Trigeminal nerve stimulation restores hippocampal dopamine deficiency to promote cognitive recovery in traumatic brain injury

Xu, Jing; Wu, Shaoling; Huo, Lifang; Zhou, Qian; Liu, Lijiaqi; Ye, Zhimin; Chen, Jie; Ma, Hongjuan; Shang, Congping; Ma, Chao

doi:10.1016/j.pneurobio.2023.102477

Cited by 3 publications

(10 citation statements)

References 56 publications

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“…Work by our lab has demonstrated that TNS in TBI reduces brain cortical TNF-α and IL-6 in rats (Chiluwal et al 2017 ), while Yang et al ( 2022 ) observed a decrease in cleaved caspase 3 expression in TBI. TNS also decreases hippocampal microglial activation in TBI, as indicated by decrease of Iba1 (Xu et al 2023 ). The anti-inflammatory effect is further confirmed by the observation that TNS reduces microthrombi density by ~ 53% following SAH in rats (Shah et al 2022 ).…”

Section: Effects Of Trigeminal Nerve Stimulationmentioning

confidence: 99%

“…TNS decreases neuroinflammation in experimental models of epilepsy and trauma (Xu et al 2023 ; Yang et al 2022 ; Chiluwal et al 2017 ; Wang et al 2016 ). In epileptic rats, TNS reduces microglial activation and hippocampal concentrations of IL-1ß and TNF-α (Wang et al 2016 ).…”

Section: Effects Of Trigeminal Nerve Stimulationmentioning

confidence: 99%

“…TNS applied to a loss of consciousness model resulted in coma score improvement alongside reduced neurological dysfunction, indicative of improved recovery (Zheng et al 2021 ). 7-day application of TNS to rats following severe TBI induction also decreases cognitive impairment, correlating with the decrease of amyloid precursor protein in the hippocampus (Xu et al 2023 ). These pre-clinical results provide context for the clinical observation that TNS promotes arousal and functional recovery for patients with pDOC (Ma et al 2023 ; Dong et al 2022 ; Wu et al 2022 ; Fan et al 2019 ).…”

Section: Effects Of Trigeminal Nerve Stimulationmentioning

confidence: 99%

“…TNS modulates multiple neurotransmission pathways within the brain, including dopamine (Xu et al 2023 ), gamma-aminobutyric acid (GABA) (Lauritsen and Silberstein 2019 ), glutamate, and hypocretin (Zheng et al 2021 ) (Fig. 3 ).…”

Section: Underlying Mechanisms Of Trigeminal Nerve Stimulationmentioning

confidence: 99%

“…TNS has been observed to induce cerebral vasodilation, modulate cerebral metabolism and neurotransmission, and decrease neuroinflammation (Xu et al 2023 ; Nash, Powell, White, et al 2023 ; Shah et al 2020 ; Chiluwal et al 2017 ; Magis et al 2017 ; Weber et al 2003 ). Systemically, it modulates the autonomic nervous system (ANS), induces peripheral vasoconstriction, decreases systemic inflammation, and modulates cardiac performance (Degiorgio et al 2011 ; Borges and Casselman 2010 ; Shankland 2000 ; Walker 1990 ).…”

Section: Introductionmentioning

confidence: 99%

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Trigeminal nerve stimulation: a current state-of-the-art review

Powell,

Lin,

Tambo

et al. 2023

Bioelectron Med

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Nearly 5 decades ago, the effect of trigeminal nerve stimulation (TNS) on cerebral blood flow was observed for the first time. This implication directly led to further investigations and TNS’ success as a therapeutic intervention. Possessing unique connections with key brain and brainstem regions, TNS has been observed to modulate cerebral vasodilation, brain metabolism, cerebral autoregulation, cerebral and systemic inflammation, and the autonomic nervous system. The unique range of effects make it a prime therapeutic modality and have led to its clinical usage in chronic conditions such as migraine, prolonged disorders of consciousness, and depression. This review aims to present a comprehensive overview of TNS research and its broader therapeutic potentialities. For the purpose of this review, PubMed and Google Scholar were searched from inception to August 28, 2023 to identify a total of 89 relevant studies, both clinical and pre-clinical. TNS harnesses the release of vasoactive neuropeptides, modulation of neurotransmission, and direct action upon the autonomic nervous system to generate a suite of powerful multitarget therapeutic effects. While TNS has been applied clinically to chronic pathological conditions, these powerful effects have recently shown great potential in a number of acute/traumatic pathologies. However, there are still key mechanistic and methodologic knowledge gaps to be solved to make TNS a viable therapeutic option in wider clinical settings. These include bimodal or paradoxical effects and mechanisms, questions regarding its safety in acute/traumatic conditions, the development of more selective stimulation methods to avoid potential maladaptive effects, and its connection to the diving reflex, a trigeminally-mediated protective endogenous reflex. The address of these questions could overcome the current limitations and allow TNS to be applied therapeutically to an innumerable number of pathologies, such that it now stands at the precipice of becoming a ground-breaking therapeutic modality.

