Costello, Harry; (2024) The cognitive and neural mechanisms of depression in Parkinson's disease. Doctoral thesis (Ph.D), UCL (University College London.

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Abstract

Depression in Parkinson’s disease (PD) is common, disabling and has poor outcomes. Dopamine has a well-established role in both reward and motivational pathways. The cardinal symptoms of PD are caused by dopaminergic neurodegeneration and consequently PD is a model of striatal and dopamine dysfunction. This thesis aims to investigate the neural and cognitive mechanisms underlying depression in PD and the role of dopamine in its aetiology and treatment. Following the general introduction, the first empirical chapter is a systematic review and meta-analysis of reward processing in PD and its relationship with dopamine state and neuropsychiatric syndromes. The analysis revealed that reward processing is impaired in PD, but this disruption varies depending on the specific cognitive subcomponent and dopamine state. The second empirical chapter investigated how progressive neurodegeneration of dopaminergic projections to the striatum over time in PD was associated with motivational symptoms of depression. I found that motivational symptoms emerge as the disease progresses, after a threshold level of dopaminergic neurodegeneration is reached. The third empirical chapter explored whether there are dissociable effects of dopaminergic medications on different depression symptom dimensions in PD. I found that treatment with dopamine agonists appears to specifically reduce motivational symptoms over time, whereas monoamine oxidase-B inhibitors may improve both depressive and motivation symptoms, albeit the latter effect is attenuated in patients with more severe dopaminergic neurodegeneration. Our willingness to exert effort for a given goal is dependent on the magnitude of the potential reward of an action. This process, termed effort-based decision making, is an essential component of motivation. In the final empirical chapter, I investigated whether dopamine-dependent disruption of effort-based decision-making is a mechanism driving depression in PD. I found that depression in PD is associated with lower sensitivity to rewards, which remains unresponsive to dopaminergic medication. In contrast, dopamine treatment improves reward sensitivity in non-depressed PD. Taken together, the studies in this thesis add new insights into the key cognitive and neural mechanisms underlying depression in PD. My final experiment identified reward sensitivity as a potential novel treatment target for PD depression that may require non-dopaminergic therapies.

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