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Title: Functional and structural characterization of mesolimbic and nigrostriatal networks in adult ADHD : identifying pathological effects and therapeutic targets
Author: Sethi, Arjun
ISNI:       0000 0004 6350 2972
Awarding Body: University of Brighton
Current Institution: University of Brighton
Date of Award: 2016
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Attention Deficit Hyperactivity Disorder (ADHD) has been widely associated with abnormalities within the dopamine system. However, the nature of these changes, and how they are targeted by medication is unclear. For instance, though childhood ADHD is robustly associated with abnormal striatal morphology in voxel-based morphometry (VBM) studies, these changes are not necessarily observed in adulthood, which has been argued to reflect normalisation with treatment and maturation. However, findings for this hypothesis are inconsistent. Moreover, although dopaminergic signalling driven by the substantia nigra/ventral tegmental area (SN/VTA) is central to most theoretical accounts of ADHD, little research has examined how this structure and its subcomponents contribute to the disorder. Finally, although mesolimbic dopamine system abnormalities have been linked to altered reinforcement learning in ADHD, the mechanisms underpinning this are unclear. Recent advancements in MR and computational methodologies are well positioned to resolve these questions. This thesis employs several such methodological advancements to clarify the role of mesolimbic and nigrostriatal systems in ADHD. Firstly, I show that by using magnetisation transfer (MT) saturation maps optimised for subcortical contrast, striatal volumetric reductions are observed in VBM analyses of adults with ADHD. Moreover, I show that T1-weighted volumes used in previous studies are insensitive to these differences, and that prior assessments may have been confounded by other factors such as altered brain iron concentration. The second line of investigation uses diffusion MRI parcellation methods to provide the first microstructural assessment of SN/VTA subcomponents in ADHD, revealing distinct functional contributions. Specifically, microstructural differences in the nigrostriatal and mesolimbic SN/VTA appear to respectively underpin trait motivation and waiting impulsivity, and also appear to be differentially targeted by long term medication. The final study uses a temporal difference (TD) model to isolate computational parameters of reinforcement learning altered in ADHD. In doing so, this reveals impaired reward learning in ADHD that is ameliorated by stimulant medication, and several mechanisms underpinning this. Namely, stimulant medication appears to improve learning rates and reduce aberrant novelty processing within the SN/VTA in a manner specific to ADHD. Collectively these findings indicate the ongoing relevance of mesolimbic and nigrostriatal systems in adult ADHD. Moreover, this work shows that appropriate application of novel methodologies has the potential to answer previously unresolved questions in the literature, as well as offering a finer-grained understanding of how these systems contribute to the disorder.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: A000 Medicine