**3. Theories**

**1. Introduction**

disorders:

**2. Key concepts**

Brain‐based hypersensitivity to environmental stimulation underlies pathological states that have been defined as "disorders of arousal" [1]. "Autonomic tuning" is the term that was historically used to describe the process of normally balanced sympathetic and parasympa‐ thetic branches of the autonomic nervous system (ANS), in contrast to the disorders of arousal which are characterized by ANS dysfunction, affective lability, anxiety, stress, and emotional

44 A Multidimensional Approach to Post-Traumatic Stress Disorder - from Theory to Practice

It is a matter of everyday experience that a person's reaction to a given situation depends very much upon his own mental physical, and emotional state. One might be said to be "set" to respond in a given manner … the autonomic response to a given stimulus may at one time be predominantly sympathetic and may at another time be pre‐dominantly parasympathetic.([2], pp. 90–91; quoted in [3], p. 179)

ANS dysregulation impacts on both physical (increasing cardiovascular risk) and mental (compromising psychological well‐being) health at multiple levels. Loss of regulation of normal autonomic control of cardiac adjustment to environmental stressors leads to negative impacts on physiological function affecting arterial blood pressure, heart rate and rhythm, and vagal afference. Allostatic load is a term that has been used for decades to describe "the wear and tear on the body" which grows over time when the individual is exposed to repeated or chronic stress [4]. Allostatic load is the physiological consequence of chronic exposure to fluctuating or heightened neural or neuroendocrine response that results from repeated or chronic stress. Thus, it is that chronic autonomic imbalance finally leads to allostasis of affective, cognitive, and behavioral level of function. The effect of heart rate variability (HRV) biofeedback (HRVB) is to manipulate peripheral autonomic state feedback to the central nervous system circuits regulating emotional, cognitive, and sensorimotor activity. The study of HRV and effects of HRVB provide important insights into the mechanisms of autonomic

arousal in normal, successful adaptation and pathological states such as PTSD.

The chapter is organized into several sections. In Section 3, the role of HRV in autonomic cardiac control as it is found in normal adaptation is described. The specific topic headings in this section are: *Autonomic cardiac regulation; HRV and HRV coherence; Neurophysiological basis of HRV: polyvagal and neurovisceral; HRV and orienting; Executive control of attention and defense;* and *Autonomic cardiac regulation and fear.* In Section 4, the topic headings *Autonomic cardiac dysre‐ gulation in PTSD* and *PTSD and attention bias* discuss the derangement of normal ANS cardiac control by PTSD. Section 5 has only one topic heading titled *Applied psychophysiological therapy for PTSD and attention bias: HRV biofeedback* which presents the case that application of the HRVB intervention is intuitively and theoretically sound. In Section 6, *Models of Autonomic Dysregu‐ lation in PTSD* is a graphic representation of our ideas of how HRV influences orienting in normal and in the PTSD phenotype. In Section 7, the topic heading *Completed Research on HRVB*

#### **3.1. Autonomic cardiac regulation**

The ANS controls how the individual appraises the valence of environmental stimuli and the responses selection consequent to the appraisal (e.g., maintenance of resting homeosta‐ sis, mobilization of defensive response, task performance, tonic immobilization, and/or af‐ filiation) by interplay between sympathetic (accelerative) and parasympathetic (decelerative) influences on the heart. This model of adaptive behavior integrates polyvagal theory [5–8]. Thus, cardiac adjustments to environmental stimuli affect the internal physio‐ logical and emotional state of the individual as well as the quality of information processing that the individual can perform during the stimulus appraisal stage of the orienting re‐ sponse. Bradycardia is adaptive in early stages of orientation to novel or potential threat, while greater HRV power serves to facilitate self‐regulation, stimulus information process‐ ing and appraisal, and appropriate response selection [9–11]. As we have previously mod‐ eled, this process occurs during the initial stage of the stimulus orienting response (OR), and it can lead to autonomic and somatic‐motor conditioning [12].

