My research is focused on the pathogenesis and treatment of obsessive compulsive disorder (OCD). Funded projects include a ten-year longitudinal observational study of 400 patients with OCD, a multicenter genetic linkage study of OCD and neurosurgical approaches to treating refractory OCD patients using the gamma knife and deep brain stimulation. We also have a multicenter translational grant that combines electrophysiology, neuroanatomy, and imaging to explore the neurocircuitry of OCD.

Biography

Steven A. Rasmussen, MD, MMS is the Interim Chair and a Professor of the Department of Psychiatry and Human Behavior at the Alpert Medical School and is the Medical Director at Butler Hospital. He has been repeatedly listed among the Best Doctor's in America as well as the most Highly Cited for Psychiatry.
Dr. Rasmussen was a member of the second graduating class of the PLME program and received his MMS and MD from Brown Medical School in 1977. He completed his residency in psychiatry at Yale in 1983. Following a two year obligation with the National Health Services Corps in North Kingdom Vermont, Dr. Rasmussen joined the Brown faculty and Butler Hospital in 1983. He is currently the Interim Chair of the Department of Psychiatry and Human Behavior at the Alpert Medical School of Brown University and has been Medical Director at Butler Hospital since 1998.
Dr. Rasmussen is an internationally recognized expert in the course and treatment of obsessive compulsive disorder (OCD). More recently his primary research interest has been in neurosurgical approaches to intractable OCD and depression and the neurocircuitry of OCD. He is currently funded by four R0-1s from the NIMH including studies of the longitudinal course of OCD, neurosurgical approaches to treatment, understanding the neurocircuitry underlying DBS effects in OCD, and a genome wide association study of OCD. He is the author or coauthor of over 100 peer reviewed publications and has given many invited presentations on the subject of OCD around the world. He has been a leader in developing bridges between campus based and hospital based brain science faculty at Brown University.

Institutions

Bh

Research Description

Our group has been studying the efficacy and safety of gamma capsulotomy in the treatment of intractable OCD. 32 patients have now been operated on and followed for a minimum of one year and a maximum of five years. 13 of these patients had a two stage surgical procedure and 17 patients have had a single stage procedure. The first group of 15 patients received bilateral single doses of 180 Gray gamma irradiation to the anterior limb of the internal capsule. At an average of eight moths following the procedure, only one out of the 15 patients was much or very much improved on the CGI. There was no significant change in Yale Brown Obsessive Compulsive Scale (YBOCS) ratings. 13 of the 15 patients received a second stage procedure that was a bilateral lesion placed just ventral to the initial lesion in the coronal plane. Six out of the 15 patients were much to very much improved at one-year follow-up. Two of 15 patients had a small asymptomatic caudate infarction following the procedure. Other adverse events included headache and cerebral edema following the procedure. No adverse effect on personality or neuropsychologic testing was found. 17 additional patients have now been given two shots bilaterally in a single stage procedure to the anterior limb of the internal capsule. Follow-up at one year has shown that forty percent of patients appear to be much or very much improved on the CGI. The rate of improvement is faster with the double shot procedure than the staged procedure, but the incidence of cerebral edema is increased with the two shot procedure. One patient out of 32 has developed a probable mild frontal syndrome with apathy and amotivation. Additional data related to the safety and efficacy of this procedure in the treatment of intractable OCD will be discussed. In summary, forty percent of previously treatment-intractable patients appear to be significantly improved with gamma capsulotomy with minimal adverse effects.

The OCD Collaborative Genetics Group has completed a genome-wide linkage study in a large collection of pedigrees segregating OCD. The results are promising; four genomic regions were identified that are likely to include susceptibility genes and merit intensive follow-up. In addition to pursuing these regions in this proposal, we propose to extend our sample with the recruitment of additional families, using the identical criteria and assessment protocol, to replicate our findings and to identify new candidate regions. To accomplish this goal, we have expanded the Collaborative group to include two additional centers, the Universities of Florida and Minnesota, and propose to collect an additional 530 families (excluding 67 that are available now). A genome-wide linkage scan, using a panel of 10,000 single nucleotide polymorphisms (SNPs), will be conducted on these additional families to replicate the original findings and, using the entire sample, to identify additional genomic susceptibility regions. Simultaneously, a sample of triads (N = 550, affected proband and both parents) will be recruited and assessed to strengthen the power of association and linkage disequilibrium in the final phase of this proposal, which is to refine the regions further and identify susceptibility genes using fine-mapping and gene sequencing techniques. Analytic strategies, already in process, using the available clinical material to refine the definition of the phenotype, will be employed to inform the molecular approaches. The present group of academic centers has collaborated over the past five years with demonstrated ability to recruit and diagnose individuals with this disorder. The clinical and genotype data from the cases will be publicly available for OCD genetics research. The results of these analyses will guide future molecular strategies to identify genes involved in the pathogenesis of OCD.

