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Effects of Propranolol on Cognition and Eye Contact in ASD 03.25.10 Effects of Propranolol on Cognition and Eye Contact in Autism Spectrum Disorder (ASD) Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Sanjida Shoma Saklayen Integrated Biomedical Sciences Graduate Program The Ohio State University 2010 Dissertation Committee: David Q. Beversdorf, Advisor Howard Gu, Advisor Sandra Kostyk Wolfgang Sadee Copyright by Sanjida Shoma Saklayen 2010 Abstract Propranolol, a nonselective beta blocker, produces noradrenergic blockade with central and peripheral nervous system effects. While propranolol is often prescribed for hypertension, it is also commonly prescribed for situational anxiety (stage fright, test anxiety, etc) due to its central activity. Previous work in this lab has examined the effect of propranolol on cognitive flexibility tasks. In a previous study in this lab, performance on simple cognitive flexibility tasks was shown to be increased in autistic individuals who take propranolol, whereas controls only exhibited improvement in difficult tasks. Our aim was to examine other possible benefits of propranolol on cognition. To do this, we compared performance on verbal fluency tasks, which require cognitive flexibility, between autistic and control individuals, under propranolol and placebo conditions. Furthermore, it is characteristic of individuals with autism to exhibit poor eye contact with others from an early age. Recent physiological evidence suggests that direct eye contact may be stressful to those affected by autism. Stress is well known to activate the noradrenergic system. Therefore, an agent that could reliably decrease the stress related to eye contact by acting to block noradrenergic activation may be beneficial to ii those affected with autism. Thus, since decreased eye contact in autistic individuals may be linked to stress and propranolol is known to decrease social stress, we proposed to determine whether autism-affected individuals would increase their eye contact when given propranolol. We hypothesized that propranolol administration, through its action of decreasing the stress response, would lead patients with autism to spend more proportionate time making eye contact, compared to placebo administration. Eye contact was measured using an ASL eyetracker and dynamic video stimuli of 16 novel faces at each of two drug condition visits. Eyetracker data was analyzed using the EyeNal and FixPlot programs by ASL. Fourteen autism subjects with age/IQ/gender matched controls were tested in the verbal fluency study and the same fourteen autism subjects participated in the eyetracking study. Results indicate significant improvements in semantic fluency in autism subjects given propranolol, relative to the placebo condition. 2x2 ANOVA in the semantic fluency task revealed a trend for an interaction effect of drug and group as well as a significant main effect of drug, driven by the ASD group. In the eyetracking study, individuals with ASD and controls had similar amounts of eye-to-eye gaze under the placebo condition, which was unexpected. However, both groups improved significantly in the propranolol condition. 2x2 ANOVA in the eyetracker task revealed a trend for an interaction effect of drug and group as well as a main effect of drug. iii Dedication Dedicated to my grandparents: The late-Syed Fariduddin Saki, “Nana” The late-Syeda Shamsun Nahar, “Nani” The late-Azimuddin Ahmed, “Dadu” Salema Azim, “Dadi” iv Acknowledgements *To my co-advisors - Dr.David Beversdorf (“Dr. B”) and Dr. Howard Gu, and my committee members, current and former - Dr. Sandra Kostyk, Dr. David Saffen, and Dr. Wolfgang Sadee, thank you for your commitment to provide me with excellent training during my graduate career. *To my lab colleagues at OSU and MU: Allen Carpenter, Patrick Hecht, Katherine Higgins, Karen Jones, Namhee Kim, Ananth Narayanan, Ryan Smith, and Catherine White, thanks for making the Beversdorf Lab a great place to work and learn. *To Dr. Shawn Christ at MU and his lab team, thank you for sharing your labspace, equipment, training and assistance. *To the faculty, staff, and students of the OSU MSP and IBGP, as well as the College of Medicine at OSU, thank you for providing comprehensive training and support. *To the OSU Neurology Department, the departments of Neurology, Radiology, and Psychology at MU, as well as the Thompson Center for the use of their resources, thank you. *To Dr. Menachem Shoham and Dr. Elizabeth Pehek of Case Western Reserve University, thank you for introducing me to research. *To all of my family and friends, I extend deepest thanks for helping me along the way - particularly to Kyle Schneider; my siblings, Sabir, Samiya, and Sabera; my mother, Syeda Saklayen, and father, Dr. Mohammad Saklayen. *To all, gratitude. v Vita May 1999……..