#### **3.2. HRV and HRV coherence**

The number of studies of the relevance of the ANS to stress and mental disorder has increased markedly in the past 20 years [13, 14]. HRV is the quantification of the variance of inter‐beat intervals (ibi) between cardiac pulses. HRV can be measured by electrocardiogram (ECG), fingertip pulse photoplethysmograph (ppg), or beat‐to‐beat (continuous) changes in arterial blood pressure. *Instantaneous heart rate* in beats per minute (bpm) can be calculated from a single ibi (with unit of seconds) as HR (bpm) = (60 s/min) × (1/ibi) = 60/ibi. On the other hand, neither ibi nor HRV can be calculated from HR in bpm because bpm is an averaged value. We have been studying and recoding HR and HRV in combat veterans for several years.

Quantification of HRV is accomplished in several different ways. The two most common types of HRV variables, and the most easily understood and physiologically interpretable, are the *time‐domain* and *frequency‐domain* variables [14, 15]. In the time domain, variance of ibi's, or power, across a recording time period is simply derived from the time intervals of either consecutive heartbeats (standard deviation of all N‐N intervals, SDNN) or the differences between consecutive intervals (square root of the mean of the sum of squares of differences between adjacent N‐N intervals, RMSSD. More variance = more power. In the frequency domain, power in units of ms2 /Hz is derived as the integral (area) under the curve of a given frequency range. Frequency‐domain measures are computed with power spectral density (PSD) analysis using fast Fourier transform of the tachygram of HR against time. The PSD graphically represents how variance or power is distributed as a function of frequency. Three main spectral components are distinguished: very low frequency (VLF, 0.003–0.05 Hz), low frequency (LF, 0.05–0.15 Hz), and high frequency (HF, 0.15–0.50 Hz). There is also an ultra‐low frequency (ULF) band of HRV cycle frequency recognized between 0.00001 and 0.003 Hz that is, a period of months—that has been receiving some attention in recent years. **Table 1** indicates how frequency ranges can be associated with physiologically and behaviorally relevant time periods.


RFB, resonant frequency breathing, BR, baroreflex.

**Table 1.** Correspondences of period, cycle, and physiological and behavioral functions in the HRV power spectrum.

There is general agreement that efferent parasympathetic output from the vagus cranial nerve is the major contributor to the HF component. HF HRV power is an indicator of respiratory sinus arrhythmia (RSA), the breath‐to‐breath heart rate fluctuation due to cardiac modulation by vagal parasympathetic output associated with respiration; in the normal state, heart rate accelerates on inspiration and decelerates on expiration during each respiratory cycle. Vagal parasympathetic output results in cardiac deceleration and higher HF HRV power. Although the mediation of HF HRV is complex, the primary source of HF HRV is mediated through the vagus nerve, such that blocking vagal activity removes virtually all HF HRV [16]. RSA results from interaction between lung and brainstem. Lung inflation activates afferent stretch receptors which results in inhibition of vagal parasympathetic cardiac outflow and increased HR; during expiration, the stretch is reduced and vagal inhibition removed leading to reduced HR. The term "vagal tone" has been used to refer to HF HRV although parasympathetic influence on cardiovascular function and HRV, through the baroreflex, extends into the LF range as well.

LF HRV power is a mixture of activity of sympathetic and parasympathetic cardiac efference and afference in feedback loops between heart and brain that control short‐term arterial blood pressure changes. "This discrepancy is due to the fact that in some conditions associated with sympathetic excitation, a decrease in the absolute power of the LF component is observed. It is important to recall that during sympathetic activation the resulting tachycardia is usually accompanied by a marked reduction in total power, whereas the reverse occurs during vagal activation" [17]. Furthermore, after reporting complete abolition of the HF and the LF 0.1 Hz peaks as a result of parasympathetic blockade, Akselrod concluded that "our data indicate that the parasympathetic nervous system (PNS) mediates heart rate fluctuations at frequencies corresponding to the low‐ and high‐frequency peaks of the power spectrum" [16].

