Spinal visceral afferents are not morphologically different from somatic afferent neurons with cell bodies in DRGs. However, they might differ by their spinal cord pathways and a number of additional functions. These are local efferent and trophic roles, both related to antidromic transport and release of chemicals and mediators via the afferent terminals to the innervated cells to influence visceral activity. Vagal visceral afferents show a great deal of diversity and coding strategies in respect to the organs these neurons serve [17–20]. The conventional view is that nociceptive information does not get transferred via fibres within the vagus nerve. However, there are data supporting participation of vagal afferents in pain directly and indirectly. The latter might include interaction with sympathetic afferents at the cervical level [21], by inhibition of nociceptive dorsal horn activity, or by mediation of unpleasant symptoms (like nausea and bloating) which can exacerbate the pain experience. It is important to note that pelvic organs receive afferent innervation from two sources, both lumbar and sacral outputs. This list of possible mechanisms of visceral afferents

in pain transmission and modulation is not exhaustive. The majority of evidence is based on animal studies, but due to high level of phylogenetic conservation, the majority of anatomical and physiological data could be applied to humans.

#### **3.2 Ascending spinal cord tracts and vagal projections**

The complexity of the afferent part of ANS is not fully discovered. New research emerges every year clarifying some and giving start to new questions. However, the situation with ascending autonomic spinal cord pathways is even more perplexing. The confusion comes from traditional descriptions of the ascending sensory pathways, including:

For the purpose of this chapter, we allocate the highest significance to destination of the tracts and interconnections to other pathways. The latter feature enhances sensory experience and responses, including neuromodulating functions. It would be also useful to pay attention to evolutional order of appearance. Here we are not going to talk in detail about anatomical position and laterality. We will briefly mention this information only for selected pathways, as it is important in relation to accessibility by pain relieving interventions (their successes or failures).

Studies of nociceptive ascending spinal cord pathways confirmed existence of a large group of tracts. Not all of them end up in the brain cortex, many relay information to various areas of phylogenetically older parts of brain. Activation of these areas together with cortex centres contributes to multidimensional pain experience and its chronicity.

Fibres making the shortest (oligosynaptic) way to the cerebral cortex belong to relatively young structures (found in higher mammals), hence, forming the lateral spinothalamic (neospinothalamic) tract. It is monosynaptic on the segment to thalamus and, therefore, the fastest one. It brings sharp and well-localised sensation (small receptive fields) with a definitive quality (burning, stinging etc) of various intensity. These signals reach out to the somatosensory cortex; therefore, alert and warn consciousness. Neospinothalamic fibres are somatotopically organised (in all connections and at all levels), crossing to the opposite side in the spinal cord, and carry only somatosensory (not visceral) nociceptive information.

The older parallel tracts, named paleospinothalamic and archispinothalamic, include one or more synapses before thalamus. They make extensive connections to brainstem and other brain structures, lack somatotopic arrangements, target internuclear

thalamus nuclei, and start subconscious autonomic and descending neuromodulating reflexes. These pathways tap into the affective dimension of pain experience.

Autonomic nociceptive signals travel via older tracts. Primary autonomic sensory neurons converge their input on the next neuron together with somatosensory afferents. This happens in the grey matter of the spinal cord. Viscero-somatic wide dynamic range neurons take input from large diameter (myelinated skin afferents) and smaller (myelinated and non-myelinated skin and deep tissue afferents) and primary visceral afferents. Visceral, as well as somatic, nociceptive information (via convergent neurons) could be transmitted via multiple pathways:

Majority of the above anatomical discoveries were done with fine antero−/retrograde tracing techniques on animals (rats, cats, and monkeys) but often the results are transferrable to humans because of high level of phylogenetical conservation. The more recent studies revealed the presence of direct tracts connecting spinal cord with cortex and subcortical telencephalon bypassing thalamus.

The significance of simultaneous activation of parallel oligo- and polysynaptic ascending nociceptive pathways is not fully researched; however, we can appreciate its contribution to vivid reality of pain or pain relief in everyday life. This is also important prediction of outcome (and duration) of pain-relieving ablative procedures [22].

The above-mentioned ascending (relaying visceral nociceptive information) tracts project signals further by connecting to RVM, DRt, pontine noradrenergic groups, the hypothalamus, amygdala, the ventrolateral medulla VLM, the NTS, the rostral ventromedial medulla, PBN, the PAG, the thalamus and cortex (parietal somatosensory, prefrontal, frontal motor, orbital and cingulated). Majority of these destinations are parts of ANS. Some of the descending circuits which originate from PAG, DRt and some other centres exhibits suppression and facilitation at spinal cord synaptic sites of ascending tracts.

Visceral pain is also transferred by midline postsynaptic dorsal column (PSDC) pathway. The axons of PSDC neurons transmit pelvic visceral nociception, they travel uncrossed in the dorsal column. The primary termination of the visceral input of the PSDC cells is the dorsal column nucleus. Pelvic visceral cancer pain responds to limited or punctate surgical midline myelotomy, thoracic visceral pain—to a lesion at the lateral edge of the gracile fasciculus, and experimental pancreatic pain to complete bilateral lesion of the gracile fasciculus [23, 24].

#### **3.3 Central ANS**

As discussed earlier, ascending ANS spinal cord tracts project to many brain locations and, therefore, are capable of production of multiple effects including

#### *The Role of Autonomic Nervous System in Pain Chronicity DOI: http://dx.doi.org/10.5772/intechopen.112154*

descending pain control. Although, autonomic nociceptive pathways do not directly influence somatic pain, both systems meet at the spinal cord level (when primary afferents converge). Non-discriminative somatosensory nociception shares (phylogenetically old) pathways with visceral afferents and, therefore, highlight the same areas of the brain. Central and, therefore, efferent parts of ANS might be involved in visceral and at the same time in somatic pain due to such overlap. This is also reflected in the fact that "Pain Matrix", network of brain centres responsible for pain processing shares key areas with the ANS.

The traditional take on these relationships is that the ANS passively responds to acute or chronic pain. Observers measure a shift of autonomic balance between sympathetic or parasympathetic tone using heart rate variability (HRV) or other tests (sudomotor activity, muscle sympathetic activity etc) or simply vital signs (heart rate, rate of breathing). We consider this topic is largely uncovered and deserves more attention.

The ANS governs body functions and influences mental state, emotions (conscious and subconscious phenomenon) and feelings (conscious phenomenon). Its centres include those of forebrain (insular and anterior cingulate cortex, amygdala, hypothalamus) and brainstem (PAG, PBN, NTS, VLM and some other parts of medulla). There is a fast-growing body of publications showing the complex relationship between pain conditions and activity of ANS centres [25]. There are many examples of this co-existence in people with diseases of various systems: cardiovascular [26]; respiratory [27, 28]; digestive [29, 30]; genitourinary [31, 32]; immune [33]; thermoregulation [34]; cerebral circulation and headaches [35–37]; sleep and circadian rhythms [38, 39]. Many of the above publications and similar are observational studies (and rarely prospective) or reviews. It is difficult to say if chronic pain was the reason for recorded changes or if pre-existing disturbances in ANS functions created vulnerability to chronic pain.

We would argue that in real life, disturbing and disabling chronic pain cannot develop without disorder of ANS control. Disturbed autonomic functions and chronic pain are in reciprocal relationship often with positive feedback: chronic pain might be a reason for autonomic symptoms and developed symptoms might reinforce and facilitate duration of pain, and they usually trigger and exacerbate each other. Therefore, frequently pre-existing autonomic derangement (even mild) due to lifestyle or any other reasons makes people more vulnerable to development of chronic pain.

