Neuropsychopharmacology (2010) 35, S1–S77 & 2010 Nature Publishing Group All rights reserved 0893-133X/10 www.neuropsychopharmacology.org S1 Monday, December 6, 2010 seemed to benefit most, suggesting that behavioral phenotypes related to fear and avoidance are important in the therapeutic response. These hypotheses are a focus of ongoing translational research by ourselves and collaborators. More long-term data are Panel Session essential to optimizing patient selection. Some will be obtained in DBS for OCD: Clinical Outcomes, Neuroimaging, Circuitry, an ongoing NIMH-supported controlled trial of DBS for OCD. An and Fear Regulation essential role would be played by creation of a data registry for patient characteristics and outcomes, as suggested by investigators in the field and by NIMH. Long-Term DBS for OCD Disclosure: B.D. Greenberg: Part 1; Medtronic, Inc.; Jazz Pharmaceu- Benjamin D. Greenberg*, Donald Malone, Wayne Goodman, Herbert ticals. Part 3; Medtronic, Inc. Ward, Michael Okun, Kelly Foote, Andre Machado, Gerhard Friehs, Ali Rezai, Nicole McLaughlin, Paul Malloy, Cynthia Kubu, Steven Rasmussen Deep Brain Stimulation for OCD: Now Different Cortical Bundles Really Get to Their Targets Butler Hospital, Providence, RI, Cleveland Clinic, Cleveland, OH, Mt. Suzanne Haber* Sinai Medical Center, New York, NY, University of Florida, Gainesville, FL, Scott and White Hospital, Temple, TX, Ohio State University University of Rochester Rochester, NY Medical Center, Columbus, OH, Butler Hospital/Brown University, Providence, RI Background: Dysfunction of the ventral prefrontal cortex (vmPFC) and orbital cortex (OFC), strongly associated with the pathophysiology Background: DBS of the Ventral Capsule/Ventral Striatum (VC/VS) for of OCD and part of the cortico-basal ganglia circuit, are connected to highly refractory obsessive-compulsive disorder (OCD) has been studied the thalamus, amygdala, and brainstem. DBS at the ventral capsule/ since 2001 in the US. The FDA approved this therapy for humanitarian ventral striatal site (VC/VS) targets this network. Each electrode has 4 use in 2009 on the basis of open-label pilot data. Although 3 year contact sites spaced strategically to potentially involve different nodal followup data have been reported, longer-term outcomes are important points within the circuit. The goal of these experiments was to: 1. 1) clinically in balancing risks, benefits, and burdens of this intensive Determine organizational rules that govern the trajectory of ventral treatment, and 2) for understanding behavioral phenotypes and PFC efferent fiber bundles; 2. Determine which bundles are affected by associated neurocircuit effects related to benefit. DBS at each contact; and 3. Develop an electric field neurostimulation Methods: Pilot patients from three US centers (Butler Hospital/Brown model around representative targets to determine likely volumes of Univ., Cleveland Clinic, Univ. Florida, N ¼ 16) were followed long- effect for the commonly used clinical parameters. itudinally between three and eight years post implantation. Methods: 3-D reconstructions of the vmPFC and OFC fiber bundles Results: Presurgical Yale-Brown OCD Scale (YBOCS) severity was were created from conventional anatomical tracings following tracer 34.4±0.6 (SEM, range 31-40), indicating severe illness in a population injections into the different prefrontal areas in primates. Human selected for surgery only after failure of aggressive behavioral electrode representations were adjusted for size and imported into the treatment and medication trials. Mean YBOCS severity at 1 year was primate 3-D model. Using neurostimulation modeling we visualized 22.4±2.3 (range 3-30), and remained essentially unchanged on a group stimulus spread at the VC/VS site to determine how different basis thereafter: year four, mean YBOCS ¼ 22.1±1.4 (range 14-33), parameter alters the inclusion of fibers at each contact. All experiments year seven: 21.0±0.25 (range 20-22). Individual means during were conducted in accordance with the ILAR Guide for the Care and long-term DBS (3-8 years) ranged from 11 to 31. Global Assessment Use of Laboratory Animals and were approved by The University of Functioning (GAF) scores were 37.1±1.6 at baseline, consistent Committee on Animal Resources. with severe impairment. GAF scores improved to a mean range of Results: Fibers from ventral prefrontal areas follow certain organiza- 52-59 over years one to seven. During followup, patients received tional rules. The route taken by fibers from different ventral prefrontal continued pharmacotherapy and behavior therapy, although the regions through the capsule depends largely on their medial-lateral number of medications prescribed decreased by one to two on location. Axons