**Figure 1.** Example of an HRV spectrum showing HRV coherence.

graphically represents how variance or power is distributed as a function of frequency. Three main spectral components are distinguished: very low frequency (VLF, 0.003–0.05 Hz), low frequency (LF, 0.05–0.15 Hz), and high frequency (HF, 0.15–0.50 Hz). There is also an ultra‐low frequency (ULF) band of HRV cycle frequency recognized between 0.00001 and 0.003 Hz that is, a period of months—that has been receiving some attention in recent years. **Table 1** indicates how frequency ranges can be associated with physiologically and behaviorally

46 A Multidimensional Approach to Post-Traumatic Stress Disorder - from Theory to Practice

86400 600 300 60 15 10 6 5 4 1 .75

Normal respiration Normal

HR

Cycles/s (Hz) 0.00001 0.002 0.003 0.017 0.067 0.100 0.167 0.200 0.250 1.000 1.33 Minutes/cycle 1440.0 10.00 5.00 1.00 0.25 0.17 0.1 8 0.07 0.02 0.01 Cycles/min 0.0007 0.1 0.2 1 4 6 10 12 15 60 80

BR

**Table 1.** Correspondences of period, cycle, and physiological and behavioral functions in the HRV power spectrum.

There is general agreement that efferent parasympathetic output from the vagus cranial nerve is the major contributor to the HF component. HF HRV power is an indicator of respiratory sinus arrhythmia (RSA), the breath‐to‐breath heart rate fluctuation due to cardiac modulation by vagal parasympathetic output associated with respiration; in the normal state, heart rate accelerates on inspiration and decelerates on expiration during each respiratory cycle. Vagal parasympathetic output results in cardiac deceleration and higher HF HRV power. Although the mediation of HF HRV is complex, the primary source of HF HRV is mediated through the vagus nerve, such that blocking vagal activity removes virtually all HF HRV [16]. RSA results from interaction between lung and brainstem. Lung inflation activates afferent stretch receptors which results in inhibition of vagal parasympathetic cardiac outflow and increased HR; during expiration, the stretch is reduced and vagal inhibition removed leading to reduced HR. The term "vagal tone" has been used to refer to HF HRV although parasympathetic influence on cardiovascular function and HRV, through the baroreflex, extends into the LF

LF HRV power is a mixture of activity of sympathetic and parasympathetic cardiac efference and afference in feedback loops between heart and brain that control short‐term arterial blood pressure changes. "This discrepancy is due to the fact that in some conditions associated with sympathetic excitation, a decrease in the absolute power of the LF component is observed. It is important to recall that during sympathetic activation the resulting tachycardia is usually accompanied by a marked reduction in total power, whereas the reverse occurs during vagal activation" [17]. Furthermore, after reporting complete abolition of the HF and the LF 0.1 Hz peaks as a result of parasympathetic blockade, Akselrod concluded that "our data indicate that

relevant time periods.

Function 24 h RFB and

RFB, resonant frequency breathing, BR, baroreflex.

Sec/cycle (Period)

range as well.

HRV coherence is a physiological state of the individual that is produced when *resonance* occurs in the cardiovascular feedback systems controlling heart rate, arterial blood pressure (baror‐ eflex), and vasomotor tone. When resonance occurs, the difference between the highest and the lowest instantaneous heart rate within one respiratory cycle is maximized [18]. It can easily be seen then that HRV coherence means that HRV of the individual is maximized. HRV coherence is operationalized as the frequency spectrum of a sine wave‐like heart rate tachy‐ gram that has a narrow, high‐amplitude peak in the LF region of the HRV power spectrum, around 0.1 Hz, with no other major peaks in the VLF or HF regions [19, 20]. An example of HRV coherence from our own recording is shown in **Figure 1**. Although there are different ways to calculate a value from the PSD that reflects HRV coherence, one well‐known method of calculating a "coherence ratio" is to (1) identify the maximum peak in the 0.04–0.26 Hz range of the HRV power spectrum (which represents parasympathetic function) and calculate the integral in a 0.030‐Hz‐wide window centered on the highest peak in that region, (2) calculate the total power of the entire spectrum, and (3) divide the parasympathetic power by (total power minus parasympathetic power) [21]. In many if not most individuals who are free from cardiovascular disease, HRV coherence can be reliably produced by diaphragmatic breathing around the 0.1 Hz cycle (six breaths per minute), which is called resonant frequency breathing (RFB) because that is the frequency when resonance of the cardiovascular system occurs. RFB is integral to the practice of HRVB (see below for more detail). HRV coherence is associated with increased emotional self‐regulation and mental alertness [20].

