Mkrtchian, Anahit;
(2022)
The motivational mechanisms driving the antidepressant effect of ketamine.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Ketamine is a rapidly-acting antidepressant and has shown to be effective in depressed individuals who have previously failed to benefit from other available treatments. An important question is how ketamine works. Addressing this might help inform more targeted and efficient treatments in the future. The aim of this thesis was to examine the neural, cognitive, and computational mechanisms underpinning the antidepressant response to ketamine in treatment-resistant depression. The work has specifically focused on motivational processing, since ketamine is particularly effective in alleviating symptoms of anhedonia, which are thought to be related to impaired reward-related function. Following a general introduction (Chapter 1), the first experimental chapter (Chapter 2) focuses on identifying suitable reward and punishment tasks for repeated testing in a clinical trial. Test retest properties of various tasks are explored in healthy individuals, assessed by both traditional measures of task performance (e.g., accuracy) and computational parameters. Chapter 3 outlines a pilot simultaneous EEGfMRI study in healthy individuals probing the neural dynamics of the motivation to exert cognitive effort, an important but understudied process in depression. The third study (Chapter 4) uses resting-state fMRI to examine how ketamine modulates fronto-striatal circuitry, which is known to drive motivational behaviour, in depressed and healthy individuals. The final experimental chapter (Chapter 5) examines which cognitive and computational measures of motivational processing (using tasks identified in Chapter 2) change following a single dose of ketamine compared to placebo in depression, using a crossover design. Based on preliminary findings, it is tentatively proposed that ketamine might affect reward processing by enhancing fronto-striatal circuitry functional connectivity, as well as by increasing exploratory behaviours, and possibly punishment learning rates. The general discussion (Chapter 6) discusses these findings in relation to contemporary models of anhedonia and antidepressant action, considering both the limitations of the work presented and possible future directions.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The motivational mechanisms driving the antidepressant effect of ketamine |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry > Mental Health Neuroscience UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10153810 |
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