The Pre-Bötzinger complex is a neuronal group in the brainstem that is proposed to be the main factor in generating respiratory rhythms [15]. Anatomical alterations of this complex have been shown to associate with distinct breathing abnormalities [16]. It is considered the central pattern generator, driving motor activities during inspiration [13]. Rythmogenesis by this complex is modulated by membrane properties and synaptic interactions and can therefore be regulated by neurotransmitters and electrical activity [14]. Although many studies confirm the importance of this complex in various aspects of breathing [17] [18] [19] [20] , it is part of a larger network that is distributed through the nervous system [14].

The extensive integration of the respiratory network includes the cardiovascular system. There are often various types of coupling between heart activity and respiration, however, the clinical applications of these phenomena are poorly understood [21]. One of these integrative phenomena is a change in heart rate according to the current phase of the respiratory cycle known as respiratory sinus arrhythmia (RSA) [22] , with heart rate quickening during inspiration and slowing during expiration [23]. Furthermore, cardiorespiratory phase synchronization and cardiorespiratory coordination can be observed during various mental and physiological states [21]. Phase synchronization is a coupling in phase while coordination is a coupling in time [21]. While these various couplings often occur simultaneously, they are fundamentally different. Synchronization is found during times of relaxation, while coordination is found in the opposite state of stress [21]. Heart rate variability of RSA is maximized at around six breaths per minute, indicating cardiorespiratory resonance [24].

The physiological significance of RSA is still mysterious; however, such significance is demonstrated to likely exist. The efficiency of pulmonary gas exchange has been shown to be improved through RSA, likely by replacing pulmonary capillary blood with each heartbeat [23]. Heart rate is determined by the firing frequency of a group of electrically active pacemaker cells in the right atrium known as the sinoatrial node [25]. The frequency of this node is determined by the balance of sympathetic and parasympathetic activity relayed to it with this activity being modulated in part by respiration in addition to the brainstem which contains projections from the cortex and limbic system [23]. During inspiration, cardiac parasympathetic neurons are hyperpolarized, and activity of the cardiac vagal nerve is nearly abolished leading to the inspiratory tachycardia of RSA [23]. During expiration, this activity is maximized leading to bradycardia [23]. Heart rate variability can be used as an index of a cardiovascular health [22] , and atypical RSA patterns have been identified with higher levels of depression and other illness [26].

In addition to effects on cardiac rhythms, respiration has also been shown to modulate blood pressure and vascular resistance. Blood pressure has been shown to correlate with respiratory rhythms [27]. It increases with inspiration and falls during the expiratory process [28]. Cerebral oxyhemoglobin concentration fluctuations overlap and correlate with frequencies of the respiratory rhythm in response to breathing patterns [29] [30].

Slowly Adapting Stretch receptors of the lungs, discovered in 1868 by Hering and Breuer, are mechanoreceptors that respond to lung inflation [31]. These receptors have been evidenced to be involved in modulating breathing pattern [32] , vascular resistance, heart rate [31] , and autonomic tone [33]. Although these mechanisms are not fully understood [31] , they are demonstrated to prevent excessive lung inflation, facilitating expiration via hyperpolarizing inputs to the brain stem in a process known as the Hering Breuer reflex [32]. The inhibitory action potentials travel along the vagus nerve to “pump” cells in the medullary region of the brainstem [34] which then inhibit inspiratory neurons involved in respiratory pattern and rhythm generation including the ventral respiratory column and the Pre-Bötzinger complex [32].

The autonomic nervous system (ANS) is the major neural network involved in respiration, playing a major role in fits interaction with circulation that was first described over eighty years ago via oscillatory discharge of the sympathetic network synchronizing with respiratory rhythm [23]. However, mechanisms of ANS modulation by respiration remain incomplete. Strong correlations have been made between respiratory patterns and autonomic activity. Faster, more irregular respiration rates are associated with sympathetic tone [35] , while slow, deep breathing has been associated with parasympathetic [36] [37] [38]. Although modulation of the ANS has regarded as purely involuntary, through voluntary modulation of respiration, it has been demonstrated that the ANS can be voluntarily influenced [35]. Long-term parasympathetic dominance can also be achieved through slow deep breathing practice over extended periods [39] , and parasympathetic activity levels are correlated with depression and the success of techniques that attenuate sadness and dysphoria [26]. In addition, slow deep breathing may allow for optimal sympathovagal balance and improved autonomic reactivity to stress due to augmented baroreflex sensitivity [38]. The baroreflex is a homeostatic mechanism in which baroreceptor neurons in various vascular tissues relay blood pressure information from stretching of vessels to the brainstem [40].