#### **3.3. Neurophysiological basis of HRV: polyvagal and neurovisceral**

The polyvagal theory of Porges [7, 22–25] describes the neurophysiological basis of the interface of autonomic state and behavior. Polyvagal theory presents the hierarchical relation among three subsystems of the autonomic nervous system supporting adaptive behaviors in response to the particular features of safety, danger, and life threat in environmental stimula‐ tion. The name of the theory "polyvagal" denotes that two vagal pathways operate in mam‐ mals. One of the vagal circuits is a vestige of an evolutionarily primordial circuit that associated with defensive responding to threat; the other vagal circuit is a relatively recent evolutionary development, one that is not observed in other animals than mammals. This newer vagal circuit produces physiological states associated with safety and affiliation, and it is crucial for social engagement. Thus, when an individual feels safe the somatic or vegetative conditions are supportive of growth and restoration ("trophotropic" [26, 27]). This newer vagal circuit is characterized by *myelinated* vagal efferent pathways, including the cardiac pacemaker to cause heart rate deceleration and inhibit the fight‐flight mechanism of the sympathetic nervous system. The stress response of the hypothalamic‐pituitary‐adrenal (HPA) axis ("ergotrophic") is dampened, and inflammation is reduced through modulation of cytokine and other immune reactions. Second, integration of nuclei in the brainstem that regulate myelinated vagus with nuclei controlling muscles of the face and head used in facial expressions occurs. As a result, neural pathways are created that enable a social engagement system with bidirectional coupling of bodily states and social behaviors such as facial expressions and prosodic vocali‐ zations [8].

The neurovisceral integration model (NvIM) suggests that vagally mediated HRV (vmHRV) represents a psychophysiological index of cognitive inhibitory control and thus is associated with emotion regulation capacity [25, 28, 29]. Executive brain areas located in prefrontal cortex exert inhibitory influence on subcortical structures, importantly the amygdala, allowing the individual to adaptively respond to demands from the environment and organize responses effectively [30–32]. Thus, at rest, active cortical brain areas are indicative of greater inhibitory and emotion regulation. The NvIM proposes that individual differences in vagal function, as indexed by HRV at rest, reflect the activity of this flexible and integrative neural network which enables effective integration of basic responses (behavioral, cognitive, and emotional) that support goal‐directed behavior. The NvIM is founded upon a complex interplay between cortical and subcortical regions of the brain that are grouped under the collective term "central autonomic network" (CAN; [33]). The CAN links the ANS to a higher‐order cognitive func‐ tioning, especially the prefrontal cortex. Many specific brain nuclei and structures are included and reciprocally interconnected in the CAN: the ventromedial prefrontal cortices, the central nucleus of the amygdala, the anterior cingulate, the insula, the paraventricular nuclei of the hypothalamus, the periaquaductual gray matter, the nucleus of the solitary tract (NST), the nucleus ambiguus, and the medullary tegmental field. Output of the widespread CAN circuitry extends to autonomic inputs to the heart, including the vagus nerve. By exerting inhibitory control over subcortical pathways, prefrontal cortex functions to enable the individual to perceive and adapt to environmental challenges through higher levels of HRV (i.e., greater vagal tone) at rest.

