Mechanisms of Repetitive Transcranial Magnetic Stimulation on Post-stroke Depression Treatment

Stroke has severe neuropsychological outcomes, the major one is post-stroke depression (PSD). Stroke survivors begin to show symptoms of depression within a few months of the incidence that overtime progresses to become a long-term ailment. As the pathophysiology for the progression of PSD is multifactorial and complex, it limits the understanding of the disease mechanism completely. Monoamine neurotransmitters have been suggested as one of the key factors in the development of depression in stroke patients. Repetitive transcranial magnetic stimulation (rTMS) has been considered as an efficient treatment for PSD, and is known for its non-invasiveness and minimal side effects. Meta-analyses and randomized clinical trials show that both high and low frequency rTMS significantly improved depressive symptoms in PSD patients, but the underlying mechanism is still unclear. The present review provides a general overview of rTMS stimulation protocols in PSD treatment, and highlights the role of monoamine neurotransmitters, such as serotonin, norepinephrine and dopamine, in the pathology, as well as in the treatment of PSD. By activating local monoamine neurotransmitters release, rTMS enhances the top-down control of prefrontal cortex and alters functional connections of multiple brain areas, which are associated with improvement of depression in the stroke patients. Moreover, rTMS has been shown to enhance glucose metabolism levels, and inhibit monoamine oxidase (MAO)-A activity through the Sirt1/MAO-A pathway. The decreased MAO-A leads to less degeneration of monoamine neurotransmitter, and provides neuroprotection. rTMS could also induce long-term potentiation or long-term depression, which leads to alterations in synaptic plasticity. As the result, brain networks connections become similar to those of normal individuals, and the long-term therapeutic effects of rTMS are maintained. In addition, brain-derived neurotrophic factor (BDNF) is also shown increased after rTMS in PSD patients, associated with serotonin elevation. The BDNF increase, which is regulated by serotonin, improves neuronal maintenance, survival and plasticity, and further positively regulating serotoninergic neuron in PSD patients.