Abstract
Changes in brain structure have been documented as physical sequelae of anorexia nervosa (AN), although the exact nature of these structural and functional alterations, as well as their impact on the maintenance and prognosis of AN, is unclear. In psychiatric disorders such as major depressive disorder, which is a common comorbidity for people with AN, problems with neuroplasticity have been postulated to be a key aspect of neuroprogression, which is a term describing the pathological reorganisation of the brain over the course of an illness.Using integrative and diverse methodologies, this exploratory thesis aimed to investigate the evidence for alterations in neuroplasticity in AN by a) examining the existing evidence for changes in the structure and function of the hippocampus in AN; b) identifying differences in inflammatory markers and brain-derived neurotrophic factor (BDNF) between AN and controls, and their relationship to hippocampal structural integrity; c) examining behavioural indices of neuroplasticity and hippocampal function in AN; and d) translating the existing and novel findings into the identification of treatments for this hard-to-treat patient group.
The first aim was addressed in a systematic scoping review of structural, functional and molecular aspects of hippocampal integrity in AN (Chapter 2). The second aim was addressed through: a meta-analysis of growth factor concentrations in AN (Chapter 3); a cross-sectional comparison of inflammatory markers between AN, people recovered from AN (recAN) and healthy controls (HC), whilst controlling for key confounds, and an investigation of the relationship between inflammatory markers and BDNF concentrations (Chapter 4); and a cross-sectional and longitudinal investigation of the association between the peripheral concentrations of two pro-inflammatory cytokines, as well as BDNF, and hippocampal structural integrity (using structural magnetic resonance imaging) in AN (Chapter 5). The third aim was addressed in three studies, the first two examining behavioural indices of hippocampal function in AN compared with HC, including pattern separation performance, autobiographical memory and episodic future thinking (the latter two were also examined in recAN) (studies 2 and 3 of Chapter 6). The third study of Chapter 6 used qualitative methodology to investigate subjective experiences of cognitive difficulties in AN and recAN. The final aim was addressed through a narrative review, investigating the theoretical rationale for the role of ketamine for the treatment of AN (Chapter 7).
Overall, there was evidence for alterations in several systems associated with hippocampal integrity. Whilst the immune-inflammatory profile was overall unremarkable in our samples, lowered concentrations of BDNF appeared to be a key feature of the acute stages of AN and increases in BDNF were associated with hippocampal structural recovery during realimentation, over and above increases in body mass index. Some cognitive functions associated with the hippocampus were unaffected in AN, such as pattern separation and the ability to generate specific details of future episodes, although others were affected, such as pattern completion and the ability to generate specific details of autobiographical memories. Participants described wider cognitive difficulties as well as specific memory difficulties that occurred during the acute stages of AN, that interfered with engagement in daily life (especially recreational endeavours) and may represent a barrier to recovery. Overall, most of the aforementioned alterations appeared to be state-related and were not apparent in recAN. Finally, there was sufficient evidence supporting the use of ketamine as a novel intervention for people with AN, as well as several other treatments that were discussed in the general thesis overview (Chapter 8).
These findings provide a preliminary starting place for new avenues of research investigating problems with neuroplasticity as a feature of neuroprogression in AN, which may aid the identification of biomarkers, phenotypes and endophenotypes, as well as novel pharmacological and psychological treatments that may be integrated into personalised treatment approaches. Importantly, these findings provide no evidence for neuroinflammation as a stable and global feature of AN, although may suggest that neuroprotection may be negatively affected in the acute stages of AN (as indicated by lowered growth factor concentrations such as BDNF and insulin growth factor-1).
| Date of Award | 1 Oct 2023 |
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| Original language | English |
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| Supervisor | Hubertus Himmerich (Supervisor) & Janet Treasure (Supervisor) |