Antagonistic and Synergistic Activation of Cardiovascular Vagal and Sympathetic Motor Outflows in Trigeminal Reflexes PDF

Mini Review published: 21 February 2017...

Mini Review published: 21 February 2017 doi: 10.3389/fneur.2017.00052 Antagonistic and Synergistic Activation of Cardiovascular vagal and Sympathetic Motor Outflows in Trigeminal Reflexes Bruno Buchholz1,2,3, Jazmín Kelly1,2,3, Eduardo A. Bernatene1,2,3, Nahuel Méndez Diodati1 and Ricardo J. Gelpi1,2,3* 1 Facultad de Medicina, Departamento de Patología, Instituto de Fisiopatología Cardiovascular (INFICA), Universidad de Buenos Aires, Buenos Aires, Argentina, 2 Facultad de Medicina, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Bioquímica y Medicina Molecular (IBIMOL), Universidad de Buenos Aires, Buenos Aires, Argentina, 3 Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina The trigeminal nerve and heart are strongly related through somato-autonomic nervous reflexes that induce rapid changes in cardiovascular function. Several trigeminal reflexes have been described, but the diving and trigeminocardiac reflexes are the most studied. The heart is a target organ dually innervated by the sympathetic and parasympathetic Edited by: systems. Thus, how cardiac function is regulated during the trigeminal reflexes is the Bernhard Schaller, result of the combination of an increased parasympathetic response and increased, University of Southampton, UK decreased, or unaltered sympathetic activity. Various hemodynamic changes occur as Reviewed by: a consequence of these alterations in autonomic tone. Often in the oxygen-conserving Helio Cesar Salgado, University of São Paulo, Brazil physiological reflexes such as the diving reflex, sympathetic/parasympathetic co-activa- Phyllis Kravet Stein, tion reduces the heart rate and either maintains or increases blood pressure. Conversely, Washington University in St. Louis, USA in the trigeminocardiac reflex, bradycardia and hypotension due to parasympathetic *Correspondence: activation and sympathetic inactivation tend to be observed. These sudden cardiac Ricardo J. Gelpi innervation disturbances may promote the generation of arrhythmias or myocardial [email protected] ischemia during surgeries in the trigeminal territory. However, the function and mecha- nisms involved in the trigeminal reflexes remain to be fully elucidated. The current review Specialty section: This article was submitted to provides a brief update and analysis of the features of these reflexes, with special focus Autonomic Neuroscience, on how the autonomic nervous system interacts with cardiovascular function. a section of the journal Frontiers in Neurology Keywords: trigeminocardiac reflex, diving reflex, heart, arrhythmia, myocardial ischemia Received: 22 September 2016 Accepted: 06 February 2017 Published: 21 February 2017 INTRODUCTION Citation: Buchholz B, Kelly J, Bernatene EA, Physiological or pathological stimulation of the trigeminal nerve can trigger sudden cardiovascular Méndez Diodati N and Gelpi RJ disturbances with the characteristic features of a nervous reflex (1). Although these trigeminal reflexes (2017) Antagonistic and Synergistic have been thoroughly described in numerous clinical–surgical situations, their physiological and Activation of Cardiovascular Vagal and Sympathetic Motor Outflows in pathophysiological mechanisms, as well as their functional significance, have not been elucidated. Trigeminal Reflexes. In 1908, Aschner (2) and Dagnini (3) described a severe reduction in heart rate as a consequence of Front. Neurol. 8:52. eyeball compression (4). In 1975, Kumada et al. described the trigeminal depressor response in an doi: 10.3389/fneur.2017.00052 experimental animal model (5). They observed that stimulation of one of the trigeminal branches Frontiers in Neurology | www.frontiersin.org 1 February 2017 | Volume 8 | Article 52 Buchholz et al. Cardiovascular Autonomic Regulation in Trigeminal Reflexes or its nuclear sensitive complex triggered a reflex that induced Kumada et al. (6) studied the respiratory effects of electrical cardiovascular symptoms including a sharp reduction of heart stimulation of the spinal trigeminal tract and its nuclei. In this rate, hypotension, apnea, and gastric hypermotility (6, 7). In 1988, research, a biphasic response could be observed: low frequency Shelly and Church suggested the term “trigeminocardiac reflex” and low intensity stimulation produced tachypnea, whereas (8), and in 1991, Lang et al. used the term trigeminocardiac reflex a slightly more intense stimulation led to expiratory apnea. to describe intense reflex bradycardia