Taken together our results suggest that supraorbital neurostimulation using the Cefaly® device decreases arousal and induces fatigue. This cannot be considered at this stage as a hypnotic effect in the sense of inducing sleep and decreasing sleep latency but rather as a sedative effect in terms of a reduction of alertness and vigilance. Interestingly, this is only the case with high (120 Hz-HFN) and not with low frequency (2.5 Hz-LFN) stimulation. LFN even has an opposite effect in one psychophysical test, the critical flicker fusion frequency. Below we will examine these results in more detail and speculate on possible mechanisms.
The Psychomotor Vigilance Task measures the reaction time (RT) and is considered as the gold standard for measuring sleepiness [21
]. That it is readily reproducible is demonstrated by the fact that during the blank condition (BC) the change compared to baseline was less than 1.5%. Sham (SC) and LFN induced non significant increases in RT of respectively 8.9 ms and 8.6 ms. By contrast, HFN increased RT by an average of 36.7 ms, i.e. by more than 10%. Critical flicker fusion frequency is known to decrease with fatigue. While unchanged during SC and minimally increased during BC (+ 0.9 Hz), it increased during LFN (+ 1.9 Hz) possibly suggesting a mild increase in vigilance. Again HFN contrasted with all other conditions by a marked decrease (-4.6 Hz) in CFFF, indicating a decrease in arousal. This result is concordant with that of the subjective fatigue rating on the Fatigue Visual Numerical Scale (FVNS). The subjects rated their fatigue higher during all experimental conditions than at baseline, which was not significant and might be related to the mental strain due to the recordings or to a learning effect in using the numerical scale. However, the increase of the FVNS score during HFN was three times greater (+ 72.1%). The d2 test for attention and concentration was in our study the only one for which the HFN condition induced no significant effect. Nevertheless the numerical changes during HFN are in line with the other results as they show a lower number of total letters marked and of correct letters marked as well as a higher number of errors. The lack of significance could have at least two explanations. First, the d2 test was administered at an earlier time point (between 10 and 15 minutes) during the experimental condition compared to the other tests (from 15 minutes onwards). The duration of HFN might thus not have been long enough to produce significant d2 test changes. Second, this test was performed only once to avoid a learning effect and the pre- and per-condition comparison had therefore to be replaced by a comparison between conditions, hence weakening the sensitivity of the test to detect a change.
To the best of our knowledge, this is the first time that the effect of transcutaneous neurostimulation on arousal and fatigue was studied in humans and there are no similar studies available in animals. The neurobiological mechanisms through which HFN induces sedation remain therefore speculative. Some insight can nonetheless be gained from the studies of transcutaneous neurostimulation in Alzheimer's patients and from those in experimental animals of the central nervous system consequences of electroacupuncture. A Dutch group reported in a series of publications that transcutaneous electrostimulation was able to improve memory, alertness [26
] and rest-activity rhythm [28
] in Alzheimer's disease. This effect was attributed to activation of the hippocampus and the suprachiasmatic nucleus both by direct spinal cord afferents [29
] and via the dorsal raphe nucleus and locus coeruleus [30
]. Although vigilance was not specifically measured in these studies, the observed cognitive and behavioural effects would suggest increased arousal and vigilance rather than sedation like in our study. This opposite effects can probably be explained by the different stimulation protocols. First, Alzheimer patients received transcutaneous neurostimulation over paravertebral back muscles daily during 6 [26
] or 3 hours [27
] for 6 weeks while we used a single 20-minute session of supraorbital neurostimulation. In a more recent randomized sham-controlled pilot trial of right median nerve stimulation, Scherder et al [32
] found no significant effect on memory in Alzheimer's disease and the same group reported that cranial electrostimulation had no effect on rest-activity rhythm neither at low frequency [33
] nor at high frequency [34
]. More interestingly, we found a hypnotic effect with high frequency (120 Hz) stimulation, whereas the beneficial effects in Alzheimer's disease were obtained with burst of stimuli (9 pulses at 160 Hz) delivered at a low frequency of 2 Hz, a frequency that in our study concordantly increased critical flicker fusion frequency. One may assume that high and low frequency stimulations can have different effects on central nervous system structures and thus on arousal, but this remains to be proven in an adequate study.
Transcranial direct current stimulation (tDCS) is able to modulate cortical activity under certain conditions and in certain brain areas. It is extremely unlikely, however, that the supraorbital TNS used in this study influences directly the underlying brain structures, i.e. the frontal lobes, for at least two reasons. First, The small electrode surface (7 cm²) and distance between the two electrodes (5 mm) restrict the skin surface affected by the current as well as current penetration into deeper structures. Second, the TNS applied current is composed of biphasic rectangular impulses with an electrical mean equal to zero, while tDCS uses a direct current. The current characteristics and the mechanisms of action are thus different between trigeminal TNS and tDCS. Moreover, in a recent study [35
], weak transcranial electrical DC or AC currents over the prefrontal cortex had no effect on mood or EEG in healthy subjects. Interestingly, sleepiness was reported rarely both in the active (0.11%) and sham stimulation groups (0.08%).
Experimental studies on the mode of action of electroacupuncture in pain are relevant to this discussion because many of the central nervous system structures activated by electroacupuncture like the monoaminergic brain stem nuclei, the hypothalamic arcuate nucleus or the periaqueductal gray matter also play a role in vigilance states (36,37,38,39). A simple straightforward explanation for the sedative effects found in our study would be an effect of the transcutaneous stimulation on monoaminergic brain stem nuclei such as locus coeruleus that receives direct spinal input [40
]. The locus coeruleus is also thought to mediate the anti-epileptic effect of high frequency transcutaneous stimulation of the ophthalmic nerve [41
]. However, in animals high frequency electroacupuncture was found to increase neuronal activity in brain stem nuclei [36
], in particular in dorsal raphe nuclei [37
]. Increased activity of these nuclei that belong to the ascending activating reticular system would be associated with increased rather than decreased arousal and vigilance. Electroacupuncture over peripheral nerves also activates the hypothalamic arcuate nucleus in animals [39
]. The arcuate nucleus plays a pivotal role in electroacupuncture-induced cardiovascular inhibition [39
], but also in vigilance states via its reciprocal connections with orexin-containing lateral hypothalamic neurons and the ventrolateral periaqueductal gray matter (38,42). A change in activity levels of the orexin-arcuate-periaqueductal gray matter circuit could occur during supraorbital neurostimulation and might explain the decrease in vigilance. Future studies of supraorbital neurostimulation coupled to functional cerebral imaging studies could verify this hypothesis. Further studies are also needed to verify whether the sedative effects of HFN as evidenced here by psychophysical tests have electroencephalographic correlates and if they are associated with hypnotic effects such as sleep latency reduction.