David R. Rosenberg - US grants

The candidate is an Assistant Professor of Psychiatry, Board Certified in General and Child Psychiatry. He is proposing a career development plan designed to acquire the necessary expertise to conduct neurodevelopmentally-informed studies of childhood Obsessive Compulsive Disorder (OCD) utilizing a systems-neuroscience approach. To achieve this aim, the candidate will acquire general clinical research skills, and focused training in neurobehavioral and neuroimaging methodologies. In recent years, there has been an increased recognition of OCD as a severe, high prevalent and chronically disabling disorder. Despite the fact that OCD is three times more common than schizophrenia and half as common as depression, there has been surprisingly little systematic investigation of the disorder. Because OCD emerges during childhood or adolescence in 33% to 50% of cases, studies of the illness during childhood near the point of illness onset are of particular importance in order to study the psychobiology of the disorder before the course of illness confounds and treatment effects confound data, and to determine whether neurodevelopmental abnormalities contribute to the etiology of the disorder. To date, however, there has been no systematic study in young- onset, medication-naive OCD patients close to the point of illness onset. Neurobiological models for OCD have consistently implicated orbital prefrontal cortical (OrbPFC) and basal ganglia circuits in the pathophysiology of this disorder, but they typically have not utilized a developmental framework for conceptualizing or studying the illness. The applicant has conducted studies demonstrating disturbances of response suppression in OCD, a neuropsychological function believed to be subserved largely by OrbPFC. A developmental neurobiologic approach to examine brain circuits involved in neuropsychiatric disorders of childhood such as OCD is critical to the understanding of how developmental brain changes can lead to psychiatric illness, and to the modification of its presentation with age. During the SDAC award period, the candidate proposes to develop expertise in: 1) clinical research methods related to diagnostic assessment, 2) the neurobehavioral and neuroimaging assessment of fronto-striatal circuitry implicated in the pathophysiology of OCD, and 3) developmentally informed strategies for studying the interplay of psychological and brain development. This training program will prepare him to undertake neurodevelopmentally informed studies of OCD designed to investigate the role of anatomic and neurophysiologic disturbances in fronto-striatal circuitry in childhood OCD.

bioimaging /biomedical imaging; disease /disorder onset; drug screening /evaluation; obsessive compulsive disorder; sign /symptom

DESCRIPTION: (Provided by applicant): In recent years, there has been increased recognition of adolescent major depressive disorder (MDD) as a severe, highly prevalent and chronically disabling disorder. By most measures, adolescent MDD is continuous with adult MDD, including clinical course, secular trends, and psychobiologic correlates. Studies of the illness during adolescence can, therefore, clarify the contribution of neurodevelopmental abnormalities to the pathogenesis of the disorder. Neurobiological models for MDD have consistently implicated temporo-limbic, prefrontal cortical and basal ganglia circuits in the pathophysiology of the disorder. Strikingly, children and adolescents with MDD have been largely overlooked in brain imaging studies. In particular, there are no published studies using magnetic resonance spectroscopy (MRS) to investigate brain chemistry in depressed children and adolescents. Yet the inclusion of children and adolescents in these types of studies is critical in order to determine whether abnormalities in brain chemistry in depressed patients are the consequence of altered development over the life span, or if they are present even early in development thus representing a risk factor for subsequent development of depression. Preliminary studies by the applicants using MRS suggest increased caudate and anterior cingulate choline concentrations in psychotropic-naive pediatric MDD patients compared to age and sex matched controls. No differences in choline levels were observed between MDD patients and controls in occipital cortex choline levels. Pilot studies showed reductions in caudate but not occipital choline concentrations after 12 weeks of effective monotherapy with the selective serotonin reuptake inhibitor (SSRI) paroxetine. In this project, proton MRS will be used for the direct, in vivo and noninvasive evaluation and comparison of the impact of paroxetine vs. cognitive behavioral therapy (CBT) on brain chemistry as related to treatment efficacy in adolescents with MDD. Such an approach will help 1) determine whether psychotropic-naive adolescents with MDD differ from healthy controls in neurochemistry and 2) determine whether effective treatment with paroxetine and CBT results in localized and treatment-specific changes in brain chemistry. An understanding of the neurochemical disturbances in MDD may be important for the development of new treatment approaches.

