Functional Imaging Investigation of Psychedelic Visual Imagery Leor Roseman 2019 Psychedelic Research Group Division of Brain Sciences | Department of Medicine | Imperial College London This thesis is submitted for the degree of Doctor of Philosophy (Ph.D) Supervised by Robin Carhart-Harris, Robert Leech and David Nutt Dedicated with love to Nameri who transformed into Emanu during the writing of this thesis, and to my beloved Noa who gave him life מוקדש באהבה לנמרי אשר הפך לעימנו בזמן כתיבת התיזה, ולנועה אהובתי אשר העניקה לו חיים Viva Famila Tiger got to hunt, Bird got to fly; Man got to sit and wonder 'why, why, why?' Tiger got to sleep, Bird got to land; Man got to tell himself he understand ― The Books of Bokonon “Don’t try to make ice-cubes out of a flowing river” ― Laura Huxley Acknowledgements Acknowledgements I would like to acknowledge all information sources which are hard to pinpoint. These include books, papers, posters, the World Wide Web and especially Wikipedia, visions, films, TV series, the news, personal intuition, music, collective knowledge, culture, and most importantly interpersonal communications. I would like to acknowledge my privileges: Man, White, Wealthy, Healthy and surrounded by Lovely Loving people. It would have been a rougher ride without these. I would like to acknowledge Caffeine, mainly in the form of double espresso, which served as an irreplaceable ally in the process of writing this thesis. I would like to acknowledge Imperial College President's PhD Scholarship Scheme for funding my PhD, Albert Hobohm who his generous donation aided me in finalizing the thesis, and the Beckley Foundation and Walcea.com crowdfunding campaign which funded the research presented in this thesis. I would like to acknowledge SCONUL Access, for allowing to explore many other libraries during my thesis writing. Out of all libraries, a special thanks to University College London (UCL) main library, where most of the writing of this thesis took place - where I consolidated knowledge, and transformed into an expert. Synchronistically, at the hospital on the other side of the road (UCLH), pretty much in the same period, Noa (my wife) has consolidated life and we transformed into parents. Baby and thesis in a condensed period of creation. I would like to acknowledge my teachers within the academia. Csaba Orban, whom patiently and passionately thought me the secrets of bash and fMRI and more importantly how to support a colleague-friend - without wanting anything in return; Marty Sereno, for the long detailed conversations and for the huge trust - a true model of compassionate wisdom; Rob Leech for the lightness in supervision and the anti-establishment vibes; David Nutt for permitting and empowering; and Robin Carhart-Harris for being the best boss-friend ever, for welcoming, trusting, allowing, gently directing, editing, and listening. 4 Acknowledgements I would like to acknowledge the rest of the psychedelic research group (PRG). Particularly Mendel Kaelen (woof woof), Chris Timmermann, Ros Watts and David Erritzoe, for passionate brainstorming, sharing beauty and being playful. Also to Luke Williams, Eduardo Schenberg, Taylor Lyons, Tobias Buchborn, Bruna Giribaldi, Eline Haijen, Hannes Kettner, Hannah Douglass, Laura Kaertner, Melissa Shukuroglou, Jonny Martell, Lisa Luan, Midge Baker Jones, Lea Mertens, and Shima Espahbodi. It feels great to belong to such a proud and smiley group of people, and it is a true privilege to have deep connections with “colleagues”. I would like to acknowledge Oliver Sacks that sparked me into neuroscience with “The man who mistook his wife for a hat”, and approved my venture into psychedelic science with his synchronized publication of Hallucinations (2012). Oliver directed many to become neuroscientists/neurologists and he has done this by being deeply humane while discussing with fascination the technicalities of the brain. May his compassion and curiosity linger in any neuroscientist he moved. The font used for this thesis, Trump Mediaeval, was used in Oliver’s Hallucinations. I would like to acknowledge Romy Lorenz. Her PhD Thesis’s acknowledgments section made me cry and revealed me how beautiful (and fun) this section can be. I would like to acknowledge my parents and their partners for unconditional love, for conditional love, and for some financial support when needed. I would like to acknowledge Adi, my sister. Her absence is my life force. I would like to acknowledge Noa, my beloved, who exercised loving altruism that allowed me to peruse my passion. Who is my best supporter and critic, and for grounding me when I fly too high. I would like to acknowledge Emanu, our baby boy, for the future – where purpose is. “We are an old family; We are a new family; We are the same family stronger than before; We honor you; We empower you; To be who you are.” “Gratitude is Heaven itself” – William Blake 5 Copyright Declaration Copyright Declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution licence (CC BY). Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work. 6 Statement of Publications Statement of Publications Parts of this thesis have been published in different journals. Parts of chapter 3 has been published in PNAS (Carhart-Harris et al. 2016). Parts of chapter 4 has been published in Human Brain Mapping (Roseman et al. 2016). Parts of section 1.7 has been published in Frontiers in pharmacology (Roseman et al. 2017). Carhart-Harris, R. L., Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy, K., ... & Nutt, D. J. (2016). Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences, 113(17), 4853-4858. Roseman, L., Sereno, M. I., Leech, R., Kaelen, M., Orban, C., McGonigle, J., ... & Carhart‐Harris, R. L. (2016). LSD alters eyes‐closed functional connectivity within the early visual cortex in a retinotopic fashion. Human brain mapping, 37(8), 3031-3040. Roseman, L., Nutt, D. J., & Carhart-Harris, R. L. (2017). Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Frontiers in pharmacology, 8, 974. 7 Statement of Originality Statement of Originality For the LSD data presented in chapters 3 and 4, the study design, recruitment of participants and fMRI scanning were performed by Robin Carhart-Harris, Mendel Kaelen, Mark Bolstridge, Suresh Muthukumaraswamy, Tim Williams and Wouter Droog, and was supervised by David Nutt and Robin Carhart-Harris. The pipeline that was used for fMRI preprocessing was developed by Csaba Orban and John McGonigle, and adapted by myself. MEG data in chapter 3 was preprocessed by Suresh Muthukumaraswamy, Eduardo Schenberg and Mednel Kaelen, the rest of the MEG analysis presented in this chapter has been conducted by myself. I declare that all other work contained within this thesis is my own, unless otherwise stated, and conforms to the rules and guidelines set out by Imperial College London. For the psilocybin data presented in chapters 3 and 5, the study design, recruitment of participants and fMRI scanning were performed by Robin Carhart-Harris, David Erritzoe, and Tim Williams, and was supervised by David Nutt and Robin Carhart- Harris. The rest of the fMRI analysis was conducted by myself. The research in this thesis received financial and intellectual support from the Beckley Foundation and was conducted as part of a wider Beckley-Imperial research programme (Principle investigators: David Nutt and Robin Carhart-Harris). Robin Carhart-Harris, David Nutt and Robert Leech supervised this thesis. 8 Funding Funding My PhD was funded by Imperial College President's PhD Scholarship. The last months of my PhD were generously funded by Albert Hobohm. The LSD research presented in this thesis was funded by the Beckley Foundation and Walacea.com crowdfunding campaign. The psilocybin research presented in this thesis was funded by Beckley Foundation, Neuropsychoanalysis Foundation, Multidisplinary Association for Psychedelic Studies (MAPS), and the Heffter Research Institute. 9 Abbreviations Abbreviations 2C-B 2,5-dimethoxy-4-bromophenethylamine 5-HT2AR Serotonin 2A Receptor 5-MeO-DMT 5-methoxy-N,N-dimethyltryptamine ACC Anterior Cingulate Cortex AFNI Analysis of Functional NeuroImages ANTS Advanced Normalization Tools ASC Altered State of Consciousness ASL Arterial Spin Labeling AUA Auditory Alterations BOLD Blood-Oxygen-Level Dependent CBF Cerebral Blood Flow CSF Cerebrospinal Fluid CSTC Cortico-Striato-Thalamic-Cortical DED Dread of Ego Dissolution DMN Default Mode Network DMT Dimenthyltryptamine DV Draining Vein ECG Electrocardiogram EEG Electroencephalography EPSC Excitatory Postsynaptic Current ERG Electroretinogram FD Frame-wise Displacement FDA Food and Drug Administration FFA Fusiform Face Area fMRI Functional Magnetic Resonance Imaging FSL FMRIB Software Library FWHM Full Width at Half-Maximun GCPR G Protein-Coupled Receptor GLM General Linear Model GM Grey Matter HRF Hemodynamic Response Function ICA Independent Component Analysis IFG Inferior Frontal Gyrus ISC Inter-Subject Synchronization IV Intravenous LGN Lateral Geniculate Nucleus 10 Abbreviations LSA d-Lysergic acid amide LSD Lysergic acid diethylamide MAOI Monoamine Oxidase Inhibitors MCC Mid-Cingulate Cortex MEG Magnetoencephalography