Transdermal neuromodulation of noradrenergic activity suppresses psychophysiological and biochemical stress responses in humans

Abstract

We engineered a transdermal neuromodulation approach that targets peripheral (cranial and spinal) nerves and utilizes their afferent pathways as signaling conduits to influence brain function. We investigated the effects of this transdermal electrical neurosignaling (TEN) method on sympathetic physiology under different experimental conditions. The TEN method involved delivering high-frequency pulsed electrical currents to ophthalmic and maxillary divisions of the right trigeminal nerve and cervical spinal nerve afferents. Under resting conditions, TEN significantly suppressed basal sympathetic tone compared to sham as indicated by functional infrared thermography of facial temperatures. In a different experiment, subjects treated with TEN reported significantly lower levels of tension and anxiety on the Profile of Mood States scale compared to sham. In a third experiment when subjects were experimentally stressed TEN produced a significant suppression of heart rate variability, galvanic skin conductance, and salivary α-amylase levels compared to sham. Collectively these observations demonstrate TEN can dampen basal sympathetic tone and attenuate sympathetic activity in response to acute stress induction. Our physiological and biochemical observations are consistent with the hypothesis that TEN modulates noradrenergic signaling to suppress sympathetic activity. We conclude that dampening sympathetic activity in such a manner represents a promising approach to managing daily stress.

Conflict of interest statement

W.J.T. is a co-founder of Thync, Inc. W.J.T., J.D.C., D.Z.W. and S.K.P. are inventors and co-inventors on issued and pending patents related to methods, systems, and devices for neuromodulation. All authors are shareholders in Thync, Inc.

Figures

Figure 1. Cranial and spinal afferent pathways provide direct inputs to neural circuits regulating psychophysiological arousal and stress responses.

The diagram illustrates trigeminal and facial nerve afferents impinging on the nucleus of the solitary tract (NTS) and trigeminal nuclei (primary sensory nucleus and spinal nucleus) in the brainstem. The NTS and trigeminal nuclei impinge on the noradrenergic locus coeruleus (LC) and other brainstem nuclei comprising a loose network of interconnected structures historically recognized as the reticular formation (RF). The major pathways and circuitry highlighted (blue) were targeted using high-frequency pulsed currents (7–11 kHz) using transdermal electrical neurosignaling (TEN) waveforms delivered to trigeminal, facial, and cervical spinal (C2/C3) afferent fibers. Trigeminal and facial nerve afferents (sensory and proprioceptive) can modulate the activity of the LC and NTS to affect psychophysiolgical arousal, the activity of the sympathoadrenal medullary (SAM) axis, biochemical stress responses, and the dorsal motor nucleus (DMN) of the vagus. The bottom-up neurosignaling pathways illustrated serve mechanisms for the regulation of cortical gain control and performance optimization by influencing a broad variety of neurophysiological and cognitive functions, as well as primary sympathetic responses to environmental stress.

Figure 2. Experimental approaches used to assess the effects of TEN on basal sympathetic tone, mood, and acute stress responses.

(a) The photographs illustrate the montage and device used to target cranial and cervical spinal afferents. (b) The photograph illustrates the testing room and shows an infrared (IR) camera, integrated heart rate and galvanic skin conductance sensors, a bar electrode used to deliver fear conditioning stimuli, and a monitor for presenting stimuli. In sub-panels (c–e) schematics illustrating the three experimental paradigms used in this study are shown. (c) The schematic depicts Experiment 1 designed to evaluate the influence of TEN and sham stimulation on a sympathetic skin response by monitoring emotional thermoregulation of facial temperatures using functional IR thermography. (d) The schematic depicts Experiment 2 designed to investigate the influence of TEN and sham stimulation on affective mood states. (e) The schematic depicts the experimental approach used to evaluate the influence of TEN and sham stimulation on psychophysiological and biochemical responses to stress. For additional details, see Methods.

Figure 3. TEN significantly modulates a sympathetic skin response and emotional thermoregulation by increasing facial temperatures as indicated by functional infrared thermography.

