At present, there is no clinically used neurophysiological biomarker to predict treatment re- sponse to selective serotonin reuptake inhibitors (SSRIs) in youth with OCD. The overall objec- tive of this K23 application is to examine the pattern of brain activity in response to symptom provocation in individuals with OCD (ages 12-17) who respond to SSRIs. The central hypothesis of this application is that clinical response to treatment with sertraline can be predicted from baseline activity in the alpha and gamma frequency bandwidths within frontal cortical circuitry. We have formulated the hypothesis on the basis of a literature review and our own preliminary data. The rationale of this line of inquiry is that by defining the baseline neurophysiologic signa- ture associated with clinical response to an SSRI we can predict treatment response. For this study, we have chosen to use magnetoencephalography (MEG) and electroencephal- goraphy as these tools together are entirely non-invasive, provide excellent spatiotemporal resolution and are well tolerated in pediatric subjects. The symptom provocation has been tai- lored to complement and expand upon prior imaging studies in OCD. Recordings will be made while healthy adolescents and adolescents with OCD view blocks of neutral and contamination relevant images. We will determine the latency of regional responses that precede and follow orbitofrontal activity in order to further our understanding of the neural circuit that supports con- tamination obsessions. This will allow us to follow the spread of neuronal activity in patients with OCD. As the adult literature suggests, quantification of frequency bandwidths is a reliable measure that can predict treatment response to an SSRI.
We aim to extend these findings to pediatric subjects to guide personalized pharmacologic treatment. We envision that the outcome of this study will be a neurophysiological marker to predict treatment response to sertraline in youth with OCD and a detailed description of the frequency and timing of elements within the circuit that supports contamination obsessions using the high spatiotemporal resolution of MEG. The principal training objective of this proposal is to prepare the candidate to become an inde- pendent clinical investigator by laying a solid foundation for her to prepare a successful R01 ap- plication. This objective will be met by building upon the candidate's basic science background facilitated through an excellent mentoring team of internal (Drs. Sallee and Epstein) and exter- nal (Drs. Rauch and Robinson) experts with support from an institution rich in training capabili- ties and research infrastructure. Educational experiences will include relevant course work, di- rected readings, seminars and most of all -- hands-on research experience guided by frequent mentor review and critique. Areas of training will include: EEG and MEG data acquisition, sta- tistical analysis and clinical trial design. Additional skills that will be honed through training will include manuscript preparation, grantsmanship and the ethical conduct of research. With this instruction it is expected that upon completion of the K23 funding, the candidate will have an independent program of translational research that will improve our understanding of the circuit- ry underlying OCD and occupy the unique position of transforming and refining treatment op- tions to provide personalized patient care.
The proposed research is relevant to public health because Obsessive Compulsive Disorder (OCD) is a debilitating neuropsychiatric disorder with a lifetime prevalence of up to 3% in the general population yet only about half of patients respond to the standard-of-care treatment. The project fits well with the mission of the NIMH as we propose a scientific study to define a biomarker of treatment response in adolescents with OCD so as to personalize treatment and reduce the burden of this illness.