Major depression is the commonest psychiatric disorder affecting 3-5% of Indian population. Although the exact pathophysiology of these disorders is unknown, drugs acting on several neurotransmitter systems such as serotonin and norepinephrine tend to clinically improve the condition in 30-50% patients. However, recurrence or relapses and partial response are common in this disabling condition (~30-40%) requiring second line of treatment strategies or add-on/adjuvant therapies. In this regard, there is expanding interest in repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) as add-on to standard medical therapies for this disabling psychiatric disorder. Although these two modes of non-invasive brain stimulation have been successfully considered as second or third lines of antidepressant managements, we are still lacking the clear understanding of combining these two modes of non-invasive modes of stimulation. Further neurophysiological modulation of excitability and plasticity when brain stimulation is being used as therapeutic strategies in patients with Major depression has not been studied. Based on scientific studies, we know that anodal and cathodal tDCS alter the excitability of stimulated region in an opposite direction in such a way that anodal facilitates long-term potentiation (LTP)-like and cathodal tDCS facilitates long-term depression (LTD)-like neuroplasticity of the stimulated region. Similarly high (>5Hz) and low (<1Hz) frequency rTMS increases or decreases the excitability of the stimulated region through plasticity effects. However, when these two modes of stimuli are given one after the other, metaplasticity sets in, resulting in changed direction of the excitability to maintain the homeostatic plasticity based on the Bienenstock--Cooper--Munro model. Thus when two protocols, which produce LTP effects are combined (say anodal tDCS and high frequency rTMS), the resultant homeostatic plasticity will bring down 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 the effect of high frequency rTMS to left dorsolateral prefrontal cortex (DLPFC) to obtain increased excitability effects in patients with Major depression. These metaplastic effects have been validated in healthy subjects and patients with migraine and also in the visual cortex. Further, the neurobiological factors and patient characteristics contributing to efficacy of these add-on antidepressant therapies in refractory depression is not established. Hence we plan to study the efficacy of dual stimulation of tDCS and high frequency rTMS at DLPFC as potential and efficacious antidepressant therapies. We would also like to use the metaplasticity effects at M1 as a predictor of efficacy for the dual stimulation along with other measures: heart rate variability (HRV) and TMS measures of excitability.