from medial regions remain in the most ventral parts, average vs. persurgical baseline in patients who improved. Adverse including the small fascicules embedded within the VS. In contrast, events related to surgery infection, hemorrhage, a single seizure) axons from lateral OFC areas travel more dorsal in the capsule. Within had resolved by months after implantation. Mood, anxiety, and each group of fibers, those traveling to the brainstem are located OCD symptoms worsened mildly, moderately, or severely when DBS ventral to those traveling to the thalamus. Electrode placements show was interrupted throughout chronic stimulation. Two of 16 patients which fibers are captured at each contact. Changing the stimulation died during followup of unrelated medical causes (in years one and parameters may or may not capture additional fiber destinations, eight). An additional 5/16 were not receiving continuous ongoing depending on the contact. stimulation for reasons including suboptimal responses and/or Conclusions: These data illustrate the organization of each prefrontal barriers to receiving device replacements over time. Patients whose cortical pathway through the internal capsule and the relationship main OCD-related impairment were due to symptoms involving between bundles arising from different cortical areas. Combining the ‘‘incompleteness’’ (aimed at attaining a feeling that actions or the fact that fibers traveling to the brainstem from each cortical area travel environment were ‘‘right’’) improved less overall than individuals ventral to those going to the thalamus from that same cortical area, whose symptoms focused on harm avoidance. But at least one with the overall medial to lateral topographic arrangement of cortical incompleteness patient was a full responder (35% + decrease in YBOCS fibers within the capsule, demonstrates a complex set of fibers severity). associated each contact. Taken together these data show that each Discussion: Therapeutic effects DBS targeting a fronto-basal brain contact captures a different combination of brainstem and thalamic network implicated in OCD and related disorders appear sustained fibers from diverse prefrontal areas. This combination will vary over years of continuing stimulation. Average severity changed from according to the stimulation parameters used. These data also suggest very severe to moderate, paralleled by improved functioning. However, that brainstem fibers may be a critical feature to the effectiveness of about one-third of patients no longer received DBS three + years after DBS for OCD. implantation. Patients with symptoms based in avoidance of harm Disclosure: S.N. Haber: Part 1; Eli Lilly Co., Medtronic. ACNP 49th Annual Conference S2 DBS-Like High Frequency Stimulation of Fibers Within the Rat of fear extinction in OCD patients using fMRI and psychophysiological Ventral Striatum Strengthens Fear Extinction and Induces Plasticity measures. OCD patients and matched healthy controls underwent a in Extinction Circuits two-day fear conditioning and extinction protocol, previously deve- Gregory J. Quirk*, Jose Rodriguez-Romaguera, Christian loped and validated. All participants underwent the experimental Bravo-Rivera, Fabricio H. M. Do Monte protocol while they are in an fMRI scanner. Skin conductance response was monitored throughout the experiment and was used as the University of Puerto Rico School of Medicine, San Juan, PR behavioral index of conditioning. On Day 1, subjects received Background: Deep brain stimulation (DBS) of the ventral capsule/ conditioning followed by extinction, using photographs of colored ventral striatum is effective in reducing depression and anxiety lights as CSs. On day 2, extinction recall was assessed (test for symptoms in refractory obsessive compulsive disorder (OCD), but extinction memory). Our preliminary data indicate that OCD patients little is known about how DBS alleviates anxiety disorders. Persistent showed intact fear acquisition and extinction training on day 1. On day avoidance responses in OCD and other anxiety disorders may be due 2, however, OCD patients showed exaggerated fear responses, indexed to a failure of extinction to reduce conditioned fear reactions. We by SCR, suggesting impaired recall of the extinction (safety) memory. therefore used a rat model to study the effects of DSB-like stimulation Functional MRI analysis shows failure to activate the vmPFC while of the ventral striatum on fear expression and extinction in an auditory OCD patients are recalling the extinction memory. These patterns of fear conditioning task. Following a recent study in anesthetized rats psychophysiological and brain dysfunctions observed in the OCD (McCraken and Grace, 2009), we targeted the nucleus accumbens core cohort