The Role of Post-Learning Reactivation in Memory Consolidation A thesis submitted to The University of Manchester for the degree of Doctor of Philosophy in the Faculty of Medical and Human Sciences 2014 James Nicholas Cousins School of Psychological Sciences Contents Page List of figures 7 List of tables 9 List of abbreviations 10 Abstract 11 Declaration 12 Copyright statement 12 Acknowledgements 13 The author 14 Rationale for submitting the thesis in alternative format 14 Chapter 1: General Introduction 15 Preface 16 The neurophysiology of sleep 19 Box 1: A brief history of memory models and reactivation 22 Sleep and memory consolidation 24 Declarative memory 26 Procedural memory 27 Reorganising memories during sleep 28 Selectivity of sleep-dependent memory consolidation 31 Sleep and memory reactivation 32 2 Spontaneous memory reactivation 32 Targeted memory reactivation 37 TMR of declarative memories 37 TMR of emotional memories 38 TMR of procedural memories 39 TMR and memory reorganisation 39 The neural signature of reactivation 41 Summary 42 Chapter 2: Establishing offline consolidation of an audio-visual procedural memory task (a pilot study) 44 Abstract 45 Introduction 45 Experiment 1 48 Introduction 48 Materials & Methods 48 Results 53 Discussion 56 Experiment 2 59 Introduction 59 Materials & Methods 60 Results 63 General Discussion 65 3 Chapter 3: Cued memory reactivation during slow-wave sleep promotes explicit knowledge of a motor sequence 67 Abstract 68 Introduction 68 Materials & Methods 70 Results 75 Discussion 81 Chapter 4: Targeted memory reactivation of motor learning during slow-wave sleep modifies plasticity in motor networks 86 Abstract 87 Introduction 87 Materials & Methods 91 Results 98 Discussion 111 Chapter 5: The effect of targeted memory reactivation during sleep on the formation of false memories 199 Abstract 120 Introduction 120 Experiment 1 125 Materials & Methods 125 Results 130 4 Discussion 137 Experiment 2 139 Introduction 139 Materials & Methods 139 Results 142 General Discussion 147 Chapter 6: General Discussion 155 Introduction 156 Summary of findings 156 Reactivation and qualitative alteration to memories during sleep 158 The emergence of explicit knowledge 158 The formation of false memories 161 Summary 162 Reactivation, procedural learning, and neural plasticity 163 Behavioural improvement of procedural memory 163 Neural plasticity of procedural memory 164 Summary 166 Reactivation in sleep and wakefulness 166 Slow-wave sleep and memory reactivation 166 REM sleep and memory reactivation 168 Wakefulness and memory reactivation 168 Other sleep stages and memory reactivation 169 5 Summary 170 Reactivation and TMR as a technique 170 When does TMR bias or interfere with consolidation? 170 Under which states of consciousness does TMR work? 171 How does TMR interact with the selective mechanism of sleep-dependent consolidation? 171 What are the practical applications of TMR? 172 How can TMR be used in future to explore other forms of sleep-dependent memory consolidation? 173 TMR and the relationship between cues and learning 173 TMR and consolidation of implicit memory 174 TMR and integration of memories 175 TMR and generalisation of memories 175 TMR and the reorganisation of memories to enhance creativity 176 TMR and the neural signature of reactivation 176 Conclusion 177 References 178 Appendix A: DRM Paradigm Word Stimuli 197 Total word count: 57,590 6 List of Figures Figure 1.1 Sleep Architecture 21 Figure 1.2 Active Systems Consolidation 24 Figure 1.3 Reactivation of neuronal firing sequences in rodents 33 Figure 1.4 Reactivation during wakefulness (Gupta et al., 2010) 34 Figure 1.5 The influence of TMR on neuronal firing sequence reactivation in rodents (Bendor & Wilson, 2012) 40 Figure 2.1 SRTT stimulus presentation for experiment 1 50 Figure 2.2 Schematic of experiment 1 procedures 52 Figure 2.3 Mean RT’s for SRTT performance across all blocks of experiment 1 54 Figure 2.4 Mean errors for SRTT performance during pre and post retention interval tests (experiment 1) 55 Figure 2.5 Mean explicit sequence knowledge for experiment 1 56 Figure 2.6 SRTT stimulus presentation for experiment 2 61 Figure 2.7 Schematic of experiment 2 procedures 62 Figure 2.8 Mean RT improvement for SRTT performance across sessions of experiment 2 64 Figure 2.9 Mean decline in accuracy for SRTT performance across sessions of experiment 2 65 Figure 3.1 Experimental procedures 71 Figure 3.2 The cueing effect and neural correlates 76 Figure 4.1 Schematic of experiment design 92 Figure 4.2 Schematic of dependent measures 94 7 Figure 4.3 Mean reaction time improvement for the SRTT after TMR 99 Figure 4.4 Correlations between the procedural-cueing-effect and fast spindles 103 Figure 4.5 Correlations between the