[unreadable] DESCRIPTION (provided by applicant): This is a planned competing renewal of the Principal Investigator's K24 Midcareer Investigator in Patient-Oriented Research (NIMH K24MH002037-05). The overall scientific objectives of this award are (1) to use time liberated by the K24 renewal award to further develop, evaluate and disseminate biological outcome markers of obsessive-compulsive disorder (OCD) and determine their relevance for improved diagnostic assessment and treatment and (2) to recruit and train junior scientists in the methods and applications of treatment outcome studies using biological markers as moderator (present at baseline) and mediator (changing with treatment) variables in childhood onset neuropsychiatric disorders. The initial K24 award, which emphasized the integration and translation of brain imaging measurement as it relates to neurodiagnostic assessment and treatment of OCD, ends in 2006. During the first 4 years of the K24 award, Dr. Rosenberg will have published more than 40 manuscripts; successfully concluded two and launched three (with two more studies in preparation) NIMH-funded translational studies combining biological and behavioral/symptomatic predictor and outcome variables in pediatric OCD and depression; developed methodological expertise unusual for a child and adolescent psychiatrist; and successfully mentored more than two dozen junior and mid-career investigators. Thus, Dr. Rosenberg more than filled the primary aims of the K24 Program Announcement, which emphasizes scientific productivity in patient-oriented research and mentoring activities. This competing continuation application sets out research, didactic, and mentoring agendas designed to make clear the added value of the K24 award. The research agenda includes further developing, evaluating and disseminating biological outcome markers in childhood onset neuropsychiatric disorders, such as OCD. Emphasis is placed on the translational components of this research toward enhanced diagnostic assessment and treatment intervention. Serving the research agenda, the didactic agenda provides for training in newer neuroimaging methods, psychiatric genetics and in relevant statistical data analyses of these complex datasets (e.g., SAS programming language). The mentoring agenda provides for ongoing and new mentoring/consultative activities and for leadership in the area of research workforce issues in child and adolescent psychiatry. By providing stable salary support uninterrupted by non- research patient care and administrative duties, the K24 competing continuation will sustain and promote practical and theoretical contributions to the candidate's chosen research area. [unreadable] [unreadable]

DESCRIPTION: (Provided by applicant): In recent years, there has been increased recognition of adolescent major depressive disorder (MDD) as a severe, highly prevalent and chronically disabling disorder. By most measures, adolescent MDD is continuous with adult MDD, including clinical course, secular trends, and psychobiologic correlates. Studies of the illness during adolescence can, therefore, clarify the contribution of neurodevelopmental abnormalities to the pathogenesis of the disorder. Neurobiological models for MDD have consistently implicated temporo-limbic, prefrontal cortical and basal ganglia circuits in the pathophysiology of the disorder. Strikingly, children and adolescents with MDD have been largely overlooked in brain imaging studies. In particular, there are no published studies using magnetic resonance spectroscopy (MRS) to investigate brain chemistry in depressed children and adolescents. Yet the inclusion of children and adolescents in these types of studies is critical in order to determine whether abnormalities in brain chemistry in depressed patients are the consequence of altered development over the life span, or if they are present even early in development thus representing a risk factor for subsequent development of depression. Preliminary studies by the applicants using MRS suggest increased caudate and anterior cingulate choline concentrations in psychotropic-naive pediatric MDD patients compared to age and sex matched controls. No differences in choline levels were observed between MDD patients and controls in occipital cortex choline levels. Pilot studies showed reductions in caudate but not occipital choline concentrations after 12 weeks of effective monotherapy with the selective serotonin reuptake inhibitor (SSRI) paroxetine. In this project, proton MRS will be used for the direct, in vivo and noninvasive evaluation and comparison of the impact of paroxetine vs. cognitive behavioral therapy (CBT) on brain chemistry as related to treatment efficacy in adolescents with MDD. Such an approach will help 1) determine whether psychotropic-naive adolescents with MDD differ from healthy controls in neurochemistry and 2) determine whether effective treatment with paroxetine and CBT results in localized and treatment-specific changes in brain chemistry. An understanding of the neurochemical disturbances in MDD may be important for the development of new treatment approaches.

