Research progress on central regulatory mechanism and parameters of percutaneous trigeminal nerve stimulation in the treatment of epilepsy_Journal of Epilepsy

Authors：

SHEN Jia ^1,2 , SUN Fanya ² , LI Rong ² , ZHU Bo ² , DING Le ² , GUO Kun ² , YONG Fang ² , GU Naibing ² ,  DI Zhengli ²

1. Medical School of Yan’an University, Yan’an 716000, China;
2. Department of Neurology, Xi'an Central Hospital, Xi’an 710000, China;

Corresponding author：

DI Zhengli, Email: dizhengli@163.com

Keywords：

Trigeminal nerve stimulation; Epilepsy; Neurotransmitters; Stimulus parameter

DOI：

10.7507/2096-0247.202403014

Video：

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External trigeminal nerve stimulation (eTNS) is a new non-invasive physical and electrical stimulation therapy based on the anatomical characteristics of the trigeminal nerve. It can control seizures by regulating epilepsia-related brainstem nuclei and part of forebrain structures, regulating neuroinflammation, improving synaptic plasticity and promoting neurogenesis, which has broad clinical application prospects. It has been approved by the European Union as an adjuvant treatment for drug-resistant epilepsy patients over the age of 9 years old. Therefore, this article mainly reviews the central nervous system regulatory mechanism of eTNS in improving epilepsy, eTNS stimulation mode and parameters.

Citation： SHEN Jia, SUN Fanya, LI Rong, ZHU Bo, DING Le, GUO Kun, YONG Fang, GU Naibing, DI Zhengli. Research progress on central regulatory mechanism and parameters of percutaneous trigeminal nerve stimulation in the treatment of epilepsy. Journal of Epilepsy, 2024, 10(4): 340-344. doi: 10.7507/2096-0247.202403014 Copy

