Post by Deborah Joye
What's the science?
The symptoms of Major Depressive Disorder can vary greatly across individuals. Many people find relief with antidepressant medications, however, medication and therapy do not work for everyone. One alternative treatment for treatment-resistant depression is repetitive transcranial magnetic stimulation (rTMS), where an electromagnetic coil is used to stimulate activity in specific brain regions. But which brain regions result in optimal relief from depressive symptoms? Two brain regions, the dorsolateral prefrontal cortex (DLPFC — important for executive functions like memory, planning, and reasoning) and the subgenual cingulate cortex (SGC — which may be overactive in treatment-resistant depression) are implicated in depression and ideal targets for treatment-resistant depression. However, the SGC lies deep within the brain and cannot be stimulated directly using rTMS. Recent work described in Fox et al., 2012 and Weigand et al., 2018 demonstrates that the DLPFC is functionally connected to the SGC, and that activity between these two regions is negatively correlated. Regions of the DLPFC that have greater connectivity with the SGC were found to yield better antidepressant outcomes when stimulated with rTMS. This week in Biological Psychiatry, Cash and colleagues aimed to replicate these earlier findings in an independent cohort as well as test the feasibility of improving treatment outcomes by personalizing rTMS treatment based on individualized functional connectivity maps.
How did they do it?
The authors measured resting brain activity and depression severity in 47 individuals with major depressive disorder using fMRI and the Montgomery–Åsberg Depression Rating Scale. Participants then underwent rTMS targeted to the left DLPFC using the recently developed F3 Beam approach - a technique for placing the electromagnetic coil on the head designed to better account for individual head shape. Functional connectivity for each individual was measured using a Pearson correlation (indicates the strength of a relationship between two variables) between brain activity in the individual’s specific DLPFC stimulation site and activity in their SGC. The authors also measured correlations in activity between a group-averaged DLPFC stimulation site (the average location of a DLPFC stimulation site in the brain across all group members) and an individual’s SGC activation to investigate whether group-averaged and individualized stimulation sites could predict SGC activity with similar accuracy. The authors then developed functional connectivity maps to compare average DLPFC-SGC connectivity between the entire depressive disorder group and an independent dataset of health individuals, to investigate depression-related differences in DLPFC-SGC connectivity. Finally, to ensure that results were specific to connections between the DLPFC and SGC, the authors assessed SGC connectivity with other brain regions, including the visual network, left temporoparietal junction, right DLPFC, and left occipital lobe.
What did they find?
First, the authors replicated previous findings by Fox et al., 2012 and Weigand et al., 2018, demonstrating that efficacy of rTMS treatment for depression is related to functional connectivity between the SGC and the DLPFC stimulation site. The authors found that group-level functional connectivity strength and individualized functional connectivity strength were similarly accurate in predicting rTMS treatment outcomes. Importantly, predicting treatment response based on an individual’s specific DLPFC stimulation site was more accurate than using the group-averaged stimulation site. Improvement in depression scores was largest when DLPFC stimulation sites had a stronger connection with SGC, which directly supports propositions from previous research. Finally, functional connectivity between the SGC and other brain regions (not the left DLPFC) was not associated with treatment outcomes, suggesting that their results are specific to DLPFC-SGC connectivity.
What's the impact?
This study validates and extends previous work by demonstrating that outcomes of rTMS for treatment-resistant depression are predicted by connectivity between the left DLPFC the SGC. The study is also the first to demonstrate that group-level and individual maps of SGC functional connectivity are both robust predictors of treatment outcomes, which could simply the logistics of incorporating rTMS into patients’ treatment plans. Further, it was previously assumed that individual functional connectivity maps might be insufficient in predicting treatment response, but this may have been improved by recent advances in MRI analysis pipelines, improving maps at the group level. Future studies may now focus on how to implement personalized rTMS to enhance treatment outcomes for patients suffering from treatment-resistant depression.
Cash et al., Subgenual Functional Connectivity Predicts Antidepressant Treatment Response to Transcranial Magnetic Stimulation: Independent Validation and Evaluation of Personalization, Biological Psychiatry (2019). Access the original scientific publication here.