What nervous system controls fight or flight

6 The Chromaffin Cells of the Vertebrate Adrenal Medulla

The flight-or-fight response is mediated by chromaffin cells of the adrenal medulla in Vertebrata; following sympathetic cholinergic input, the activation of mainly nicotinic receptors provokes action potentials and the neurohemal release of adrenaline or noradrenaline, leading to a state of whole-animal arousal in the face of potential danger (Cannon, 1915; Feldberg et al., 1934; Douglas and Rubin, 1963; Brandt et al., 1976; Colomer et al., 2011). Chromaffin cells range from oval, to polygonal, to columnar in shape, and are grouped together primarily near medullary veins (Colomer et al., 2011). Grynszpan-Wynograd and Nicolas (1980) employed electron microscopy to establish that chromaffin cells from guinea pigs, hamsters, and rats have bands or even loops of gap junctions rather than more dense plaques. Immunostaining, Northern blot analysis, and/or polymerase chain reaction then indicated that the rat adrenal medulla expressed connexin 43 (Meda et al., 1993) as well as connexin 36 (Martin et al., 2003), whereas the most abundant gap junction protein in human chromaffin cells was connexin 50 (Willenberg et al., 2006).

Dual recordings from rat adrenal medullary slices initially showed that adjacent chromaffin cells were coupled by nonrectifying, voltage-independent electrical synapses (Martin et al., 2001, 2003). However, a large variance in the coupling coefficient (from less than 0.1 to approaching 1) was also observed, which in itself could have been due to multiple cell coupling (Martin et al., 2001). Lucifer yellow fills of single chromaffin cells lead to dye spread to one or two neighboring cells about 30% of the time, and this was lessened by treatment with the gap junction blocker, carbenoxolone (Davidson and Baumgarten, 1988; Martin et al., 2001). Imaging these slices uncovered either spontaneous or nicotine-induced synchronous Ca2+ oscillations; moreover, action potential firing in one chromaffin cell resulted in catecholamine release, as detected by amperometry, from an adjacent cell, but only if that cell was coupled (Martin et al., 2001). In whole mice, carbenoxolone lowered splanchnic nerve-evoked catecholamine secretion from intact adrenal medulla, whereas connexin 36 knockdown animals had a paucity of secretion to similar stimulation (Desarménien et al., 2013). This indicates how electrical synapses can enlist partnered neuroendocrine cells and bring about concerted hormone exocytosis. Thus, despite likely not being a syncytium, the presence of gap junctions, in combination with an essentially simultaneous and widespread cholinergic input, may allow for multichromaffin cell recruitment.

Subsequent work suggested that chromaffin cell electrical coupling is regulated by presynaptically released acetylcholine. Specifically, short-term (minutes) incubation of rat adrenal medullary slices in the general noncompetitive nicotinic antagonist, hexamethonium (Paton and Zaimis, 1948; Tauc and Gerschenfeld, 1961), increased the frequency of Lucifer yellow dye spread from one chromaffin cell to another, elevated the conductance of the electrical synapse between paired cells, and enhanced the degree of Ca2+ oscillation propagating from cell to cell (Martin et al., 2003). Furthermore, removal of cholinergic afferents, through splanchnicectomy, resulted in greater dye spread (Martin et al., 2003). Adrenal medullary coupling was also regulated by cold stress, which led to more connexin 36 and 43 being expressed, as well as stronger chromaffin cell electrical synapses and Ca2+ oscillations (Colomer et al., 2008; Desarménien et al., 2013). This plasticity may be used by chromaffin cells to fortify coupling and maintain hormone release in the face of diminished chemical input or adverse conditions.

“Fight-or-Flight” Responsea

Generate discussion regarding the phenomenon of fight or flight. Encourage the parents to discuss what they know about the phenomenon of the fight-or-flight response and its origins.

The response consists of elevated arousal; increased heart rate, pulse, and breathing; increased strength in large skeletal muscles; and shifting into a highly instinctive, primitive state of mind (residing in the amgdala) that is bent on survival. Blood rushes to the major vital organs including the heart and lungs and to large skeletal muscles but notably away from the frontal lobes and rational decision-making parts of the brain (prefrontal cortex). The body is deliberately routing all resources, that is, blood flow to only the most vital, life-sustaining areas, of which the frontal lobes is not one.

