Psychophysiology. Today and Tomorrow

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In sub-panels c — e schematics illustrating the three experimental paradigms used in this study are shown. For additional details, see Methods. In Experiment 1, to begin evaluating the influence of TEN on sympathetic activity, we monitored a sympathetic skin response SSR using functional infrared thermography of facial regions Figs 2c and 3. Thermoregulation of skin temperature is influenced by physiological homeostasis, as well as changes in autonomic nervous system activity imparted by emotional responses to stimuli 26 , Functional infrared thermography has shown that increased sympathetic activity leads to the rapid temperature decreases of the nasal and mouth regions of non-human primates 28 , 29 , as well as several facial regions of humans 30 , 31 , Conversely decreased sympathetic activity, increased positive emotional states or relaxation lead to temperature increases of several facial regions of humans including the forehead, nose, cheeks, and mouth region including the chin 33 , 34 , The vertical dahsed lines in the line plots illustrates the termination of sham or TEN treatments.

Briefly, volunteer subjects were randomly assigned to one of the two treatment groups and blinded to the experimental condition. There were no significant differences in the average temperatures of the facial regions between subjects during the five-minute baseline period Fig. A two-way repeated measures ANOVA with time as the within subject factor and treatment condition sham versus TEN as the between subjects factor was conducted on each facial region monitored: forehead, chin, cheek and nose. This main effect was subsumed by significant treatment-by-time interactions.

These data indicate that TEN can significantly dampen basal sympathetic tone compared to sham in a manner sufficient to modulate emotional thermoregulation as reflected in temperature changes of the face. In Experiment 2 Fig. As described above volunteer subjects were seated in a testing booth Fig. Ten minutes following the completion of their treatment, subjects completed the item POMS survey Fig. These data demonstrate that TEN significantly reduced self-reported tension and anxiety compared to sham when subjects are not challenged or presented other environmental stimuli.

Data obtained from Experiment 2 are illustrated. In Experiment 3 Fig. We examined the influence of TEN on heart rate variability HRV , a common biometric of psychophysiological arousal reflecting autonomic function including parasympathetic and sympathetic nervous system activity 37 , A similar trend was observed for the power of the HF component 0. These data indicate TEN treatment significantly suppressed sympathetic activity in response to the delivery of unconditioned fear stimuli electrical shocks as indicated by the GSC component of the SSR.

The onset of the classical fear-conditioning paradigm fear onset , delivery of unconditioned stimuli US; electrical shocks; blue , and onset of the time-pressured cognitive battery are marked. For clarity, the area marked by the shaded rectangular box is shown at a higher temporal resolution and amplitude scale inset. Ten minutes after the stress trial, the average levels of sAA for the sham group had increased 0. Thirty minutes after the stress trial, the average sAA levels for the sham group had increased 6.

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While sAA is reflective of NE levels and acute SAM axis activity, cortisol is another stress biomarker, which has a slower onset, longer acting time course, and is under hormonal control of the hypothalamic-pituitary-adrenal HPA axis. Salivary cortisol levels did not significantly differ between sham and TEN treatments at any of the time points tested.

At baseline the salivary cortisol concentration for sham was 0. Ten minutes after the stress paradigm the salivary cortisol concentration for sham was 0.

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Thirty minutes after the stress paradigm the salivary cortisol concentration for sham was 0. A series of one-way ANOVAs revealed there were no significant differences between sham and TEN treated subjects in error rates or reaction times for congruent and incongruent tasks Table 1. We assessed differences in the incidence frequency , duration in minutes , and severity eight point scale of the most common side effects associated with electrical neurostimulation using subject self-reports.

TEN and sham groups had similar incidence rates of side effects with similar severity and durations Table 2. Notably, there were no reports of headaches, nausea, or hearing changes. Further, no severe adverse events were reported. Evidence accumulated in Experiment 1 demonstrating TEN affected emotional thermoregulation by significantly increasing facial temperatures compared to sham is indicative of dampened basal sympathetic activity Fig. These observations are consistent with other reports investigating sympathetic skin responses SSR using functional infrared thermography that have shown increased sympathetic activity causes a decrease of facial temperatures while decreased sympathetic activity or relaxed mental states evoke increased thermal fluctuations of the face 28 , 29 , 30 , 31 , 32 , 33 , 34 , When we challenged subjects in Experiment 3 and induced acute stress using a classical fear-conditioning paradigm, we observed that TEN significantly suppressed stimulus-evoked galvanic skin responses, which represent another component of the SSR Fig.

