Benjamin D. Greenberg, M.D., Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Treatment-resistant obsessive-compulsive disorder (OCD) remains a significant public health problem. Despite aggressive conventional treatment, suffering and functional impairment may continue, degrading quality of life. Our three collaborative pilot studies suggest that deep brain stimulation (DBS) of the ventral anterior limb of internal capsule and adjacent ventral striatum (VC/VS) is effective in otherwise resistant OCD. The devices (made by Medtronic, Inc.) are uniquely FDA-approved for brain stimulation, with proven efficacy and safety in Parkinson disease, tremor, and dystonia. In seven years of pilot OCD work, the brain target has been refined and effective DBS parameters identified. We propose a more definitive controlled trial. This collaborative, five-year study involves the three U.S. sites most experienced in DBS for OCD, including the NIMH pilot trial site. Forty-five patients will enroll in a randomized, parallel, controlled design. We will use well-established procedures to determine if patients are resistant to medication and behavior therapies. Independent assessments of diagnosis, treatment history, and the consent process will be required for enrollment. Patients will enroll, 11-12/year, over the first four years. We will compare masked active to sham stimulation over three months to obtain primary efficacy and safety data. The criterion for DBS response will be categorical and strict: improvement in both symptoms (a 35% Yale-Brown Obsessive- Compulsive Scale score reduction) and in global functioning. After the three-month controlled phase, open DBS will continue for 1-4 years to obtain long-term effectiveness and safety data. Positron emission tomography at baseline will be used to obtain brain metabolic predictors of response. A repeat scan after at least three months of stimulation will test the hypothesis that activity in corticobasal networks implicated in OCD will change after DBS. If successful, reversible DBS will offer hope to severely affected people with few treatment options. The imaging data will provide unique insight into brain networks predicting and mediating the response to DBS for intractable OCD. [unreadable] [unreadable] [unreadable]

A core feature of OCD is heightened anxiety resulting in avoidance of situations including rewarding activities. This suggests an abnormal balance between instrumental responses to avoid potentially negative stimuli and those to pursue reward. The most effective behavioral treatment for OCD (exposure and ritual prevention - ERP) teaches patients to extinguish avoidant and compulsive responses to feared situations. However, by definition ERP is unsuccessful for DBS candidates. Clinical experience indicates that patients unable to benefit from ERP before DBS did so afterwards, describing reduced avoidance of OCD triggers and increased pursuit of pleasurable activities. For this reason, measuring both extinction learning and regional brain metabolism in DBS patients is a promising route to improving our understanding of the neural circuitry involved in both ERP and DBS. Project 1 will assess how optimal DBS stimulation at the most clinically effective ventral capsule/ventral striatum (VCA/S) target changes activity within the orbital and medial PFC-BG circuits which have been strongly implicated in reward and avoidance, using FDG PET to measure brain metabolism. The PET experiments will test the hypothesis, informed by preliminary results (P1) and results from rat experiments (P4), that relative OFC and vmPFC activity will shift in favor of vmPFC after chronic DBS. We will interpret these network effects, and refine regions for PET analyses, in the context of the avoidance-reward network derived from information provided by P2, P3, & P4. Subsequent experiments in PI will test the hypothesis that chronic VCA/S DBS is associated with enhanced extinction, which in turn will correlate with improvement in OCD. Moreover, since the components of fronto-striatal circuitry that are implicated in OCD are also involved in both avoidance and reward across species, P1 will adapt and test a new paradigm, originally developed as a primate model (see P3), to assess avoidance- reward competition in OCD patients before and after DBS. Finally, data from P5 & P6 will provide critical information for developing hypotheses about mechanisms underlying changes in PET metabolic measures after DBS. They will also suggesting potential improvements in stimulation devices and paradigms to more effectively modify the circuits involved. RELEVANCE (See instructions): P1 will advance knowledge of brain circuit changes after DBS, and of the roles of extinction learning/recall and avoidance-reward competition as endophenotypes for processes in the development and maintenance of OCD symptoms. Better understanding changes in these circuits and behavioral endophenotypes will aid development of more targeted and effective treatments for OCD and related disorders

