**3. The anatomical substrates for pain: potential targets for neuromodulation**

The sensation of acute pain originates from stimulation of nociceptors. Nociceptive input has different modalities; thermal, chemical or mechanical; that are all capable of causing pain. Receptor types and ion channels will differ dependent on the stimulus and intensity, but with free nerve endings transmitting the noxious information to Aδ and C afferents. The TRP channels for transduction of noxious temperature sensation are well characterized [10, 11], with less known about mechanical pain [12]. Myelinated, high velocity (20 m/s) Aδ fibers and un-myelinated, low velocity (2 m/s) and C fibers transmit nociceptive information from the periphery to the dorsal horn. Both Aδ and C afferent fibers terminate in the dorsal horn of the spinal cord, where afferent input is organized in the rexed laminae; finer diameter fibers terminate more laterally, and larger fibers more medially. Large diameter Aβ fibers conveying innocuous touch can modulate nociception transmission as formulated by the gate-control theory of pain. This theory represented a ground breaking advance in the understanding of the peripheral and spinal processing of nociceptive inputs that led to the development of therapeutic neuromodulation interventions [13]. There is transmission from the spinal cord via multiple ascending pathways; spinothalamic, spinoreticular, spinomesencephalic, and spinocervical pathways [14]. The thalamus is an important site of nociceptive transmission to different brain regions known to be involved in pain processing and interpretation. Additionally significant modulation of afferent input occurs at the thalamus that has led to the region being one of the first supraspinal areas targeted in neuromodulation interventions. The multiple cortical and sub-cortical regions of the brain that are involved in pain processing and modulation have become known as the pain neuromatrix [15], or the pain connectome [16]. Particularly critical to the modulation of pain is the descending pain pathways providing endogenous inhibitory control of nociceptive input.

Chronic pain typically is defined as pain that lasts 3-6 months, with the pain experienced no longer associated with a tissue injury. Chronic pain can result from defects in different sites of the pain processing pathways [17] and is often associated with both peripheral and central sensitization [18]. The pain processing network is known to be complex and distributed. In the brain, painful stimuli is known to lead to activation in diverse brain regions; including the frontal lobe, anterior cingulate cortex (ACC), primary motor cortex (M1), primary sensory cortex (S1), secondary sensory cortex (S2), insular; hypothalamus; nucleus cuneiformis; periaqueductal grey; rostral ventromedial medulla; as observed via fMRI studies [19]. The development of chronic pain is thought not just to involve neural changes but also alterations in glia [20]. These glial changes are thought to partly underlie alterations in pain transmission and the formation of chronic pain circuitry. Imaging studies show that chronic pain leads to structural and functional changes in multiple brain regions [21]. Chronic pain has also been reported to be associated with dysregulation of both the sympathetic and parasympathetic nervous systems [22]. Therefore, the potential targets for non-invasive neuromodulation for pain relief are diverse and could be within the central or peripheral nervous systems.

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

experience.

aspects.

and improvements in vision and audition measured via sensory detection thresholds, the efficacy of a potential neuromodulation intervention to alleviate pain is far harder to determine. Currently there is not an established biomarker for pain, and objective measurement of an individual's pain levels either before or after an intervention is difficult due to the subjectivity inherent in the pain

Pain involves multiple processing regions from the periphery through to the brain and therefore, successful neuromodulation for pain relief has a number of possible targets. A clear premise of clinical neuromodulation is that pathological alterations in neuronal function are targeted, but for chronic pain these alterations can occur due to dysfunctions at a number of different sites within the multiple interconnected pain processing pathways. Additionally the mechanisms underlying the persistence of pain long after the initial injury, and the formation of a chronic pain state, still remain elusive. Pain, particularly chronic pain, is typically regarded as a human phenomenon, with other animals simply experiencing nociception; a stimuli that generates a reflexive response but without key aspects that encompass pain; that is without cognitive and emotional evaluative

Neuromodulation, particularly non-invasive neuromodulation, is a rapidly emerging field for therapeutic interventions and although the effects of stimulation are evident, many questions remain open; what patient groups will this technique be effective for?; what stimulation parameters should be used for optimum efficacy?; what is the most efficacious target for pain relief? Furthermore the mechanisms underlying neuromodulation has not been completely established. Therefore, taken together, the design of optimum neuromodulation protocols and targets for pain