#### **3.4 Efferent ANS**

In many sources, the ANS is considered a binary structure with sympathetic and parasympathetic divisions. For simplicity of teaching, the efferent output of the ANS is divided into craniosacral (parasympathetic) and thoracolumbar (sympathetic), with opposite effects on target organs. However, this is true only for a few targets; many internal organs, glands, skin structures and blood vessels are innervated only by one division. If both divisions are involved, they do not produce opposite responses (stimulation vs. suppression) or each branch functions under different conditions. So, the correct view is that ANS divisions work synergistically to provide stability of the internal environment and provide with the adaptive responses for internal organs and somatic structures.

The anatomy of the efferent ANS is more complex than that of the somatic motor system. It has preganglionic segments, ganglions, and postganglionic motor neurons. Detailed structure of the efferent ANS is well described in the literature. We will touch only upon its relevance for CP development and perpetuation.

A vital point supporting our view is based on the involuntary reflexes which are delivered by autonomic efferent fibres to visceral and somatic targets. The afferent information for this activity comes from visceral or somatic sources, but the central nuclei belong to the ANS. Physiological reflexes might change under pathological conditions as well as the homeostatic control of internal organ functions. This could lead to a variety of symptoms and painful conditions. These changes might replace the original programs and become chronic through learning and neuroplasticity mechanisms. Altered function (i.e., bowel contraction, acid production or abnormal blood supply) might cause more pain and unpleasant sensations perceived through the ANS.

Pain inherently boosts pathological neuroplasticity through reinforcement learning where the insula plays an important role [40, 41]. The underlying mechanisms could negatively affect physiological training-induced neuroplasticity in physical tasks [42]. However, the precise effect of pain (acute, experimental, or chronic) on motor skill learning is the subject of debate as no strong evidence has been provided by research [43]. The longer the duration of reflex changes, and of pain, the more complex the situation becomes and the more challenging and less successful treatment is. At some point, the pain condition reaches an irreversible phase [44], when treatment pursues palliative outcomes.

Examples of altered reflexes affecting visceral organs could be Irritable Bowel Disease (IBS), where pain is linked to abnormal gut motility, or urinary bladder conditions, when disturbing symptoms of urgency, incontinence and spasms convolute with pain. As for somatic organs affected by pathologically-changed autonomic reflexes, (e.g., skin thermoregulation) the afferent part is mediated by somatosensory afferents, but the central control (hypothalamus) and efferent output (sudomotor, vasomotor and pilomotor nerve fibres) is provided by the ANS [45].

Recent research has revealed an interesting relationship between autonomic and somatic neurons, which might explain muscle weakness in certain painful conditions with altered sympathetic outflow to muscles, for example CRPS. Sympathetic efferent fibres innervate neuromuscular junctions and are vital for maintenance and function of synapses between somatic motor nerves and muscles [46, 47].

In *The Senses: A Comprehensive Reference, Second Edition (2020)*, chapter 5–21 [48] possible means by which the sympathetic nervous system could influence CP in somatic tissues are summarised. These are as follows: sympathetic-somatic afferent coupling; sensitisation of somatic nociceptors; neurogenic inflammation; and central changes in sympathetic pathways with the release of a variety of neuroactive substances and participation of neuroendocrine system. Earlie, Prof Jänig [49] discussed sympathetic (other than sudo−/pilomotor or vasoconstrictor) innervation of skin and deep somatic tissues, including muscles (vasodilators) and bones (peptidergic neurons, probably affecting mineralisation).

ANS involvement in musculoskeletal pain was investigated on the model of delayed onset muscle soreness (DOMS). Fleckenstein *et al* set out to discover to what extent sympathetically mediated pain (SMP) is responsible for exercise-induced acute muscle pain or damage in the upper limb [50]. They found that sympathetic regional (stellate ganglion) blockade causes pain relieving and anti-inflammatory effects. They suggested mechanisms for these effects which outlasted local anaesthetic block. These could be due to interruption of the vicious cycle of pain and local reflexes [51], allowing a reboot or a change in cytokine profile from pro- to anti-inflammatory [52]. There is also a possibility of changing of sympathetic and parasympathetic balance secondary to regional sympathetic outflow interruption. In fact, these effects might

follow any peripheral neural injection as autonomic fibres will always be affected by local anaesthetic due to the abundance of peripheral ANS fibres, as it was mentioned above.

*Conclusion:* Complexity (of all parts) and ample presence of the ANS; interconnections within and with the SomNS; active control of body functions (involved in pain mechanisms), emotions and behaviour; neuroplasticity of reflexes support evidence of global and fundamental role of the ANS in pain development and chronicity.

#### **4. Epidemiology**

Epidemiological studies have highlighted the prevalence of different pain conditions and their risk factors. Despite ongoing research, some of these facts (e.g., uneven gender distribution, drug sensitivity with therapeutic response, associations with other diseases) are difficult to explain. ANS imbalance might be one of the reasons we overlook.

Gender difference in pain prevalence, sensitivity and analgesic response has been reported in the literature [3, 53]. Women experience more severe pain and report it more frequently. They develop pain in more anatomical sites and for a longer time, with a higher prevalence across the majority of pain conditions. But some painful disorders are strikingly more frequently seen in women: fibromyalgia; pelvic and musculoskeletal pain; and temporo-mandibular joint pain amongst others. This is routinely attributed to genetic factors, sex hormone profile and cyclical changes in serum concentrations, tissue nerve density, and psychological factors, but rarely to ANS input.

Previous research has shown that women have a prevailing parasympathetic tone whereas men have a prevailing sympathetic tone. This difference disappears after the age of 55 years [54]. Sympathetic system activation has been reported in CP states. We do not know how the parasympathetic division contributes, but this certainly involves complex, multilevel and non-linear interrelationships between the sympathetic division and other determinants.

One of the conditions which is three to four times more common in females is complex regional pain syndrome (CRPS). Reported risk factors for CRPS include: history of migraine; osteoporosis; asthma; and angiotensin converting enzyme (ACE) inhibitor therapy. The latter two are associated with parasympathetic predominance, but osteoporosis is considered more related to sympathetic activation [55].

Neurotransmitters are used in experimental research to obtain strong evidence on the mode of activity of ANS structures in question. Drugs which we prescribe for treatment of any illness might intentionally (indication) or unintentionally (sideeffect) shift the balance between autonomic divisions. This is mediated through direct or indirect effects on adrenal and acetylcholine receptors in peripheral or central ANS. For instance, many antihypertensives suppress sympathetic outflow, whilst some antidepressants block and some opioids stimulate cholinergic pathways. Thus, treatment of comorbidities might affect pain conditions and vice versa. This is also important when pain-relieving drugs are chosen for a particular individual.

Time course of chronic diseases corresponds to constant changes which the ANS undergoes due to ageing, adjustment to climate, food habits, physical activity and many other factors. For example, asthma is more prevalent in boys, but later in life becomes more prevalent in women. This probably is due to a shift in autonomic balance which affects ANS airway control.

*Conclusion:* When we assess a case of CP it is essential to understand how it is related to excess or insufficient activity in each ANS division. This might influence our choice of drugs, interventions and other treatment methods, as well as help prognosticate. Coexisting medical conditions might give us a clue about autonomic balance and its dynamics, however, future research with appropriate questions and a fresh view on the problem might shed more light on the matter. The role of the parasympathetic system in developing CP has not been fully elucidated.