1.	Wang Y, Chen Z. An update for epilepsy research and antiepileptic drug development: Toward precise circuit therapy. Pharmacol Ther, 2019, 201: 77-93.
2.	Degiorgio CM, Fanselow EE, Schrader LM, et al. Trigeminal nerve stimulation: seminal animal and human studies for epilepsy and depression. Neurosurg Clin N Am, 2011, 22(4): 449-456.
3.	Pop J, Murray D, Markovic D, et al. Acute and long-term safety of external trigeminal nerve stimulation for drug-resistant epilepsy. Epilepsy Behav, 2011, 22(3): 574-576.
4.	Soss J, Heck C, Murray D, et al. A prospective long-term study of external trigeminal nerve stimulation for drug-resistant epilepsy. Epilepsy Behav, 2015, 42: 44-47.
5.	Bhandare AM, Kapoor K, Farnham MM, et al. Microglia PACAP and glutamate: Friends or foes in seizure-induced autonomic dysfunction and SUDEP? Respir Physiol Neurobiol, 2016, 226: 39-50.
6.	Mercante B, Enrico P, Floris G, et al. Trigeminal nerve stimulation induces Fos immunoreactivity in selected brain regions, increases hippocampal cell proliferation and reduces seizure severity in rats. Neuroscience, 2017, 361: 69-80.
7.	Mazarati AM, Lewis ML, Pittman QJ. Neurobehavioral comorbidities of epilepsy: role of inflammation. Epilepsia, 2017, 58(Suppl 3): 48-56.
8.	Iori V, Frigerio F, Vezzani A. Modulation of neuronal excitability by immune mediators in epilepsy. Curr Opin Pharmacol, 2016, 26: 118-123.
9.	Akyuz E, Polat AK, Eroglu E, et al. Revisiting the role of neurotransmitters in epilepsy: an updated review. Life Sci, 2021, 265: 118826.
10.	Cheng HM, Gao CS, Lou QW, et al. The diverse role of the raphe 5-HTergic systems in epilepsy. Acta Pharmacol Sin, 2022, 43(11): 2777-2788.
11.	Ma DL, Tang YC, Chen PM, et al. Reorganization of CA3 area of the mouse hippocampus after pilocarpine induced temporal lobe epilepsy with special reference to the CA3-septum pathway. J Neurosci Res, 2006, 83(2): 318-331.
12.	Pollak Dorocic I, Furth D, Xuan Y, et al. A whole-brain atlas of inputs to serotonergic neurons of the dorsal and median raphe nuclei. Neuron, 2014, 83(3): 663-678.
13.	Commons KG. Ascending serotonin neuron diversity under two umbrellas. Brain Struct Funct, 2016, 221(7): 3347-3360.
14.	Brust RD, Corcoran AE, Richerson GB, et al. Functional and developmental identification of a molecular subtype of brain serotonergic neuron specialized to regulate breathing dynamics. Cell Rep, 2014, 9(6): 2152-2165.
15.	Mason P. Contributions of the medullary raphe and ventromedial reticular region to pain modulation and other homeostatic functions. Annu Rev Neurosci, 2001, 24: 737-777.
16.	Zhang H, Zhao H, Zeng C, et al. Optogenetic activation of 5-HT neurons in the dorsal raphe suppresses seizure-induced respiratory arrest and produces anticonvulsant effect in the DBA/1 mouse SUDEP model. Neurobiol Dis, 2018, 110: 47-58.
17.	Iidaka T. Fluctuations in arousal correlate with neural activity in the human thalamus. Cereb Cortex Commun, 2021, 2(3): tgab055.
18.	Shiozawa P, Silva ME, Carvalho TC, et al. Transcutaneous vagus and trigeminal nerve stimulation for neuropsychiatric disorders: a systematic review. Arq Neuropsiquiatr, 2014, 72(7): 542-547.
19.	Bari AA, Pouratian N. Brain imaging correlates of peripheral nerve stimulation. Surg Neurol Int, 2012, 3(Suppl 4): S260-268.