DESCRIPTION (provided by applicant): Deficient inhibitory control is a central feature of numerous mental disorders, including attention deficit hyperactivity disorder, substance abuse and dependence, and obsessive- compulsive disorder (OCD). As of yet, there are no established interventions broadly targeting deficits in inhibitory control, despite the relevance o this behavioral dimension to a range of disorders. Transcranial direct current stimulation (tDCS), a type of weak, noninvasive brain stimulation, has been found to improve inhibitory control in healthy individuals during laboratory tests and across behavioral training sessions when applied over the right inferior frontal gyrus (rIFG). Our long-term goal is to leverage a well-developed body of literature on the neural basis of response control and extend these findings in healthy populations in order to develop more effective treatment approaches for clinical populations with deficits in behavioral inhibition. This project will investigate a novel intervention using tDCS to enhance inhibitory control in one clinical population where problems with behavioral inhibition characterize the disorder: OCD. In the present study, 32 participants with OCD will be urn randomized to receive either active or sham tDCS over rIFG, delivered over 10 sessions in combination with exposure and response prevention (ERP). ERP is a first-line behavioral therapy for OCD which relies heavily on inhibition of OCD-related behaviors (i.e., compulsions). Given that problems with behavioral inhibition are a hallmark of OCD and that ERP relies heavily on successful inhibitory control, we expect that enhancing inhibitory control with tDCS in combination with ERP will ultimately lead to improved efficacy and/or efficiency of treatment outcomes. With this long-term objective in mind, our primary aim for this R21 Exploratory/Developmental Research Grant is to establish feasibility and acceptability of the research procedures and clinical intervention. We hypothesize that OCD patients will tolerate this combined ERP + tDCS treatment approach and will find it acceptable, as determined by rates of recruitment, treatment completion, and self-report. Our secondary aim is to gather evidence on preliminary efficacy of tDCS over rIFG as an adjunct to ERP for OCD. We hypothesize that patients in the group receiving ERP + active tDCS will show greater reduction in symptom severity over 10 sessions of the combined treatment than those receiving ERP + sham tDCS. Finally, we will aim to characterize the relationship between measures of inhibitory control and outcome of the combined intervention, using a traditional laboratory measure of inhibitory control as well as a face-valid, clinically relevant measure of OCD-related inhibitory control. For this aim, we hypothesize that response inhibition, as measured by the stop signal task, will improve more after ERP plus active vs. sham tDCS; that improvement in OCD severity will correspond to improved inhibitory control on the stop signal task; and that patients receiving ERP plus active tDCS will report less difficulty inhibiting compulsions during ERP exercises on a visual analog scale than those receiving ERP plus sham tDCS.

PROJECT SUMMARY The goals of this project are to improve our understanding of the effects of noninvasive neuromodulation on frontostriatal circuitry in OCD, and to work towards individualized device-based treatment. P4 proposes a series of related, small-scale mechanistic studies which are not intended as treatment trials. Our underlying rationale springs from longstanding research suggesting that cingulotomy is effective in intractable OCD. P4, working in close collaboration with Projects 1, 2 and 3, will first delineate specific brain areas within the dorsal anterior cingulate cortex (dACC), and presupplementary motor area (pSMA), that serve as critical connection nodes mediating neural network abnormalities in OCD. Next, P4 will identify which of three methods of noninvasive stimulation, targeting the same region; will most effectively modulate the network away from abnormalities seen in symptomatic individuals with OCD. We will use these methods to affect activity locally in the dACC and its functional connections. In each case, we will administer open-label stimulation to 20 OCD patients on consecutive weekdays for 6 weeks. MRI will be obtained before and after 6 weeks of stimulation. fMRI-measured activation of dACC during the MSIT task will serve as a biomarker of local dACC responsivity, rs-fMRI will be used to measure functional connectivity of dACC to the network. YBOCS OCD severity will be the primary clinical endpoint in analysis of how local dACC activation and connectivity are associated with symptom change. The simulation methods are: 1) tDCS over dACC-pSMA, representing neuromodulation below threshold for action potential generation. Our pilot work with tDCS in healthy participants suggests that the method might alter a behavioral endpoint (physical distress tolerance) plausibly linked to dACC function. 2) Deep TMS to target dACC directly, using the ?HAC? coil. Our colleagues have recent promising pilot data suggesting that high-frequency deep TMS to dACC, pSMA and other regions of overlying cortex produces therapeutic effects in OCD, associated with normalization of a physiological marker of dACC function, also abnormal in OCD. 3) Focal TMS to pSMA bilaterally. Focal rTMS, delivered chronically to the pSMA appears to show a therapeutic signal in OCD. The pSMA target was based on our group's previous work with TMS in OCD. This will lay the groundwork for application of these noninvasive neuromodulation methods to the large population of OCD sufferers experiencing inadequate improvement after conventional treatments