…….Centerville High School, Centerville, OH 2001-2003……………Research Assistant, Department of Psychiatry, Case Western 2003…………………….B.A. Biochemistry and Psychology, with honors, Case Western 2003 to present ……Graduate Associate and Fellow (2006-2009), The Ohio State University Publications Saklayen SS, Mabrouk O, Pehek EA. (2003) “Negative Feedback Regulation of Nigrostriatal Dopamine Release: Mediation by Striatal D1 Receptors.” JPET 311 (1); 342-348. Cao R, Lee B, Cho HY, Saklayen SS, Obrietan K. (2008). “Photic Regulation of the mTOR Signaling Pathway in the Suprachiasmatic Circadian Clock.” Mol Cell Neurosci 38 (3); 312-324. Fields of Study Major Field: Integrated Biomedical Sciences Graduate Program Areas of Interest: Biology of Neurological Disorders and Translational Research Minor Field: Neuroscience vi Table of Contents Abstract…………………………………………………………………………………………………………………………….ii Dedication………………………………………………………………………………………………………………………..iv Acknowledgements…………………………………………………………………………………………………………..v Vita…………………………………………………………………………………………………………………………………..vi List of Tables….…………………………………………………………………………………………………………......viii List of Figures……………………………………………………………………………………………………………........ix Chapter 1: Introduction….…………………………………………………………………………………………………1 Chapter 2: Effect of Propranolol on Verbal Fluency in ASD……………………………………………..29 Chapter 3: Effect of Propranolol on Eye Contact in ASD………………………………………………… 54 Chapter 4: Discussion……………………………………………………………………………………………………..84 Chapter 5: Future Directions……….……………………………………………………………………………….…94 References……………………………………………………………………………………………………………………..99 Appendix A: Verbal Fluency data …….…………………………………………………………………...........123 Appendix B: Eye Contact data……..………………………………………………………………………………..126 vii List of Tables Table 1. Demographic and diagnostic data for ASD group………………………………………….....34 Table 2. Mean words generated…..………………………………….…………………………………………….41 Table 3. Demographic and diagnostic data for ASD group………………….…………………………..58 Table 4. Terminology……………………..……………………………………………………………………………….68 Table 5. Proportionate time on the eyes and Total time on AOIs…………………………………….75 viii List of Figures Figure 1. Norepinephrine…..……………………………………………………………………………………………..8 Figure 2. Norepinephrine synthesis…………………………………………………………………………………..9 Figure 3. Semantic network restriction in ASD………………………………………………………………..18 Figure 4. Remote eyetracker…………..………………………………………………………………………………20 Figure 5. Propranolol……………………………………………………………………………………………………..24 Figure 6. Blood pressure……………….…………………………………………………………………………….….38 Figure 7. Heart rate…………………….…………………………………………………………………………………..39 Figure 8. Semantic verbal fluency……………………………………………………………………………………42 Figure 9. Individual scores on semantic fluency task………………………………………………………43 Figure 10. Individuals with Asperger’s syndrome vs. individuals with autism…………………44 Figure 11. Phonemic verbal fluency………………………………………………………………………………..45 Figure 12. Individual scores on phonemic fluency task…………………………………………...........46 Figure 13. Eyetracker calibration……….……………………………………………………………………………60 Figure 14. Areas of interest…………………………………………………………………………………………….63 Figure 15. Sample .eyd file………………………………………………………………………………………………65 Figure 16. Visualizing eye data……………………………………………………………………………………….66 ix Figure 17. Blood pressure……………………………………………………………………………………………….71 Figure 18. Heart rate……………………………………………………………………………………………………….72 Figure 19. Amount of fixation on individual facial features by group and drug ……………….76 Figure 20. Proportionate time spent on the eyes……………………………………………………….……77 x CHAPTER 1: INTRODUCTION Dr. Temple Grandin designs plans for facilities that handle livestock. Her purpose is to alleviate animal stress and to help develop more humane methods of slaughter in the meat industry [1]. She has designed major facilities of this type that are located around the world and at this time, the majority of beef cattle in the United States are handled in a restraining system of her design [1]. Grandin also teaches about livestock behavior and facility design at the university level and she is currently the author of over three-hundred scholarly articles and seven books. Despite her current professional success, when she was a child, Grandin did not learn to speak until she was beyond the age of three [2]. Unable to verbalize her needs, her early attempts to communicate were primarily through screams and humming noises [2-3]. When she was diagnosed with autism in 1950, her doctors recommended that she be institutionalized for her condition [2-3]. Several years later, in her book, entitled Emergence: Labeled Autistic , Grandin described her experiences in rising above societal and
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