#### **5. Pathophysiology**

Practice makes perfect. This maxim is fully applicable to ANS design and functioning, but it requires a few clarifying comments. The ANS functions according to inherited programs (reflexes), and by learned behaviour patterns, which are established and maintained since birth and childhood [56]. This is achieved through learning by continuous feedback from internal and external environments, and neuroplastic changes which strengthen the neural circuits. Training of the nervous system is ongoing; it happens with or without our conscious acknowledgement and regardless of its value for the individual: regularly used activity gets reinforced; unused gets forgotten. For instance, one can develop insomnia when sleep routine is regularly disrupted by shift work or chaotic lifestyle. However, reintroduction of sleep hygiene will assist restoration of normal night sleep patterns. The same principle is employed in biofeedback bowel [57] or bladder training [58] for certain ANS disorders. In this subsection we discuss a few important consequences of autonomic dysfunction which impact on chronic pain development.

Any medical condition is associated with disturbed function of one or another organ, and therefore, with the disturbance of autonomic regulation of the corresponding physiological system. The opposite statement is also true: disturbed autonomic regulation will cause symptom development (into a medical condition) or prevent recovery from a condition-inducing event. This could be applied to acute pain as a symptom of a condition in question, or to chronic pain as a disease on its own.

A degree of autonomic disturbance might vary with different types of pain, the part(s) of nervous system involved, and anatomical region(s) affected. ANS dysfunction can be of local or global significance, and of mild or more severe presentation. We can associate diseases limited by anatomical region with the corresponding typical pain picture, but systemic medical conditions (e.g., diabetes, cardiovascular and lung diseases, rheumatoid arthritis, sickle cell disease) contribute to many chronic pain states. That is why the situation with diagnosis of disease causation and with recognition of factors leading to pain chronicity is not straightforward. Traditionally, abnormal ANS function and its diagnosis is overlooked in many (especially somatic) pain states, therefore the prescribed treatment often addresses only local symptoms, rather than pathophysiology of the underlying mechanisms.

For many chronic diseases we should recognise a reversible preliminary phase with subtle signs, which are usually below the threshold of current medical tests. Over a period of time autonomic regulation becomes progressively abnormal, but due to built-in robustness of the ANS, clinically significant deviation from medical norms might manifest years after. The preliminary phase is not usually identified, and underlying issues are not corrected. Partially this is because subclinical signs do not fall into pathological zones, but rather into domains of fitness or risk factors. This is a field of preventive medicine which, unfortunately, is largely unfamiliar to the general

public. The quality of life at this stage deteriorates slowly and patients usually adapt to these changes without noticing the ongoing problem.

The important question at this stage is whether a single organ autonomic dysfunction develops in isolation in a particular chronic pain state, or whether it is always a part of the more systemic trend. The diagnostic value of many available tests of ANS status in pre-clinical phase and in even in mild cases is questionable. Their results are frequently reported as negative (or mildly abnormal) as often subjective severity of symptoms of ANS dysfunction do not match objectively measured parameters [59].

From our clinical observations when patients are convinced that their symptoms fit into a picture of Postural Orthostatic Tachycardia Syndrome (POTS), interstitial cystitis or CRPS but investigations do not support their perceptions our attempts to reassure them often fail. At that point our misunderstanding of the situation, broken relationship with patient, and lack of tests with higher resolution or sensitivity (they define disease criteria) leads to delayed diagnosis and treatment. On the other hand, labelling patients with the above diagnoses without sufficient evidence may medicalise them for life and prevent recovery. This unfortunate dilemma is one of the innate weaknesses of medical practice. It is triggered by the patient's suffering from severe presenting symptoms.

The definition of suffering according to the Oxford English Dictionary is as follows: "the state of undergoing pain, distress, or hardship". In CP all three entities pain, distress and hardship—are intertwined, making it difficult to address them. The relationship between chronic pain, distress and hardship is well recognised. It dwells in emotional, social, and behavioural domains, and often is maintained by general symptoms (fatigue, chest tightness, mental fog and memory disturbances, sleep disorders and many others).

Sometimes the above constellation of symptoms is explained as an affective component of pain (linking it to the use of the old somatic nociceptive pathways), which is only partially true, as in fully developed CP we deal with neuroplasticity of nervous system where the ANS is responsible for many of these consequences [60–62]. Supporting evidence from research shows sympathetic hyperactivity in mental fatigue [63], significant and substantial ANS role in memory consolidation during sleep [64], association of mental fog and autonomic hyperarousal [65], abnormal autonomic sleep regulation in CP [66], and activation of autonomic pathways for chest pain and dyspnoea [67].

When medical professionals meet distressed patients who do not have clearly visible pathology which could explain the high degree of suffering, they often refer to these cases as those with functional (neurological) symptoms. However, many of these 'unexplained' symptoms could be due to disorganised activity of the ANS. We support the idea that suffering in CP could not happen without inherent participation of the ANS. This is because of a few reasons. ANS reaction to any pain or insult is inseparable to pain, even if pain is of somatic origin. Chronicity of pain and suffering is always at least partially driven by local or global dysfunction of the ANS. This includes control by emotional and behavioural centres, and often is not related to the severity of the index trauma.

CP patients develop maladaptive emotions and demonstrate changed behaviour. This includes poor coping and passive [68] strategies, fear-avoidance, and lack of motivation to invest efforts for their recovery, and social withdrawal. The ANS plays an important role in these changes. An experimental study [69] demonstrated that visceral pain response might relate to personality type, and it discovered sympathetic and parasympathetic co-activation in response to somatic and visceral pain. It is well known that the longer the chronic pain condition lasts and the more prominent are the patient's passive approach, sick role, and other maladaptive psychological trends, the worse these features become, and patients with these symptoms are less likely to improve.

Finally, we should not forget that autonomic dysfunction in control of inflammation and immunity [33, 70–72], endocrine system [48], circadian rhythms [39, 73–77], tissue regeneration [78–80], including ANS itself [81] also contributes to chronic pain development and its chronicity.

*Conclusion:* The reciprocal relationship between pain and ANS control of involuntary body functions, emotions, behaviour and body regeneration makes the ANS an integral and indispensable player in a drama of CP. The earliest phase of autonomic dysfunction is not recognised and corrected.

#### **6. Diagnostics**

In this subsection we review diagnostic investigations currently available for assessment of ANS activity and discuss their limitations. We also describe potential tests (based on autonomic features) which might be applicable for pain assessment.

Heart rate variability (HRV) is one such non-invasive tool which is used in lab research, for diagnostic purposes, or in everyday life to monitor cardiorespiratory fitness. HRV employs electrocardiography (ECG) or plethysmography (PPG) for measuring distances between electrical heart complexes (or beats) over a period of time. The raw data obtained from ECG or PPG are calculated into various indexes which (as per convention) might describe activity of ANS branches.

Although HRV uses cardiac electrical activity for calculations, it shows not only good predictability of mortality in the heart conditions, but also demonstrates abnormalities in ANS performance in many diseases and pain states. However, HRV is not condition-specific. Additionally, there is no validated scale that can diagnose a degree of autonomic dysfunction in a particular illness.

HRV is a cheap, easy to use and widely accepted tool. For a full analysis it requires only a budget peripheral wearable device and a smartphone application. The analysis is based on mathematical calculations: descriptive statistics for time domain and spectral analysis for frequency domain. The latter uses the term "power" in relation to the energy within a particular frequency band, which should not be confused with biological "strength" of ANS divisions.

We do not know what the power of the ANS is and how to physically measure it. With HRV we might see a snapshot of the balance between sympathetic and parasympathetic activity. Whether this balance is on proportionally suppressed or enhanced divisions it is not possible to say. Furthermore, autonomic activity might be disturbed only in one organ or system, or in case of global autonomic failure, different organs might be affected unequally. These points should be taken into consideration when interpreting a HRV report in relation to a particular pathology.