observed in three patients On the other hand, gastric hypermotility as a consequence undergoing maxillofacial surgeries (9). In later years, Schaller of increased vagal tone was also observed, thus constituting and colleagues (10, 11) first published the occurrence of a central itself as an actual trigeminovagal reflex (6) (Figure 1). Based reflex in humans during cerebellopontine angle and brainstem on hemodynamic analysis, the trigeminocardiac reflex behaves surgeries and merged these peripheral and central responses into in a similar manner to the baroreceptor reflexes, in which a single autonomic reflex, which is now generally accepted as the bradycardia and reduced systemic blood pressure can also be trigeminocardiac reflex. observed as a consequence of vagal activation and sympathetic These reflexes represent somato-autonomic responses where inhibition (7). As a variant of the trigeminocardiac reflex, the the trigeminal nerve is the afferent pathway, the vagus and sympa- oculocardiac reflex generates the same synergistic sympa- thetic nerves are the efferent pathways, and numerous brainstem thetic/parasympathetic output and produces bradycardia and nuclei serve as integration centers (12). Although these reflexes ­hypotension (Table 1). share certain anatomical structures, the stimuli by which they are triggered and the responses they elicit are not necessarily DIVING REFLEX equal. The trigeminal reflexes can be triggered by stimuli sensed by thermoreceptors in the facial skin (diving reflex) (13), nasal Oxygen deprivation, even for brief periods of time, can be highly mucosa (nasopharyngeal reflex) (14), and eyeball (oculocardiac detrimental. However, many species, such as diving birds, mam- reflex) (4, 15). They can also be activated by direct stimulation of mals, and even human beings, have adapted to withstand hypoxia some trigeminal branches and the trigeminal nuclear complex of or anoxia for longer periods (18). One of the most important the brainstem (trigeminocardiac reflex) (16). physiological adaptations that allow these animals to withstand the lack of oxygen during apnea is the diving reflex (13). Facial TRIGEMINOCARDIAC REFLEX submersion in water rapidly triggers a heart rate reduction by vagal activation, an increase in blood pressure by sympathetic The trigeminocardiac reflex is a brainstem reflex that has been hyperactivity, and apnea. In humans, the autonomic response demonstrated both clinically and experimentally (17). Schaller can often be intense: the heart rate can drop to 20–30 beats/min, et al. defined the reflex from a clinical point of view as hypo- and the increased peripheral vascular resistance can raise blood tension with a 20% drop in mean arterial blood pressure and pressure to critical levels. This is not observed in other species bradycardia lower than 60 beats/min in response to surgical that are specialized in the art of diving because they are able manipulation of the trigeminal nerve trunk or disturbances to maintain blood pressure within physiological ranges despite in the territory of one of its branches. This concept was increased sympathetic tone. later redefined by including autonomic symptoms such as a An important modulator of autonomic activity during diving decrease in cardiovascular function less than 20%. This new is apnea, which can result by two different mechanisms. First, trigeminocardiac reflex definition is even more inclusive for apnea can occur voluntarily; in this situation, a person con- clinical studies (12). In severe instances, this response can sciously inhibits the respiratory centers via a centrally induced sometimes lead to asystole. They can be classified into two pathway. An example is simple breath holding. Second, apnea subtypes, depending on which sensory territory is stimulated: can occur in a reflexive manner following stimulation of cold the central trigeminocardiac reflex (ganglion to nucleus) and receptors in the facial skin, eyes, and nasal cavity. At the same the peripheral trigeminocardiac reflex (peripheral divisions time, changes in pulmonary volumes due to apnea can modify to ganglion). The peripheral trigeminocardiac reflex can be the autonomic tone, leading to cardiovascular changes (13). further subdivided into ophthalmocardiac and maxilloman- Apnea alone is sufficient to trigger the diving response; however, dibulocardiac reflexes (16). a greater response is seen when coupled with stimulation of In anesthetized rabbits, trigeminal system stimulation facial cold receptors, as with face immersion. This particularly reduced heart rate by 13%, mean arterial pressure by 