This particular observation suggests TEN suppressed sympathetic activity, in part, by modulating noradrenergic signaling pathways since previous studies have shown sAA levels to be predictive of plasma norepinephrine NE concentrations 42 , 43 , 44 , 45 , 46 , 47 , Taken together our observations indicate that TEN influences sympathetic activity, in part, by acting on noradrenergic signaling: TEN can dampen basal sympathetic tone, reduce tension and anxiety, and suppress psychophysiological and biochemical responses elicited by acute stress.

Based on anatomical, physiological, and biochemical observations reported here and elsewhere in the literature, we propose that TEN transmitted via cranial nerve and cervical spinal afferent pathways modulated the activity of the locus coeruleus LC and noradrenergic signaling to attenuate sympathetic activity and physiological stress.

We developed the TEN method used in this study to target the ophthalmic and maxillary branches of the trigeminal nerve, the temporal branch of the facial nerve, and cervical spinal nerves Fig. Trigeminal nuclei in the brain stem provide inputs to the LC and establish neural pathways by which trigeminal afferents can modulate noradrenergic activity Fig. Afferent projections from cervical spinal pathways provide another pathway by which TEN could have modulated the LC It has indeed been shown that afferent sensory stimulation rapidly increases the firing rates of NE neurons in the LC 50 , In turn, modulation of NE signaling would have an impact on sympathoadrenal medullary SAM axis activity as further discussed below.

In addition, pathways emerging from the primary sensory and spinal nuclei of the trigeminal nerve, sensory afferents from the facial nerve, project to the NTS, which also influences the activity of neurons in the RAS including the LC.

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The NTS also influences the activity of the dorsal motor nucleus DMN of the vagus, which sends preganglionic parasympathetic fibers to various target organs and regulates physiological homeostasis. At present, we cannot rule out the possibility that TEN may have also affected parasympathetic activity; however, our targeting approaches are anatomically and physiologically consistent with effects on sympathetic activity that involve impingement upon the LC. We chose to implement high-frequency pulsing parameters for the development and implementation of TEN since it minimized the activation of neuromuscular and pain fibers.

One must also consider evidence dating back to the dawn of modern electrophysiology demonstrating that high-frequency currents can effectively stimulate peripheral nerves through a variety of mechanisms including by avoiding a refractory period The precise actions of TEN on the activity of specific nerve fiber types or afferent pathways is presently unknown.

Future studies using electrophysiological approaches will need to be conducted to accurately characterize the influence of TEN on nerve fiber activity and downstream brain circuitry. We hypothesize that through cranial and cervical spinal nerve afferent pathways TEN drives LC activity into a sympatholytic phasic firing mode by diminishing high levels of stress-induced tonic activity Fig. The LC exhibits two essential types of neural discharges tonic and phasic that modulate cognition and behavior.

These phasic and tonic LC discharge patterns favor different modes of signal processing and behaviors in a manner dependent upon the level of afferent drive 19 , 55 , In response to sensory and environmental cues, neurons in the LC have been shown to undergo shifts from a tonic to a phasic firing mode Based on experimental observations in animal models, the magnitude of endogenous phasic LC activity depends on the level of tonic LC activity Fig. Under stress, tonic activity is high and phasic activity is diminished Fig. Likewise when tonic activity is extremely low, such as during slow wave sleep, phasic activity is also diminished 56 , 58 , These observations reinforce the notion that appropriate levels of arousal stemming from a balance between tonic and phasic LC discharges and noradrenergic activity are necessary for maintaining optimal behavioral flexibility and performance 19 , 55 , This model incorporates observations that stress leads to high levels of tonic activity in the LC while sensory stimulation black triangles triggers phasic activity especially when tonic activity is low 50 , 51 , 56 , 57 , 58 , As illustrated stress red acts on LC neurons to increase their tonic firing rates thereby driving sympathetic activity and increasing SAM axis activation.


We hypothesize that TEN blue biases LC activity through afferent pathways in a manner that increases phasic firing, reduces tonic activity, and suppresses sympathetic tone and SAM axis activation. Similarly, we observed that TEN significantly attenuated the levels of sAA following stress induction as discussed above Fig. Interestingly, clonidine inhibits the tonic activity of LC neurons without suppressing phasic activity Others have also reported the oral administration of clonidine to healthy subjects significantly reduces the LF component of HRV, as well as lowers plasma concentrations of NE 64 , Similar to these actions of clonidine, we found that TEN treatments produced a significant decrease in the LF component of HRV during the stress trial compared to sham Fig.

Further experiments involving human pharmacology will be required to fully delineate the molecular mechanisms of action underlying the ability of TEN to inhibit sympathetic activity. These will be important studies given the growing interest of utilizing peripheral nerve pathways to affect brain function, such as efforts exploring the development of electroceuticals The safety of TEN is supported by a long history of peripheral electrical neurostimulation obtained over more than four decades.