Chronic pain is a global health problem with both a high economic cost in addition to its substantial detrimental impact on quality of life [3]. Remarkably lifetime prevalence of chronic pain has been put as high as 50% of the global population [4, 5]. Chronic pain is the most common co-morbidity for a disease, with pain as the most frequent reason for seeking healthcare. Recently chronic pain has been recognized by the World Health Organization as a disease and included in the international classification of diseases (ICD-11) [6]. However, treatment interventions are lacking; pharmacological interventions providing inadequate pain relief with the mismanagement of opioids well documented as both increasing mortality and exacerbating pain. For neuromodulation to be an effective alternative for analgesia, an understanding of the mechanisms leading to pain conditions and the networks that enhance pain or inhibit pain is essential. For therapeutic benefit, neurostimulation techniques should modulate the nervous system in a non-destructive way with reversible effects that can be applied long term and have specificity to a targeted network. Further the intervention should be controlled dependent on individual patient requirements [7]. Recently a number of new non-invasive techniques have emerged; weak electric currents applied transcranially to cortical or sub-cortical site are proposed as interventions for a number of diseases that are associated with pathological alterations in neuronal excitability [8, 9], including chronic pain. Further the recent development of transcutaneous vagal nerve stimulation also offers therapeutic potential for some pain patients. Although these novel non-invasive interventions offer

**2. Importance of developing neuromodulation for pain relief**

relief is an area that still requires development.

**192**

### **3.1 Primary motor cortex**

Electrical stimulation of the primary motor cortex (M1) is long established as an effective treatment for pain. Originally this intervention was limited to invasive epidural electrode implantation, and so associated with the risk of surgery [23]. More recently non-invasive cortical stimulation has emerged as an interesting, effective, and promising modality in the investigation of novel approaches for pain relief [24]. The motor cortex represents a cortical region with high intra-cortical connectivity as well as connectivity to sub-cortical regions. There are a number of explanations for the efficacy of M1 stimulation [25]. M1- thalamic connectivity is thought to be particularly significant in neuromodulation effects [26]. Efficacy of M1 neuromodulation is also proposed to be due to inhibitory effects via the limbic, cortical and subcortical brain areas involved in descending modulatory pain control. Further M1 tDCS has been shown to reduce secondary hyperalgesia and enhances descending modulatory control [27].

### *3.1.1 Monitoring the efficacy of M1 stimulation*

The measurement of pain in a clinical setting has been typically through visual analogue scales (VAS) and numerical rating scales (NRS). However many studies now include pain threshold testing via standardized quantitative sensory testing (QST) which involves testing across different modalities of nociceptive stimuli so that a pain modulation profile can be monitored pre and post treatment intervention [28]. MRI studies have examined resting-state functional connectivity alterations in pain patients before and after intervention with tDCS and found alterations in connectivity within pain processing areas that correlate with a reduction in pain in these patients [29].

Neurophysiological techniques have also been used to monitor changes in cortical excitability after the application of electric currents so that these changes may be correlated with pain measures. Increased excitability of the corticospinal tract (CST) as measured by the standard neurophysiological technique of motor evoked potentials (MEPs) have shown that increased CST excitability is associated with analgesic effects [30] and beneficial outcomes for patients [31]. Other neurophysiological measures that have been shown to have value include intracortical disinhibition. A number of studies have observed that there is a reduction in intracortical inhibition and an increase in intracortical facilitation, suggesting that motor cortex inhibition is dysregulated in chronic pain patients [32] and so providing a neurophysiological basis for monitoring efficacy of neuromodulation protocols.

### **3.2 Endogenous descending control of pain**

It is well known that once a nociceptive stimuli has been identified, the typical response across all animals is rapid reflexive movement away from the source of the noxious stimulus combined with an autonomic response which acts to optimize the animal's ability to escape from threats. The periaqueductal gray (PAG) has a critical role in the response to threatening stimuli, both aversion and the autonomic response [33, 34]. The PAG is also a key component of the endogenous descending pain pathway [35]. It receives nociceptive input from spinal, subcortical and cortical inputs, and projects to the rostral ventromedial medulla (RVM) and also to cortical areas and the spinal cord. The initial rodent studies of PAG stimulation demonstrated a large analgesic effect subsequent to stimulation [36]. Subsequently, PAG stimulation has shown anti-nociceptive effects from rodents to man and is now known as an essential circuit for opioid based analgesia. However, it is also established that the PAG and descending pathways play a complex role in pain and can facilitate as

**195**

*From Mechanisms to Analgesia: Towards the Use of Non-Invasive Neuromodulation for Pain…*

well as inhibit pain. Importantly, these endogenous descending pain pathways are thought to be defective in some patients, leading to chronic pain. To improve and develop neuromodulatory interventions it would be ideal to first characterize the integrity of the patient's descending modulatory pathway and subsequently monitor the effect of an intervention on this pathway. Two experimental observations using psychophysical methods are thought to enable important insights in the endogenous descending modulatory control and have generated interest in pain research. These are offset analgesia (OA) [37] and conditioned pain modulation (CPM) [38]. It would be useful if these methods could monitor the efficacy of neurostimulation