20.	Moseley BD, Degiorgio CM. Refractory status epilepticus treated with trigeminal nerve stimulation. Epilepsy Res, 2014, 108(3): 600-603.
21.	Wang QQ, Zhu LJ, Wang XH, et al. Chronic trigeminal nerve stimulation protects against seizures, cognitive impairments, hippocampal apoptosis, and inflammatory responses in epileptic rats. J Mol Neurosci, 2016, 59(1): 78-89.
22.	Magdaleno-Madrigal VM, Valdes-Cruz A, Martinez-Vargas D, et al. Effect of electrical stimulation of the nucleus of the solitary tract on the development of electrical amygdaloid kindling in the cat. Epilepsia, 2002, 43(9): 964-969.
23.	Kolling N, Wittmann MK, Behrens T E, et al. Value, search, persistence and model updating in anterior cingulate cortex. Nat Neurosci, 2016, 19(10): 1280-1285.
24.	Shenhav A, Cohen JD, Botvinick MM. Dorsal anterior cingulate cortex and the value of control. Nat Neurosci, 2016, 19(10): 1286-1291.
25.	Shiozawa P, DA Silva ME, Netto GT, et al. Effect of a 10-day trigeminal nerve stimulation (TNS) protocol for treating major depressive disorder: a phase II, sham-controlled, randomized clinical trial. Epilepsy Behav, 2015, 44: 23-26.
26.	Pilurzi G, Mercante B, Ginatempo F, et al. Transcutaneous trigeminal nerve stimulation induces a long-term depression-like plasticity of the human blink reflex. Exp Brain Res, 2016, 234(2): 453-461.
27.	Mercante B, Loi N, Ginatempo F, et al. Transcutaneous trigeminal nerve stimulation modulates the hand blink reflex. Sci Rep, 2020, 10(1): 21116.
28.	Grimonprez A, Raedt R, Baeken C, et al. The antidepressant mechanism of action of vagus nerve stimulation: evidence from preclinical studies. Neurosci Biobehav Rev, 2015, 56: 26-34.
29.	Fanselow EE, Reid AP, Nicolelis MA. Reduction of pentylenetetrazole-induced seizure activity in awake rats by seizure-triggered trigeminal nerve stimulation. J Neurosci, 2000, 20(21): 8160-8168.
30.	Mercante B, Pilurzi G, Ginatempo F, et al. Trigeminal nerve stimulation modulates brainstem more than cortical excitability in healthy humans. Exp Brain Res, 2015, 233(11): 3301-3311.
31.	Chan AY, Rolston JD, Rao VR, et al. Effect of neurostimulation on cognition and mood in refractory epilepsy. Epilepsia Open, 2018, 3(1): 18-29.
32.	Ryvlin P, Rheims S, Hirsch L J, et al. Neuromodulation in epilepsy: state-of-the-art approved therapies. Lancet Neurol, 2021, 20(12): 1038-1047.
33.	Vetkas A, Fomenko A, Germann J, et al. Deep brain stimulation targets in epilepsy: systematic review and meta-analysis of anterior and centromedian thalamic nuclei and hippocampus. Epilepsia, 2022, 63(3): 513-524.
34.	Arzimanoglou A, Brandl U, Cross JH, et al. Epilepsy and cannabidiol: a guide to treatment. Epileptic Disord, 2020, 22(1): 1-14.
35.	Degiorgio CM, Shewmon DA, Whitehurst T. Trigeminal nerve stimulation for epilepsy. Neurology, 2003, 61(3): 421-422.
36.	Gil-lopez F, Boget T, Manzanares I, et al. External trigeminal nerve stimulation for drug resistant epilepsy: a randomized controlled trial. Brain Stimul, 2020, 13(5): 1245-1253.
37.	Olivie L, Giraldez BG, Sierra-Marcos A, et al. External trigeminal nerve stimulation: a long term follow up study. Seizure, 2019, 69: 218-220.
38.	Cook IA, Abarms M, Leuchter AF. Trigeminal nerve stimulation for comorbid posttraumatic stress disorder and major depressive disorder. Neuromodulation, 2016, 19(3): 299-305.