Converging evidence suggests that these core sets of neural structures are responsible for not only inhibition but also the regulation of the ANS activity and reactivity. The heart and other peripheral organs are under tonic inhibitory control by the ANS. More specifically, this influence is characterized by a relative dominance of the parasympathetic nervous system (PNS) over influences of the sympathetic nervous system (SNS). Vagal parasympathetic control represents the major descending inhibitory pathway (DIP), adaptively regulating physiolog‐ ical functions shaped by psychological processes including emotion regulation. The NvIM posits that vagally mediated HRV may be more than just a simple index of healthy heart function, and also serves as readily available measure and index of the degree to which the brain's integrative system for adaptive regulation provides flexible control over the periphery.

#### **3.4. HRV and orienting**

(RFB) because that is the frequency when resonance of the cardiovascular system occurs. RFB is integral to the practice of HRVB (see below for more detail). HRV coherence is associated

The polyvagal theory of Porges [7, 22–25] describes the neurophysiological basis of the interface of autonomic state and behavior. Polyvagal theory presents the hierarchical relation among three subsystems of the autonomic nervous system supporting adaptive behaviors in response to the particular features of safety, danger, and life threat in environmental stimula‐ tion. The name of the theory "polyvagal" denotes that two vagal pathways operate in mam‐ mals. One of the vagal circuits is a vestige of an evolutionarily primordial circuit that associated with defensive responding to threat; the other vagal circuit is a relatively recent evolutionary development, one that is not observed in other animals than mammals. This newer vagal circuit produces physiological states associated with safety and affiliation, and it is crucial for social engagement. Thus, when an individual feels safe the somatic or vegetative conditions are supportive of growth and restoration ("trophotropic" [26, 27]). This newer vagal circuit is characterized by *myelinated* vagal efferent pathways, including the cardiac pacemaker to cause heart rate deceleration and inhibit the fight‐flight mechanism of the sympathetic nervous system. The stress response of the hypothalamic‐pituitary‐adrenal (HPA) axis ("ergotrophic") is dampened, and inflammation is reduced through modulation of cytokine and other immune reactions. Second, integration of nuclei in the brainstem that regulate myelinated vagus with nuclei controlling muscles of the face and head used in facial expressions occurs. As a result, neural pathways are created that enable a social engagement system with bidirectional coupling of bodily states and social behaviors such as facial expressions and prosodic vocali‐

The neurovisceral integration model (NvIM) suggests that vagally mediated HRV (vmHRV) represents a psychophysiological index of cognitive inhibitory control and thus is associated with emotion regulation capacity [25, 28, 29]. Executive brain areas located in prefrontal cortex exert inhibitory influence on subcortical structures, importantly the amygdala, allowing the individual to adaptively respond to demands from the environment and organize responses effectively [30–32]. Thus, at rest, active cortical brain areas are indicative of greater inhibitory and emotion regulation. The NvIM proposes that individual differences in vagal function, as indexed by HRV at rest, reflect the activity of this flexible and integrative neural network which enables effective integration of basic responses (behavioral, cognitive, and emotional) that support goal‐directed behavior. The NvIM is founded upon a complex interplay between cortical and subcortical regions of the brain that are grouped under the collective term "central autonomic network" (CAN; [33]). The CAN links the ANS to a higher‐order cognitive func‐ tioning, especially the prefrontal cortex. Many specific brain nuclei and structures are included and reciprocally interconnected in the CAN: the ventromedial prefrontal cortices, the central nucleus of the amygdala, the anterior cingulate, the insula, the paraventricular nuclei of the hypothalamus, the periaquaductual gray matter, the nucleus of the solitary tract (NST), the nucleus ambiguus, and the medullary tegmental field. Output of the widespread CAN

with increased emotional self‐regulation and mental alertness [20].