Offset analgesia (OA) is a phenomenon observed in both experimental and clinical studies [39]. OA is defined as a disproportionate reduction in pain after a very slight decrease in experimental pain stimulus intensity. The size of the OA effect is very large, with the effect thought to be over 250% when compared with equivalent

Conditioned pain modulation (CPM) represents the phenomenon of 'pain inhibits pain' and is thought to be the human counterpart to descending noxious inhibitory control (DNIC) that has strong electrophysiological evidence in rodent pain models [44]. Although DNIC was observed in rats in the 1970s, the human counterpart as observed through psychophysical methods is much more recent [38]. While there is increasing evidence that deficits in CPM can predict the development of chronic pain the reliability of the response has been questioned and there are a

Patients with knee osteoarthritis have also been found to have defects in the descending pain control that can be characterized by defects in CPM. Further CPM paradigms have been used to monitor the effect of neuromodulation interventions on the endogenous inhibitory pathways in experimental pain in healthy participants [45] and clinical pain in Fibromyalgia patients [46]. As well as M1 stimulation influencing descending pain pathways it is possible that prefrontal stimulation may also modulate PAG due to the known connectivity [47]. Prefrontal tDCS is a common target for tDCS for pain modulation [25, 48], but not currently assessed in the context of descending pain pathways as monitored via CPM protocols. However patient studies using tDCS of the left dorsolateral prefrontal cortex have suggested efficacy is achieved via enhancement of descending pain modulation as well as known cognitive effects of this stimulation [49]. The link between PAG and cerebellar circuitry [50] may suggest that cerebellar tDCS could also influence PAG. Experimental pain studies have

The physiological mechanism and function of this phenomenon is not completely understood, but there is substantial interest in OA due to the apparent analgesia that it can convey in the presence of a previously painful heat stimulus. Additionally deficits in OA has been demonstrated in a number of different clinical group of chronic pain patients, and therefore a psychophysical OA protocol could be incorporated as part of a diagnostic protocol for chronic pain patients [40]. However, there is debate over whether OA could be used as a means to monitor the success of pharmacological interventions [41, 42] and suggests that this protocol requires reliability testing prior to use for the assessment of intervention efficacy. fMRI evidence has suggested that the PAG is activated during OA suggesting that the descending control pain pathway

*DOI: http://dx.doi.org/10.5772/intechopen.93277*

*3.2.1 Offset analgesia*

increases in pain intensity [39].

*3.2.2 Conditioned pain modulation*

protocols aimed at enhancing inhibitory pain pathways.

is important in the experience of this phenomenon [43].

number of alternative protocols in the literature [38].

*From Mechanisms to Analgesia: Towards the Use of Non-Invasive Neuromodulation for Pain… DOI: http://dx.doi.org/10.5772/intechopen.93277*

well as inhibit pain. Importantly, these endogenous descending pain pathways are thought to be defective in some patients, leading to chronic pain. To improve and develop neuromodulatory interventions it would be ideal to first characterize the integrity of the patient's descending modulatory pathway and subsequently monitor the effect of an intervention on this pathway. Two experimental observations using psychophysical methods are thought to enable important insights in the endogenous descending modulatory control and have generated interest in pain research. These are offset analgesia (OA) [37] and conditioned pain modulation (CPM) [38]. It would be useful if these methods could monitor the efficacy of neurostimulation protocols aimed at enhancing inhibitory pain pathways.

### *3.2.1 Offset analgesia*

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

Electrical stimulation of the primary motor cortex (M1) is long established as an effective treatment for pain. Originally this intervention was limited to invasive epidural electrode implantation, and so associated with the risk of surgery [23]. More recently non-invasive cortical stimulation has emerged as an interesting, effective, and promising modality in the investigation of novel approaches for pain relief [24]. The motor cortex represents a cortical region with high intra-cortical connectivity as well as connectivity to sub-cortical regions. There are a number of explanations for the efficacy of M1 stimulation [25]. M1- thalamic connectivity is thought to be particularly significant in neuromodulation effects [26]. Efficacy of M1 neuromodulation is also proposed to be due to inhibitory effects via the limbic, cortical and subcortical brain areas involved in descending modulatory pain control. Further M1 tDCS has been shown to reduce secondary hyperalgesia and