We have discussed in the previous section the role the efferent, cardiac vagal nerve plays in RSA , however there is a deeper relationship between the ANS and respiration. The reflex mechanisms and stretch receptor activities we described converge at the central respiratory centers of the brainstem which also control tones of the ANS [38]. Suppression of sympathetic input by increasing tidal volume during inspiration suggests that slowly adapting stretch receptor activity is a major link between respiration and the ANS.

Emotions have been thoroughly linked to breathing [41] , ANS activity [42] , cardiorespiratory coupling, and other physiological changes throughout the body [43]. Respiratory activity is not only determined by interactions among the brainstem and cortical structures, but also the limbic system (specifically the amygdala) [43] , which is a functional correlate of emotion [44]. Respiratory patterns can be changed dramatically by emotions [43]. For instance, anxiety can significantly increase expiratory time [45]. When anxiety increases the respiration rate, activity synchronized with respiration can be observed in the limbic system [46]. Voluntarily modulating breathing pattern to those patterns associated with certain emotions may trigger neurological and physiological mechanisms triggered by the corresponding emotions [43]. As an integral part of yogic and breathing exercise, conscious modulation of breathing pattern or focused attention on spontaneous breathing can allow one to change their emotional state [47] [48]. Certain members of the military use such conscious breathing techniques to regain composure during stressful combat situations [49].

Several limbic and paralimbic areas are involved in breathing changes associated with emotional processing [50] , and amygdala activity is synchronized with each breath [51]. Detection of emotion via facial expressions occurs more quickly during inspiration compared to expiration, suggesting that synchrony in the amygdala is dependent upon respiratory phase [52]. Irregular patterns of respiration are associated with more stressed states of mind, demonstrated by studies revealing these patterns in patients with panic disorder [53]. Although much research has been conducted on correlations and mechanisms behind the respiration-emotion connection, there has been little discussion on the functional purposes behind why such a connection exists. A major hypothesis was proposed that the connection fulfills response requirements of the emotional situation [41].

Influence by respiration on sensory perception has in part been substantiated through studies on visual and auditory signal detection, revealing that the threshold for signal detection of hard to perceive stimuli is higher during inspiration compared to expiration [54]. During controlled breathing, reaction times are significantly longer during expiration compared to inspiration [55]. Natural, involuntary breathing showed similar extension of reaction time during expiration when the detection tasks are more complex [52]. Pain is experienced as less severe during expiration compared to inspiration [56] , and focused, slow breathing in general has been shown to reduce pain [57].

A basic function of motor control, the force generated upon muscle contraction, has been significantly correlated with the respiratory cycle. Handgrip force is notably stronger during forced expiration than during forced inspiration [58]. Eye movements have been demonstrated to be phase locked to respiration [59]. Motion tracking precision and response latency with finger movements has also been shown to be differentiated during inspiration and expiration [60]. These effects may occur via respiratory modulation of neural communications between the motor cortex and motor neurons in the spinal cord [61].

As part of an embodied cognitive architecture, respiration should show direct influence on cognitive processes. This has been shown in studies with variations during inspiration and expiration. Memory retrieval has been shown to be more accurate when the memories are accessed during inspiration compared to expiration [52]. Neuronal oscillations in the gamma range are correlated with a wide variety of cognitive activities such as attention [62] , problem solving [63] , and decision making [64]. Findings that respiration can modulate gamma oscillations in the neocortex suggest that respiration can modulate cognition [65].

Although conscious control and awareness of breathing has been used therapeutically since prehistoric times [66] , the mechanisms underlying its efficacy remains poorly understood. Although neuronal oscillations have been known to lock to breathing cycles in the olfactory bulb since the 1940’s [67] , recent findings have begun to suggest that breathing can act as a global organizer of neuronal oscillations throughout the human brain [52] [68]. By modulating intrinsic gamma network oscillations, respiration may organize cortical excitability [69]. These entrainments have been observed in multiple brain regions, however, they are most prominent in the frontal lobe [70] (Figure 1). Gamma-respiration coupling is dominant during awake states while it is diminished during REM sleep when theta coupling increases [71]. The lack of recognition of these oscillatory influences may have negatively altered results of previous studies on oscillatory coupling and cross-regional synchrony in the brain as the authors did not recognize certain rhythms appearing due to respiration [70].