1. Wang Y, Chen Z. An update for epilepsy research and antiepileptic drug development: Toward precise circuit therapy. Pharmacol Ther, 2019, 201: 77-93.
2. Degiorgio CM, Fanselow EE, Schrader LM, et al. Trigeminal nerve stimulation: seminal animal and human studies for epilepsy and depression. Neurosurg Clin N Am, 2011, 22(4): 449-456.
3. Pop J, Murray D, Markovic D, et al. Acute and long-term safety of external trigeminal nerve stimulation for drug-resistant epilepsy. Epilepsy Behav, 2011, 22(3): 574-576.
4. Soss J, Heck C, Murray D, et al. A prospective long-term study of external trigeminal nerve stimulation for drug-resistant epilepsy. Epilepsy Behav, 2015, 42: 44-47.
5. Bhandare AM, Kapoor K, Farnham MM, et al. Microglia PACAP and glutamate: Friends or foes in seizure-induced autonomic dysfunction and SUDEP? Respir Physiol Neurobiol, 2016, 226: 39-50.
6. Mercante B, Enrico P, Floris G, et al. Trigeminal nerve stimulation induces Fos immunoreactivity in selected brain regions, increases hippocampal cell proliferation and reduces seizure severity in rats. Neuroscience, 2017, 361: 69-80.
7. Mazarati AM, Lewis ML, Pittman QJ. Neurobehavioral comorbidities of epilepsy: role of inflammation. Epilepsia, 2017, 58(Suppl 3): 48-56.
8. Iori V, Frigerio F, Vezzani A. Modulation of neuronal excitability by immune mediators in epilepsy. Curr Opin Pharmacol, 2016, 26: 118-123.
9. Akyuz E, Polat AK, Eroglu E, et al. Revisiting the role of neurotransmitters in epilepsy: an updated review. Life Sci, 2021, 265: 118826.
10. Cheng HM, Gao CS, Lou QW, et al. The diverse role of the raphe 5-HTergic systems in epilepsy. Acta Pharmacol Sin, 2022, 43(11): 2777-2788.
11. Ma DL, Tang YC, Chen PM, et al. Reorganization of CA3 area of the mouse hippocampus after pilocarpine induced temporal lobe epilepsy with special reference to the CA3-septum pathway. J Neurosci Res, 2006, 83(2): 318-331.
12. Pollak Dorocic I, Furth D, Xuan Y, et al. A whole-brain atlas of inputs to serotonergic neurons of the dorsal and median raphe nuclei. Neuron, 2014, 83(3): 663-678.
13. Commons KG. Ascending serotonin neuron diversity under two umbrellas. Brain Struct Funct, 2016, 221(7): 3347-3360.
14. Brust RD, Corcoran AE, Richerson GB, et al. Functional and developmental identification of a molecular subtype of brain serotonergic neuron specialized to regulate breathing dynamics. Cell Rep, 2014, 9(6): 2152-2165.
15. Mason P. Contributions of the medullary raphe and ventromedial reticular region to pain modulation and other homeostatic functions. Annu Rev Neurosci, 2001, 24: 737-777.
16. Zhang H, Zhao H, Zeng C, et al. Optogenetic activation of 5-HT neurons in the dorsal raphe suppresses seizure-induced respiratory arrest and produces anticonvulsant effect in the DBA/1 mouse SUDEP model. Neurobiol Dis, 2018, 110: 47-58.
17. Iidaka T. Fluctuations in arousal correlate with neural activity in the human thalamus. Cereb Cortex Commun, 2021, 2(3): tgab055.
18. Shiozawa P, Silva ME, Carvalho TC, et al. Transcutaneous vagus and trigeminal nerve stimulation for neuropsychiatric disorders: a systematic review. Arq Neuropsiquiatr, 2014, 72(7): 542-547.
19. Bari AA, Pouratian N. Brain imaging correlates of peripheral nerve stimulation. Surg Neurol Int, 2012, 3(Suppl 4): S260-268.
20. Moseley BD, Degiorgio CM. Refractory status epilepticus treated with trigeminal nerve stimulation. Epilepsy Res, 2014, 108(3): 600-603.
21. Wang QQ, Zhu LJ, Wang XH, et al. Chronic trigeminal nerve stimulation protects against seizures, cognitive impairments, hippocampal apoptosis, and inflammatory responses in epileptic rats. J Mol Neurosci, 2016, 59(1): 78-89.
22. Magdaleno-Madrigal VM, Valdes-Cruz A, Martinez-Vargas D, et al. Effect of electrical stimulation of the nucleus of the solitary tract on the development of electrical amygdaloid kindling in the cat. Epilepsia, 2002, 43(9): 964-969.
23. Kolling N, Wittmann MK, Behrens T E, et al. Value, search, persistence and model updating in anterior cingulate cortex. Nat Neurosci, 2016, 19(10): 1280-1285.
24. Shenhav A, Cohen JD, Botvinick MM. Dorsal anterior cingulate cortex and the value of control. Nat Neurosci, 2016, 19(10): 1286-1291.
25. Shiozawa P, DA Silva ME, Netto GT, et al. Effect of a 10-day trigeminal nerve stimulation (TNS) protocol for treating major depressive disorder: a phase II, sham-controlled, randomized clinical trial. Epilepsy Behav, 2015, 44: 23-26.
26. Pilurzi G, Mercante B, Ginatempo F, et al. Transcutaneous trigeminal nerve stimulation induces a long-term depression-like plasticity of the human blink reflex. Exp Brain Res, 2016, 234(2): 453-461.
27. Mercante B, Loi N, Ginatempo F, et al. Transcutaneous trigeminal nerve stimulation modulates the hand blink reflex. Sci Rep, 2020, 10(1): 21116.
28. Grimonprez A, Raedt R, Baeken C, et al. The antidepressant mechanism of action of vagus nerve stimulation: evidence from preclinical studies. Neurosci Biobehav Rev, 2015, 56: 26-34.
29. Fanselow EE, Reid AP, Nicolelis MA. Reduction of pentylenetetrazole-induced seizure activity in awake rats by seizure-triggered trigeminal nerve stimulation. J Neurosci, 2000, 20(21): 8160-8168.
30. Mercante B, Pilurzi G, Ginatempo F, et al. Trigeminal nerve stimulation modulates brainstem more than cortical excitability in healthy humans. Exp Brain Res, 2015, 233(11): 3301-3311.
31. Chan AY, Rolston JD, Rao VR, et al. Effect of neurostimulation on cognition and mood in refractory epilepsy. Epilepsia Open, 2018, 3(1): 18-29.
32. Ryvlin P, Rheims S, Hirsch L J, et al. Neuromodulation in epilepsy: state-of-the-art approved therapies. Lancet Neurol, 2021, 20(12): 1038-1047.
33. Vetkas A, Fomenko A, Germann J, et al. Deep brain stimulation targets in epilepsy: systematic review and meta-analysis of anterior and centromedian thalamic nuclei and hippocampus. Epilepsia, 2022, 63(3): 513-524.
34. Arzimanoglou A, Brandl U, Cross JH, et al. Epilepsy and cannabidiol: a guide to treatment. Epileptic Disord, 2020, 22(1): 1-14.
35. Degiorgio CM, Shewmon DA, Whitehurst T. Trigeminal nerve stimulation for epilepsy. Neurology, 2003, 61(3): 421-422.
36. Gil-lopez F, Boget T, Manzanares I, et al. External trigeminal nerve stimulation for drug resistant epilepsy: a randomized controlled trial. Brain Stimul, 2020, 13(5): 1245-1253.
37. Olivie L, Giraldez BG, Sierra-Marcos A, et al. External trigeminal nerve stimulation: a long term follow up study. Seizure, 2019, 69: 218-220.
38. Cook IA, Abarms M, Leuchter AF. Trigeminal nerve stimulation for comorbid posttraumatic stress disorder and major depressive disorder. Neuromodulation, 2016, 19(3): 299-305.

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