Some of these devices are intended for over-the-counter cosmetic applications of transcutaneous electrical nerve stimulation TENS and affect the maxillary branch of the trigeminal nerve, which has some overlap with neural pathways we targeted.

One example device is the Bio-medical Research BMR Face device, which is an over-the-counter TENS device designed to target the trigeminal nerve and provide neuromuscular electrical stimulation NMES waveforms to encourage facial rejuvenation for aesthetic purposes. Consistent with these results, on an acute level we found that TEN did not elicit any significant side effects Table 2. Further, TEN did not have any significant effect on cognitive performance or reaction times Table 1.

Other observations demonstrating the chronic safety profile of TEN have been recently reported Based collectively on these observations, we conclude TEN provides low-risk and reliable approach to modulating psychophysiological arousal. In summary our observations demonstrate that, compared to sham, TEN significantly dampened basal sympathetic tone, significantly decreased tension and anxiety, and significantly suppressed the physiological and biochemical responses to acute stress induction.

While further experiments including electrophysiological assays and pharmacological manipulations will be required to test this hypothesis, as well as to investigate the influence of TEN on signaling cascades downstream of the LC and NE, our basic observations have provocative implications for the management of stress and optimization of brain health. All subjects provided written informed consent prior to experimentation.


We conducted three independent experiments in this study using different groups of volunteer subjects. All experiments were designed using a between subjects approach. All subjects were blinded to the study conditions. Experiment 1 Fig. Experiment 2 Fig.

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Experiment 3 Fig. Prior to this study, we spent two years developing and investigating a variety of electrical neuromodulation waveforms and approaches. Subjects were only able to control the stimulus intensity within the ranges indicated, but not the frequency of stimuli. Subjects were not able to distinguish any differences between the sensations elicited by the real TEN or sham waveforms. During both the real TEN and sham stimulus protocols, subjects were instructed to adjust the current output of a medical-grade wearable TEN device Thync, Inc.

The anterior electrode positioned over F8 was a 4. Subjects were assigned to experimental conditions using a randomization method or a counterbalancing approach. Subjects were always kept blind to all experimental conditions. In Experiment 1 Fig. Images were then stored for later offline image analysis. Regions of interest were positioned and tracked on the forehead, cheeks, nose, and chin region of the face Fig.

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These average temperatures were analyzed and expressed as a percent change from baseline Fig. Immediately following stimulation, participants completed the POMS survey 36 , which is a item scale designed to assess transient affective states and comprises six subscales: Anger-Hostility 11 items , Depression-Dejection 14 items , Fatigue-Inertia 8 items , Vigor-Activity 6 items , Tension-Anxiety 3 items , and Confusion-Bewilderment 3 items.

Reliabilities of the subscales ranged from 0. All participants were tested between the hours of and to limit variability introduced by circadian fluctuations in salivary analytes see Salivary collection and stress biomarker assays below. The stress trial Fig. Both the classical fear-conditioning paradigm and the time-constrained series of cognitive tests are known to induce acute stress and increase sympathetic activity 69 , 70 , 71 , Before the beginning of the stress trial, participants were instructed that when the computer monitor they were seated in front of began to flash still images instead of the baseline period video that they would be given an electrical shock every time an image of lightning appeared.

The transition from baseline videos to still images during the fear-conditioning portion of the stress trail induced an anticipatory increase in acute stress as reflected by instantaneous changes in GSC Fig.

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  5. The Flanker task is a selective attention task in which participants indicate the direction of a target stimulus that is flanked by stimuli that are oriented in the same direction congruent , in the opposite direction incongruent , or a neutral direction as the response target. The n-back, which assesses working memory, has participants view a sequence of stimuli and indicate when the current stimulus matches the stimuli from n steps earlier in the sequence.

    In this case, subjects were instructed to get to 2 back as quickly and accurately as possible. The Stroop task tests sematic memory by having participants indicate the color of the ink in which a color word is written as fast as possible. Trials can be congruent, the text color and the word refer to the same color, or incongruent, the ink color and the word refer to different colors, which can lead to frustration and itself induce acute stress 71 , Reaction times and accuracy were measured for all tests and analyzed off-line in subsequent analyses.

    We acquired cardiac activity and electrodermal activity during the stress trial using a Shimmer3 optical heart rate monitor integrated with a GSC sensor.

    After providing informed consent, participants rinsed their mouths in preparation for contributing a saliva assay and were then seated in a quiet room during which they self-reported basic demographic information.

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