Neural Mechanisms Underlying Attention Deficits in Posttraumatic Stress Disorder by Stefanie Russman Block A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Psychology) in The University of Michigan 2018 Doctoral Committee: Professor Israel Liberzon, Chair Assistant Professor Luke W. Hyde Research Assistant Professor Anthony P. King Associate Professor Sekhar C. Sripada Associate Professor Daniel H. Weissma Stefanie Russman Block [email protected] ORCID iD: 0000-0002-7528-0882 © Stefanie Russman Block 2017 DEDICATION To all those suffering from mental illness, and to all those with an insatiable curiosity for knowledge. ii ACKNOWLEDGEMENTS I am deeply grateful to everyone on my dissertation committee: Dr. Israel Liberzon for his support and guidance throughout the years, Dr. Anthony King for allowing me to test my hypotheses in his data set, Dr. Daniel Weissman for his input on task design and teaching mentorship, Dr. Chandra Sripada for help with fMRI methodology and use of ADHD measures, and Dr. Luke Hyde for his positive role in shaping the Clinical Science program. I am grateful to everyone in the Psychiatric Affective Neuroimaging Lab and the Trauma, Stress and Anxiety Research Program. Specifically, I would like to thank my research assistants – Michaela Milillo, Lisa Blake, Rachel John, Nicole Corso and Damaris Pop – for their help with subject recruitment, data collection and data analyses, Nita Patel for conducting the MRI scans, Dr. Liz Duval for clinical supervision, IRB assistance, and moral support, Dr. Rebecca Sripada for her contribution to the ideas in Experiment 1 and showing me the ropes of neuroimaging analyses, Yana Lokshina for her help with data analyses, and Dr. Jim Abelson for his feedback on the ideas and presentation of this dissertation. Lastly, I would like to thank Mike Angstadt and Daniel Kessler for their support with analyses. I would also like to thank all of participants who took part in the study, everyone in the Clinical Science area, and my funding sources: the UM Depression Center Strategic Translational Research Award, APA Division 19 Student Research Grant, UM Psychology Department, Rackham Graduate School, Oleshansky Memorial Fund, and the VA Ann Arbor MRI Pilot Scan Program. Lastly, I am also grateful to my parents, Rebecca and Richard Block, for their unwavering support, my husband, Charles Russman for his unconditional love, my in-laws, Helaine and Larry Russman, for treating me like their own daughter, and my siters and brother- in-law, Caryn and Adam Russman, for making me a part of the family. iii TABLE OF CONTENTS DEDICATION ………………………………………………………………………..... ii ACKNOWLEDGEMENTS ……………………………………………………………. iii LIST OF TABLES ……………………………………………………………………... viii LIST OF FIGURES ……………………………………………………………………. x LIST OF APPENDICES ……………………………………………………………….. xii ABSTRACT …………………………………………………………………....…….… xiii CHAPTER I. Introduction ………………………………………………………………………… 1 What is attention?………………………………………………………………... 2 Neural circuitry of attention ……………………………………………………... 4 Posner’s attention model……………………………………………………. 4 Intrinsic connectivity networks of attention………………………………... 6 Integration of Posner’s model with intrinsic connectivity networks……….. 8 Attention Deficits in PTSD ……………………………………………………… 9 Attention Deficit Hyperactivity Disorder and PTSD ………………………. 9 PTSD performance on traditional neuropsychological tests.…….................. 11 Evidence for attention deficits in PTSD according to the Posner model…… 16 Abnormalities of intrinsic connectivity networks in PTSD………………….. 20 Methodological strengths and weakness…………………………………………. 22 Specific aims……………………………………………………………………… 25 II. Experiment 1: Behavioral and neural correlates of disrupted orienting............. 28 attention in posttraumatic stress disorder Materials and methods …………………………………………………………… 31 Participants………………………………………………………………….. 31 Measures……………………………………………………………………. 33 Data analyses………………………………………………………………. 35 iv Results ……………………………………………………………………………. 37 Demographics……………………………………………………………….. 37 ANT results..………………………………………………………………… 38 MRI results………………………………………………………………….. 40 Discussion………………………………………………………………………… 43 Attentional performance and PTSD…………………………………………. 43 Attentional performance and intrinsic network connectivity……………….. 45 Limitations ………………………………………………………………….. 48 Conclusion…………………………………………………………………... 49 III. Experiment 2: Resting-state functional connectivity predicts neural functioning on the ANT…………………………………………………………... 64 Methods …………………………………………………………………………. 66 Participants…………………………………………………………………... 67 Measures…………………………………………………………………….. 70 Procedure……………………………………………………………………. 70 FMRI data acquisition………………...…………………………………….. 70 Data Analyses……………………………………………………………….. 