Master of Science
Major depressive disorder (MDD) is a highly debilitating neuropsychiatric illness which has been linked with increases in both peripheral and central inflammation, as well as with changes in connectivity. Although countless studies have investigated these two topics, the relationship between neuroinflammation and functional/structural connectivity has not been explored. Using [18F]FEPPA PET imaging, we measured translocator protein-related (TSPO) microglial activity in the subgenual anterior cingulate cortex (sgACC) and insula and confirmed significantly increased [18F]FEPPA uptake in depressed patients (N=12) compared to healthy controls (N=23). Using a seed-based ROI analysis of fMRI data, we found that patients show overall decreased connectivity between the sgACC and the insula. To test the relationship between inflammation and brain connectivity, we performed regressions which found functional (sgACC-insula) and structural (cingulum bundle) connectivity to be significant factors in explaining the microglial activity in the left sgACC. Our study suggests that neuroinflammation relates to network function in MDD.
Summary for Lay Audience
Major depressive disorder is a brain illness which affects many people worldwide. The main symptoms are depressed mood and loss of pleasure, with additional symptoms such as lack of concentration and fatigue. Previous studies have shown that there are a variety of reasons why depression could occur, but the focus of the current thesis is the inflammation hypothesis. In the brain, when the inflammatory response is activated, microglia, the resident immune cells in the brain, will become activated. Microglia influence the body’s inflammatory response, and their activation can be measured through positron emission tomography (PET) imaging of a protein on their surface. It has been shown in the past that certain areas of the brain have greater microglial activity in depression.
The functioning of different brain areas also plays a role in the development of depression. The simultaneous activation of areas such as the anterior cingulate cortex and the insula can be disrupted due to depression; this simultaneous activation represents an activation-related connectivity between the regions. Those two areas are involved in mood and self-examination. We can measure levels of activation of specific brain areas with magnetic resonance imaging (MRI). What we do not know is how disrupted brain connectivity is related to microglial activity in these areas.
The first goal of this thesis was to measure brain inflammation through microglial activity, particularly in areas noted by other studies. The second goal was to measure brain connectivity between these areas in the brain. The third goal was to see if brain connectivity and microglial activity are related in any way. We expected increased inflammation and decreased brain activity in depressed individuals. We also expected that they would be related to one another.
We found that, as we predicted, in these brain areas inflammation was increased and brain activity was decreased in depression. We next found that brain connectivity is related to inflammation. We believe that the continuous study of the neurological basis for depression will help physicians and pharmaceutical scientists develop new and more specific treatments to better the lives of the many of those who suffer from depression worldwide.
Cakmak, Jasmine D., "The Functional and Structural Consequences of Aberrant Microglial Activity in Major Depressive Disorder" (2021). Electronic Thesis and Dissertation Repository. 8143.
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