Thus, a person experiencing a fight-or-flight response might feel dizzy, lightheaded, or confused. This response is a vestige of cavemen times, when early man had to be on guard and have the capacity to launch instantly into a physical state in which he was prepared to run away or fight when faced by that saber-toothed tiger or wooly mammoth. Ask the caregivers “What happens to people when they feel threatened or experience the fight-or-flight response?” and write down the ideas they generate on the dry erase board. The list may ultimately resemble the following:

Increased breathing rate

Increased heart rate

Increased blood flow to large organs

Increased blood flow to large skeletal muscles

Decreased blood flow to the frontal lobes

Increased blood flow to the primitive part of the brain.

Facilitate discussion with the parents regarding the fact that arousal states (along with most emotional states)—as most people know and have experienced—are usually contagious. That, too, probably conferred early evolutionary advantage and so has been preserved in the species. It is rare, however, that the fight-or-flight response is apropos in modern society. People no longer face saber-toothed tigers or their modern-day equivalent. Discuss with parents, that, unfortunately, many youngsters are sensitized to enter this high-arousal state with minimal provocation. Their central nervous system wiring is functioning as though “short-circuited” and vulnerable to misfiring out of cue. In fact, there is a burgeoning body of literature, growing out of functional brain imaging studies, that is amassing evidence demonstrating a pattern of amygdala hyperactivation (emotion) coupled with prefrontal cortex and anterior cingulate (rational decision-making) hypoactivation, in adults and youngsters with anxiety and mood disorders (Wegbreit, Cushman, Puzia, et al., 2014). This robust scientific finding can help answer parental inquiry as to “Why is my child/teen struggling with emotional regulation?” Caregivers can likewise become sensitized to activation of their own threat or “fight-or-flight” response; especially if they have a long history of managing frequent escalations in their teens. In short, both their teens’ and their own arousal system can become “twitchy” and prone to firing and misfiring, akin to a “hair-pin” trigger.

Greene (2001) suggests that youth lose at least 30 IQ points when they become hyperaroused. They become more primitive and less capable of rational, logical, reasonable thought and conversation. If their parents likewise become hyperaroused, it as though gasoline has been poured on a fire, with both parties operating in a primitive, low-intellect, aggressive state. Ask the parents to reflect on an instance during which they entered this high-adrenaline state themselves. Encourage them to recollect the event in vivid detail and to share highlights with the workshop. Ask, “When highly aroused, what becomes of one’s ability to think clearly, to reason, to negotiate, or to problem-solve?” A hyperaroused person loses much of his or her capacity for rational thought along with 30 IQ points and instead becomes braced for action, either defending against or evading danger, a primitive being. Their higher-level brain functions shut down, leaving only the most primitive part of the brain engaged and functional. You might orient the group to reference the psychological mindset of a threatened individual as being controlled by their “savage” brain (amygdala) which is more powerful but much dumber than their “civilized” brain (frontal lobes or prefrontal cortex). The former is comprised purely of brute force, but lacking intellect and capacity for reason. The latter brain regions are admittedly less powerful, but much more intelligent, effective, sophisticated, and mature.

Catecholamines

Catecholamines are the primary mediators of the fight-or-flight response. Norepinephrine is the major neurotransmitter in the peripheral sympathetic nervous system, whereas epinephrine is the primary hormone secreted by the adrenal medulla. The release of both is increased during stress. Their effect on target tissues is mediated by 6α- and 3β-adrenoceptor subtypes.

Epinephrine affects mitochondrial metabolism mainly by mobilizing body energy stores to augment the availability of substrates for oxidation. Epinephrine stimulates both lipolysis and glycogenolysis (most notably in the skeletal muscle) by interacting with the β1- and β2-adrenoceptors. It also acts through the Gs-protein-coupled β2-adrenergic receptor to stimulate adenyl cyclase activity and cAMP production, leading to the activation of the protein kinase A (PKA). This signaling pathway is responsible for the modulation of numerous processes and notably gene transcription through the phosphorylation of CREB.

