We conducted a retrospective pilot study in a sample of 16 patients suffering from TRD who all underwent a cerebral perfusion SPECT with 99mTc-HMPAO and a metabolic PET with 18F-FDG. No relevant clinical changes were found upon evaluation at these two-time points, especially for disease characteristics and treatments. Whole-brain voxel-based analysis reveals inconsistent results between SPECT perfusion and PET metabolism, and could thus at least in part explain previous variability of findings in the literature for these two biomarkers6. Significant negative correlations were found with SPECT perfusion between number of episodes and the right insula perfusion, and between the depression duration and bilateral ACC perfusion, while no relationship was obtained for PET metabolism.
Number of episodes and illness duration are considered as risk factors of pharmaco-resistance and involved in depression recurrence9,10. They also may signal risk of residual symptoms such as sleep disturbances, executive impairments and anxiety11. Correlations with these two variables have already been described in few previous neuroimaging studies. A voxel-based study of 127 subjects suffering from TRD showed a weak negative correlation between the duration of illness and brain 99mTc-ECD SPECT perfusion in bilateral cingulate and orbital cortices12. A recent MRI meta-analysis including morphometry studies found a significant gray matter reduction in the rostral part of the anterior cingulum related to illness duration and repeated depressive episodes13. Moreover, our findings are concordant with another 18F-FDG PET study: in 18 hospitalized patients with unipolar depression, Mayberg et al. revealed no significant relationship between brain metabolism and illness chronicity14.
The insula and anterior cingulum cortices are known to be involved in TRD6,15. The insula is particularly involved in the emotional identification a stimulus, and in the affective state in response to it. Resting-state hyperactivity of the insula has been linked in MDD to pathological self-focused mental ruminative behaviors16. On the other hand, the ACC modulates the link between ventral and dorsal networks involved in regulation of emotion. Dorsal ACC is specifically implicated in executive functions through the cognitive control network and its subgenual subdivision focused on emotional experience and processing17. Furthermore, the insula and ACC both belong to the salience network which participates in judgement alteration and negative thoughts in MDD18. They also both interact with the default mode network, and contribute to the alteration of attentional system and to the introspection in MDD19.
PET is one of the main neuroimaging techniques evaluated in recent psychiatry research15. Indeed, PET is usually preferred to SPECT because of better spatial resolution. Cerebral glucose metabolism and cerebral perfusion have been considered as coupled for a long time because the brain consumes roughly 20% of total body oxygen and 25% of total body glucose. The most important energy source for the brain is the adenosine triphosphate (ATP), produced almost entirely by the oxidative metabolism of glucose20. However, their consistent correlations are presently questioned, in part justified by other mechanisms of blood flow regulation which could produce a different cartography of cerebral perfusion from the metabolic one. This has already been highlighted in healthy subjects21. Furthermore, neurovascular uncoupling between glucose and oxygen metabolism, via oxygen depletion and induction of downstream hypoxia response pathways, could play a key role in neurodegenerative diseases22. And it does not seem excluded that psychiatric disease could also increase differences between brain metabolic and perfusion cartographies, involving the same neurovascular uncoupling mechanisms.
The main limitations were a retrospective design and a small sample size. Our results concerned patients with TRD, and they are not generalizable to all patients suffering from MDD. The interval delay between the two acquisitions was significant and resulted in mild differences considering age and disease duration, which were ultimately irrelevant in number of months. To our knowledge, this is the first study which focuses on a single group of patients. This choice produced a better homogeneity by excluding interindividual differences.