There have been attempts to match HRV with organ-specific physiological activity. For instance, by parallel measurement of HRV and of high-resolution manometry of colon [82]. This experiment showed parasympathetic activation and sympathetic withdrawal during triggered propulsive colonic activity.

Clinical tests require laboratory conditions for measurements, calibrated and medically certified equipment, and professional interpretations. These tests investigate a single organ or a system specific autonomic dysfunction, but they are often invasive and might require anaesthetic input. For example, those used in cardiovascular medicine (e.g., tilt table test with plasma catecholamine concentration measurement), in urology

(e.g., urodynamic tests), neurology (e.g., skin biopsy for nerve fibre density, nerve conduction studies, sudomotor activity and recordings of muscle sympathetic nerve activity), gastroenterology (e.g., gut motility, food transit, bacterial overgrowth).

Non-invasive options include disease specific questionnaires for organ function and thermography, a measurement of the surface temperature from the distance by thermal camera. The latter is useful in diseases with local change of blood supply, like in vascular abnormalities (vessel stenosis or arterio-venous malformation), regional sympathetic activity suppression (disease or local anaesthetic injection) or its excess (Raynaud's or iatrogenic). CP conditions which manifest with skin temperature changes include CRPS, neuropathic pain with neurogenic inflammation, ischaemic pain and some others [83].

Pupillometry (PPM) is another window into ANS activity. The size of the pupil depends upon the rhythmical activity of a sphincter (parasympathetic control) and dilator (sympathetic innervation), triggered by the amount of light reaching the retina. Despite a growing body of research in anaesthesia and acute perioperative pain management which use PPM for assessment of pain [84, 85] and drug effects, the utility of this non-invasive method has not been fully established.

Facial expressions (FE) and emotion recognition is a complex field (the ANS plays a major role in it) where stable prediction is not technically achieved. FE have been used in acute pain assessment for a long time, but not in CP. Computer vision techniques often employ facial action coding systems (FACS) which detect face geometry and movement patterns [86, 87].

We suggest that in CP sufferers, FE could be used to assess the effect of painrelieving intervention. According to clinical observations (unpublished data of the first author—DK), successful interventions in cancer pain dramatically change the quality of FE. For example, if a patient smiles before a procedure, it looks unnatural, forced or laboured. When the pain is relieved by intervention the smile becomes more natural with genuine facial mimic. This is a promising area for research of the role of the ANS in CP and pain relief with an objective and quantitative outcome.

Parameters of voice and of speech change under stress, emotional and cognitive load, pathological conditions and via ANS influence [88, 89]. A few voice-forming and modulating muscles are innervated by autonomic motor nerve fibres. Voice analysis could be used for monitoring of therapy and prediction of deterioration during the course of disease [90]. It is becoming more popular for pain assessment with the arrival of Artificial Intelligence (AI) based software [91].

*Conclusion:* Testing ANS state is essential in CP management; it demonstrates universal autonomic participation in CP. Clinical tests could be condition-specific, but invasive and demanding (equipment, staff etc.). Non-invasive methods are becoming more available for personal use (HRV, thermography), but some are still under-developed (pupillometry, facial and voice analysis). The resolution of existing tests is still low for the early recognition of pathology. Tests give a cross-sectional view (snapshot) on the condition but cannot provide longitudinal data for the evaluation of underlying pathophysiology. The latter could be addressed with the use of wearable multi-modal biosensing systems [92, 93].

#### **7. Treatment**

This section bears a dual purpose. It speculates on how the ANS could shape the outcomes of conventional pain-relieving procedures, and highlights the potential therapeutic interventions for disturbed ANS control. We discuss peripheral nerve blocks, epidural blocks and neuromodulation.

 Unfortunately, pain returns if nerve blockade fades away. However, for post-operative analgesia significantly lower concentrations of LA than for surgery are required as there is no ongoing tissue damage.

In CP an injection of Lidocaine (LA) could provide a relieving effect of significantly longer duration (sometimes for several months or years) than the length of the nerve block [94].

First, we would like to describe thoracic differential epidural (TDE) blockade which is used as a diagnostic tool for abdominal pain to discriminate between somatic, visceral or central pain, and to predict response to visceral nerve block [95]. This intervention exploits two facts: smaller diameter visceral nociceptive afferents are blocked by a lower concentration of LA; and pain relief in visceral pain lasts longer than anaesthetic block duration [96]. This intervention showed that in many patients with pancreatitis, pain is of somatic nature [97].

Using the example of TDE, we might generalise that the therapeutic effect of epidural or peripheral nerve injection (beyond the LA duration) for musculoskeletal (somatic) pain could be due to concomitant sympathetic blockade.

Spinal cord stimulation (SCS) can provide pain relief and improvement of other symptoms in visceral and somatic pain by neuromodulation of various targets within the spinal cord. For example, SCS for refractory abdominal pain can improve chronic nausea and vomiting [100]. For neuropathic visceral abdominal pain, clinicians target the upper-mid thoracic level where splanchnic nerves emerge from the spinal cord. Improvement of gastroparesis and intestinal motility is highly suggestive of sympathetic blockade produced by SCS. However, available studies do not demonstrate consistent ANS reaction to SCS in sudomotor activity [101], heart rate variability (HRV), baroreceptor reflex sensitivity (BRS) and muscle sympathetic nerve activity (MSNA). Nor do they provide a plausible hypothesis for mechanisms of pain relief related to autonomic control [102]. This is another important area for future research.

Similarly to SCS, sacral nerve stimulation (SaNS) for pelvic organ dysfunction (bladder and rectal control) can also result in improvement in pain control [103] related to treated conditions.

Percutaneous tibial (somatic peripheral nerve) nerve stimulation (PTNS), which is used to improve urinary bladder control in Overactive Bladder, is an effective and minimally invasive technique [104]. It requires multiple sessions to achieve prolonged effect. PTNS also relieves chronic pelvic pain [105]. The mechanism of action is unknown but clinically it improves autonomic reflexes of the targeted organs. We can speculate about two possibilities:

Percutaneous or surgical vagal nerve stimulation has been suggested for many conditions caused by or associated with autonomic dysfunction [106–112], but the main indications are refractory epilepsy and certain mood disorders.

Non-medical options to maintain healthy ANS activity, which frequently involves parasympathetic stimulation and sympathetic withdrawal, include:

*Conclusion:* When planning pain-relieving interventions, healthcare professionals should consider treatment of underlying ANS dysfunction.

#### **8. Traditional medicine (TM)**

Traditional medical practices always acknowledge the complex relationship between organs and somatic tissues. It is reflected in diagnostic methods and in the holistic approach to treatment.

One of the unique methods used by many systems is the pulse diagnostic tool. It requires years to master but is claimed to provide invaluable information about any organ in the body. In general, it is probably an ancient equivalent of HRV, but much more sophisticated in the amount of detailed information it might provide an experienced practitioner.

Many traditions use a quasi-anatomical system: a whole-body map covered with lines or meridians (channels or vessels) with named points with very precise locations. The 'vital energy' freely flows through these structures controlling the activity of different physiological systems (lungs, bowel, liver, stomach etc.). There are 12 principal meridians in Traditional Chinese Medicine (TCM). There is no equivalent concept in western medicine.

The 24-hour biorhythm cycle allocates time of the highest and of the lowest activity to each channel. For example, the first meridian (Lungs) is the most active between 3 and 5 AM and 12 hours later (3 and 5 PM) it is in the lowest energy state. This circadian clock schedule correlates with clinical observations. For instance, maximum activity in the lung meridian corresponds to the peak of nocturnal asthma attacks. Maximum activity of the second meridian (Bowel) falls between 5 and 7 AM when people wake up after the night sleep and open their bowel. The next meridian (Stomach) is the most active when people normally have their breakfast, between 7 and 9 AM, and so on.

