CES thus appears to result in similar cortical deactivation patterns for 0.5- and 100-Hz, but is associated with stronger alterations in functional connectivity for 100-Hz stimulation. Moreover, cortical deactivation patterns differed from those associated with current intensity, suggesting that cortical deactivation may depend more on frequency than intensity of stimulation. These results may help shed light on potential mechanisms of action

of Inhibitors,research,lifescience,medical CES. Previously proposed mechanisms have included changes in brain oscillation patterns, neurotransmitter and endorphin release, interruption of ongoing cortical activity, or secondary effects from peripheral nerve stimulation (Zaghi et al. 2009). These proposed mechanisms may not be mutually exclusive. For example, the oscillating current from CES may reach the cortex where it may interrupt INNO-406 price normal resting state cortical activity, resulting in deactivation. In doing so, CES may alter brain oscillation patterns. The observation of reduced Inhibitors,research,lifescience,medical BOLD signal associated with stimulation in the current study fits with previous EEG studies of CES that demonstrated downward shift in mean or median alpha frequency with stimulation (Itil et al. 1972; Schroeder and Barr 2001), as lower frequency brain activity has been

found to be associated with lower BOLD signal in studies of simultaneous Inhibitors,research,lifescience,medical colocalized electrophysiological and fMRI recordings (Magri et al. in press) and in epilepsy (Archer et al. 2003). The different alterations in connectivity observed

in this study with Inhibitors,research,lifescience,medical 100-Hz relative to 0.5-Hz stimulation could be related to the overlapping but somewhat differential effects of these frequencies on EEG patterns found in previous studies (Schroeder and Barr 2001). The observation that 100-Hz but not 0.5-Hz stimulation significantly affected connectivity in the DMN in this study may be related to previous observations that 100-Hz but not 0.5-Hz affects the beta band, which has been found to correlate strongly with activity in the DMN (Mantini et al. 2007; Inhibitors,research,lifescience,medical Laufs 2008). In regards to how the current reaches the brain, because this study used earlobe electrodes, the alternating microcurrent may initially stimulate afferent branches of cranial nerves. Stimulation may initially occur at branches of the facial, glossopharyngeal, and/or the vagus nerves that originate near the electrode placement on the earlobe, then are carried to the brainstem, FK866 in vitro the thalamus, and finally the cortex. Two different clinically effective frequencies (100 or 0.5 Hz) were associated with brain deactivation, but the amplitude of current was not. This provides additional mechanistic evidence that CES may exert its effects through interruption of normal cortical activity, possibly through the introduction of high- or low-frequency noise that interferes with certain brain oscillation patterns. The results of this study may have several important clinical implications.