**2. Pain and pain processing**

Noxious stimuli are detected by the free endings of pseudounipolar neurons (Aδ or C fibers) which project to the dorsal horn of the spinal cord to synapse with second-order neurons in laminae I–II and V–VII [2]. Type I small-diameter thinly myelinated Aδ fibers respond to strong mechanical stimuli; type II Aδ nociceptors respond to noxious thermal stimuli; unmyelinated C-fiber nociceptors respond to thermal, mechanical, and chemical stimuli [2]. Neurons of laminae I and V relay signals along the spinothalamic and spinoreticulothalamic tracts to supraspinal sites including the thalamus, parabrachial nucleus, and amygdala and to higher cortical centers such as the primary somatosensory cortex (S1), secondary somatosensory cortex (S2), dorsolateral prefrontal cortex (DLPFC), and primary motor cortex (M1). Taken together, the combined activity of both cortical and subcortical regions that form a distributed brain network associated with pain processing is referred to as the pain "neuromatrix" [8]. The ventroposterior lateral and medial nuclei of the thalamus, S1 and S2 are concerned with the sensorydiscriminative component of pain, encoding location, and duration of pain, whereas the medial nuclei of the thalamus and anterior cingulate cortex (ACC) are regions suggested to underlie the cognitive-evaluative aspect of pain, including pain-related learning [2]. Descending pathways pass through the periaqueductal gray matter (PAG), which has been long established as important in the endogenous modulation of pain via early electrical stimulation studies [9]. The PAG is part of a central circuit that controls nociceptive transmission at the level of the spinal cord dorsal horn via a relay in the rostral ventromedial medulla (RVM) [10]. The PAG receives direct projections from a number of medial prefrontal cortical areas, including the ACC, the amygdala, and the hypothalamus [11–14], with a primary output to the RVM critical to descending pain modulation. The PAG-RVM system's critical role in the central control of nociception has been demonstrated by lesion studies [15]. Taken together, these studies indicate that the intensity of pain will be the consequence and composite of interactions between ascending nociceptive inputs and descending antinociceptive controls. Dysregulations in any aspect of these networks may underlie vulnerability factors for the development of chronic pain [16].

#### **2.1. Pain and the chronification of pain**

model systems. Its critical function as a sense for survival is reflected by its emergence early developmentally. In all animals, the characteristic perception of nociceptive stimuli is rapid reflexive movement away from the source of the noxious stimulus (nocifensive behavior) and autonomic responses that optimize the ability to escape from threats [2]. In humans, pain encompasses not only these sensorimotor responses but critically also the cognitive evaluative component, and the IASP definition encompasses the subjectivity of the pain phenomenon.

Chronic pain represents a significant health burden worldwide with over 1.5 million people suffering from chronic pain globally [3]. Nearly 20% of those in Europe are believed to be in chronic pain, and lifetime prevalence of chronic pain worldwide has been put as high as 55.2% of the population [4, 5]. The experience of pain is known to have a substantial detrimental impact on an individual's quality of life and mental health status. Extensive research has documented the high correlation between pain and mental health difficulties, not just within clinical cohorts but also in community-based studies [6]. Pain can therefore be seen as an important risk factor for the development of psychiatric conditions, for instance, depression. Furthermore, there is a reciprocal nature to the interaction, with depression likely to exacerbate the individual's experience of pain [7]. Overall, the consequence is not just on the individual but also the societal economic burden of pain will be further compounded by the economic burden of

Noxious stimuli are detected by the free endings of pseudounipolar neurons (Aδ or C fibers) which project to the dorsal horn of the spinal cord to synapse with second-order neurons in laminae I–II and V–VII [2]. Type I small-diameter thinly myelinated Aδ fibers respond to strong mechanical stimuli; type II Aδ nociceptors respond to noxious thermal stimuli; unmyelinated C-fiber nociceptors respond to thermal, mechanical, and chemical stimuli [2]. Neurons of laminae I and V relay signals along the spinothalamic and spinoreticulothalamic tracts to supraspinal sites including the thalamus, parabrachial nucleus, and amygdala and to higher cortical centers such as the primary somatosensory cortex (S1), secondary somatosensory cortex (S2), dorsolateral prefrontal cortex (DLPFC), and primary motor cortex (M1). Taken together, the combined activity of both cortical and subcortical regions that form a distributed brain network associated with pain processing is referred to as the pain "neuromatrix" [8]. The ventroposterior lateral and medial nuclei of the thalamus, S1 and S2 are concerned with the sensorydiscriminative component of pain, encoding location, and duration of pain, whereas the medial nuclei of the thalamus and anterior cingulate cortex (ACC) are regions suggested to underlie the cognitive-evaluative aspect of pain, including pain-related learning [2]. Descending pathways pass through the periaqueductal gray matter (PAG), which has been long established as important in the endogenous modulation of pain via early electrical stimulation studies [9]. The PAG is part of a central circuit that controls nociceptive transmission at the level of the spinal cord dorsal horn via a relay in the rostral ventromedial medulla (RVM) [10]. The PAG receives direct projections from a number of medial prefrontal cortical areas, including the ACC, the amygdala, and the hypothalamus [11–14], with a primary output to the RVM critical

the concomitant mental health difficulties of those experiencing it chronically.