explicit-cueing-effect and EEG features 104 Figure 4.6 Slow-wave sleep modulated increases in activity after targeted-memory reactivation 106 Figure 4.7 Rapid-eye movement sleep modulated increases in activity after targeted-memory reactivation 108 Figure 4.8 Regions of increased functional connectivity after TMR 109 Figure 5.1 Schematic of experiment 1 procedures 127 Figure 5.2 Mean free recall proportions for word and location recall in experiment 1 133 Figure 5.3 Mean proportion of word and location recall for the sound-association test in experiment 1 134 Figure 5.4 Mean location recall for the recognition test in experiment 1 135 Figure 5.5 Schematic of experiment 2 procedures 141 Figure 5.6 Mean free recall proportions for word and location recall in experiment 2 144 Figure 5.7 Mean recognition memory proportions in experiment 2 (d’) 145 Figure 5.8 Mean recognition memory proportions for control and distractor words in experiment 2 146 8 List of Tables Table 3.1 All SRTT and explicit recall data from experimental and control-groups 78 Table 3.2 Total time spent in sleep stages 80 Table 4.1 Total time spent in sleep stages 102 Table 4.2 Coordinates of local maxima for brain regions showing greater activity for cued relative to the uncued sequence (N=22), modulated by SWS and REM-sleep 107 Table 4.3 Coordinates of local maxima for brain regions showing greater functional connectivity (PPI) for cued relative to the uncued sequence (N=22) 110 Table 5.1 Mean and standard error of the proportion of all recall and recognition responses, and signal detection measures (d’) 132 Table 5.2 Mean and standard error of the proportion of location responses for both free recall and recognition tests 136 Table 5.3 Mean and standard error for all participants responses to free recall and recognition testing in experiment 2, including d’ indices 143 Table 5.4 Mean and standard error for location memory in all tests of experiment 2 147 9 List of Abbreviations TMR Targeted Memory Reactivation REM Rapid-Eye Movement NREM Non-Rapid-Eye Movement SWS Slow-Wave Sleep SWA Slow-Wave Activity SHY Synaptic Homeostasis Hypothesis iOtA Information Overlap to Abstract MSL Motor Sequence Learning SRTT Serial Reaction Time Task M1 Primary Motor Cortex SMA Supplementary Motor Area MTL Medial Temporal Lobe mPFC Medial Prefrontal Cortex dlPFC Dorso-Lateral Prefrontal Cortex vlPFC Ventro- Lateral Prefrontal Cortex ERP Event-Related Potential fMRI Functional Magnetic Resonance Imaging EEG Electroencephalography PSG Polysomnography MEG Magnetoencephalography tDCS Transcranial Direct-Current Stimulation BOLD Blood-Oxygen Level Dependent MVPA Multi-Voxel Pattern Analysis EPI Echo-Planar Imaging HRF Hemodynamic Response Function 10 Abstract The role of post-learning reactivation in memory consolidation James Cousins, The University of Manchester For the degree of Doctor of Philosophy (PhD) 26th September 2014 Memories are gradually consolidated after learning, and subsequent offline periods containing sleep are suggested to support the stabilisation, enhancement, reorganisation and integration of representations within long-term memory networks. The spontaneous reactivation of specific memory traces during sleep is proposed as a key mechanism underlying sleep-dependent consolidation, but the neurophysiological underpinnings of this ‘memory replay’ remain unclear. The research described in this thesis utilised a method of manipulating memory reactivation during sleep (targeted memory reactivation), in combination with behavioural experimentation, polysomnography (PSG), electroencephalography (EEG), and functional magnetic resonance imaging (fMRI), to refine current understanding of the neural processes underlying sleep- dependent memory consolidation. In Chapter 2 we developed a motor sequence learning paradigm that combined visuo- motor performance with sound stimuli, which enabled the targeted memory reactivation (TMR) of specific motor memories during sleep in subsequent chapters via the replay of the associated sounds during sleep. Chapter 3 used this task to cue the reactivation of a learned motor sequence during slow-wave sleep (SWS), which enhanced motor skill for the cued sequence relative to an uncued sequence, and also made the sequence of motor movements more available for conscious recall. Furthermore, these effects were associated with key neural features of sleep (slow oscillations and spindles). These findings indicate that reactivation not only enhances procedural memories, but plays a part in the reorganisation of representations that leads to the emergence of explicit knowledge. A great deal of research has shown that the neural systems supporting procedural memories evolve over time, particularly within cortico-striatal and cortico-