Another major mitochondria-targeted effect of catecholamines is the enhancement of thermogenesis, which occurs primarily in the brown adipose tissue, which is highly innervated by sympathetic nerve terminals. During this process, energy derived from the oxidation of fuel substrates is dissipated as heat rather than being stored as ATP (uncoupling). Uncoupling occurs via β3-adrenergic stimulation and the downstream regulation of specific uncoupling proteins (UCPs). The inner mitochondrial membrane in brown adipose tissue contains UCP-1. Other known UCPs include UCP-2, which is widely expressed, and UCP-3, which seems to be expressed primarily in the skeletal muscles, heart, and brown adipose tissue, which are controlled by thyroid hormone and leptin. Several pharmaceutical companies have worked on the development of β3-adrenoceptor agonists to stimulate UCP-1 in brown adipocytes and increase energy expenditure in obese patients. Unfortunately, these drugs often have adverse side effects on the cardiovascular system and poor bioavailability.

The peroxisome proliferator-activated receptor γ co-activator (PGC-)1α controls adaptive thermogenesis in adipose tissue and skeletal muscle by stimulating mitochondrial biogenesis and oxidative phosphorylation. Stress, fasting, and exercise activate the PGC-1α through different signaling pathways, including β-adrenergic (β3/cAMP), Ca2+-dependent, NO and mitogen-activated protein kinase (MAPK) pathways. PGC-1α, in turn, activates the expression of nuclear respiratory factor (NRF)-1 and-2, estrogen-related receptor (ERR-)α, and PPAR-α, which regulate the mitochondrial biogenesis and fatty acid oxidation pathways. NRF-1 and NRF-2 regulate the expression of Tfam, a nuclear-encoded transcription factor that binds regulatory sites on mtDNA and is essential for the replication and transcription of the mitochondrial genome. Furthermore, NRF-1 and NRF-2 regulate the expression of nuclear genes encoding respiratory chain subunits and other proteins required for mitochondrial function.

Muscle Tone and Locomotion

RAS is a phylogenetically conserved system that modulates fight-or-flight responses. During waking, our ability to detect predator or prey is essential to survival. RAS is linked to the motor system in order to optimize attack or escape. During REM sleep, atonia keeps us from acting out our dreams. Only our diaphragm and eye muscles appear to be acting out dream content. During waking, RAS can modulate muscle tone and locomotion via reticulospinal systems. For example, in a standing individual, there is tonic activation of antigravity, mainly extensor, muscles. Before the first step can be taken, there must be flexion (i.e., a release from extensor bias). The startle response, a rapid response to a supramaximal stimulus, is basically an induced flexor response, placing the body in a ‘ready’ position. The startle response is composed of a short latency activation of muscle activity (the ready condition), followed by a brief inhibition (the ‘reset’ state) and then a long latency activation (the ‘go’ condition). The intermediate latency inhibition is thought to be part of the modulation of the startle response by cholinergic RAS neurons, and it may represent a ‘resetting’ of motor programs which allow the subsequent selection of response strategies – the triggering of attack or escape movements.

There appear to be multiple descending pathways by which RAS modulates muscle tone and locomotion. PIA can be activated by cholinergic agonists to induce REM sleep with atonia and PGO waves. Lesions of this region produce an animal exhibiting REM sleep without atonia, although such lesions may damage passing axons. Presumably, outputs from this region activate reticulospinal systems that lead to profound hyperpolarization of motor neurons, which is the mechanism responsible for the atonia of REM sleep. Cholinergic projections to the medioventral medulla appear to elicit increases in muscle tone and controlled locomotion. Outputs from this region activate reticulospinal systems that trigger spinal pattern generators to induce stepping. Electrical stimulation of the pontine and medullary reticular formation is known to induce decreased muscle tone at some sites while producing stepping movements at other sites. This suggests the presence of a heterogeneous, distributed system of muscle tone and locomotor control.