48 A Multidimensional Approach to Post-Traumatic Stress Disorder - from Theory to Practice

**3.3. Neurophysiological basis of HRV: polyvagal and neurovisceral**

zations [8].

Autonomic cardiac adjustments to environmental stimulation are an integral part of the orienting response (OR) to stimulation in the environment. Deceleration of HR is identifiable during the OR, while acceleration of HR reflects response selection of a defense response after a stimulus is cognitively appraised to be dangerous or threatening. The direction of attention (externally toward environmental information vs internally for information processing) and change in heart rate (deceleration vs acceleration, respectively) are linked. Lacey and Lacey [34, 35] put forward the "intake‐rejection hypothesis", proposing that attention to cognitive tasks can be directed toward the environment (intake of the environment) or it can be directed toward internal processing (rejection of the environment). Cardiac deceleration occurs during externally directed tasks (e.g., visual attention and search, empathic listening) due to activation of the parasympathetic branch of the autonomic nervous system. Cardiac acceleration occurs during internally directed tasks (e.g., mental arithmetic or imagery, response selection and output or performance) due to activation of the sympathetic branch of autonomic nervous system via release of norepinephrine from locus coeruleus to stellate ganglion of the heart [36].

Autonomic cardiac adjustments to environmental stimulation are furthermore and more basically an integral part of the OR. Orienting is the enhancement of stimulus reception by information processing and appraisal. Early work in this area determined that a deceleration of HR is identifiable during the orienting response, while HR acceleration reflects selection of a behavioral defense response (DR) after stimulus information appraisal indicated the need for it [37, 38]. The history of theory and research on the OR and DR (defense response) includes the role of general psychophysiological measures and phasic cardiac responses in both humans and animals. Obrist called this "cardiovascular learning" [39, 40]. Autonomic substrates of cardiac responding have behavioral significance for the OR and DR, and reveal that cardiac deceleration is necessary for stimulus appraisal after vigilance in orienting, and cardiac acceleration is necessary for defensive response selection [41, 42].

Currently, however, the construct of attention is considerably more complex than is described by intake‐rejection hypothesis. Although attention is being defined and measured using varied behavioral tasks, such as spatial cueing, sustained vigilance, and selective focus, the many different types of attention have been grouped into three basic categories, labeled as "alerting," "orienting," and "executive" [43]. Critically, the basic premise that cardiac deceleration is necessary for successful externally directed attention has held up and found new life in the widely accepted practice of employing HRVB for optimal performance enhancement, notably sports preperformance preparation (e.g., [44]).

#### **3.5. Executive control of attention and defense**

The human brain is equipped with various executive functions such as selective attention to deal with the vast amount of information flow from the external world in a seemingly effortless manner [45]. Emotional stimuli with their perceptual properties and biological significance must have attentional prioritization in order for adaptation to occur. For example, a dot‐probe task was used to investigate whether task‐irrelevant auditory emotional information can provide cues for orientation of auditory spatial attention [46]. In this experiment, participants were significantly faster to locate a target when it replaced the negative cue compared to when it replaced the neutral cue, while the positive cues did not produce a clear attentional bias. The results indicate that negative affect can provide cues for the orientation of spatial attention in the auditory domain. By way of possible mechanism for this effect, it has been shown that negative emotion induced by visual stimuli can affect auditory event‐related potentials (ERPs) as early as 20 ms after stimulus onset [47], and more generally that scalp potentials are associated reflect autonomic activity associated with behavioral responding [48].

The pressures of evolution have hardwired in humans a set of inborn and automatically activated defense behaviors, termed "the defense cascade." The first step in the defense cascade is arousal; if danger or threat is then perceived, the next step is activation of flight or fight, while freezing is an alternate response at this stage, a "flight‐or‐fight response put on hold." Tonic, collapsed, or passive immobility (also called fear bradycardia) is the response of last resort, when active fight or flight defense responses have failed and the threat to survival is imminent and inescapable. Each of these defense reactions has a distinctive autonomic pattern mediated by neural pathways. Freezing differs importantly from immobility in the cardiac state: accelerated heart rate characterizes freezing and decelerated heart rate characterizes immobility. The defense cascade is known to activate neural structures that are also central to the CAN: the extended amygdala, hypothalamus, periaqueductal gray (PAG), ventral pontine tegmentum, ventral and dorsal medulla, vagal and sympathetic nuclei, and spinal cord [49].

