Results from this study suggest that 0.5- and 100-Hz CES causes cortical brain deactivation in midline prefrontal and parietal regions. In addition, 100-Hz stimulation significantly altered connectivity within the DMN. 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 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 normal resting state cortical activity, resulting in deactivation. In doing so, CES may alter brain oscillation patterns. The observation of reduced 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 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 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
; 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, 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. Applying AC to the brain at different frequencies may alter communication between nodes of the DMN. Studies in clinical populations, including anxiety disorders and depression, have found abnormalities in these intrinsic connectivity networks (for review see [Broyd et al. 2009
]). One study found that anxiety disorder patients, when presented with threat-related words, demonstrated decreased activity in regions that overlap with the DMN including the posterior cingulate cortex (PCC) and inferior parietal lobule, as well as medial prefrontal cortex and thalamus (Zhao et al. 2007
). Liao et al. (2010)
found decreased functional connectivity in individuals with social anxiety disorder within the SMN and DMN (Liao et al. 2010
). In addition, individuals with both acute (Mantini et al. 2009
) and chronic pain (Baliki et al. 2008
) have been shown to have abnormal functional connectivity in the DMN.
How the specific effects of CES on brain deactivation and on intrinsic connectivity networks translate to impacting clinical symptoms still remains to be investigated. In patients with anxiety and those with depression, one possibility is that alterations of the DMN may have a therapeutic effect of disengaging worry- or rumination-promoting internal dialogue (Hamilton et al. 2011
) and/or promoting attention to external stimuli. One way this may occur is that increasing connectivity within the DMN between the PCC and supramarginal gyrus and postcentral gyrus (as found in this study) may lead to increased integration of external sensory information (Bear 1983
). With an improved understanding of these processes, it may be possible that CES parameters such as frequency could be tuned for individuals to therapeutically target different connections within abnormally functioning intrinsic connectivity networks.
This study has several limitations to consider. The small sample size may have resulted in insufficient power to detect smaller changes in resting brain activity. Another limitation is that we did not use a pure sham condition. Rather, we tested sensory thresholds prior to scanning to ensure that participants could not detect if the stimulation was on or off, effectively incorporating control blocks (used as “baseline”) within the experimental design, from which to compare to “on” stimulation blocks. Although we used these same individualized subsensory currents during the experiment, we did not have an accurate way of verifying if participants perceived the stimulation during the scan block by block, as this would have interrupted the “resting state” nature of the experiment. However, questioning participants after the scan revealed that only one participant reported feeling a constant (nonalternating) “sensation” on the left earlobe, which was inconsistent with the pattern of CES used in the experiment and instead likely due to the pressure of the headphone. Another limitation comes from the fact that the stimulation was brief and intermittent in this experiment, limiting the ability to extrapolate findings to changes over longer durations of treatment. In addition, since this was a nonclinical sample, anxiety levels were low before and after stimulation; this limits the ability to understand immediate effects, if any, on this symptom domain. Similar studies in clinical populations are needed to further elucidate how cortical deactivation and changes in intrinsic connectivity networks may translate to therapeutic mechanisms of action.