine's Research Pathway and the American Board of Psychiatry and Neurology's Triple Board Program that has been implemented at three sites nationally - Yale, University of Colorado and Duke. At Yale, this program, entitled, the "Albert J. Solnit Integrated Child and Adolescent Psychiatry (ICAP) Residency Training Pathway," was implemented in 2004 with the admission of two outstanding individuals committed to careers in academic child psychiatry. This ICAP Research Pathway at Yale is one part of our interdisciplinary research training program. I also plan to prepare a conference grant to support a national forum for future academic child psychiatrists that are enrolled in one of the ICAP Research Pathway programs at sites around the country. Finally, I am looking forward to completing my work as the Co-chair of the National Psychiatry Training Council with the introduction of carefully crafted model curricula in other psychiatric subspecialties of addiction psychiatry and geriatric psychiatry.

[unreadable] DESCRIPTION (provided by applicant): Tourette syndrome (TS) and related neuropsychiatric conditions affect as many as 0.3 -1% of the population. They are chronic, relapsing disorders that can be associated with marked impairment and disability. Although clinical care has improved over the past decade, a significant number of patients fail to respond to the available treatments or experience intolerable side effects. Most of the widely used interventions result in at best a 30 to 40% reduction in tic severity. Although the etiology of TS is unknown, emerging knowledge concerning the underlying neurocircuitry has been used to guide the design of focal brain stimulation strategies to study and treat tic disorders. Transcranial magnetic stimulation (TMS) has been used to investigate TS for the past decade and repetitive TMS (rTMS) has been used as an investigational intervention for severe TS for at least the last five years. Initial rTMS studies targeting motor and premotor cortical sites with either 1 Hz or 15 Hz have had limited or no success in treating individuals with severe TS. However, the recent study by Mantovani et al. (2006) which targeted the Supplementary Motor Area (SMA) was the first to demonstrate that 1 Hz rTMS produced clinically significant improvement (67% reduction in tic severity) in five patients with TS. Two of these patients experienced a complete remission of their tic symptoms. These improvements were maintained for three months. This was an open study in which patients were treated five days a week for two weeks, for a total of 10 treatments. No major side effects were noted during the course of treatment or the subsequent three months. This Phase II clinical trial proposes to replicate the Mantovani et al. (2006) study using a sham stimulation control condition. We anticipate screening 50 patients and selecting 30 patients to participate in a randomized clinical trial (15 randomized to sham and 15 to active rTMS). Two sites will administer rTMS, Yale and Columbia. We will monitor the effects of these interventions using a blind, independent evaluator. This pilot/feasibility study will allow us to make accurate power estimates for a subsequent R01 to test the efficacy and side effects of rTMS to the SMA in a larger sample, and to examine side effects, secondary electrophysiological outcomes (paired-pulse TMS to measure the excitability of the motor cortex), secondary clinical outcomes (obsessive-compulsive symptoms, depressive symptoms, and attention deficit hyperactivity disorder symptoms), and the relative impact of concurrently administered medications. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This project will evaluate and refine an innovative multi-component, neuroscience based, non- pharmacologic intervention for Attention Deficit Hyperactivity Disorder (ADHD). ADHD affects >5% of children, disrupts psychosocial development, and has broad negative outcomes. Pharmacotherapy is often of limited benefit, subject to misuse and associated with unwanted side effects. The proposed treatment program is innovative in: use of a computer based treatment delivery system to apply new knowledge of neuroplasticity in clinical care; transformation of existing approaches to physical education based on cognitive neuroscience; and use of an evidence based intervention from social psychology to enhance delivery and effectiveness of neuroscience based interventions. Synergistic integration of brain, body and social interventions provides a paradigm appropriate to address the complexities of neurodevelopmental disorders. The innovative computer programs have multiple newly patented capabilities not present in any previous computerized cognitive treatment exercises. Innovative physical exercises activate the same neurocognitive systems targeted by the computer exercises but in the context of whole body