Abnormal flow of 'energy' (deficiency or excess and blockage) in one or more channels is the reason for symptoms of disease. Needling of the points according to the acupuncture recipe restores 'energy' flow and cures the disease and relieves pain (Yuan 2015). The choice of acupoints depends on the diagnosis, biorhythms and relationship between meridians. For example, neck and shoulder pain could be related to abnormal energy situations in gallbladder, bladder or large intestine meridians. Points could be chosen on these meridians or on others (via laws of relationship), around the painful area or distant to it; and they vary on a different time or day.

There are, of course, other than acupuncture treatment methods in TM: medications, breathing practices, postures and movements. The latter two could be organ

specific, and they are synchronised with breathing to optimise vital energy and its circulation.

*Conclusion:* TM uses a holistic approach. It operates at the levels of aetiology and pathophysiology rather than symptoms as western medicine does. Similarly to the ANS, the Meridian system functions according to biological rhythms and connects organs and somatic tissues (skin, muscles, bones, ligaments and joints).

#### **9. Conclusion**

CP is considered incurable as per current beliefs, personal experience of medical professionals and statistics. So, in a pain clinic, in the media and in professional literature, patients once diagnosed with CP receive the same message, they have to live with it. The present situation is maintained by the ignorance of already known facts. However, progress is being fuelled by breakthroughs in related fields across multiple disciplines. We propose that pain becomes chronic through significant input from the ANS. Autonomic dysfunction (subclinical or apparent, local or global) provides the background for suboptimal organ activity and subsequently leads to the development of chronic symptoms, including pain, or the transition from existing acute pain into CP.

We would like to bring attention to the mind-blowing complexity and ample presence [48, 49, 121] of the ANS in our lives, as well as to its important role in CP and pain chronicity. This chapter serves only to outline a topic which could easily fill a whole book and warrants ongoing research. Current evidence from evolutionary biology, anatomy, epidemiology, pathophysiology, diagnostics, and pain medicine (western and traditional) supports our view and paves the way for future work. However, even now, people might change their view on the topic and this could lead to improved outcomes in CP management. Therefore, the main takeaway message is that we have to seek the signs of ANS dysfunction in any CP condition and address the underlying mechanisms.

### **Conflict of interest**

The authors declare no conflict of interest.

*The Role of Autonomic Nervous System in Pain Chronicity DOI: http://dx.doi.org/10.5772/intechopen.112154*

#### **Author details**

Dmitry Kruglov1,2\* and Dermot McGuckin1,3

1 Pain Management Centre, National Hospital for Neurology and Neurosurgery, London, UK

2 University College London Hospital, London, UK

3 Research Department of Targeted Intervention, Division of Surgery and Interventional Science, University College London, London, UK

\*Address all correspondence to<EMAIL_ADDRESS>
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**Chapter 4**

## Exploring Cardiac Responses of Pain and Distress

*Mona Elsayed and Elizabeth Barbara Torres*

#### **Abstract**

Pain and distress stand at the intersection of multiple health crises and are leading contributors to disability. Current pain assessments rely on self-reports—which assume a capacity to understand and verbalize mental/emotional states—and behavioral observation which can be subject to limitations and misinterpretation. Methods to evaluate pain/distress can be substantially enhanced with biometrics that incorporate the physiological aspects of the full pain experience. This chapter explores how induced pressure pain influences cardiac activity elicited via the autonomic nervous system. We aim to uncover signatures in cardiac responses via personalized analysis of the frequencies and the timings of the heart's inter-beat-interval. Autonomic responses such as cardiac activity serve as inevitable processes, which cannot be volitionally controlled—they exhibit a narrow range of dynamics, helping provide robust signatures of the body's responses to pain/distress. We find that pain elicits shifts in the heart rate variability metrics of the cardiac signal, alluding to changes in sympathetic and parasympathetic nervous system activation. Unique relationships are also observed between metrics obtained from the physiological data and self-reported pain ratings. The implications of this work are discussed in the context of precision medicine with possible applications in clinical populations such as autism.

**Keywords:** cardiac, pain, distress, sympathetic, biometric, ECG, HRV, autism, ASD

#### **1. Introduction**

Pain and distress are intrinsically undesirable experiences that are implicated in a variety of physical and mental illnesses. Pain stands at the intersection of multiple health crises, contributing to the opioid epidemic, health disparities, disability, and chronic pain [1, 2]. At least 125 million Americans suffer from acute or chronic pain, and this epidemic has been the root cause of the opioid crisis that arose in the late 1990s [2]. The increased use and misuse of opioids has led to over 47,000 deaths in the United States between 2013 and 2017 alone [3]. Thus, gaining a complete understanding of the neurobiological underpinnings of pain can lead to the most effective solutions to this epidemic [2].

Pain is yet to be explored and digitally characterized in terms of its effects on the autonomic nervous system (ANS). Aside from potential tissue damage, pain is associated with sensory, motor, cognitive, and social components [1]. Investigating pain thus requires multidisciplinary approaches that can integrate insights from

psychology (behavior, cognition, sensation, perception), neuroscience (nervous system physiology), and psychiatry (social/clinical research). An objective and noninvasive assessment of pain is also yet to be discovered and utilized in the clinical realm.

Traditional self-report techniques to assess pain are useful and convenient in the clinical realm however, they should be complemented with more objective approaches. Current pain assessments rely on surveys and questionnaires such as numerical rating scales, illustrative visual analog scales, and verbal rating scales which rely on semantic descriptors such as 'moderate' and 'severe' [4, 5]. Such assessments often assume the individual has the capacity to understand and verbalize mental/emotional states, making them disadvantageous for minimally verbal individuals or those with disabilities or neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Autistic children may experience difficulties in expressing their internal emotional states (hunger, pain, fatigue, etc.), leading to increased stress, tantrums/outbursts, and meltdowns. While external behavioral measures may be helpful in understanding such states, internal states may easily be masked or differently expressed across individuals, leading to interpretation errors. Thus, evaluating nervous system physiology in such populations can greatly enhance approaches that only rely on self-report measures and/or observing external behaviors.

In this work we evaluate the effect of pain on autonomic cardiac regulation, an inevitable process that cannot be consciously controlled during experimental tasks. The current study ultimately aims to develop digital biomarkers that can be used to detect pain and distress from cardiac activity elicited via the autonomic system. With the advent of wearable sensing technologies, it is possible to track physiologically relevant signals (electrocardiography/ECG) to help assess an individual's autonomic states. This study will utilize a multifaceted approach that investigates the effects of pain on cardiac reactivity in relation to self-reports of pain and pain sensitivity. With ECG sensors, we track the dynamics of heart signals and characterize how pain influences autonomic regulation. Pain-related biosignatures obtained via wearable sensors as the person

#### **Figure 1.**

*Integration of subjective and objective metrics to assess states of pain and distress. (A) Self-reports of pain and pain sensitivity levels are assessed by numeric rating scales traditionally used in healthcare settings to assess pain. (B) Wearable sensors that can track heart signals serve as a proxy for autonomic nervous system activity.*

*Exploring Cardiac Responses of Pain and Distress DOI: http://dx.doi.org/10.5772/intechopen.111890*

experiences physical pain are compared to the results of pain assessments self-reported by the individual. This integrative approach (**Figure 1**) leverages information from the autonomic systems to help in developing a clearer psychophysiological understanding of pain and ultimately aims to create robust techniques to assess pain and distress in those who have difficulty expressing it and in the general population.

