Evaluation of left dorsolateral prefrontal cortex volume as a predictor of clinical response to the use of theta-burst stimulation in the treatment of unipolar depression

Abstract

Major Depressive Disorder (MDD) is a disabling condition associated with personal, social and economic impairments. The treatment of choice for depression is pharmacological, but presents side effects and limited response. Non-invasive neuromodulation techniques are safe and effective in the treatment of MDD, having as mechanisms of action the increase in brain activity and induction of neuroplasticity by the activation of the left dorsolateral prefrontal cortex (l-dlPFC) through direct electrical currents or electromagnetic pulses l-dlPFC is a critical area in the pathophysiology of depression, and its activity restoration has been associated with improvement in depressive symptoms. The clinical results of neuromodulation, although promising, are still modest. Still, its mechanisms of action are unknown. In that way, the identification of response predictors can help both in the early identification of responders, saving time and resources, as well as elucidating those action mechanisms and contributing to the development of the technique. Recently, a study by our group with FAPESP support (JP 12/20911-5) based on secondary data from a pivotal clinical trial (Brunoni et al., 2017, NEJM) showed that the antidepressant clinical response resulting from transcranial electrical stimulation was directly associated with higher volumes of l-dlPFC (Bulubas et al., 2019). Despite our promising findings, these were exploratory, limited to a sample of 15 participants and not yet investigated for transcranial magnetic stimulation. Continuing our group's pioneering lines of research, which involve financial support in FAPESP's neuromodulation and neuroimaging areas (APR grants 18/10861-7 and PT 19/06009-6, and independent grants DD 19/07256-7 and PD 20/03235-2) and the Academy of Medical Sciences - UK (Newton Advanced Fellowship NAFR 12\1010), the main objective of this project is to investigate whether the volume of l-dlPFC, obtained through structural magnetic resonance imaging of the brain (Phillips Apparatus, 3T , INRAD-HCFMUSP), predicts antidepressant response of 20 sessions of TBS in a sample of 50 patients with MDD, who will be evaluated with clinical depression scales over 6 weeks of treatment. Analogously to the results obtained in our previous study, our hypothesis is that a greater volume of DLPFCe will be associated with a greater antidepressant response. As secondary objectives, we will evaluate other regions of interest (ROIs) in the pathophysiology of MDD, such as other areas of the prefrontal cortex, in both hemispheres, and the anterior cingulate cortex bilaterally. Our hypothesis is that the volume of the prefrontal cortex and anterior cingulate cortex, bilaterally, will be predictors of antidepressant response in TBS over 6 weeks of treatment. Volumetric measurements will be obtained using the Freesurfer software and following pre-established routines. In the statistical analysis, we will use mixed linear models having antidepressant scores as dependent variable and treatment time, structural volumes of ROIs and interactions as independent variable, having subjects as random effects. The results of this study will contribute to a better understanding of the mechanisms of action of this neuromodulation technique in depression, in addition to having a potential clinical benefit in identifying early response predictors. (AU)