and inter-personal activity, particularly important for ADHD. The social level intervention facilitates participation in the computer and physical activities and it itself also activates target self-regulatory systems. Neuroplastic potential upon which our intervention is based has been dramatically demonstrated in animal and human studies. It has been successfully harnessed for treatment of adult neuropathology but application to childhood disorders has been remarkably absent despite greater plasticity during childhood. As with other clinically relevant advances in basic science, advances are also necessary in methods for treatment delivery if the new discoveries are to be applied effectively. Based on preliminary studies and discussions with the children using prototype programs, we have created innovative game-like computer programs that engage and activate targeted neurocognitive systems with the intensity and consistency that preclinical studies indicate is necessary. Moreover, new research also demonstrates the complexity of neurodevelopment disorders and their treatment due to the interplay of genetic, environmental, physiological, psychological, social, primary and compensatory processes. For example, core features of ADHD alter interactions with the environment in ways that aggravate the symptoms themselves, create additional problems and block effective delivery of treatment. New paradigms that synergistically integrate brain, behavior and social perspectives and methods are therefore needed to treat these disorders. Our program is designed for six to eight year old children in order to intervene precisely when the clinically relevant neurofunctional systems are actively developing and when clinical symptoms first appear.

Abstract/Summary Attention-Deficit/Hyperactivity Disorder (ADHD) affects 11% of children and leads to adverse outcomes[1,2]. These include impaired psychosocial, educational, and neuropsychological development, lower achievement levels across domains, and distress, often continuing into adulthood[3?7]. Medications, while often effective in reducing certain ADHD symptoms, have many disadvantages, including misuse and side effects[8?15]. Behavioral interventions do not have these adverse effects, but they are not as effective[9,10]. Mindfulness has been the subject of increasing academic and clinical attention[16]. In recent years, it has been studied in adult populations for a variety of medical and psychiatric conditions, and it is known to be effective across disorders, including ADHD[17?34]. Moreover, we and others have shown that it improves attention and emotion regulation, and alters resting state brain activity and connectivity[35,36]. However, investigations in children and adolescents are far less common[37?40]. To our knowledge, mindfulness as an intervention for ADHD in elementary school children has not been systematically and rigorously studied. We propose to evaluate the feasibility and acceptability of Mindfulness-Based ADHD Treatment for Children (MBAT-C), a novel neuroscience-informed intervention for elementary school children, in an underserved area. MBAT-C is designed for children at precisely the age when ADHD-relevant neurocognitive systems are developing and clinical symptoms begin to appear. There is reason to believe that this innovative treatment will succeed in treating ADHD, given the overlap between neuroscientific mechanisms by which mindfulness exerts its effects and the neurobiology of ADHD[41?44]. Proposed mechanisms of mindfulness include modulation of subsystems of attention, suggesting that a treatment program that targets the attention regulation capacities impaired in elementary school children with ADHD may be efficacious. Forty-five children from Southwest Community Health Center in Bridgeport, CT will be recruited to participate in this randomized- controlled feasibility trial that will compare MBAT-C and medication. Aim 1 is to finalize the MBAT-C manual. Aim 2 is to evaluate the feasibility of MBAT-C on indices of recruitment, randomization, attendance, medication adherence, participation, retention, homework completion, acceptance, and teacher fidelity. Aim 3 is to preliminarily evaluate (within group) pre-, post-, and follow-up measures of ADHD severity, behavior, attention, executive function, working memory, and mindfulness. In accordance with the National Center for Complementary and Integrative Medicine?s framework for developing mind and body interventions, data from this feasibility study will be used in subsequent mechanism- based, multi-site feasibility, and multi-site efficacy studies that will be funded by R61/R33, U01, UG3/UH3+U24 grants, respectively, as well as a K23 training grant. The ultimate goal is to develop a non-pharmacologic intervention for children with ADHD with the efficacy of pharmacotherapy, but without its side effects.