The hypothalamus (paraventricular nucleus) plays a major role in arousal by increasing sympathetic viscereomotor tone and in striated muscles of the somatomotor nervous system. The body becomes prepared for action by vasoconstriction of blood vessels to the salivary glands (dry mouth) and tension one in the laryngeal muscles of the back. Smooth and striated muscles contract, heart rate and respiration accelerate, and posture is stabilized [49].

#### **3.6. Autonomic cardiac regulation and fear**

Currently, however, the construct of attention is considerably more complex than is described by intake‐rejection hypothesis. Although attention is being defined and measured using varied behavioral tasks, such as spatial cueing, sustained vigilance, and selective focus, the many different types of attention have been grouped into three basic categories, labeled as "alerting," "orienting," and "executive" [43]. Critically, the basic premise that cardiac deceleration is necessary for successful externally directed attention has held up and found new life in the widely accepted practice of employing HRVB for optimal performance enhancement, notably

50 A Multidimensional Approach to Post-Traumatic Stress Disorder - from Theory to Practice

The human brain is equipped with various executive functions such as selective attention to deal with the vast amount of information flow from the external world in a seemingly effortless manner [45]. Emotional stimuli with their perceptual properties and biological significance must have attentional prioritization in order for adaptation to occur. For example, a dot‐probe task was used to investigate whether task‐irrelevant auditory emotional information can provide cues for orientation of auditory spatial attention [46]. In this experiment, participants were significantly faster to locate a target when it replaced the negative cue compared to when it replaced the neutral cue, while the positive cues did not produce a clear attentional bias. The results indicate that negative affect can provide cues for the orientation of spatial attention in the auditory domain. By way of possible mechanism for this effect, it has been shown that negative emotion induced by visual stimuli can affect auditory event‐related potentials (ERPs) as early as 20 ms after stimulus onset [47], and more generally that scalp potentials are

associated reflect autonomic activity associated with behavioral responding [48].

The pressures of evolution have hardwired in humans a set of inborn and automatically activated defense behaviors, termed "the defense cascade." The first step in the defense cascade is arousal; if danger or threat is then perceived, the next step is activation of flight or fight, while freezing is an alternate response at this stage, a "flight‐or‐fight response put on hold." Tonic, collapsed, or passive immobility (also called fear bradycardia) is the response of last resort, when active fight or flight defense responses have failed and the threat to survival is imminent and inescapable. Each of these defense reactions has a distinctive autonomic pattern mediated by neural pathways. Freezing differs importantly from immobility in the cardiac state: accelerated heart rate characterizes freezing and decelerated heart rate characterizes immobility. The defense cascade is known to activate neural structures that are also central to the CAN: the extended amygdala, hypothalamus, periaqueductal gray (PAG), ventral pontine tegmentum, ventral and dorsal medulla, vagal and sympathetic nuclei, and spinal cord [49].

The hypothalamus (paraventricular nucleus) plays a major role in arousal by increasing sympathetic viscereomotor tone and in striated muscles of the somatomotor nervous system. The body becomes prepared for action by vasoconstriction of blood vessels to the salivary glands (dry mouth) and tension one in the laryngeal muscles of the back. Smooth and striated

muscles contract, heart rate and respiration accelerate, and posture is stabilized [49].

sports preperformance preparation (e.g., [44]).

**3.5. Executive control of attention and defense**

Fear is an emotion caused by the cognition that a stimulus perceived in the environment is dangerous, threatening, or likely to cause pain. Fear causes a change in brain and autonomic system, and ultimately a change in behavior, such as running away, hiding, or freezing.

