What's the role of the amygdala in chronic pain?: evidence from magnetic resonance imaging studies in humans

The amygdala is most known for its role in fear, threat, relevance processing but also aversive conditioning, is part of nociceptive pathways and has extensive reciprocal connections to many pain-implicated brain areas yet less than 5% of human pain imaging studies report the amygdala. The aim of this thesis is therefore to evaluate the amygdala’s role in pain and pain progression mechanisms. Thus chapter 1 describes this relationship from conceptual and preclinical perspectives and elaborates on possible reasons for its infrequent appearance in human pain literature whilst chapters 4 and 5 evaluate it empirically and try to mitigate some of the knowledge gaps. Specifically, chapter 4 examined amygdala morphometry in chronic knee Osteoarthritis pain patients with voxel-based morphometry, hypothesizing increased amygdala gray matter density in pain patients relative to controls in line with some preclinical reports on stress-induced amygdala hypertrophy. This hypothesis could not be confirmed or refuted because extracting gray matter probabilities from quality-controlled gray matter segmentations with an accurate amygdala mask revealed practically no variance in either patients or controls, suggesting that this parameter reflected segmentation quality rather than neurobiological qualities. It is therefore advised not to use this parameter for clinically motivated questions regarding the amygdala unless gray matter atrophy is expected. Chapter 5 investigated pain-related alterations to amygdalae functional networks in the same patient and control population. It was hypothesized that chronic pain would be linked with decreased amygdala-vmPFC connectivity because of proposed inhibitory mechanisms from animal pain work but increased amygdala-dmPFC connectivity because of human imaging studies linking this connection to aversive amplification. Furthermore, sex-effects were hypothesized. The first hypothesis could not be tested. Interestingly, findings supported the second hypothesis but in the opposite direction and future work is advised to investigate the discrepancy of this finding further as it has clinical relevance for serotonergic drugs. Unexpectedly, connectivity between the amygdala and the postcentral gyrus was also altered in chronic12 pain patients relative to controls; this results should be investigated further as the postcentral gyrus is often part of imaging results in human pain but hardly discussed yet it was recently linked to genetic predisposition for anxiety disorders. Results are also suggestive of sex-effects in that the amygdala dmPFC connectivity alteration was not found in post-hoc subsample analysis in males whilst subanalyses in females did not show alterations in amygdala postcentral gyrus connectivity. This should be followed up as it may help to understand why females are more prone to develop chronic pain. The last chapter reviews findings of this thesis and suggests further empirical avenue