What Do We Often Try to Control? The Fight-or-Flight Response

Physiological Mechanism of GAD

When threats are perceived, anxiety is accompanied by a fight or flight response. The main purpose of this physiological reactivity is to prime our body for combat and survival. This reaction requires a sudden increase in energy for immediate action. Such sudden activation evokes various types of changes in our physiological systems. Traditionally, the fight or flight response has been thought to involve a general discharge of the sympathetic nervous system, which consists of one of the two sub-components of the autonomic nervous system. Anxiety disorders are characterized by heightened reactivity of the sympathetic nervous system. However, as the source of anxiety differs across different types of anxiety disorders, it is possible that each anxiety disorder may have a different pattern in its physiological reactivity (Friedman and Thayer, 1998; Lyonfields et al., 1995). Although only a few studies have assessed physiological states in individuals with GAD, examining physiological characteristics could be helpful in understanding the unique nature of the disorder.

In GAD, the fear is not about imminent danger but instead it is about potential future threats. For this reason, researchers have theorized that the physiological response in GAD may be more chronic and less variable than in other anxiety disorders. There is some evidence to support this theory. Although the general physiological activity in GAD tends to be similar to that of most other anxiety disorders, all showing lower heart rate variability (higher heart rate) compared to non-anxious individuals (Licht et al., 2009; Pittig et al., 2013), those with panic disorder and GAD tended to have higher heart rate during hyperventilation whereas those with social anxiety disorder and obsessive compulsive disorder did not (Pittig et al., 2013). Also, studies have found that such higher baseline sympathetic arousal tends to predict lesser reactivity to a laboratory stressor (Fisher et al., 2010; Llera and Newman, 2010). Taken together, these results suggest that GAD and worry are related to more chronic activation which may reduce the sudden increase in energy (negative contrast) needed for the fight or flight response.

Similarly, GAD has been linked to distinct patterns of parasympathetic regulation. Specifically, individuals with GAD demonstrated significantly lower vagal tone at baseline as compared to non-anxious controls (Lyonfields et al., 1995; Thayer et al., 1996). Vagal tone has been thought to be the key element of the parasympathetic nervous system, which regulates the resting state of the internal organ systems. Findings of restricted vagal tone indicate that those with GAD may be characterized by their deficient parasympathetic control. Similarly, during a 4-day ecological momentary assessment, researchers found that patients with GAD had lesser respiratory sinus arrhythmia than control participants (Hoehn-Saric et al., 2004). Respiratory sinus arrhythmia is heart rate variability in synchrony with respiration, which indicates the level of parasympathetic nervous system activity.

More recent studies have suggested that worry plays a causal role in autonomic nervous system activity. Worry leads to increased sympathetic nervous system activity and decreased parasympathetic activity. Specifically, during worry inductions, GAD patients showed increased cardiovascular activity, higher electrodermal activity and reduced heart rate variability (Brosschot et al., 2005; Lyonfields et al., 1995; Pieper et al., 2010; Thayer et al., 1996). In addition, laboratory-based experimental studies also showed that worry evoked decreased heart rate variability in response to threat exposure (Fisher and Newman, 2013; Kircanski et al., 2016b). These results show that worry may facilitate autonomic inflexibility and anxious arousal in GAD.

Coping

As described, many kinds of stress that lead to fight-or-flight responses increase Tc, whereas long-lasting, inescapable stress that leads to passive coping decreases it. Furthermore, differences in coping strategies affect the recovery from stress (Kant et al., 1991; Meerlo et al., 1999). For example, after introducing experimental rats to an aggressive conspecific for 1 hour, circadian body temperature rhythms were disrupted for several days. Rats that did not counterattack took a longer time to recover than animals that fought back (Meerlo et al., 1999).

Another example was demonstrated where two rats received the same around-the-clock intermittent signaled foot shock for 2 weeks. One rat could control and terminate the shock (stress-controlled); however, another rat was yoked to the controlling rat (stress-uncontrolled) such that the controlling rat and the yoked rat received shocks of the same duration, but only the controlling rat could terminate shock. Both stress groups had decreased amplitude of Tc rhythms compared to control animals, while the yoked animals were more severely disrupted and remained disrupted for a longer period than the stress-controlled animals (Kant et al., 1991).