36%, total intense cardiovascular reflex response manifests itself as a conse- peripheral vascular resistance by 35%, and cardiac output by a quence of both facial stimulation and apnea. Fagius and Sundlöf comparatively modest 5%, whereas stroke volume increased by studied sympathetic activity in the peroneal nerve and skin of 6% (7). Bilateral vagal section does not reverse hypotension and patients after cold water submersion and reported differences only partially reverses the decrease in heart rate. This experi- in autonomic regulation between muscle and cutaneous blood ment demonstrates that hypotension is independent of heart flow. They observed increased activity of the nerves innervating rate reduction and occurs as a result of vasodilation induced by muscle vessels, accompanied by 30–50% reduction in blood flow the sustained decrease in peripheral vascular sympathetic tone. as a consequence of higher peripheral vascular resistance (19). In contrast, heart rate reduction occurs via a combination of However, they also found decreased sympathetic conductivity parasympathetic activation and sympathetic inhibition. Using a toward the cutaneous vascular beds, which have a larger role in different experimental model in rabbits breathing spontaneously, thermoregulation and sweating. Increased sympathetic tone in Frontiers in Neurology | www.frontiersin.org 2 February 2017 | Volume 8 | Article 52 Buchholz et al. Cardiovascular Autonomic Regulation in Trigeminal Reflexes Figure 1 | Schematic illustration of the autonomic neural pathways and effectors activated as a consequence of trigeminal nerve stimulation. Protection reflexes like the diving, the nasopharyngeal, or the oculocardiac reflex involve simultaneous co-activation of both autonomic limbs (blue symbols). The trigeminocardiac reflex induces a strong depressor response by a reciprocal activation of the parasympathetic system and an inhibition of the sympathetic system (red symbols). Table 1 | Summary of the principal characteristics of the trigeminal reflex subtypes. Trigeminal reflex Triggered by Efferent pathway Arterial Heart Gastric Splenic Peripheral Breathing pressure rate motility contraction vascular tone Trigeminocardiac reflex Direct stimulation of the trigeminal Parasympathetic ↑ ↓ ↓ ↑ ? ↓ Apnea nerve Sympathetic ↓ Diving reflex Thermoreceptors in the facial skin Parasympathetic ↑ ↑ ↓ – ↑ ↑ Apnea Sympathetic ↑ Nasopharyngeal reflex Nasal mucosa irritation Parasympathetic ↑ = ↓ – ↑ ↑ Apnea Sympathetic ↑ Oculocardiac reflex Physical stimulation of the eye or Parasympathetic ↑ ↓ ↓ ↑ ? ↓ Apnea adnexa Sympathetic ↑ ?, Not known. the splanchnic vessels and splenic capsule was also observed (18). hemoglobin circulating in the blood, it would be expected that The contraction of the spleen provides an additional blood volume oxygen transport would also be enhanced. that aids in stabilizing blood pressure despite the decreased heart The diving reflex in human beings can be modified by many rate. Since contraction of the spleen also increases hematocrit and factors, but the most important are water temperature, oxygen Frontiers in Neurology | www.frontiersin.org 3 February 2017 | Volume 8 | Article 52 Buchholz et al. Cardiovascular Autonomic Regulation in Trigeminal Reflexes tension in the arterial blood, and emotional factors (20). Previous maintenance or increase of peripheral arterial pressure (13, 14). studies showed a clear inverse relationship between the tempera- On the other hand, the trigeminocardiac reflex is characterized ture of the water in which the face is immersed and the magnitude by parasympathetic activation and sympathetic inhibition, of the diving bradycardia. Interestingly, there may not be a similar which simultaneously reduce heart rate and blood pressure (6) close dependence on temperature for the reduction in limb (Figure 1; Table 1). blood flow. With respect to blood oxygen, diving bradycardia Some studies have clarified the factors that condition trigemi- is increased if subjects have been breath holding or exercising nal stimulation responses. First, the type of stimulus triggering immediately before performing apnea with face immersion. Such the reflex should be taken into consideration. Pressor responses observations suggest the possibility that a reduction in the arterial are frequently reported, indicating an increase in the peripheral oxygen tension potentiates the diving reflex. Finally, higher brain sympathetic tone in response to physiological stimuli, such as functions have profound effects on the development of the diving irritation of the nasal mucous membrane (14) or stimulation of reflex in humans. When subjects are distracted, diving bradycar- the thermal nerve endings of facial skin (25). Conversely, in surgi- dia fails to occur despite the face being under water. On the other cal or experimental stimulations of the trigeminal nerve trunk in hand, fear can powerfully accentuate the diving response. anesthetized patients, important reductions can be observed both Physiologically, the diving reflex slows down oxygen uptake in sympathetic tone and blood pressure (16). Stimulus intensity, from the lungs and reduces the rate of arterial blood desaturation, frequency, and duration, as well as the type of afferent nervous slowing the depletion of both lung and blood oxygen stores. In fibers involved in the reflexogenic response, should also be taken addition, blood flow is redistributed so that the brain and heart into account. are preferentially perfused. This reduces oxygen delivery to the The second aspect to consider is the administration of differ- peripheral capillary beds by stopping blood flow with intense ent analgesics and anesthetics that may modulate the trigemi- vasoconstriction (18). Therefore, the diving reflex is one of the nal–vagal reflexes in variable and unpredictable ways (26–29). most powerful somato-autonomic reflexes of the organism, and This is of particular importance for the trigeminocardiac reflex, it is an important life protection mechanism in naturally diving since numerous studies reported autonomic reaction differences animals. As one might expect, the usual response in the human based on the use of these drugs (30). Therefore, anesthesia being, a terrestrial animal, is quantitatively less efficient than that type and depth are important factors to consider in the clinical seen in the natural divers. management of patients undergoing surgical interventions in the trigeminal territory who are at potential risk of cardiovascular NASOPHARYNGEAL REFLEX depression (31–33). The last aspect to consider is species differences. In diving This is a well-demonstrated variation of the diving reflex, acti- animals such as seals, the diving reflex increases sympathetic tone vated by stimulation of the nasal mucosa (14). The nasopharyn- and allows preservation of blood pressure within physiological geal reflex can be activated by irritating gases, water, or electrical ranges. In humans, however, the sympathetic response of the stimulation. The ethmoidal nerve plays an important role in this diving reflex is more intense and may increase blood pressure to mechanism by innervating the nasal passages and external nares, critical values (30). and it is fundamental in protecting the upper airway (21, 22). Studies in dogs verified that nasal stimulation increases parasym- pathetic vagal tone, which reduces heart rate and, consequently, HEMODYNAMIC CHANGES DURING cardiac output. Conversely, the nasopharyngeal reflex increases TRIGEMINAL REFLEXES sympathetic tone, leading to greater peripheral vascular resistance (with the exception of carotid resistance), therefore maintain- Bradycardia and blood pressure modifications are the most ing stable blood pressure values (23) (Table 1). The differential evident hemodynamic changes induced by these reflexes. The changes in vascular flow at the carotid level suggest blood flow sudden changes that occur in these reflexogenic adaptations redistribution to the brain. The aforementioned physiological may impact patients with cardiovascular disease, inducing features of the nasopharyngeal reflex demonstrate its role as a severe and sometimes lethal complications. Various authors powerful oxygen-preserving reflex, similar to the diving reflex. reported complications in patients with coronary disease, and severe arrhythmias such as asystole and ventricular fibrillations as a consequence of the trigeminocardiac reflex during neuro- ANTAGONISM AND SYNERGISM IN surgeries (34, 35). Although not experimentally demonstrated, SYMPATHETIC/PARASYMPATHETIC coronary spasm might be a key factor in the pathophysiology INTERACTION of these complications. Cholinergic discharge in coronary arteries damaged by atherosclerosis could trigger paradoxical Although the trigeminal reflexes have many aspects in common vasoconstriction. Also, the sympathetic co-activations that often (e.g., the anatomical substrate), their cardiovascular responses occur due to trigeminal reflexes may produce vasospasm and may differ depending on the sympathetic/parasympathetic decreased blood flow to the myocardium. This cardiac sympa- interaction (24). As already mentioned, the diving reflex elicits thetic co-activation