Sites and mechanisms of trigeminal nerve stimulation: a human and animal study

Trigeminal nerve stimulation (TNS) has proven efficacious in the treatment of several neurological disorders, but sites and mechanisms of action are still unknown. TNS effects were investigated on: intracortical circuits and sensorimotor integration at cortical level (Study 1), brainstem excitability and plasticity (Study 2), in healthy subjects; hippocampal neurogenesis (Study 3), in rats. TNS consisted of 20min bilateral stimulation of the infraorbital nerve.Study 1: Short- and long-interval intracortical inhibition, intracortical facilitation, short- and long-afferent inhibition were assessed using transcranial magnetic stimulation in 17 volunteers before and after TNS.Study 2: The R1 and R2 areas of the blink reflex (BR) were measured before and after 0, 15, 30, 45min from TNS delivery.Study 3: Hippocampal neurogenesis was evaluated in 18 male Sprague-Dawley rats after 24h from TNS, through immunohistochemical labeling of newly formed brain cells.Results.Study 1: cortical excitability and sensorimotor integration were unaltered by TNS.Study 2: The R2 area of the BR was significantly reduced after TNS at all time points tested. By contrast, R1 area was unaffected.Study 3: The number of newly formed cells in the dentate gyrus was significantly increased after TNS.These data suggest that TNS mainly acts on brainstem polysynaptic circuits with a minor role in modifying the activity of higher-level structures. Acute TNS induces a long-lasting inhibition of the R2 component of the BR, which resembles a long-term depression-like effects. In the rat TNS promotes new cell proliferation in the hippocampus, which supports the notion of an involvement of hippocampal plasticity in the TNS effects described in several neurological conditions.