Systemic inflammation can induce either fever or hypothermia. Both thermoregulatory responses are proposed to have adaptive values and are assumed to be complementary strategies of survival in systemic inflammation (Romanovsky and Szekely, 1998). Likewise, stress-induced hyperthermia, which is associated with active coping and energy utilization to survive fight-or-flight situations, and hypothermia, which is associated with passive coping to save energy to survive long-lasting difficult situations, may also be two adaptive strategies to survive stressful situations.

C Limbic stabilization

The amygdala is activated by fear, anxiety and stress (the fight-or-flight response), and the hypothalamus controls all autonomic functioning including muscle tension, electrodermal response, heart rate, arterial tone, body temperature, eating and satiety. Because AVE can be used to produce hand-temperature normalization, muscle relaxation, reduced electro-dermal activity, reduced heart rate and reduced hypertension, it is speculated that AVE may produce a calming effect on these limbic structures. AVE therefore lends itself very well to stabilizing panic and anxiety. When using white light as the stimulus, measures of finger temperature, electromyograph (EMG), electro-dermal response (EDR), and heart-rate variability (HRV) have been dramatically improved within 10 minutes.

Figure 8.6 shows increasing (normalizing) finger temperature in one subject. Figure 8.7 shows decreased electrodermal response using white-light AVE (DAVID system) at alpha frequencies. Notice that the normalization effect begins following roughly 6 minutes of AVE.

Sympathetic nervous system

The classical description of the ANS response to stress in the “fight or flight” response by Cannon (1929) has focused on the stereotypical and global activation of the sympathetic nervous system (SNS). However, despite the integrated nature of the response to different stressors, there is considerable variability in the target specificity of the peripheral output. At the level of the paraventricular nucleus of the hypothalamus, the cells that give rise to major classes of visceromotor projections are separate, suggesting that they are not necessarily called into play in a stereotyped “all or none” matter, but rather that they may be differentially recruited (Swanson and Kuypers, 1980). Evidence supports a functionally distinct branch of the SNS dedicated specifically to immune modulation (Felten, 2000; Jänig and Habler, 2000). Noradrenergic sympathetic nerve fibers innervate the vasculature and parenchyma of lymphoid organs, including the gut (Felten et al., 1991). These nerves and their principal neurotransmitter norepinephrine can influence: (1) basic immune cell function, such as proliferation, differentiation, cell trafficking, and cytokine production; (2) acquired immune responses; and (3) autoimmune reactivity in susceptible strains (Felten, 2000). For example, activation of the sympathetic system causes systemic secretion of interleukin-6 (IL-6) from immune cells. IL-6, by inhibiting tumor necrosis factor-alpha and IL-1α, and by activating the HPA axis, participates in the stress-induced suppression of the immune-inflammatory reactions (Perlstein et al., 1993). Stress-related increases in plasma epinephrine (and glucocorticoids) play an important role in the facilitation of memory in amygdala–hippocampal circuits, including in the development of conditioned fear (Cahill et al., 1994). Epinephrine-stimulated vagal feedback has also been implicated in the activation of endogenous pain modulation circuits (Fillingim and Maixner, 1995). Several polymorphisms in genes related to the noradrenergic system (including catechol-O-methyltransferase and beta-adrenergic receptors) have been identified as vulnerability factors to develop persistent pain disorders (Diatchenko et al., 2007), suggesting a prominent role for the peripheral and central components of the SNS in the pathophysiology of temporomandibular joint disorder and comorbid disorders, such as IBS and FD.

Abstract

The chapter begins with an introduction to the human body’s “fight-or-flight” response to threat, describing the anatomical and physiological foundation for the sympathetic and parasympathetic nervous systems, which balance each other to keep the body in homeostasis, or normal function. Many common examples are given of the responses of both the sympathetic and parasympathetic nervous systems during various situations perceived as threatening. The polygraph is shown to be a system designed to measure the related physiological responses, however small, that occur during deceptive behavior, and the author examines in some detail the various theories behind why telling a lie should evoke these physical threat responses in humans, providing research results showing that it does indeed occur. The author then briefly relates the anatomical/physiological responses to interviewer technique and observations when using the Forensic Assessment, making the point that a Forensic Assessment Interview must therefore be set up as a scientific experiment in which the only stimulus is the interviewer’s question and all extraneous stimuli are controlled.