(a) Pseudo-colored infrared (IR) images are shown for representative subjects from the sham (top) and TEN (bottom) treatment groups obtained in Experiment 1. The average baseline temperature and time points corresponding to 5, 10, and 20 min following the onset of a 15 min sham or TEN treatment are illustrated. (b) Histograms (left) illustrate the average baseline temperatures obtained from the foreheads, noses, chins and cheeks (Supplementary Figure 1) of subjects during the 5 min baseline period prior to sham or TEN treatment. The lineplots (right) illustrate the average percentage change in temperature (ΔT) of foreheads, noses, chins and cheeks of subjects at time points corresponding to 2nd, 5th, 10th, and 20th min period after the onset of sham (black) or TEN (blue) treatment (Supplementary Videos 1 and 2). The vertical dahsed lines in the line plots illustrates the termination of sham or TEN treatments. The P values for groups differences calculated from repeated measures analysis ANOVA’s are shown and an asterisk indicates a significant group difference at P < 0.05. For clarity all data have been shown as mean ± SEM.

Figure 4. TEN significantly reduces anxiety and tension compared to sham.

Data obtained from Experiment 2 are illustrated. The histograms illustrate the mean ± SD scores obtained from TEN and sham treatment groups on the Profile of Mood State (POMS) subscales: Fatigue/Inertia, Vigor/Activity, Confusion/Bewilderment, Anger/Hostility, Depression/Dejection, and Anxiety/Tension. Following a 15 min treatment session, subjects in the TEN group reported significantly less Anxiety/Tension on the POMS survey compared to the sham treatment group. An asterisk indicates a significant difference at P 

Figure 5. TEN suppresses changes in HRV induced by experimentally induced stress.

The histograms illustrate the average HR (a), R-R interval (b), SDNN (c), LF power (d), HF power (e), and LF/HF (f) HRV responses mediated by sham and TEN treatments in response to the induction of acute stress. An asterisk indicates a significant difference with P < 0.05. All data shown are mean ± SD.

Figure 6. TEN attenuates anticipatory and event-related changes in GSC during classical fear-conditioning.

(a) Representative raw GSC traces obtained from a subjects treated with sham or TEN during the experimental paradigm designed to induce acute stress (Fig. 2e). 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. Note differences in the amplitude of event-related GSC changes (ΔGSC; see Methods) between the treatment groups illustrate TEN-mediated reduction in sympathetic drive. (b) The line plot illustrates a different GSC profile obtained from a subject treated with TEN during the fear-conditioning component of the stress trial. As also shown in panel a, all subjects exhibited the same type of response where there was a sharp anticipatory increase in GSC (ΔGSCfear) at the onset of the fear-conditioning component of the stress trial before the delivery of the first US. All subjects also exhibited transient GSC increases (ΔGSCshock) in response to the delivery of each US as illustrated. For clarity, the area marked by the shaded rectangular box is shown at a higher temporal resolution and amplitude scale (inset). (c) The histograms illustrate the average ΔGSC for the TEN and sham treatment groups obtained during the fear-conditioning phase of the stress trial. An asterisk indicates a significant difference with P < 0.05. All data shown are mean ± SD.

Figure 7. TEN reduces salivary α-amylase levels in response to acute stress.

The histograms illustrate the average levels of α-amylase (a) and cortisol concentration (b) in saliva samples taken before (baseline), 10 min, and 30 min after the stress trial for sham and TEN treatment groups. An asterisk indicates a significant difference with P < 0.05. All data shown are mean ± SD.

Figure 8. Neurons in the LC dynamically shift between tonic and phasic firing modes as a function of afferent activity and stress.

(a) The figure illustrates a working model of neuronal activity patterns exhibited by the LC under different levels of stress and arousal as observed from experimental animal models. 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. (b) Facial and trigeminal nerve afferents, as well as the pons portion of the circuit diagram from Fig. 1 are shown (left). 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. Our observations suggest this partial mechanism of action, at a first station of information processing in the brain, may involve increased α2 adrenergic activity as depicted.