The measurement of pain in a clinical setting has been typically through visual analogue scales (VAS) and numerical rating scales (NRS). However many studies now include pain threshold testing via standardized quantitative sensory testing (QST) which involves testing across different modalities of nociceptive stimuli so that a pain modulation profile can be monitored pre and post treatment intervention [28]. MRI studies have examined resting-state functional connectivity alterations in pain patients before and after intervention with tDCS and found alterations in connectivity within pain processing areas that correlate with a reduction in pain in these patients [29]. Neurophysiological techniques have also been used to monitor changes in cortical excitability after the application of electric currents so that these changes may be correlated with pain measures. Increased excitability of the corticospinal tract (CST) as measured by the standard neurophysiological technique of motor evoked potentials (MEPs) have shown that increased CST excitability is associated with analgesic effects [30] and beneficial outcomes for patients [31]. Other neurophysiological measures that have been shown to have value include intracortical disinhibition. A number of studies have observed that there is a reduction in intracortical inhibition and an increase in intracortical facilitation, suggesting that motor cortex inhibition is dysregulated in chronic pain patients [32] and so providing a neurophysiological basis for monitoring efficacy of neuromodulation protocols.

It is well known that once a nociceptive stimuli has been identified, the typical response across all animals is rapid reflexive movement away from the source of the noxious stimulus combined with an autonomic response which acts to optimize the animal's ability to escape from threats. The periaqueductal gray (PAG) has a critical role in the response to threatening stimuli, both aversion and the autonomic response [33, 34]. The PAG is also a key component of the endogenous descending pain pathway [35]. It receives nociceptive input from spinal, subcortical and cortical inputs, and projects to the rostral ventromedial medulla (RVM) and also to cortical areas and the spinal cord. The initial rodent studies of PAG stimulation demonstrated a large analgesic effect subsequent to stimulation [36]. Subsequently, PAG stimulation has shown anti-nociceptive effects from rodents to man and is now known as an essential circuit for opioid based analgesia. However, it is also established that the PAG and descending pathways play a complex role in pain and can facilitate as

**3.1 Primary motor cortex**

enhances descending modulatory control [27].

*3.1.1 Monitoring the efficacy of M1 stimulation*

**3.2 Endogenous descending control of pain**

**194**

Offset analgesia (OA) is a phenomenon observed in both experimental and clinical studies [39]. OA is defined as a disproportionate reduction in pain after a very slight decrease in experimental pain stimulus intensity. The size of the OA effect is very large, with the effect thought to be over 250% when compared with equivalent increases in pain intensity [39].

The physiological mechanism and function of this phenomenon is not completely understood, but there is substantial interest in OA due to the apparent analgesia that it can convey in the presence of a previously painful heat stimulus. Additionally deficits in OA has been demonstrated in a number of different clinical group of chronic pain patients, and therefore a psychophysical OA protocol could be incorporated as part of a diagnostic protocol for chronic pain patients [40]. However, there is debate over whether OA could be used as a means to monitor the success of pharmacological interventions [41, 42] and suggests that this protocol requires reliability testing prior to use for the assessment of intervention efficacy. fMRI evidence has suggested that the PAG is activated during OA suggesting that the descending control pain pathway is important in the experience of this phenomenon [43].

### *3.2.2 Conditioned pain modulation*

Conditioned pain modulation (CPM) represents the phenomenon of 'pain inhibits pain' and is thought to be the human counterpart to descending noxious inhibitory control (DNIC) that has strong electrophysiological evidence in rodent pain models [44]. Although DNIC was observed in rats in the 1970s, the human counterpart as observed through psychophysical methods is much more recent [38]. While there is increasing evidence that deficits in CPM can predict the development of chronic pain the reliability of the response has been questioned and there are a number of alternative protocols in the literature [38].

Patients with knee osteoarthritis have also been found to have defects in the descending pain control that can be characterized by defects in CPM. Further CPM paradigms have been used to monitor the effect of neuromodulation interventions on the endogenous inhibitory pathways in experimental pain in healthy participants [45] and clinical pain in Fibromyalgia patients [46]. As well as M1 stimulation influencing descending pain pathways it is possible that prefrontal stimulation may also modulate PAG due to the known connectivity [47]. Prefrontal tDCS is a common target for tDCS for pain modulation [25, 48], but not currently assessed in the context of descending pain pathways as monitored via CPM protocols. However patient studies using tDCS of the left dorsolateral prefrontal cortex have suggested efficacy is achieved via enhancement of descending pain modulation as well as known cognitive effects of this stimulation [49]. The link between PAG and cerebellar circuitry [50] may suggest that cerebellar tDCS could also influence PAG. Experimental pain studies have

explored the use of cerebellar tDCS as a target for modulating pain thresholds [51], but there are currently only a few studies.