The goal of this grant is to delineate the neural network and physiology underlying the effects of deep brain stimulation (DBS) for OCD using a series of integrated translational experiments that involve: 1. functional neuroimaging in humans (aim 1), 2. tract tracing in nonhuman primates (aim 2), and 3. electrophysiology in rodents (aim 3). A better understanding of the underlying neural circuitry of psychiatric disorders is a key element for developing the next generation of effective treatments. The frontobasal ganglia circuit is implicated in several major psychiatric disorders, including OCD. Converging evidence focuses on the ventromedial prefrontal cortical-basal ganglia circuitry. In particular, correction of hyperactivity in orbital frontal cortex (OFC) is a common factor across effective pharmacological, behavioral, and neurosurgical therapies. Furthermore, our pilot studies using DBS, a proven therapy for intractable movement disorders, show that the most promising target for DBS for OCD is in the ventral anterior internal capsule (VC) and adjacent ventral striatum (VS). Importantly, the ventromedial prefrontal cortical-subcortical afferent and efferent projections course through and converge at this location. However, there are several specific pathways at this site that may modulate OFC activity. We will focus on two competing hypotheses: 1. that DBS acts primarily via fibers directly connecting the OFC with the thalamus (aims 1, 2.1, 3.1, and 3.2) and 2. that DBS indirectly modulates OFC activity primarily through its stimulation of the VS pathways (aims 1, 2.2, and 3.3). Furthermore, an additional goal of the experiments is to delineate other key structures and transmitters, most specifically dopamine (DA), and serotonin (5HT), that may be involved at different loci of DBS in the VS (aim 2.3).

Aim 1. Functional Neuroimaging in Humans: Aim 1 will delineate the brain activation profile associated with acute VC/VS DBS in OCD by using PET measures of regional cerebral blood flow (rCBF). Initial treatment data suggest that stimulation at the two ventral contacts (#0 and #1) of the DBS electrode, corresponding with locations in VS and VC respectively, is associated with optimal therapeutic response. Preliminary PET data indicate that acute stimulation at the #0 contact alone is associated with activation of OFC, area 25, striatum, pallidum and thalamus.

1.1) will delineate the activation profile associated with acute DBS at contacts #0+1 vs. control conditions. We hypothesize that acute DBS at contacts #0+1 vs. DBS off (as well as vs. DBS on at contact #3, a dorsal stimulation control condition) will yield activation of OFC, area 24, area 25, striatum, insular cortex, pallidum, and medial thalamus.
1.2) will dissect out component contributions of individual contacts separately (#0 alone vs. off; #1 alone vs. off). We hypothesize that #0 vs. off will yield activation of OFC (medial area 11), area 25, ventral striatum, ventral pallidum, and medial thalamus. We hypothesize that #1 vs. off will yield activation of OFC (lateral area 11), area 24, insular cortex, central striatum, central pallidum and medial thalamus.
1.3) will test for significant correlations between brain activation during acute DBS and clinical outcome. We hypothesize that activation in OFC during acute DBS will be correlated with clinical response to chronic DBS.

Aim 2. Neuroanatomical studies in non-human primates. Aim 2 will test the hypothesis that DBS at different locations within the VC and VS will involve separate components of the ventromedial prefrontal cortical-subcortical pathways. Using anterograde tracer injections, we will determine the course taken by fibers from different orbital and medial prefrontal and thalamic regions at three different sites (two at different dorso/ventral locations within the main VC and one in the ventral VS). A three-dimensional model will be created to illustrate which fiber bundles are affected at different DBS points. Finally, since DA and 5HT fibers ascend through this forebrain region and their terminal distributions vary in different regions of prefrontal cortex, aim 2.3 will focus on the organization and position of these ascending fibers.

2.1) will delineate the pathways that pass through two different loci of the VC. We predict that sites in the VC connect areas 24 and lateral OFC (lateral area 11, area 13, and 12) to specific thalamic and subthalamic regions.
2.2) will delineate both the pathways that pass through, and those that terminate within, the VS. We predict that fiber bundles embedded within the VS carry ascending and descending connections of areas 25 and medial OFC (medial area 11, 14, and 13a/b), including connections with the amygdala, hypothalamus, and midline thalamic n. Furthermore, fibers that terminate in the VS, in addition to those originating in prefrontal regions, will also include ascending fibers from the amygdala, thalamus, ventral tegmental area, and dorsal raphe n.
2.3) will identify the organization of DA and 5HT fibers at each part of the network. Using material from Aim 2.1 and 2.2, sections will be doubled-labeled for DA and 5HT immunohistochemistry to determine their course through the VC and VS as well as the relationship between their cortical terminal fields and ascending pathways from thalamus and amygdala.