ADMINISTRATIVE CORE PROJECT SUMMARY The Administrative Core of the Butler COBRE Center for Neuromodulation (CCN) will be based at Butler Hospital. It will have leadership and administrative structures to support the PI, Deputy Director, Associate Director, Project Leaders, and the two research cores. It will build programs to ensure that the CCN achieves its scientific and technical goals of supporting rigorous research, building new, sustainable infrastructure and developing the careers of new faculty members. The Administrative Core will monitor participation of all project leaders and mentors; evaluate, facilitate, and track progress, and take steps to ensure fulfillment of the research and mentorship goals of the COBRE. Core services will include assisting and supporting COBRE investigators with preparation and submission of IRB protocol applications, manuscript submissions for publication, and grant applications. It will liaison closely with and provide administrative support for the CCN Research Cores. The Administrative Core will manage the pilot grant program; collect and maintain financial records for all CCN projects and for other COBRE activities and function; track use and fees invoice for use of Research Cores, prepare the annual Progress Report; coordinate of the activities of the Internal Mentoring and Advisory Committee, the External Advisory Committee, and the Institutional Advisory Committee; organize the COBRE Center?s annual retreat and regular research meetings; and facilitate dissemination of results and sharing of COBRE resources. The Administrative Core will also manage interactions with other Rhode Island COBREs and IDeA Networks of Biomedical Research Excellence (INBRE) Centers in Rhode Island, as well as with collaborating entities at, or affiliated with, Brown University, including the Brown Institute for Brain Science (BIBS), and the Center for Neurorestoration and Neurotechnology (CfNN). Key functions of the core will be governance, communication, and evaluation. !

PROJECT SUMMARY The COBRE Center for Neuromodulation (CCN) will be centered at Butler Hospital, a freestanding psychiatric and neuropsychiatric hospital affiliated with the Alpert Medical School at Brown University. This COBRE will create key infrastructure and support a core group of interdisciplinary investigators to build a self-sustaining center of excellence in clinical-translational brain research. Its overall goal is to advance the use of noninvasive neuromodulation in circuit-based therapies for neuropsychiatric disorders. This application brings together three highly promising junior investigators, who will use methods of noninvasive brain stimulation (transcranial magnetic and transcranial electrical stimulation) and neuroimaging tools (structural and functional MRI). They will work together on clinical-translational research on brain circuits relating to symptoms and dimensions of illness. Their areas of interest are impulsive behavior, PTSD, and obsessive-compulsive disorder (OCD). Using experienced, highly skilled mentors working within the structure of an Administrative Core, the CCN will advance the careers of these talented young researchers towards the next level of research independence. The CCN will support two new research cores: the Design and Analysis Core (DAC) and the Neuroimaging and Neuromodulation Core (NNC) at Butler Hospital. These cores will provide essential infrastructure needed to successfully carry out each project. This includes statistical and methodological consultation and expertise needed to design and analyze the studies proposed (DAC), and equipment, technical support, and expertise necessary for stimulation implementation and acquisition of neuroimaging data (NNC). The Administrative Core will also support pilot grants relating to our theme of translational research in neural circuits and disease. These grants will be awarded yearly in years 2 to 5 of the Center. The CCN will establish Butler Hospital as a national leader in this exciting field of translational medicine, which will expand research and clinical application of noninvasive brain stimulation across disorders of brain and behavior. It will unify an interdisciplinary community in clinical-translational research of neuropsychiatric illness, for the ultimate benefit of patients.