70 Results …………………………………………………………………………… 75 ANT behavior……………………………………………………………….. 75 ANT task activation……………………………………………………….. 76 ANT task connectivity…………………………………………………….. 77 Resting-state functional connectivity……………………………………….. 78 v Discussion ……...................................................................................................... 86 Modified Attention Network Task activates intrinsic connectivity networks 87 Resting-state nodes predict different patterns of task activation……………... 88 RsFC differentially predicts cue and target processing………………………. 91 RsFC inversely predicts on-task connectivity …………………………….…. 93 RsFC between canonical network nodes is not a strong predictor of behavior 95 Limitations…………………………………………………………………… 98 Conclusion …………………………………………………………………… 99 IV. Experiment 3: Neural Mechanisms of Attention Deficits in PTSD……….…… 142 Methods……………………………………………………………………………. 145 Participants………………………………………………………………………… 146 Measures……………………………………………………………………... 146 Procedure…………………………………………………………………….. 146 Data Analyses………………………………………………………………... 146 Results……………………………………………………………………………… 151 Demographics……………………………………………………………….. 151 Part 1. ANT behavior and neural correlates…………………………………. 152 Part 2. Resting-state connectivity independent of task performance………… 160 Part 3. Exploratory analyses…………………………………………………. 161 Discussion ……...………………………………………………………………….. 162 PTSD deficits in utilization of spatial information….......…………………... 163 Salience network intrusions during spatial cue processing in PTSD……….. 166 Abnormal default mode network functional during target processing in…… 167 PTSD PTSD participants show increased demands on task positive regions………. 169 Trauma exposed controls also show differential attention processing………. 170 Failure to replicate resting-state functional connectivity abnormalities in…… 172 PTSD Limitations…………………………………………………………………………… 174 vi Conclusion…………………………………………………………………………… 175 V. General Discussion………………………………………………………………… 193 APPENDICIES ………………………………………………………………………… 196 REFERENCES ………………………………………………………………………… 265 vii LIST OF TABLES 2.1. Demographic and clinical characteristics of participants………………………….. 51 2.2. Regions of interest for connectivity analyses ……………………………………… 52 2.3. Reaction time on the ANT in the PTSD and control group………………………... 53 2.4. Accuracy on the ANT in the PTSD and control group…………………………….. 54 2.5. Correlation of DAN (MFG seed) connectivity with the orienting effect…………… 55 2.6. Correlation of SN (dACC seed) connectivity with the orienting effect……………. 56 3.1. Demographic and clinical characteristics of participants………………………….... 100 3.2. Neural activation during the ANT in all participants……………………………….. 102 3.3. Neural activation during the ANT in NTC group…………………………………… 103 3.4. On-task connectivity: PPI results of the ANT in all participants…………………… 104 3.5. On-task connectivity: PPI results of the ANT in NTC group………………………. 105 3.6. Resting-state functional connectivity of VAN, DAN, SN and DMN in all………… 106 participants 3.7. Resting-state functional connectivity of VAN, DAN, SN and DMN in NTC group.. 107 3.8. Correlation of testing-state functional connectivity with ANT performance in all... 108 participants 3.9. Correlation of testing-state functional connectivity with ANT performance in…. 110 NTC group 3.10. VAN connectivity predictors of neural activation during Alerting in all participants 111 3.11. VAN connectivity predictors of neural activation during Alerting in NTC group….. 112 3.12. DAN connectivity predictors of neural activation during Orienting in all………….. 113 participants 3.13. DAN connectivity predictors of neural activation during Orienting in NTC group... 114 3.14. VAN and DAN connectivity predictors of neural activation during Validity in all… 115 participants 3.15. VAN and DAN connectivity predictors of neural activation during Validity………. 116 in NTC group viii 3.16. VAN and DAN connectivity predictors of neural activation during ………………. 117 Disengagement in all participants 3.17. VAN and DAN connectivity predictors of neural activation during ……………… 118 Disengagement in NTC group 3.18. SN (dACC seed) connectivity predictors of neural activation during ……………… 119 Conflict in all participants 3.19. SN (dACC seed) connectivity predictors of neural activation during ……………… 120 Conflict in NTC group 3.20. Resting-state connectivity predictors of functional connectivity during the ANT in.. 121 all participants 3.21. Resting-state connectivity predictors of functional connectivity during the ANT in.. 123 NTC group 3.22. Results summary of resting-state functional connectivity predicting task positive… 125 neutral and negative activity and connectivity on the ANT