Aim 3: Electrophysiological studies of DBS in a rat model. Aim 3 will determine which candidate pathway (direct, via the thalamus; or indirect, via the VS and ventral pallidum) activated during DBS primarily modulates OFC activity patterns. We will examine the impact of stimulation within a site that is homologous to the VC/VS of primates (i.e., the core of the accumbens) on the electrophysiological activity of OFC output neurons. The functional hypothesis is that DBS affects OFC as a consequence of repetitive stimulation, and this occurs via induction of LTP within either the OFC-medial dorsal thalamus (MD) pathway or the OFC-accumbens pathway. We plan to evaluate this by examining the effects of high- versus low-frequency stimulation within the core of the nucleus accumbens on baseline and stimulation-evoked changes in population activity of layer-three and layer-five pyramidal neurons within the OFC, and how this response is affected by selective elimination of alternate pathways.

3.1) will transect OFC pathways to the caudal to the stimulation site to evaluate the contribution of OFC-MD afferents on changes in OFC activity.
3.2) will transect OFC pathways rostral to the stimulation site to evaluate the contribution of OFC neuron antidromic activation to changes in OFC activity.
3.3) will use ibotenic acid lesions of nucleus accumbens neurons to evaluate the contribution of accumbens efferent pathways

By delineating the effects of stimulation on individual pathways likely to be involved in DBS, these experiments will provide a critical foundation for examining how modulation of activity within these pathways may ultimately lead to novel therapeutic strategies for the treatment of psychiatric disorders. The long-term goal of this line of investigation is to understand the mechanisms by which specific circuits are likely to play a primary role in the therapeutic response and to use this information to optimize treatments.

The overall goal of this proposal is to complete the first definitive controlled trial of a neurosurgical procedure for a severe psychiatric illness. Our preliminary data shows promising therapeutic effects of DBS in the treatment of refractory OCD. The target stimulation site, the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS), was based on ten years of our preliminary work in lesion and DBS procedures for OCD. In addition to our empirical data there is a well-defined theoretical rationale, as the VC/VS contains neuronal connections consistently implicated in OCD. In contrast to lesions, DBS is reversible and adjustable and has been refined during approved use in over 30,000 patients worldwide for medically intractable Parkinson's disease and tremor. In six years of preliminary work we have refined the surgical targeting, stimulation parameters, and patient selection, permitting the design of a definitive trial. Collection of definitive controlled data is the essential next step in the development of DBS for OCD as well as for other psychiatric indications such as severe, intractable depression. This therapy offers potential relief to thousands afflicted with otherwise untreatable illness.

We will use a parallel controlled design to compare effects of three months of double-masked sham versus active DBS on OCD severity. We propose a five-year study in order to gather crucial long-term effectiveness and tolerability data. A total of 45 patients (six per year in years one through four will be enrolled at three sites. The primary efficacy measure will be the YBOCS. We will also assess effects on comorbid depression, functioning, and quality of life, as well as potential adverse effects in multiple domains. Patients will have positron emission tomography (PET) scans at baseline and after three months of DBS, to test hypotheses that 1) frontobasal brain metabolism will change with response, and 2) frontobasal metabolism before surgery will predict response. Our specific aims are to determine the following:

1. Efficacy of DBS in OCD: To determine the effects of three months of masked VC/VS stimulation on OCD symptoms, functioning, and quality of life in patients with treatment-resistant OCD compared to sham stimulation. The primary working hypotheses for Aim 1 are: A) three months of DBS using the technique developed in our pilot work will result in improvement in OCD and in global functioning defined as a 35% or greater YBOCS score decrease plus a minimum GAF score of 50, and B) response will persist with open DBS for one to four years. The secondary working hypotheses for Aim 1 are: A) compared to sham stimulation, three months of blinded active DBS will be associated with improvements in quality of life on the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q); and B) these benefits will persist during one to four years of open stimulation.

2. Safety and Tolerability of Chronic DBS in Intractable OCD: To obtain comprehensive data on adverse effects including changes in personality, neuropsychological function, psychiatric symptoms, and neurological status, and other potential adverse effects. The neuropsychological battery will emphasize features of cognition, personality, and behavior attributed to the frontobasal networks that we expect to modulate. The working hypothesis for Aim 2 is that implantation and chronic DBS will have an adverse effect profile superior to that in our own prospective study of gamma knife capsulotomy for refractory OCD assessed cumulatively at 12 months.