#### **2. Cardiac signals as a proxy for autonomic nervous system (ANS) regulation**

Heart activity is under the dynamic control of the sympathetic cardiac nerves and the parasympathetic vagus nerve via the autonomic branches of the peripheral nervous system (NS). The ANS is largely responsible for maintaining the body's overall homeostasis [5]. The sympathetic NS works to increase heart rate while the parasympathetic NS serves as the brakes that turn the cardiac activity back to normal functioning. Sensory neurons between the brain, spinal cord, and cardiac muscles engage in continuous feedback loops, consistently influencing each other via reafferent signals (**Figure 2A**).

Fluctuations in sympathetic and parasympathetic activity can allude to unique physiological responses related to stress and anxiety. Exposure to painful stimuli and/ or discomfort and distress can activate the sympathetic NS which elicits the excitatory fight-or-flight response [6]. Previous studies on stress and autonomic responses such as cardiac reactivities provide insight into the physiology of pain sensation [7, 8]. Heart rate variability (HRV) analyses have proven reliable and advantageous in evaluating autonomic functions in this regard [9, 10]. HRV metrics represent the various statistics of the inter-beat- interval (IBI), the timing between beats in a cardiac signal (**Figure 2B**). HRV is widely used to evaluate sympathetic and parasympathetic

#### **Figure 2.**

*Cardiac responses as a proxy for autonomic nervous system function. (A) The sympathetic nervous system is responsible for increasing cardiac contractions during states of distress/anxiety while the parasympathetic nervous system serves as the brakes on the sympathetic system, modulating cardiac activity during resting states. Parasympathetic activity is guided by the vagal nerve, which governs heart rate variability (HRV) and allows for adaptive behaviors. Sensory neurons via the spinal cord allow for two-way communication between the heart and the brain. (B) Cardiac signals exhibit a unique QRS pattern where the timing between R-peaks (IBI) can serve as a proxy for sympathetic and parasympathetic activity.*

NS activity via various time and frequency-domain parameters. Improper balance between these two systems is often associated with cardiac pathologies such as strokes and heart attacks [9].

Previous work on HRV and stress have shown that when humans experience mental/physical strain, the parasympathetic NS's control over the heart decreases while sympathetic NS activity increases [11–13]. In such studies, physical strain was induced by having subjects perform intensive exercises [12], and mental strain was induced by asking subjects to solve difficult puzzles or arithmetic problems [13]. From these studies we find a clear interaction between the ANS and the nociceptive system as pain may often induce both mental and/or physical strain and distress [5, 6].

#### **2.1 Autonomic dysregulation: social and emotional components**

The autonomic nervous system plays an important role in socio-emotional learning and control [14]. Balanced vagal tone via the parasympathetic NS (responsible for modulating heart-rate) allows for swift engagement and disengagement with people, which is important for building social communication skills [15]. Social skills development during early childhood predicts a range of positive outcomes (in communication, assertiveness, role transitions, etc.) along with the formation and management of family and peer relationships throughout the lifespan [16]. Increased vagal tone is also associated with higher facial expressivity levels [17]. Decreased vagal tone can lead to dysregulated heart-rate (HR) modulation which may in turn lead to social interaction difficulties [15]. Imbalanced autonomic activity can also contribute to socio-emotional dysregulation during dyadic interactions in children diagnosed or at-risk for psychopathologies [18].

Symptoms of ASD are proposed to be associated with autonomic dysfunctions. Previous studies show that children with ASD and Intellectual Disability (ID) exhibit low parasympathetic activity during high anxiety conditions [19]. Autonomic dysregulation is also apparent in autistic children compared to typically developing (TD) controls [20]. When comparing the cardiac and electrodermal activity of autistics and neurotypicals, those with ASD exhibited dampened HR reactivity and skin conductance responses to visual and auditory social stimuli (face images and speech sounds) and during social interactions (role play) [21, 22]. More recent work demonstrated that the non-linear metrics of HRV show decreased autonomic modulation in autistic individuals compared to controls during resting conditions [23]. During facial expression tasks where subjects were asked to draw, interpret, and recognize different emotions, the ASD group showed lower parasympathetic modulation compared to controls, alluding to the elicitation of cognitive stress. Such autonomic dysregulation was also correlated with autism severity [24]. During social attention tasks, autistic subjects similarly showed reduced parasympathetic modulation, suggesting that autonomic dysregulation may underly social deficits in ASD [25].

Such findings are in line with the Polyvagal Theory which suggests that social behaviors may arise from the autonomic nervous system, with efficient vagal/parasympathetic control preventing sympathetic overactivation and thus contributing to better socio-emotional skills [26]. In ASD, the 'vagal brakes' on the sympathetic system may be compromised, leading to sympathetic hyperarousal and increased distress, which may impair behavioral adaptation/control and the ability to satisfactorily reciprocate social interactions [27]. Thus, assessing autonomic modulation may prove useful in understanding social–emotional responses, adaptive behaviors, and ultimately in screening and tracking symptoms associated with ASD.

#### **3. Experimental approach: autonomic biomarkers**

In this work, we explore the cardiac activity of neurotypical (TD) and autistic (ASD) individuals. Autonomic responses were proxied via the electrical activity of the heart. Electrocardiographic (ECG) activity was captured via wearable biosensors placed on the chest at the standardized lead II position via gel adhesives.

At the beginning of the study, TD participants were asked to rate their perceived pain sensitivity (PPS) relative to other people on a scale of 0–10, where zero represents complete insensitivity and a 10 represents extreme sensitivity [28].

Participants were seated at a table where they performed a Resting Task under control and experimental conditions. In the control condition of the study, the participants performed the Resting Task by sitting in a relaxed position and avoiding excess movement for about two minutes. This task was used to establish baseline autonomic NS activity as no movement or cognitive effort was required. During the experimental/pain condition of the study (only conducted with TD subjects), sustained pressure pain was introduced via a manual blood pressure cuff. This pain induction method serves as a modified version of the submaximal effort tourniquet test [28] which is found to mimic pathological pain [29]. In this procedure, the blood pressure cuff (standard sphygmomanometer/tourniquet) was placed around the non-dominant arm of the participant (above the elbow) and was gradually inflated to a pressure level of about 200 mmHg [30]. The cuff was inflated at this level for the entirety of the task and was deflated right after task completion. Right before cuff deflation, TD subjects verbally reported their pain level using a Numeric Rating Scale (NRS) ranging from 1 to 10, where a 1 indicates minimal to no pain, 4–6 indicates moderate pain, and a 10 indicates extreme pain [31]. Participants in the ASD group performed the Resting Task only under the control condition.

#### **3.1 Analytical approach to assess cardiac activity**

Electrocardiographic (ECG) data typically includes consecutive QRS complexes representing each heartbeat in the cardiac signal (**Figure 2B**). The R-peaks (sharp spikes) within QRS complexes are traditionally used to assess the timing between consecutive heartbeats (known as the R-R or inter-beat interval). Accurately detecting R-peaks is essential for assessing the fluctuations in the inter-beat interval (IBI) signal and in computing various heart rate variability (HRV) parameters. ECG signals may easily be corrupted by various artifacts such as baseline wandering and electrode movement [32]. To clean the raw ECG data, signal-processing filters were used to minimize excess noise/frequencies outside the range of a typical ECG recording [33]. After preprocessing of the ECG data, R-peaks were detected via a simple peak detection algorithm in MATLAB (MathWorks) software, and the IBI signal was obtained by computing the time between consecutive R-peaks. The statistics of the IBI signal were then evaluated via various frequency and time-domain metrics.