DESCRIPTION (provided by applicant): This is a competitive renewal application of the Principal Investigator's grant award RO1MH59299. Obsessive compulsive disorder (OCD) is a severe, highly prevalent and chronically disabling disorder that emerges during childhood or adolescence in as many as 80% of all cases. The clinical phenomenology/nosology and empirical treatment for pediatric OCD have been well delineated making pediatric OCD a leading candidate for developmental neurobiologic study. OCD is also less vulnerable to ambiguities in expression across the lifetime and permits us to study the disorder close to illness onset while remaining applicable to adult subjects. The overall goal of this project, which combines treatment and magnetic resonance imaging expertise at Wayne State University, is to further explicate the underlying neurobiology of pediatric OCD. The effectiveness of treatment with either a selective serotonin reuptake inhibitor (SSRI) or cognitive behavioral therapy (CBT) for pediatric OCD has been demonstrated. Exciting new pilot data under NIMH grant mechanisms (R01MH59299, K24MH02037) suggest that both the SSRI, paroxetine, and CBT return neurobiological functioning toward normal in pediatric OCD patients who improve symptomatically, but perhaps through different mechanisms. This convergence of findings from neurodiagnostic and treatment research presents a unique opportunity to deepen our understanding of the etiopathogenesis of pediatric OCD in the context of the clinically relevant question, "Which treatments for which child with which set of subgrouping characteristics (e.g., SSRI or CBT for patients with increased choline and decreased N-acetyl-aspartate)?" Recent developments in neuroimaging allow for the direct and noninvasive monitoring of brain neurochemistry in multiple brain regions via proton magnetic resonance spectroscopic imaging (1H MRSI). Compounds that can be measured include the putative neuronal marker, N-acetyl-aspartate (NAA), and choline (Cho). Preliminary studies suggest localized functional neurochemical marker alterations in ventral prefrontal-striatal-thalamic circuitry. No alterations were observed in regions not implicated in the pathogenesis of OCD, e.g., dorsolateral prefrontal cortex, parietal white matter and occipital cortex. Using targeted 1H MRSI to define the primary dependent variables, we propose to employ a 2 (treatment) x 5 (repeated assessments) experimental design to further explicate the neurochemistry of childhood OCD before and during 12 weeks of acute treatment with either paroxetine or CBT and after 6 months of naturalistic follow-up treatment. An untreated normal control group is included to characterize selected MRI markers with regard to normalization with treatment. This combination of biological and behavioral/symptomatic predictor and outcome variables enacts the call for translation approaches to mental illness and may potentially lead to a better mechanistic understanding of pediatric OCD and, in turn, to new diagnostic and treatment approaches.

DESCRIPTION (provided by applicant): This is a planned competing renewal of the Principal Investigator's K24 Midcareer Investigator in Patient-Oriented Research (NIMH K24MH002037-05). The overall scientific objectives of this award are (1) to use time liberated by the K24 renewal award to further develop, evaluate and disseminate biological outcome markers of obsessive-compulsive disorder (OCD) and determine their relevance for improved diagnostic assessment and treatment and (2) to recruit and train junior scientists in the methods and applications of treatment outcome studies using biological markers as moderator (present at baseline) and mediator (changing with treatment) variables in childhood onset neuropsychiatric disorders. The initial K24 award, which emphasized the integration and translation of brain imaging measurement as it relates to neurodiagnostic assessment and treatment of OCD, ends in 2006. During the first 4 years of the K24 award, Dr. Rosenberg will have published more than 40 manuscripts;successfully concluded two and launched three (with two more studies in preparation) NIMH-funded translational studies combining biological and behavioral/symptomatic predictor and outcome variables in pediatric OCD and depression;developed methodological expertise unusual for a child and adolescent psychiatrist;and successfully mentored more than two dozen junior and mid-career investigators. Thus, Dr. Rosenberg more than filled the primary aims of the K24 Program Announcement, which emphasizes scientific productivity in patient-oriented research and mentoring activities. This competing continuation application sets out research, didactic, and mentoring agendas designed to make clear the added value of the K24 award. The research agenda includes further developing, evaluating and disseminating biological outcome markers in childhood onset neuropsychiatric disorders, such as OCD. Emphasis is placed on the translational components of this research toward enhanced diagnostic assessment and treatment intervention. Serving the research agenda, the didactic agenda provides for training in newer neuroimaging methods, psychiatric genetics and in relevant statistical data analyses of these complex datasets (e.g., SAS programming language). The mentoring agenda provides for ongoing and new mentoring/consultative activities and for leadership in the area of research workforce issues in child and adolescent psychiatry. By providing stable salary support uninterrupted by non- research patient care and administrative duties, the K24 competing continuation will sustain and promote practical and theoretical contributions to the candidate's chosen research area.