3. PET neuroimaging predictors of response and changes with chronic treatment. To determine patterns of brain metabolism at presurgical baseline that predict response to DBS and to determine changes in metabolism after successful DBS. The working hypotheses for Aim 3: A) at presurgical baseline, fluorodeoxyglucose (FDG) metabolism in corticobasal regions implicated in OCD pathophysiology (orbitofrontal cortex, striatum, anterior and posterior cingulate cortex, and midline thalamus) will predict the degree of eventual response to chronic DBS, and B) that three months of chronic DBS will be associated with metabolic reductions in these same regions.

We propose to continue the Longitudinal Brown Obsessive Compulsive Study (LBOCS), a unique, naturalistic, prospective study of 400 subjects whose primary reason for seeking treatment was OCD, for an additional five years of follow-up. This will enable us to obtain a minimum of seven years of follow-up on all subjects and to incorporate new assessments and data analysis methods in order to address important unanswered questions while developing a comprehensive picture of the longitudinal course and outcome of OCD. It will provide important new and clinically relevant information about prognosis, rates of remission and relapse, predictors of remission and relapse and treatment received that will in turn have significant implications for public health policy.

Our specific aims are to (1) determine the course, stability, and outcome of selected OCD phenotypes (2) collect comprehensive treatment data on the long term effects of SRIs, augmenting medications, and cognitive behavior therapy (3) to determine the patterns of course and outcome of a clinical sample of children and adolescents with OCD and compare them to a clinical sample of adults with OCD. Subjects will be evaluated at one-year intervals with instruments that obtain detailed information on symptom status and severity, diagnostic status, treatment received, psychosocial functioning, and other domains. Since the last submission we have added new assessments that measure stressful life events, underlying mood- and anxiety-related traits, and symptom severity independent of diagnosis and functioning; we have also incorporated new data analysis methods in order to answer important questions about OCD. To have sufficient statistical power to test our hypotheses, five more years of prospective observation are needed.

The LBOCS data set is unique in its large number of subjects, comprehensiveness of assessment, and length of prospective follow-up. This proposal will allow us to more completely investigate the aims and hypotheses of the previously funded grant and to add new, previously unexplored aims and hypotheses generated by findings from LBOCS and other investigators during the past four years. Continuation of LBOCS is expected to shed new light on clinically and theoretically important, innovative questions about an understudied major psychiatric disorder that have not been adequately addressed by previous research.

Awards

Sigma Xi, Scientific Research Society
Listed in The Best Doctors in America, 1999-2006
Listed in top 25 Highly Cited for Psychiatry, 2003-2006
Exemplary Psychiatrist Award, National Alliance for the Mentally Ill (NAMI), 2001
DSM-IV Committee for Anxiety Disorders, 1994
Clinical Psychopathology Review Committee, National Institute of Mental Health (NIMH), 1994-1998
Pioneer in Radiosurgery Award, Leksell Gamma Knife Society, 2006

Affiliations

Society for Neuroscience
Member Scientific Advisory Board Obsessive Compulsive Foundation
American Psychiatric Association
Associate Editor Journal of Clinical Psychiatry

Funded Research

ACTIVE

RO-1 MH60218 (PI Steven Rasmussen) 8/1/06- 8/1/11
National Institute of Mental Health (NIMH) $400,120 (initial period direct costs)
Longitudinal Prospective Study of Obsessive Compulsive Disorder
This study investigates the longitudinal course of obsessive compulsive disorder with a focus on diagnostic status, symptom severity, treatment utilization, psychosocial impairment, and quality of life over time.

R01 MH076179-01A1 7/1/06 – 6/30/11
NIMH $700,038 (Year 1 Direct Costs)
Controlled Trial of DBS for OCD
A multicenter controlled study of deep brain stimulation of the internal capsule for intractable OCD, including FDG-PET imaging pre- and post-DBS.

R0-1 MH073111-01A1 (S. Haber, PI) 12/1/2005 – 11/31/2010
NIMH / National Institute on Drug Abuse (NIDA) $55,922 (Year 1 Direct Costs)
Neural Networks in OCD
This translational study aims to understand the mechanisms of therapeutic action of deep brain stimulation in OCD using neuroimaging in patients, neuroanatomy in primates, and electrophysiology in rodents.

5/01/06-5/01/07
Medtronics $105,000
A Pilot Study of Deep Brain Stimulation of the Anterior Capsule for Treatment of Intractable OCD
This study is an initial pilot study of the efficacy and safety of deep brain stimulation in the treatment of patients with intractable obsessive compulsive disorder.

5/01/06-5/01/07
Medtronics $120,000
A Pilot Study of Deep Brain Stimulation of the Anterior Capsule for Treatment Intractable Depression
This study is an initial pilot study of the efficacy and safety of deep brain stimulation in the treatment of patients with intractable depression.

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