The respiration entrainment of neural networks has been proposed to contribute to information processing [72] , information transfer [71] , and linking distributed cell assemblies [70]. The possibility of these entrainments being due to mechanical artifacts has been voided by the demonstration that the entrainments

are specific to grey matter versus white matter or cerebrospinal fluid [68]. Therefore, these neuronal entrainments must have a physiologic function and we propose they are part of an embodied cognitive architecture influencing conscious processes. Oscillatory activity in the brain is hierarchically organized such that higher frequency oscillations are modulated by lower frequencies [73]. Low frequency oscillations such as respiratory rhythms tend to be coherent over large distances and well suited for interregional communication [74]. Therefore, respiration rhythms may provide a foundation for the distributed, more locally functioning higher neural frequencies to organize upon [68]. These insights may provide mechanisms involved in therapeutic breathing exercises.

The main source of the electrical current we are proposing generated during respiration arises via common redox reactions, which release electrons from the oxygen molecules being brought into the lungs during inspiration. In addition, we propose more speculative means of current generation to be researched including currents by the mechanical stretching of slowly-adapting stretch receptors as well as when carbon dioxide is exchanged into the volume of air in the lungs. During inspiration, these electrons produce hyperpolarization in cell membranes throughout the body by traveling throughout bodily tissues leading to the effects on the body, perception, and cognition we have discussed (Figure 2). During expiration, the cellular membranes are globally depolarized, likely stimulating respiratory drive [87]. It is by this mechanism that respiration plays a fundamental role in an embodied cognitive architecture. These sources of electrical current are described below.

We propound that the electrons released via these sources we shall describe hyperpolarize cells throughout the body not through free electrons accumulating within cells, but via the acceptance of these electrons by intracellular proteins and acids. Membrane impermeable organic acids and proteins exist at a greater concentration within the cell and balance the intracellular positive charge held by the large amount potassium ions within when they possess a negative charge [88]. According to our hypothesis, membrane-permeable electrons become situated within the cell by being accepted by these internal acids and proteins which cannot diffuse out of the cell. These become anions which act to hyperpolarize the cell. As anions they are the main source of negative charge within the cell of a resting membrane and a major component of the cytoplasm.

Recent evidence suggests that organisms may harness some features of quantum mechanical effects for physiological use [89]. We suggest in light of modern research in quantum biology, the transport of electrons throughout the body

may be assisted by quantum tunneling. Quantum tunneling is the ability of small particles such as electrons to pass through energy barriers [90]. Enzymes have been demonstrated to use quantum tunneling to transport electrons long distances (tens of angstroms) between redox centers during cellular respiration [89] [91] [92]. Via quantum tunneling, we believe electrons harvested from inspiration may be transferred across energy barriers during the redox reactions we have described.

In addition to the bodily and cognitive modulations by these respiratory electrical currents we have proposed, we assert they play a central role in the maintenance of the respiratory pattern itself, thus being part of its own central pattern generator. This pattern occurs in a cyclical manner with each phase being a phase of respiration, beginning with the harvesting of electrons from the sources discussed (Figure 4). The electrical currents that spread throughout the body then cause a slight hyperpolarization of all cells. This inhibition along with inhibitory currents from the stretch receptors influences the respiratory center strong enough to cause the Pre-Bötzinger complex to cease its signals to the motor activities driving inspiration; thus, the mechanism of the Hering Breuer reflex is extended by our hypothesis beyond the stretch receptors. These inhibitory currents also inhibit the sympathetic nervous system and increase vagal tone. We propound that through global hyperpolarization and then depolarization among expiration, they produce the respiratory rhythms that have been identified in the brain, heart, and vascular tissues.

Once inspiration ceases primarily due to the inhibition to respiratory centers

in the brainstem, the diaphragm relaxes and due to the elasticity of the lungs, the natural composure of the chest wall and abdominal structures compress the lungs in a recoil effect [106]. Upon expiration, the global hyperpolarization of cells begins to reverse as a mechanism of homeostasis. This depolarization causes the stimulation of the sympathetic nervous system, as well as having effects on global oscillatory rhythms. The global depolarization then stimulates respiratory drive, initiating inspiration and restarting the respiratory cycle.