DESCRIPTION (provided by applicant): This is a competitive renewal application of the Wayne State Principal Investigator's (Rosenberg) grant award, R01MH59299. Obsessive compulsive disorder (OCD) is a severe, prevalent, and chronically disabling disorder that emerges during childhood in as many as 50% of all cases. The overall goal of this project, which combines the unique clinical assessment, magnetic resonance imaging, and genetics expertise of three performance sites - Wayne State (neuroimaging of pediatric OCD), University of Michigan (family and molecular genetic studies of early-onset OCD) and University of Toronto (extensive genetic studies of glutamate receptor and transporter genes in OCD) - is to exploit the emerging field of imaging genetics in a critical test of the glutamate hypothesis of OCD. Preliminary studies from Rosenberg's group (R01MH59299, K24MH02037) suggest that a glutamatergically-mediated thalamocortical-striatal dysfunction may serve as a pathophysiological marker in pediatric OCD. Independent findings by the Hanna (R01MH53876, K20MH01065) and the Arnold and Kennedy groups demonstrate a significant association of the glutamate transporter gene, SLC1A1, and glutamate receptor gene, GRIN2B, with early-onset OCD. Building on long-standing existing collaborations among the three sites, exciting new pilot data in pediatric OCD patients demonstrates a significant association between regional brain glutamatergic concentrations, particularly in the anterior cingulate and the GRIN2B-rs1019385 polymorphism. Significant associations between increased left, but not right orbital frontal and increased anterior cingulate volume (R>L) with the rs1805476 variant of GRIN2B were identified in OCD patients. The GRIN2B-rs1019385 variant exhibited a non-significant trend towards association with decreased left but not right caudate volume. The SLC1A1 rs3056-AA genotype was significantly associated with increased right and left thalamic volume. Thus, GRIN2B and SLC1A1 sequence variations may be associated with differences in volume and glutamatergic concentrations within brain regions implicated in the pathogenesis of OCD. High field (3 Tesla) proton magnetic resonance spectroscopy (1H MRS) can uniquely distinguish the subcomponents of the glutamatergic resonance (glutamate and glutamine), as well as measure other compounds including the putative neuronal marker, N-acetyl-aspartate, choline compounds and creatine. Targeted 1H MRS and volumetric imaging at 3T at the Children's Hospital of Michigan at Wayne State will be combined with genotyping of 37 polymorphisms in the genes encoding GRIN2B and SLC1A1 (University of Toronto) to examine the effects of these variants on thalamocortical-striatal circuitry in 200 pediatric OCD patients, 7-19 years, and 200 age and sex-matched healthy controls. The combined study of biological, genetic and behavioral/symptom variables enacts the call for translational approaches to mental illness outlined in PA-07- 092, Collaborative R01s for Clinical and Services Studies of Mental Disorders, which may lead to a better understanding of pediatric OCD and, in turn, to new diagnostic and treatment approaches. PUBLIC HEALTH RELEVANCE: Obsessive-compulsive disorder (OCD) is a chronic and disabling disorder that costs the economy over $2 billion annually and affects approximately one million children and adolescents in the United States, making it a significant public health problem. There is a pressing need for studies that shed light on the biology of the disorder in order to improve our ability to diagnose, treat, and prevent the disorder. By combining brain imaging and genetics, as we do in this proposal, we can better understand the biology of pediatric OCD and, in turn, develop more effective treatments for this severe form of childhood psychopathology.