#### **3.2 Cardiac activity metrics of the autonomic system**

Changes in heart rate are the result of autonomic control via the sympathetic (excitatory) and parasympathetic (inhibitory) nervous systems (NS), which are informative in assessing how pain and distress influence the autonomic system [5]. HRV describes fluctuations in instantaneous heart rate (the oscillations between two consecutive heartbeats), where greater variability often reflects

enhanced vagal tone (heart rate regulation). The activities of the parasympathetic and sympathetic NS can be inferred from the Power Spectral Density (PSD) and Poincaré plots of the HRV signal (**Figure 3**). The high frequency (HF) component of the PSD (150–400 mHz range) is associated with parasympathetic activity and a general decrease in heart rate [34]. The low frequency (LF) component of the PSD (40–150 mHz range) is associated with sympathetic NS activity and blood pressure control [34]. The LF/HF ratio reflects the sympatho-vagal balance – the contribution of the sympathetic NS in controlling the heart compared to the parasympathetic NS [9]. Increases in the ratio between the LF and HF components (LF/HF ratio) have been previously associated with stress and intense exercise [12, 13]. The LF and HF components were computed by integrating the PSD over the associated frequency range.

Poincaré plots are also used to assess sympathetic and parasympathetic activation via time-domain metrics. Pioncaré plots serve as a geometrical and nonlinear method to assess the dynamics of HRV and are formed via a scatter of the IBI interval against the preceding IBI interval [35]. The width of the scatter is used to determine the SD1 parameter, which reflects parasympathetic NS activity and is correlated with HF power [36, 37]. The length of the scatter is used to determine the SD2 parameter, which reflects sympathetic NS activity and is correlated with LF power [36].

The PhysioNet Cardiovascular Signal Toolbox was also used to assess the ECG time series. This open-source toolbox is designed to assess HRV via standardized algorithms [38]. With this toolbox we windowed the IBI series and obtained a distribution of LF, HF, LF/HF, SD1, SD2, and SD2/SD1 parameters. To better visualize which frequencies (in the LF and HF ranges) dominated the cardiac signal across time, continuous wavelet transforms (CWT) or magnitude scalograms were used to visualize and evaluate temporal changes in frequency power and provide a personalized assessment of the autonomic activity (**Figure 4A**).

#### **Figure 3.**

*Analytical pipeline to assess autonomic activity via cardiac signals. The timing between R peaks (red markers) of the original ECG data are extracted to obtain the IBI signal. The IBI signal is then assessed in the frequency domain (power spectrum) to obtain LF (sympathetic) and HF (parasympathetic) components. The same IBI signal is assessed in the time domain (Poincaré plot) to obtain the SD2 (sympathetic) and SD1 (parasympathetic) parameters.*

*Exploring Cardiac Responses of Pain and Distress DOI: http://dx.doi.org/10.5772/intechopen.111890*

#### **Figure 4.**

*Cardiac responses across control and pain conditions in TD subjects. (A) CWT plots (or magnitude scalograms of the frequencies present in the heart signal across time) demonstrate higher magnitudes in the LF range corresponding to sympathetic nervous system activation in the pain compared to the control condition. (B) Violin plots from data accumulated across subjects demonstrate that the LF/HF and SD2/SD1 ratios (indicative of sympathetic NS arousal and/or parasympathetic NS inhibition) of the control vs. pain condition arise from different distributions, with the median for these ratios being higher for the pain condition. (C) Schematic of the effects of pain and pain-related distress on the autonomic system and the corresponding changes observed in the HRV metrics in the time (SD2 and SD1) and frequency (LF and HF) domains.*

#### **3.3 Integrating cardiac biometrics with self-report data**

To explore the relationship between self-reported responses and the cardiac biometric data, scatter plots were made comparing each subject's ratings against the absolute difference between the HRV metrics (obtained from the experimental and control conditions). Numeric scale pain ratings of the experimentally induced pressure pain were also compared to the perceived pain sensitivity (PPS) ratings. Scatterplots were used to assess possible relationships between PPS ratings and changes in the biometrics obtained from the cardiac signal. Such methods allow us to evaluate the correspondence between physiological metrics and common psychological assessments of pain.

#### **4. Results: autonomic responses of distress**

#### **4.1 Heart rate variability (frequency + time-domain metrics)**

HRV results were compared across control and pain conditions for TD subjects (**Figure 4**). Frequency-domain analysis of the IBI data demonstrated that the pain condition often elicited an increase in LF power (corresponding to sympathetic NS activation) and/or a decrease in HF power (corresponding to parasympathetic NS activity) for TD subjects. Such frequency changes can be visualized qualitatively across the entirety of the task via CWT plots (**Figure 4A**). The LF/HF and SD2/ SD1 ratios (where an increase represents sympathetic NS activation or parasympathetic NS inhibition) were also computed across the control and pain conditions. Violin plots demonstrated changes in the shape of the probability density of these

parameters across participants (**Figure 4B**). For the pain condition, there was a general increase in both ratios based on data accumulated across TD subjects. Nonparametric Kruskal-Wallis tests indicated that the LF/HF and SD2/SD1 ratios across the control and pain conditions come from significantly different distributions: *χ* 2 (1,175) =14.37, *p* < 0.001 and *χ* 2 (1,179) = 12.44, *p* < 0.001, respectively.

#### *4.1.1 The unique case of a subject with chronic pain*

Heart data analyses for a subject known to experience chronic pain led to unique findings compared to the remaining participants. The CWT plots of this subject consistently exhibited high LF power specifically in the 100–150 mHz range (**Figure 5**). This pattern was observed across both control and pain conditions. It is important to note that while this participant did experience the experimentally induced pressure sensation during the pain condition, they were accustomed to experiencing a consistent level of pain throughout their daily life. These results emphasize the importance of analyzing at the biophysical data in a personalized manner before calculating summary statistics or assessing trends based on the entire sample.

#### **4.2 Self-reported pain ratings and HRV parameters**

When exploring the self-reported measures, we find that perceived pain sensitivity (PPS) generally corresponded with the pain ratings reported during the study (**Figure 6A**). This indicated that participants could accurately approximate their pain sensitivity levels compared to others. To assess the relationship between objective and self-reported measures, we compared the HRV parameters of the cardiac signal with each subject's ratings during the pain condition of the Resting Task. The absolute difference (Diff) in the SD2 parameter (indicative of sympathetic NS activity) was computed to assess how much each subjects' cardiac signatures during the pain experience deviated from those of the control condition (SD2 Diff). This deviation in the SD2 parameter appeared to positively correlate with self-reported pain ratings and

#### **Figure 5.**

*Cardiac activity of a participant with chronic pain. CWT plots consistently showed high magnitude in the 100–150 mHZ range (corresponding to LF power) regardless of whether pressure pain was or was not (control condition) introduced during the resting task.*

*Exploring Cardiac Responses of Pain and Distress DOI: http://dx.doi.org/10.5772/intechopen.111890*

#### **Figure 6.**

*Integrating self-reported measures with autonomic HRV biometrics. (A) Participants with higher perceived pain sensitivity (PPS) levels typically reported the induced pressure pain to be of a higher intensity on the 1–10 numeric rating scale. (B) The absolute difference in the SD2 biometric between the control and pain condition (SD2 Diff) generally corresponded with higher self-reported pain ratings and perceived pain sensitivity levels.*

#### **Figure 7.**

*Comparing cardiac responses of TD and ASD participants. (A) Cardiac activity of neurotypical (TD) participants during the pain condition exhibited higher power in the LF range of the magnitude scalogram compared to the control condition where no pressure pain was induced. (B) For ASD participants at baseline, we observe a similar pattern of higher power in the LF range that mimics what is observed in TD participants during the pain condition.*

perceived pain sensitivity (**Figure 6B-C**). This indicates that it is possible to elucidate relationships between objective and subjective measures of pain sensation.