**2. Pain and pain processing**

104 Transcranial Magnetic Stimulation in Neuropsychiatry

While acute pain is highly functional to survival and an adaptive sense that is protective against tissue damage, the mechanisms behind the development from this protective function to the maladaptive disease of chronic pain in a proportion of individuals remain elusive. Chronic pain is defined as pain that persists for 3–6 months after the initial nociceptive stimuli [17]. Methodologies that have potential to predict individual patients with pain who are at risk of developing chronic pain would be particularly valuable at helping to understand the physiological mechanisms behind this very detrimental disease process. Recent research suggests that the use of computational machine learning methods to analyze large data sets of medical and demographic characteristics collected from patients who develop chronic pain patients may aid understanding of the risk factors underlying chronification and a possible chronic pain phenotype [18]. This is an interesting concept, though ultimately dependent on the relevant predictors of pain chronification being in the analyzed data set. For instance, while there has been recent interest in the use of quantitative sensory testing to characterize individual differences in pain sensitivity, thorough assessment of pain thresholds across a variety of modalities, this is by no means standard. That limitation aside, greater understanding of pain chronification is essential for the development of interventions for chronic pain and increased understanding of how to effectively disrupt the transition into a disease state. In the future, the inclusion of larger data sets will inevitably increase the predictive value of this emerging technique.

Chronic pain is characterized by increases in neuronal excitability leading to increased pain perception. These increases in excitability are believed to occur both peripherally and centrally, factoring into the overall elevated perceived pain. To date, research has predominately focused on spinal cord mechanisms. This perhaps is somewhat related to availability of appropriate animal models and the existing strong scientific basis. However, it is well established that spinal cord excitability can be modulated by descending pathways. Given the role of descending pathways in modulating excitability in the spinal cord, the input and impact of a wide range of cortical areas in perceived pain should be systematically considered and characterized. These cortical areas will not just include those directly related to sensorimotor processing but also encompass those areas important for the cognitive evaluative and emotional response to pain. NIBS techniques may provide a tool that can enable further insight into the mechanisms of pain processing from periphery through to cortex that may in turn reveal potential therapeutics for the treatment of chronic pain conditions.

Further, pain is categorized by the IASP as either neuropathic or nociceptive [19]. Neuropathic pain is a pain that is caused by a disorder of the somatosensory system and typically leads to symptoms that include hyperalgesia, allodynia, and pain in the absence of stimulation. Nociceptive pain is a pain that arises from damage to non neural tissue via the activation of nociceptors. Another consideration is that although there is a broad distinction into neuropathic and nociceptive pain, there can be overlap in the two forms of pain, as well as the fact that pain can arise from a vast range of different underlying pathologies.

associated with a direct stimulation of pyramidal neurons. The indirect activation is believed

Neurostimulation Techniques for the Modulation of Pain

http://dx.doi.org/10.5772/intechopen.79406

107

Invasive neuromodulatory devices have been the subject of research for much longer noninvasive neuromodulatory techniques, including randomized controlled trials. By reason of their very invasive nature, and obvious ethical constraints, the effectiveness and consequences of SCS, MCS, and DBS have only be assessed in patients and not experimentally investigated in healthy volunteers, which may have limited the development of different stimulation protocols. Therefore, unlike these invasive stimulators, NIBS techniques potentially enable another important distinction to be considered, the difference in response to neuromodulation in chronic pain patient groups compared with healthy individuals exposed to experimental pain

**4. Functional magnetic resonance imaging (fMRI) and chronic pain**

chronic pain states have stronger cognitive-evaluative aspect of pain [16].

Functional magnetic resonance imaging (fMRI) was first used in the area of pain in order to demonstrate the brain areas responsible for pain perception and part of the pain "neuromatrix" [28]. Subsequently, differences in the structure and function of pain patients compared with healthy controls have been observed through fMRI of experimental pain in both groups [29]. Chronic pain patients show similar activation but with a decrease in thalamic and ACC activation. Activity in the prefrontal cortex (PFC) typically shows an increase in clinical pain conditions. This preferential activation of PFC in chronic pain conditions advocates that

As well as functional changes, structural changes have been observed through MRI in patients experiencing long-term pain. Chronic pain patients are found to show neuronal loss in significant pain pathways including the thalamus and the lateral prefrontal cortex [30]. Fibromyalgia, a patient group with a particularly complex range of sensorimotor symptoms, shows gray matter loss in the DLPFC [31], and this is believed to be consistent across different chronic pain patient groups. For instance, patients with chronic lower back pain also show reductions in gray matter in distributed regions of the pain "neuromatrix," including DLPFC. This decrease in gray matter also occurs in prolonged pain states in the general population as well as clinical groups [32], and on resolution of persistent pain, for instance when a patient with knee osteoarthritis (OA) undergoes knee arthroplasty, gray matter levels increase

fMRI has also been used to demonstrate the effectiveness of neuromodulatory interventions, as well as the scope of the effect of stimulation. For instance, functional connectivity changes were observed in a group of neuropathic pain patients who had undergone SCS. After implantation, decreased connectivity was found between somatosensory and limbic areas of the brain, showing how central changes can be mediated by SCS [28]. Studies using combined NIBS/fMRI may provide interesting insights on the effect of neuromodulation protocols on changes in functional connectivity of the pain neuromatrix as has been done in other treat-

to be optimal for MCS analgesia.

or experiencing acute pain.

in parallel.

ment interventions [33].