? DESCRIPTION (provided by applicant): Obsessive-compulsive behaviors (OCB) are common in children and adolescents. In addition to being the core features of obsessive-compulsive disorder (OCD), OCB are often associated in youth with tic, grooming, generalized anxiety, and autistic spectrum disorders. This competitive renewal application combines the unique clinical assessment, magnetic resonance imaging, and genetics expertise of three performance sites: Wayne State University (WSU), University of Michigan (UM), and the Hospital for Sick Children, affiliated with the University of Toronto (UT). The overall goal of this project - which extends prior and existing NIMH-funded research including Drs. Rosenberg and Diwadkar's neurodiagnostic imaging-genetic studies (K24MH02037; R01MH59299), Dr. Hanna's family, molecular genetic, and action monitoring studies (R01MH53876; R01MH59299; K20MH01065; R01MH101493) and Dr. Arnold and colleagues' extensive genetic studies in pediatric OCD (R01MH59299; R01MH101493) - is to exploit the emerging field of imaging genetics to 1) determine the relationship between alterations in functional connectivity of fronto-striatal-thalamic circuitry (FSTC) as measured by task and resting state functional magnetic resonance imaging (fMRI) and childhood OCB; 2) identify common, rare, and novel genetic variants associated with alterations in connectivity of FSTC as measured by fMRI; 3) clarify whether fMRI measured alterations in FSTC are potential intermediate phenotypes of OCB by determining whether they mediate the effects of genetic variants on OCB; and 4) combine structural MRI data from this study and our previous imaging genetics study to identify genetic variants associated with anterior cingulate volume and other FSTC structures in 1000 youth. The Child Behavior Checklist Obsessive-Compulsive Scale (CBCL-OCS) shows substantial heritability in pediatric twin studies. Heritability of structural and functional abnormalities in STC has also been demonstrated in OCD patients and their unaffected relatives. By using a research design consistent with the Research Domain Criteria (RDoC), targeted high field (3 Tesla) fMRI at WSU will be combined with comprehensive genomic assessment in 200 child psychiatric outpatients with CBCL-OCS scores = 5, 200 child psychiatric outpatients with CBL-OCS scores < 5, and 200 matched healthy controls aged 8-18 years. We will examine for common and rare genomic variants associated with FSTC dysregulation and conduct whole genome sequencing (WGS) in 60 subjects with FSTC dysregulation in the highest 10% of the distribution and compare to 60 subjects with FSTC dysregulation in the lowest 10% of the distribution to identify rare and novel variants of possible clinical significance. This unique study enacts the call for translational approaches to mental illness outlined in PAR- 14-165 by examining multiple genomic variants in FSTC in a spectrum of common, but understudied disorders in youth. Our work will provide a better understanding of the impact of genetic variants on FSTC dysregulation in the pathogenesis of OCB and lead to new diagnostic, treatment, and prevention strategies.

PROJECT SUMMARY/ABSTRACT This is a competitive renewal of grant award R01MH59299, enhanced by significant new in vivo multi-modal functional imaging directions (1H fMRS and fMRI). These innovations facilitate a never-before attempted understanding of specific aspects of dysfunctional neurobiology in youth with Obsessive Compulsive Disorder (OCD). OCD is a severe, prevalent, and chronically disabling disorder emerging during childhood/adolescence (80% of cases) with well-delineated clinical phenomenology/nosology. However, the relationship between the clinical phenomenology and modes of brain dysfunction is only generally understood. For example, our prior work using 1H MRS and fMRI has implicated general neurochemistry and function of the dorsal anterior cingulate cortex (dACC). However, dACC engages in contextually dependent excitatory or inhibitory modes of behavior/control that are likely to induce changes in the steady-state excitatory and inhibitory (E/I) synaptic drive of the dACC. However, which of these response modes (and the shift in the E/I balance they induce) is particularly relevant to OCD, and its sensitivity to OCD dimensions (Obsessions or Compulsions) and comorbid anxiety symptoms are completely unknown. Here, we aim to parse apart dysfunction in excitatory and/or inhibitory tone of the dACC in relation to OCD. In doing so, we provide a transformative extension of evidence supported under prior grant iterations demonstrating dysfunctional activation and connectivity of the dACC in OCD youth. Now, we use specifically designed motor paradigms with distinct excitatory or inhibitory response modes which induce complementary demands on dACC function. The tasks are administered during multi- modal functional imaging acquisition that includes ¹H fMRS and fMRI. 1H fMRS, which permits understanding of the functional biochemistry of the dACC, is uncoupled from hemodynamics and is ideally suited to investigate functional imbalances in the E/I synaptic drive of the dACC. In the same participants and using the same tasks, fMRI will be acquired in the service of understanding changes in task-induced whole brain network dynamics and connectomics. This unique project combines the clinical and multi-modal functional neuroimaging expertise at Wayne State University to achieve a transformative explication of the dysfunctional neurobiology of OCD. The combination of ¹H fMRS and fMRI will be acquired in 100 OCD youth and 100 matched healthy controls (12 - 19 years), allowing us to measure: a) brain function via glutamate modulation (¹H fMRS) and the BOLD signal (fMRI); b) brain plasticity related to shifts in the E/I synaptic drive (1H fMRS); and c) network dynamics and connectomics (fMRI). In addition to providing compelling and clinically relevant in vivo characterization of disordered excitatory vs. inhibitory signaling in the pathophysiology of OCD, the proposal provides a scientific blueprint for how multi-modal imaging can explicate in vivo brain function. The accumulated knowledge will promote better diagnostic and treatment approaches through a more detailed characterization of OCD pathophysiology.