1 NIBS as a research tool in studying and enhancing episodic memory in the left prefrontal cortex By Angela MEDVEDEVA A thesis submitted to Kingston University London For the degree of Doctor of Philosophy In the department of Psychology February 2019 2 Abstract In the absence of effective treatments for memory disorders including dementia, NIBS methods are being tested for studying and enhancing memory. Anodal transcranial direct-current stimulation (atDCS) is a safe, non-invasive method of stimulating the brain and modulating neural activity through electrodes placed on the scalp. Controversy has surrounded the implementation of atDCS as a research and clinical tool because of inconsistency in effects and a limited understanding of atDCS parameters and mechanisms. Heterogeneity in atDCS parameters across studies could contribute to the inconsistency in effects. Thus, the current research included a systematic methodological investigation of atDCS as a potential research and clinical tool. Two meta-analyses and a set of five methodological experiments analysed the efficacy of atDCS given a consistent set of parameters. In younger adults, atDCS led to a weak and volatile effect under certain conditions that fluctuated with modifications to verbal stimuli and sample size. While there was a robust improvement in memory following atDCS over the left PFC in Experiment 1, this effect did not remain consistent in direct and conceptual replications. The meta- analyses provided support to this investigation by demonstrating that when effect sizes were pooled together across all eligible published studies, the average effect size was close to zero. When only the studies in the current investigation were pooled together, the effect size was larger but also non-significant. Thus, the results inform future considerations of atDCS as a research and clinical tool and provide recommendations for the limited applications of atDCS with a framework for applying effective parameters that take into account individual differences. Furthermore, through the course of the investigation of atDCS, novel findings about episodic memory processes and neural correlates were revealed, confirming the importance of activity in the ventrolateral prefrontal cortex (VLPFC) to episodic memory formation. These findings on VLPFC function were further extended with an investigation of the cognitive mechanisms of atDCS effects on VLPFC 3 function in Chapter 6 and an examination of the time window and process in the VLPFC that was most crucial to memory formation with repetitive transcranial magnetic stimulation (rTMS) in Chapter 7. Together, the findings contributed to developing a clearer understanding of atDCS effects on episodic memory and the episodic processes that occur in the VLPFC. This understanding can inform future research in NIBS with other cognitive functions and the development of memory interventions that can target the VLPFC. 4 Acknowledgements I would like to thank my supervisors Dr Giulia Galli, Professor Frédéric Vallée- Tourangeau, and Professor Philip Terry for their direction and support. Thank you to Dr Sabira Mannan, Dr Vincent Giampietro, and Dr Oleg Medvedev for additional support throughout the PhD. Thank you to Dr Dritan Nikolla for additional guidance and instruction. Thank you to Dr Fatima Felisberti, Professor Carlo Miniussi, Professor Adrian Coyle, and Dr Marco Sandrini. I would like to thank Rebecca Saw for her friendship and collaboration. Thank you to Alexandra Petrovskaya, Dr Matteo Feurra, Dr Giorgio Fuggetta, and Dr Oleg Medvedev for collaboration. I would also like to thank my research assistants Ezgi Kosar and Roberta Allegretta. Thank you to co-authors Dr Matteo Feurra, Dr Miroslav Sirota, Dr Miguel Vadillo, and Maurizio Materassi. I would like to thank my participants for participating (sometimes more than once) in the experiments and for being so patient and eager. Thank you to fellow PhD students Jawaria, Rose, Wendy, and Zoë. Thank you to my friends and family. Your support and encouragement have been invaluable. Thank you to Father; without you this would not have been possible. 5 Contents Acronyms ............................................................................................................................ 12 Preface ................................................................................................................................. 13 Chapter 1: General Introduction.......................................................................................... 18 Importance of Prefrontal Cortex ...................................................................................... 19 Importance of Studying Episodic Memory ..................................................................... 27 Aims of the Thesis ........................................................................................................... 28 Chapter 2: Foundations of Non-Invasive Brain Stimulation .............................................. 30 Overview ......................................................................................................................... 30 TMS ................................................................................................................................. 30 Effects of TMS............................................................................................................. 31 Transcranial Direct-Current Stimulation (tDCS) ............................................................ 38 tDCS effects on motor cortex. ..................................................................................... 40 Safety Considerations ...................................................................................................... 50 Designing Experiments with NIBS ................................................................................. 52 Assessments of tDCS effects. ...................................................................................... 60 Parameters of TMS. ..................................................................................................... 63 Advantages and limitations of tDCS and TMS. .......................................................... 64 Chapter 3: Foundations of Episodic Memory ..................................................................... 65 Overview ......................................................................................................................... 65 The Definition of Episodic Memory ............................................................................... 65 Distinctions between short-term and long-term memory. ........................................... 67 Overview of Episodic Memory Processes in the PFC: Cognitive, Anatomical, and Neurobiological Level ..................................................................................................... 67 Attentional and perceptual processes leading to memory. .......................................... 70 Episodic Memory Processes in the PFC. ..................................................................... 72 Episodic Memory in the Laboratory and PFC involvement ............................................ 80 Tasks. ........................................................................................................................... 80 Encoding tasks and levels of processing...................................................................... 82 Intentional vs incidental encoding. .............................................................................. 87 Item-specific vs relational encoding. ........................................................................... 88 Retrieval tasks and recollection. .................................................................................. 90 Generalisability and ecological validity of laboratory memory studies. ..................... 93 Chapter 4: Assessing tDCS as a Research Tool: A Systematic Review and Meta-Analysis of the Effects of tDCS on Episodic Memory ...................................................................... 96 Abstract ........................................................................................................................... 96 Introduction ..................................................................................................................... 96 Aims. .......................................................................................................................... 108 Method ........................................................................................................................... 110 6 Literature review. ....................................................................................................... 110 Eligibility criteria. ...................................................................................................... 110 Data extraction. .......................................................................................................... 113 Characteristics of the studies. .................................................................................... 113 Results ........................................................................................................................... 130 Effects of anodal tDCS. ............................................................................................. 130 Effects of cathodal tDCS. .......................................................................................... 131 Moderator analyses. ..................................................................................................