was studied by Nalivaiko et al. in rabbits via strong synergistic co-activation of the sympathetic/parasympa- electrocardiogram, which confirmed the presence of profound thetic systems, allowing for heart rate reduction with concurrent co-activation during the nasopharyngeal reflex (36). Intense Frontiers in Neurology | www.frontiersin.org 4 February 2017 | Volume 8 | Article 52 Buchholz et al. Cardiovascular Autonomic Regulation in Trigeminal Reflexes changes in autonomic tone following trigeminal stimulation may of cardiovascular autonomic tone can often generate electrical engender electrical instabilities, which in turn may predispose instabilities, predisposing to cardiac arrhythmias and myocardial patients to arrhythmias and imbalances between myocardial ischemia. Differences in hemodynamic responses to trigeminal oxygen supply and demand. stimulation depend upon the antagonistic or synergistic interac- We previously demonstrated that short-term vagal electro- tion of the sympathetic and parasympathetic systems. Future stimulation in rabbits can generate critical changes in myocardial investigations will be needed to understand the molecular oxygen consumption in the context of coronary ischemia and rep- mechanisms and functional purposes of the trigeminal reflexes. erfusion (37). It is interesting to consider that oxygen consumption This knowledge is of paramount importance for appropriate may vary intensely, to the point of increasing or reducing infarct management of patients affected during surgeries in the trigemi- size depending on the sympathetic/parasympathetic interaction nal territory. (38). When vagal activation antagonizes the sympathetic system, both infarct size and oxygen consumption are reduced. However, AUTHOR CONTRIBUTIONS we observe an opposite situation when the sympathetic system is co-activated during vagus nerve stimulation. This shows how BB brought the manuscript to fruition through the collection of both divisions of the autonomic nervous system interaction is historical and current trends in trigeminal reflexes and composed fundamental for correct interpretation of the trigeminal reflexes. early drafts of the manuscript and figure. JK contributed to each Even though by definition a major vagal discharge is present, the section including major revisions, current trends, and research sympathetic tone fluctuates between an increase and a decrease. in each aspects of the manuscript. EB and ND contributed to It is therefore a critical variable to consider because it can develop revisions and facilitated with manuscript editing and figure numerous complications that may be catastrophic during medi- assembly. RG provided critical feedback and manuscript revi- cal interventions in the trigeminal nerve territory. sions, significant intellectual commentary on the manuscript, and final approval of the version to be published. CONCLUSION FUNDING Stimulation of the trigeminal nerve or the territories innervated by its branches can trigger deep hemodynamic changes due to This work was supported by a research grant from National neurogenic somato-autonomic responses such as the diving and Agency for Scientific and Technological Promotion (ANPCyT, trigeminocardiac reflexes. Although they can act as extremely PICT 2795) and the University of Buenos Aires (UBACyT efficient oxygen-conserving reflexes, the sudden disturbances 20020130100557BA). REFERENCES 11. Schaller B, Cornelius JF, Sandu N, Ottaviani G, Perez-Pinzon MA. Oxygen-conserving reflexes of the brain: the current molecular knowl- 1. Lemaitre F, Chowdhury T, Schaller B. The trigeminocardiac reflex – a com- edge. 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This is an cular effects of pentobarbital anesthesia during trigeminal stimulation in cats. open-access article distributed under the terms of the Creative Commons Attribution Int J Oral Sci (2012) 4(1):24–9. doi:10.1038/ijos.2012.7 License (CC BY). The use, distribution or reproduction in other forums is permit- 31. Choi SH, Lee SJ, Kim SH, Kim JH, Kwon HH, Shin YS, et al. Single bolus of ted, provided the original author(s) or licensor are credited and that the original intravenous ketamine for anesthetic induction decreases oculocardiac reflex publication in this journal is cited, in accordance with accepted academic practice. in children undergoing strabismus surgery. Acta Anaesthesiol Scand (2007) No use, distribution or reproduction is permitted which does not comply with these 51:759–62. doi:10.1111/j.1399-6576.2007.01329.x terms. Frontiers in Neurology | www.frontiersin.org 6 February 2017 | Volume 8 | Article 52