The effects of ketamine on functional brain networks in awake nonhuman primates and the therapeutic potential for treatment of substance abuse Pubblico
Maltbie, Eric (Fall 2017)
Abstract
At present, there is considerable interest in improving the understanding of the unique effects of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine. Sub-anesthetic infusions of ketamine induce acute psychotomimetic effects, but also produce prolonged neurobiological changes with therapeutic efficacy for treating depression in human subjects. However, the underlying mechanisms mediating these effects remain poorly understood. Building on the recent development of methodology allowing for the collection of quality pharmacological MRI (phMRI) data in awake nonhuman primates (NHPs), this dissertation examines the neural circuitry underlying both the psychotomimetic and therapeutic effects of ketamine. Ketamine induced robust and extensive brain activation and strengthened functional connectivity (FC) in several brain networks, including fronto-striatal circuitry known to be disrupted by cocaine. Subsequently, the efficacy of ketamine for the treatment of cocaine abuse was investigated. Ketamine pretreatment attenuated both the effects of cocaine on fronto-striatal (and whole-brain) FC and cocaine-seeking behavior. In conclusion, phMRI in awake NHPs enables valuable, behaviorally relevant translational imaging models. Ketamine increases FC in fronto-striatal circuits responsible for executive control over reward-based decision making and attenuates the effects of cocaine on both FC and behavior. These findings support the therapeutic potential of ketamine in the treatment of substance use disorders.
Table of Contents
Chapter 1: Ketamine and pharmacological imaging: use of functional magnetic resonance imaging to evaluate mechanisms of action 1
1.1 Context, Author’s Contribution, and Acknowledgement of Reproduction 2
1.2 Abstract 2
1.3 Introduction 3
1.3.1 - Neural Mechanisms 4
1.4 Pharmacological Imaging Methods 6
1.4.1 - Brain Activation 7
1.4.2 - Functional Connectivity 8
1.5 Pharmacological Imaging and the Behavioral Effects
of Ketamine 10
1.5.1 - Psychotomimetic effects 10
1.5.2 - Antidepressant effects 19
1.6 Discussion 21
1.7 Future Directions 23
1.7.1 - phMRI and ketamine mechanism of action 23
1.7.2 - phMRI and translational models 25
1.8 Conclusions 27
1.9 Dissertation Overview 28
Chapter 2: Ketamine-induced effects on brain activation in conscious nonhuman primates 35
2.1 Context, Author’s Contribution, and Acknowledgement of Reproduction 36
2.2 Abstract 36
2.3 Introduction 37
2.4 Materials and Methods 40
2.4.1 - Subjects 40
2.4.2 - MRI data acquisition 41
2.4.3 - Drug infusion protocols 42
2.4.4 - Pharmacological MRI data analysis 43
2.4.5 - Clinical ratings of behavior 50
2.5 Results 51
2.5.1 - Blood plasma drug levels 51
2.5.2 - Ketamine-induced BOLD activation 51
2.5.3 - Reduction in ketamine-induced activation by risperidone pretreatment 52
2.5.4 - Ketamine-induced effects within a priori ROIs 52
2.5.5 - ROI-averaged Group-mean Time Courses 53
2.5.6 - Clinical ratings of behavior 53
2.6 Discussion 53
Chapter 3: Ketamine-induced effects on functional connectivity in conscious nonhuman primates 69
3.1 Context, Author’s Contribution, and Acknowledgement of Reproduction 70
3.2 Abstract 70
3.3 Introduction 71
3.4 Materials and Methods 74
3.4.1 - Subjects 74
3.4.2 - Drug infusion protocols 75
3.4.3 - fMRI Data Analysis 76
3.5 Results 79
3.5.1 - Blood plasma drug levels 79
3.5.2 - Ketamine-induced changes in FC to dlPFC 79
3.5.3 - Ketamine-induced changes in FC to SgC 80
3.5.4 - Ketamine-induced changes in FC to Amygdala 80
3.5.5 - Ketamine-induced changes in FC to Nucleus Accumbens 81
3.5.6 - Ketamine-induced changes in FC to other ROIs 81
3.5.7 - Ketamine-induced inter-hemispheric asymmetry in FC networks 82
3.6 Discussion 83
3.6.1 - Insights into the results of the ketamine drug infusion phMRI study 86
3.6.2 - Limitations 86
3.7 Conclusions 88
Chapter 4: Effects of ketamine treatment on cocaine-induced changes to functional connectivity in conscious nonhuman primates 107
4.1 Context, Author’s Contribution, and Acknowledgement of Reproduction 108
4.2 Abstract 108
4.3 Introduction 110
4.4 Methods 112
4.4.1 - Subjects 112
4.4.2 - Surgery and habituation to MRI 112
4.4.3 - MRI data acquisition 113
4.4.4 - Drug infusion protocol 113
4.4.5 - fMRI Data Quality Control 114
4.4.6 - Ketamine treatment 114
4.4.7 - fMRI preprocessing and spatial normalization 114
4.4.8 - FC analysis 115
4.4.9 - Data Analysis 116
4.4.10 - Cocaine Self-administration 116
4.4.11 - Experimental timeline 116
4.5 Results 117
4.5.1 - Acute cocaine administration robustly decreased FC 117
4.5.2 - Ketamine pretreatment attenuated cocaine-induced changes in FC 118
4.5.3 - The effects of cocaine on FC predicted response rates during self- administration 119
4.5.4 - Chronic cocaine self-administration robustly decreased FC 119
4.5.5 - Acute effects of cocaine on FC following chronic self-administration 120
4.5.6 - Effects of ketamine pretreatment on FC after self-administration 121
4.5.7 - Individual subject results for dlPFC-NAcc FC 122
4.6 Discussion 123
4.6.1 - Limitations 126
4.7 Conclusions 127
Chapter 5: Investigating the effects of ketamine treatment on reinstatement and reacquisition of cocaine self-administration in rhesus monkeys 138
5.1 Context, Author’s Contribution, and Acknowledgement of Reproduction 139
5.2 Abstract 139
5.3 Introduction 140
5.4 Methods 142
5.4.1 - Subjects 142
5.4.2 - Surgery 142
5.4.3 - Cocaine self-administration 143
5.4.4 - Ketamine treatment 144
5.4.5 - Reinstatement 144
5.4.6 - Reacquisition 145
5.4.7 - Data analysis 146
5.5 Results 146
5.5.1 - Self-administration 146
5.5.2 - Reinstatement 147
5.5.3 - Reacquisition 148
5.6 Discussion 149
Chapter 6: Clinical use of ketamine, future directions, and
limitations 158
6.1 - Results Summary 159
6.2 - Clinical use of sub-anesthetic ketamine treatment 163
6.3 - Future directions for translational models using phMRI in awake NHPs 164
6.4 - Limitations 165
6.5 - Conclusions 167
Appendix: Complete list of publications to which the author has contributed during his graduate training 168
References 169
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