The effect of trigeminal nerve stimulation (TNS) on the noradrenergic signaling in the brains of healthy volunteers
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1
Ghent University, Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology (LCEN3), Belgium
Introduction
Trigeminal nerve stimulation (TNS) is currently under investigation as a non-invasive treatment for refractory epilepsy. In TNS the trigeminal nerve is stimulated through an electrode placed on the forehead. The number of open label and randomized controlled trials with TNS in epilepsy are limited, which show encouraging results of responder rate and seizure frequency reduction. Based on the anatomical projections of the vagus nerve and trigeminal nerve to the brainstem nucleus of the solitary tract and locus coeruleus, the mechanism of action of TNS is hypothesized to be similar to that of invasive vagus nerve stimulation (VNS) (1). Previous experiments at the LCEN3-lab demonstrated in a translational setting using hippocampal microdialysis and lesioning experiments in epileptic rats, that VNS-induced NA release plays a crucial role in the seizure suppressing mechanism of action of VNS (2). Non-invasive measurements of VNS-induced NA release by means of P300 event-related potential recordings in epilepsy patients was able to distinguish responders and non-responders to VNS treatment (3).
Methods
To investigate the effect of TNS on the noradrenergic signaling in the brain, we performed a pilot study in which P300 event-related potentials were recorded in 21 healthy volunteers (10 M, 11 F) between 18 and 30 years old. The P300 event-related potential can be extracted from the EEG and is elicited by performing an auditory oddball paradigm, in which a random sequence of frequent low standard tones and rare high oddball tones are presented. The subject was instructed to press a predefined button after presentation of an oddball tone while ignoring the standard tones. Each subject performed the auditory oddball task in three conditions: TNS (120 Hz, 250 μs, 30s ON/30s OFF), sham stimulation (2 Hz, 250 μs, 1s ON/90s OFF) and no stimulation. The stimulation intensity was defined individually on beforehand to the maximum tolerable output current of TNS (range: 2.8 mA – 7.4 mA). The conditions were randomized and separated by a 30-minute break to avoid a carry-over effect.
Results
There was no statistically significant effect of the stimulation condition on the mean P300 amplitude or latency. However, the analysis showed a higher P300 amplitude in the condition TNS compared to no stimulation. This increase was higher than the pre-defined cut-off score of > 1 μV, which was considered as clinically relevant based on the results of a similar study with P300 measurements in epilepsy patients treated with VNS (3). Based on the statistical analysis it cannot be concluded that the conditions sham and no stimulation were equivalent. There was a statistically significant difference in mean P300 amplitude for the variable “sex”, in which females had a significantly higher P300 amplitude compared to males. Variables “age”, “tobacco use”, “alcohol use” and “coffee consumption” did not influence the mean P300 amplitude. The P300 latency was not affected by any tested variable.
Conclusions
In conclusion, although not statistically significant, TNS induced a clinically relevant increase in P300 amplitude compared to no stimulation, reflective of noradrenalin release in the brain. More volunteers will be recruited to investigate whether this clinically relevant effect might also become statistically significant.
Résumé en Français:
Le nerf trijumeau est un nerf cranien transmetteur de la douleur mais aussi de mouvement. Des travaux récents ont montré que sa stimulation avait un effet bénéfique sur les épileptiques. Ce travail vise à déterminer les conditions optimales de stimulation à appliquer et à affiner ce traitement parmi des sous-groupes de patients épileptiques.
Samenvatting in het Nederlands:
De nervus vagus is een hersenzenuw die verantwoordelijk is voor ervaren van pijn in het gezicht, maar ook instaat voor beweging van het gezicht. Recent onderzoek heeft aangetoond dat stimulatie van deze zenuw een positief effect heeft op aanvallen bij mensen met epilepsie. Dit werk heeft als doel de voorwaarden om optimaal te kunnen stimuleren te bepalen en subgroepen van patiënten met epilepsie die het meest baat zouden hebben bij deze behandeling, te identificeren.
References
(1) Fanselow E. (2012) Central mechanisms of cranial nerve stimulation for epilepsy. Surgical Neurology International 2(3)S247-254
(2) Raedt R., Clinckers R., Mollet L., Vonck K., El Tahry R., Wyckhuys T., De Herdt V., Carrette E., Wadman W., Michotte Y., Smolders I., Boon P. and Meurs A. (2011) Increased hippocampal noradrenaline is a biomarker for efficacy of vagus nerve stimulation in a limbic seizure model. Journal of Neurochemistry 117:461-469
(3) De Taeye L., Vonck K., van Bochove M., Boon P., Van Roost D., Mollet L., Meurs A., De Herdt V., Carrette E., Dauwe I., Gadeyne S., van Mierlo P., Verguts T. and Raedt R. (2014) The P3 Event-Related Potential is a Biomarker for the Efficacy of Vagus Nerve Stimulation in Patients with Epilepsy. Neurotherapeutics 11(3):612-622
Keywords:
Epilepsy,
trigeminal nerve stimulation,
P300 event-related potential,
noradrenalin,
mechanism of action
Conference:
6th Belgian Brain Congress, MONS, Belgium, 8 Oct - 8 Oct, 2016.
Presentation Type:
Poster Presentation
Topic:
Brain and brain diseases: between heredity and environment
Citation:
Gadeyne
S,
Bourgeois
A,
Boon
P,
Carrette
E,
Carrette
S,
Raedt
R and
Vonck
K
(2016). The effect of trigeminal nerve stimulation (TNS) on the noradrenergic signaling in the brains of healthy volunteers.
Conference Abstract:
6th Belgian Brain Congress.
doi: 10.3389/conf.fnagi.2016.03.00032
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Received:
30 Jun 2016;
Published Online:
04 Jul 2016.
*
Correspondence:
Miss. Stefanie Gadeyne, Ghent University, Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology (LCEN3), Ghent, Belgium, Stefanie.Gadeyne@UGent.be