Electrical Stimulation of the Infraorbital Nerve Induces Diving Reflex in a Dose-Controlled Manner

Shah, Kevin; Sonti, Anup N.; Wu, Yi-Chen; Powell, Keren; Doobay, Mohini; Narayan, Raj K.; Li, Chunyan

doi:10.1109/embc44109.2020.9176845

Cited by 3 publications

(12 citation statements)

References 14 publications

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“…TNS increases CBF in both healthy and pathological conditions (White and Powell et al 2021 ; Suzuki et al 1990 ). This increase has been observed, in pre-clinical models, to range from 15% (Suzuki et al 1990 ) to upwards of 50% (Shah et al 2020 ). TNS can increase CBF in different manners, including a rapid, direct increase (Weber et al 2003 ; Suzuki et al 1990 ), a gradual, graded increase (Shah et al 2020 ), and in an oscillatory pattern (Li et al 2021a , b (a)), to induce different effects suitable for specific disorders.…”

Section: Effects Of Trigeminal Nerve Stimulationmentioning

confidence: 88%

“…This increase has been observed, in pre-clinical models, to range from 15% (Suzuki et al 1990 ) to upwards of 50% (Shah et al 2020 ). TNS can increase CBF in different manners, including a rapid, direct increase (Weber et al 2003 ; Suzuki et al 1990 ), a gradual, graded increase (Shah et al 2020 ), and in an oscillatory pattern (Li et al 2021a , b (a)), to induce different effects suitable for specific disorders. The observation that the increase in CBF was independent of BP (Li et al 2021a , b (b); Gürelik et al 2004 ) and was not abrogated by parasympathetic blockade (Lang and Zimmer 1974 ), indicated cerebral vasodilation is a key underlying factor.…”

Section: Effects Of Trigeminal Nerve Stimulationmentioning

confidence: 88%

“…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: 88%

Section: Effects Of Trigeminal Nerve Stimulationmentioning

confidence: 88%

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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“…Given these factors, it is possible that the diving reflex may be able to target multiple points in the timeline of TBI’s pathogenic progression and represents a promising avenue for future research. However, natural stimulation of the diving reflex has yet to be adopted for routine treatment of TBI for various reasons, including the limited currently available methods of induction (cold water facial cooling), its yet-to-be-defined dose–response, variable reproducibility, and challenges of implementing the diving reflex in the clinical setting [ 168 ]. Electrical stimulation of the trigeminal nerve has demonstrated the ability to induce the endogenous diving reflex in a reproducible, dose-controlled manner and thus may represent a more practical application of this neuroprotective endogenous mechanism in TBI [ 168 , 169 , 170 ].…”

Section: Discussionmentioning

confidence: 99%

Multi-Mechanistic Approaches to the Treatment of Traumatic Brain Injury: A Review

Lynch

Narayan

2023

JCM

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Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Despite extensive research efforts, the majority of trialed monotherapies to date have failed to demonstrate significant benefit. It has been suggested that this is due to the complex pathophysiology of TBI, which may possibly be addressed by a combination of therapeutic interventions. In this article, we have reviewed combinations of different pharmacologic treatments, combinations of non-pharmacologic interventions, and combined pharmacologic and non-pharmacologic interventions for TBI. Both preclinical and clinical studies have been included. While promising results have been found in animal models, clinical trials of combination therapies have not yet shown clear benefit. This may possibly be due to their application without consideration of the evolving pathophysiology of TBI. Improvements of this paradigm may come from novel interventions guided by multimodal neuromonitoring and multimodal imaging techniques, as well as the application of multi-targeted non-pharmacologic and endogenous therapies. There also needs to be a greater representation of female subjects in preclinical and clinical studies.

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“…Its induction involves the concurrent stimulation of trigeminal sensory afferents and the onset of apnea, thereby triggering a sequence of physiological adaptations aimed at enhancing cerebral perfusion [18,19]. Notably, DR enhances cerebral perfusion through potent and targeted cerebral vasodilation [20,21]. This effect is discernible not only within the cortical regions but also extends to subcortical areas such as the hippocampus and thalamus [20], which are distinguished by a prevalence of microvasculature over large vessels [22–24].…”

Section: Introductionmentioning

confidence: 99%

Intrinsic diving reflex enhances cognitive performance by alleviating microvascular dysfunction in vascular cognitive impairment

Tambo,

Powell,

Wadolowski

et al. 2024

Preprint

Self Cite

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Vascular cognitive impairment (VCI) stands as the second-most prominent contributor to cognitive decline, lacking efficacious interventions. Chronic cerebral hypoperfusion (CCH) triggers microvascular dysfunction, which plays a critical role in VCI pathophysiology, emerging as a pivotal therapeutic target. While interventions addressing facets of microvascular dysfunction like angiogenesis and blood-brain barrier functionality show promise, the evaluation of microvascular constriction, another key component, remains unexplored. The diving reflex (DR) represents an oxygen-conserving response, characterized by robust vasodilation and potentially also inducing angiogenesis. In this investigation, we studied DR's functionality and underlying mechanisms within a rat bilateral common carotid artery occlusion induced CCH model. Remarkably, progressive hippocampal microvascular constriction exhibited strong correlations with short-term memory impairment during both early (R2=0.641) and late phases (R2=0.721) of CCH. Implementation of DR led to a significant reduction in microvascular constriction within the hippocampus (~2.8-fold) and striatum (~1.5-fold), accompanied by enhanced vasodilatory capacity and heightened expression of vasoactive neuropeptides. Furthermore, DR attenuated microvascular degeneration across various brain subregions affected by CCH, concomitant with increased levels of multiple angiogenic factors. The reinforced microvascular integrity facilitated by DR corresponded with significantly improved short-term recognition memory and long-term spatial memory functions observed during the late phase of CCH. The comprehensive and synergistic effects of DR on various aspects of microvascular function and cognitive preservation highlight its potential as a disease-modifying therapeutic strategy in VCI.

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Electrical Stimulation of the Infraorbital Nerve Induces Diving Reflex in a Dose-Controlled Manner

Cited by 3 publications

References 14 publications

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

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

Multi-Mechanistic Approaches to the Treatment of Traumatic Brain Injury: A Review

Intrinsic diving reflex enhances cognitive performance by alleviating microvascular dysfunction in vascular cognitive impairment

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