Heart rate (HR) conditioning in rabbits (*Oryctolagus cuniculus*) is a widely used model of classical Pavlovian fear conditioning of autonomic responding. Acquisition and retention of conditioned bradycardia (deceleration of heart rate) in the rabbit is useful because the rabbit is a species considered by many as an ideal intact preparation for the study of neural mecha‐ nisms of associative learning, and in particular, cardiovascular conditioning. The neural mechanisms underlying HR conditioning have been widely researched in rabbits and other species including humans, with studies concentrating on vagal‐mediated, parasympathetic cardiovascular changes, sympathetic‐mediated changes, emotional/affective learning compo‐ nents involving the amygdala and prefrontal cortex and extrapyramidal system including some but not all cerebellar structures [50].

Up until his death in 2011, Donald A. Powell was for decades a leading researcher in classical (Pavlovian) conditioning of autonomic and somatomotor function and the founder of our laboratory. His major findings (summarized below) continue to guide the work in our laboratory at the present time. A fear conditioning paradigm was used to concomitantly condition autonomic (cardiac adjustments) and somatic (eyeblink) function [51]. This approach was applied to a classical conditioning model of PTSD in veterans and a parallel translational lesion model of conditioning in rabbits [52, 53]. Dr. Powell's research elucidated two separable neural circuits with different fear conditioning parameters: the cortico‐limbic circuit control‐ ling autonomic conditioning and an extrapyramidal neural circuit controlling skeletal, or somatomotor, conditioning.

Lesions of substantia nigra prevented acquisition of the eyeblink conditioned response and had no effect on conditioned bradycardia [54, 55]. While medial prefrontal cortex (mPFC) is not critical for acquisition of somatomotor conditioning [56], post‐training lesioning of mPFC impaired performance of the conditioned eyeblink response [57–59]. Moreover, while deep nuclei of the cerebellum are understood to be necessary for eyeblink conditioning [60], manipulation of this extrapyramidal substrate does not affect heart rate conditioning [61].

In contrast, lesion studies demonstrated that conditioning of autonomic cardiovascular control requires intact function of a cortico‐limbic circuit [62, 63]. Acquisition of conditioned brady‐ cardia in the rabbit is dependent on a prefrontal‐amygdala pathway, and the major structures in this pathway are medial prefrontal cortex [64–66] and central nucleus of the amygdala. Interestingly, subiculum of the hippocampus was not found to be necessary for acquisition of conditioned bradycardia in this paradigm [67]. Furthermore, autonomic cardiac conditioning is rapid compared to somatomotor eyeblink conditioning. In animals, conditioned slowing of heart rate was shown to occur within the first 3–5 conditioning trials, whereas eyeblink conditioning requires many more trials, in the range of 50–60 [68]. Similarly, heart rate conditioning in humans was more quickly acquired with shorter interstimulus interval than eyeblink [69]. At the single neuron recording level, mPFC processing of stimulus information appears to be driving decelerative heart rate‐conditioned responding [70].

Since the same set of stimulus contingencies will classically condition both autonomic function and somatomotor behavior, the existence of a process that integrates the two would be expected. The septo‐hippocampal system may be the brain circuit that performs this activity. Extinction of classically conditioned bradycardia is delayed by vasopressin, which increases peripheral vascular resistance and arterial blood pressure, a result that seemingly increases the autonomic conditioning cortico‐limbic circuit to include hypothalamus and pituitary [71]. Intraseptal injection of the antimuscarinic anticholinergic scopolamine in the concomitant autonomic and somatomotor conditioning paradigm enhanced cardiac deceleration and impaired eyeblink conditioning [72]. Thus, there may be a central border zone cardiac‐somatic linkage [39] that couples and uncouples cortico‐limbic (stimulus registration and appraisal) from neostriatal (response selection) activities [73]. More research is needed in this area to integrate these crucially important past and current constructs of arousal, attention, and behavior.