#### **4.3 Autonomic responses in ASD subjects at baseline**

When assessing the cardiac activity of autistic participants during the control condition of the Resting Task, we see a pattern in the CWT magnitude scalograms that mimics what was observed in TD participants at baseline (**Figure 7**). This indicated that autistic individuals may be experiencing sympathetic hyperarousal or have dampened parasympathetic nervous system regulation at baseline.

#### **5. Discussion**

The goal of this work was to assess changes in autonomic nervous system responses when the body experienced physical pain. We aimed to determine whether pain could be objectively characterized via heart rate variability metrics and how these metrics would compare to self-reported measures of pain. The pressure pain's influence on cardiac activity was apparent in the HRV metrics of the ECG signal. In the TD group, the induced pain led to increases in LF power. For most subjects, we also saw a corresponding decrease in HF power, which ultimately led to an increased LF/HF ratio. Such changes in the frequency-domain metrics suggest that the pressure pain led to sympathetic nervous system activation [25]. Interestingly, when assessing the cardiac activity of a participant who experienced chronic pain, we detected a consistent band of LF power (sympathetic activity) dominating the signal across both the control and pain conditions. This may indicate that the subject's chronic pain elicits a cardiac response that is impervious to the experimentally induced pressure pain. The finding that this subject's baseline cardiac activity resembles that of TD subjects under the pain condition helps provide some external validity to the pain induction procedure and provides further evidence for how pain can lead to increases in LF power and the LF/HF ratio. When evaluating HRV metrics in the time-domain via Poincaré plots, we generally observed an increase in the SD2, a decrease in the SD1, and an increase in the SD2/SD1 ratio, each of which are associated with sympathetic NS overdrive [35]. We find similar patterns of sympathetic hyperarousal in autistic individuals at baseline.

In this work, the physiological HRV metrics also complemented self-report measures. In general, we found that subjects have an accurate perception of their pain sensitivity level, as their PPS ratings appeared to positively correlate with their self-reported pain ratings. When assessing the relation between HRV metrics of the cardiac signal and the self-reported responses, we observed that higher deviations in the SD2 between the baseline and pain condition corresponded to higher PPS and numeric pain ratings. Such findings indicate that objective and nonlinear measures of HRV such as the SD2 parameter can be informative in understanding an individual's pain levels and their general pain sensitivity.

#### **5.1 Study implications and future work**

With this work we can begin to understand the relationship between pain, psychological responses, and physiological activity. This study demonstrated that the influence of pain on the body can be characterized via the statistics obtained from

#### *Exploring Cardiac Responses of Pain and Distress DOI: http://dx.doi.org/10.5772/intechopen.111890*

cardiac signals and that such biometrics can inform current subjective approaches. The findings of this study have several clinical implications. Characterizing the effects of sustained pressure on cardiac functioning of healthy individuals can help in the development of accurate and objective digital biomarkers of pain sensation. Such objective assessments are vital to understanding whether and how individuals who may have difficulty communicating their pain – such as those with Autism Spectrum Disorder (1 of 59 in the US), Intellectual Disability, or impaired communication skills – experience pain under normal conditions [39–41]. Individuals with Intellectual Disability experience chronic pain that often goes unnoticed and untreated [41]. Autistic individuals often exhibit higher sensitivity to painful stimuli and generally have trouble communicating their emotional or mental states to others [39, 40]. During states of sympathetic overdrive (as commonly observed in ASD), it is difficult for the parasympathetic system to acquire the predictability needed for expressing internal mental and emotional states and reciprocating social interactions. Thus, there is an urgent need to develop objective methods to characterize and understand pain and distress in such individuals. Detecting any form of autonomic dysregulation may indeed help us understand the hypersensitivities and socio-emotional difficulties observed in ASD. Such assessments can ultimately contribute to early diagnoses and mitigated distress for families and non-speaking populations at large.

Pain is a multi-faceted construct, associated with multiple biological, sensory, cognitive, and social components [1]. Thus, it must be explored via a multidimensional psychophysiological approach. Future work aims to explore the sensory-motor and socio-emotional aspects of the pain experience. This can be done by assessing the facial expression and movement activity of participants as they perform motorcognitive tasks while experiencing pain. While the autonomic system provides a bounty of information about the underlying physiology of pain and distress, we cannot forget about the contribution of the overarching peripheral nervous system that works to guide sensation, perception, decision-making, movement, and overall behavior. Recent work by Ryu and Torres has indeed connected voluntary control of motor output to the autonomic system in neurotypical individuals [42]. This work demonstrated that the heart plays a vital role in agency, highlighting the delicate balance between autonomy and control. From this previous work we learned that the cardiac signal leads the motor signal when a movement is intended but lags it when the movement is unintended [42]. Besides differentiating between deliberate and spontaneous motions, the cardiac code can help us begin the path of characterizing and distinguishing different types of afferent feedback, including those from kinesthetic and somatic pain signals. Further evaluating the autonomic system can help us deconvolve the continuous efferent stream of voluntary movements from the afferent consequences that they themselves cause. Understanding such relations will help us derive causal mechanisms of the nervous systems, beyond mere correlations. Such work highlights the importance of exploring the peripheral nervous system (including the autonomic branches) as a whole, as it can play key roles in the multi-faceted nature of pain and distress.

#### **6. Conclusions**

This work provides an innovative approach to better understand the mechanisms by which experimentally induced pain – that mimics pathological pain [28] – influences the autonomic nervous system via evaluating cardiac signals. From this work,

we learn that pain can interfere with autonomic regulation, eliciting sympathetic overdrive. The cardiac reactivities also appear to correspond with self-reports of pain and pain sensitivity. The observed patterns of autonomic dysregulation (sympathetic hyperarousal) during the physical pain experience in TD individuals mimic the cardiac responses observed in ASD participants at baseline. The unique results observed in ASD and chronic pain subjects highlight the importance of a personalized approach to assessing data. Such methodologies lend themselves to the Precision Medicine platform which helps inform the development of personalized treatments [43]. Our psychophysiological approach can ultimately help create robust techniques to detect pain and aid in the development of personalized interventions that are tailored to each individual's autonomic functioning. The added convenience of using wearable sensors makes this technique flexible and translatable for use in healthcare settings. The digital biometrics explored in this work open a new realm of research that can help us scientifically understand and characterize pain in a variety of neurodevelopmental disorders and in those with communication disabilities. Ultimately, such research can lead to new methods of identifying and alleviating pain and distress, improving the quality of life of individuals across the globe.

#### **Additional information**

Portions of this book chapter are derived from the thesis project titled "Characterization of Psychophysiological Responses to Pressure Pain" authored by Mona Elsayed, which is available on the Rutgers University repository platforms, dated October 2021. The thesis work has not been peer-reviewed nor published elsewhere.

#### **Acknowledgements**

We thank all members of the Sensory Motor Integration Lab (SMIL), and all the families and participants who made this work possible. This work was supported by the Nancy Lurie Marks Family Foundation Development Career Award to EBT and the New Jersey Governor's Council for Research and Treatment of Autism to EBT (CAUT14APL018).

#### **Conflict of interest**

The authors declare no conflict of interest.

*Exploring Cardiac Responses of Pain and Distress DOI: http://dx.doi.org/10.5772/intechopen.111890*

#### **Author details**

Mona Elsayed\* and Elizabeth Barbara Torres Rutgers University, Piscataway, NJ, USA

\*Address all correspondence to<EMAIL_ADDRESS>
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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