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Section: Effects Of Trigeminal Nerve Stimulationmentioning

confidence: 99%

Section: Effects Of Trigeminal Nerve Stimulationmentioning

confidence: 99%

Section: Effects Of Trigeminal Nerve Stimulationmentioning

confidence: 99%

Section: Underlying Mechanisms Of Trigeminal Nerve Stimulationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Trigeminal nerve stimulation: a current state-of-the-art review

Powell,

Lin,

Tambo

et al. 2023

Bioelectron Med

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Trigeminal nerve electrical stimulation attenuates early traumatic brain injury through the TLR4/NF-κB/NLRP3 signaling pathway mediated by orexin-A/OX1R system

Kang,

Zhou,

Xiong

et al. 2024

Aging

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Background: Traumatic brain injury (TBI) is a significant contributor to global mortality and disability, and emerging evidence indicates that trigeminal nerve electrical stimulation (TNS) is a promising therapeutic intervention for neurological impairment following TBI. However, the precise mechanisms underlying the neuroprotective effects of TNS in TBI are poorly understood. Thus, the objective of this study was to investigate the potential involvement of the orexin-A (OX-A)/orexin receptor 1 (OX1R) mediated TLR4/NF-κB/NLRP3 signaling pathway in the neuroprotective effects of TNS in rats with TBI. Methods: Sprague-Dawley rats were randomly assigned to four groups: sham, TBI, TBI+TNS+SB334867, and TBI+TNS. TBI was induced using a modified Feeney’s method, and subsequent behavioral assessments were conducted to evaluate neurological function. The trigeminal nerve trunk was isolated, and TNS was administered following the establishment of the TBI model. The levels of neuroinflammation, brain tissue damage, and proteins associated with the OX1R/TLR4/NF-κB/NLRP3 signaling pathway were assessed using hematoxylin-eosin staining, Nissl staining, western blot analysis, quantitative real-time polymerase chain reaction, and immunofluorescence techniques. Results: The findings of our study indicate that TNS effectively mitigated tissue damage, reduced brain edema, and alleviated neurological deficits in rats with TBI. Furthermore, TNS demonstrated the ability to attenuate neuroinflammation levels and inhibit the expression of proteins associated with the TLR4/NF-κB/NLRP3 signaling pathway. However, it is important to note that the aforementioned effects of TNS were reversible upon intracerebroventricular injection of an OX1R antagonist. Conclusion: TNS may prevent brain damage and relieve neurological deficits after a TBI by inhibiting inflammation, possibly via the TLR4/NF-κB/NLRP3 signaling pathway mediated by OX-A/OX1R.

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Cognitive Functions following Trigeminal Neuromodulation

Mercante,

Enrico,

Deriu

2023

Biomedicines

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Vast scientific effort in recent years have been focused on the search for effective and safe treatments for cognitive decline. In this regard, non-invasive neuromodulation has gained increasing attention for its reported effectiveness in promoting the recovery of multiple cognitive domains after central nervous system damage. In this short review, we discuss the available evidence supporting a possible cognitive effect of trigeminal nerve stimulation (TNS). In particular, we ask that, while TNS has been widely and successfully used in the treatment of various neuropsychiatric conditions, as far as research in the cognitive field is concerned, where does TNS stand? The trigeminal nerve is the largest cranial nerve, conveying the sensory information from the face to the trigeminal sensory nuclei, and from there to the thalamus and up to the somatosensory cortex. On these bases, a bottom-up mechanism has been proposed, positing that TNS-induced modulation of the brainstem noradrenergic system may affect the function of the brain networks involved in cognition. Nevertheless, despite the promising theories, to date, the use of TNS for cognitive empowering and/or cognitive decline treatment has several challenges ahead of it, mainly due to little uniformity of the stimulation protocols. However, as the field continues to grow, standardization of practice will allow for data comparisons across studies, leading to optimized protocols targeting specific brain circuitries, which may, in turn, influence cognition in a designed manner.

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Trigeminal nerve stimulation restores hippocampal dopamine deficiency to promote cognitive recovery in traumatic brain injury

Cited by 3 publications

References 56 publications

Trigeminal nerve stimulation: a current state-of-the-art review

Trigeminal nerve stimulation: a current state-of-the-art review

Trigeminal nerve electrical stimulation attenuates early traumatic brain injury through the TLR4/NF-κB/NLRP3 signaling pathway mediated by orexin-A/OX1R system

Cognitive Functions following Trigeminal Neuromodulation

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