Neuro-cardiac predictors of treatment response to rTMS in depression: a mechanistic study using interleaved TMS-fMRI

Major depressive disorder (MDD) is the leading cause of disability in the world. In Canada, the lifetime prevalence of MDD is 12% and about 1.76 million Canadians suffer from MDD in any given year. Heart beat is controlled by the brain and is regular but flexible to change in response to environmental and internal stimuli. This is a healthy feature of the heart known as heart rate variability (HRV). MDD has been associated to diminished HRV (i.e. less flexible/adaptable heart rate), and this is believed to be a reflection of abnormal brain function cause by MDD. Repetitive transcranial magnetic stimulation (rTMS) is a treatment that stimulates specific areas of the brain by means of small currents while the person is comfortably sitting in a chair. rTMS is associate to significant improvement in approximately 50% of MDD patients and is usually well tolerated. Studies have demonstrated that rTMS may be associated to changes in HRV, but there have been no studies providing direct evidence that brain changes induced by rTMS are responsible for those changes in HRV. The goal of this study is to test the hypothesis that rTMS induces changes in connectivity between the area of the brain stimulated with rTMS (dorsolateral prefrontal cortex) and deeper areas in the brain associated to heart rate regulation (anterior cingulate cortex). The methodology to test his hypothesis directly is to use a complex method that obtains three sources of data at the same time to test for direct causality. This method consists of capturing both fMRI data and electrocardiogram data at the same time that TMS is stimulating the brain. Experiments will be conducted in a group of healthy volunteers as well as patients with depression. The results of this study may have profound implications in both our understanding of the causes of depression as well as the mechanism of action of rTMS and pave the way to the testing of reliable, feasible, and easy to access biomarkers of response in rTMS.