Investigating the efficacy of dual stimulation of tDCS and rTMS Neuro-modulation therapy of Major depression

Majordepression is the commonest psychiatric disorder affecting 3-5% of Indianpopulation. Although the exact pathophysiology of these disordersis unknown, drugs acting on several neurotransmitter systems such as serotoninand norepinephrine tend to clinically improve the condition in 30-50% patients.However, recurrence or relapses and partial response are common in thisdisabling condition (~30-40%) requiring second line of treatmentstrategies or add-on/adjuvant therapies. In this regard, there is expandinginterest in repetitive transcranial magnetic stimulation (rTMS) andtranscranial direct current stimulation (tDCS) as add-on to standard medicaltherapies for this disabling psychiatric disorder. Although thesetwo modes of non-invasive brain stimulation have been successfully consideredas second or third lines of antidepressant managements, we are still lackingthe clear understanding of combining these two modes of non-invasive modes ofstimulation. Further neurophysiological modulation of excitability and plasticitywhen brain stimulation is being used as therapeutic strategies in patients withMajor depression has not been studied. Based on scientific studies, we knowthat anodal and cathodal tDCS alter the excitability of stimulated region in anopposite direction in such a way that anodal facilitates long-term potentiation(LTP)-like and cathodal tDCS facilitates long-term depression (LTD)-likeneuroplasticity of the stimulated region. Similarly high (>5Hz)and low (<1Hz) frequency rTMS increases or decreases the excitability of thestimulated region through plasticity effects. However, when thesetwo modes of stimuli are given one after the other, metaplasticity sets in,resulting in changed direction of the excitability to maintain the homeostaticplasticity based on the Bienenstock--Cooper--Munro model.Thus when two protocols, which produce LTP effects are combined (say anodaltDCS and high frequency rTMS), the resultant homeostatic plasticity will bringdown the excitability in such a way that finally resulting in LTD-like effect.Hence we propose to use cathodal tDCS instead of anodal to potentiate theeffect of high frequency rTMS to left dorsolateral prefrontal cortex (DLPFC) toobtain increased excitability effects in patients with Major depression. Thesemetaplastic effects have been validated in healthy subjects andpatients with migraine and also in the visual cortex.Further, the neurobiological factors and patient characteristics contributingto efficacy of these add-on antidepressant therapies in refractory depressionis not established. Hence we plan to study the efficacy of dual stimulation oftDCS and high frequency rTMS at DLPFC as potential and efficaciousantidepressant therapies. We would also like to use the metaplasticity effectsat M1 as a predictor of efficacy for the dual stimulation along with othermeasures: heart rate variability (HRV) and TMS measures of excitability.