**3. Neurostimulation for pain modulation**

The use of electricity to alleviate pain has a long history, with the reported use of the electric emissions from the Nile catfish for pain relief in 3100 BC. Although there has been use of electrical stimulation continually, the groundbreaking gate control theory of Melzack and Wall published in 1965 changed the field and provided a strong basis for the design of appropriate interventions [20]. The theory proposes that the balance of activation between small- and larger diameter fibers determines the level of pain signaled. Small-diameter C fibers will open the "gate," and Aβ fibers (that signal innocuous touch), having a larger diameter, will close the "gate." Due to differences in the threshold of activation of these fibers in response to imposed electrical stimulation on a mixed nerve, a simple intervention to shift the balance of activation is possible. Neuromodulation of pain through electrical stimulation of implanted electrodes has substantial supportive evidence since its initial introduction in spinal cord stimulation (SCS) in 1967 [21] and is accepted as a standard form of treatment for intractable chronic neuropathic pain. Many of these implantable neurostimulation devices were adapted from the design of cardiac pacemakers, and their design and stimulation parameters have not changed substantially since their initial introduction. However, differences do exist among SCSs; for instance, some are based on tonic stimulation, whereas others on burst stimulation, and the stimulation frequency can be varied.

Other invasive stimulators have targeted pain pathways in the brain to alleviate pain, often utilizing the knowledge of role of the thalamus as having a critical role in sensory processing. Deep brain stimulation (DBS) has been applied to different thalamic nuclei, including the ventral posteromedial sensory nuclei and ventral posterolateral sensory nuclei and the centromedian-parafascicular intralaminar region. There is widely varying reports of the effectiveness of DBS of the thalamus but with the strongest response believed to be in patients with neuropathic pain [22]. DBS has also included stimulation of the ACC, with the aim of reducing the affective component of chronic pain, and this has been shown to be effective within small studies [23].

The primary motor cortex (M1) was the first cortical target that was proven to be efficacious in chronic pain treatment [24]. Motor Cortex Stimulation (MCS), where epidural electrodes are implanted has been shown to be a particularly useful intervention for neuropathic pain that is not responsive to pharmacological interventions [25, 26]. The primary motor cortex (M1) is somatotopically arranged and receives inputs from three main sources. These are [1] the peripheral body via the thalamic relay nuclei-somatosensory cortex system, from the premotor cortex and from the sensory association areas of the cortex; [2] the basal ganglia; and [3] from the cerebellum. Therefore, there is considerably overlap with motor processing areas and those associated with the pain neuromatrix. It is believed that cathodal MCS is associated with an indirect stimulation of pyramidal neurons via interneurons, whereas anodal MCS is associated with a direct stimulation of pyramidal neurons. The indirect activation is believed to be optimal for MCS analgesia.

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

The use of electricity to alleviate pain has a long history, with the reported use of the electric emissions from the Nile catfish for pain relief in 3100 BC. Although there has been use of electrical stimulation continually, the groundbreaking gate control theory of Melzack and Wall published in 1965 changed the field and provided a strong basis for the design of appropriate interventions [20]. The theory proposes that the balance of activation between small- and larger diameter fibers determines the level of pain signaled. Small-diameter C fibers will open the "gate," and Aβ fibers (that signal innocuous touch), having a larger diameter, will close the "gate." Due to differences in the threshold of activation of these fibers in response to imposed electrical stimulation on a mixed nerve, a simple intervention to shift the balance of activation is possible. Neuromodulation of pain through electrical stimulation of implanted electrodes has substantial supportive evidence since its initial introduction in spinal cord stimulation (SCS) in 1967 [21] and is accepted as a standard form of treatment for intractable chronic neuropathic pain. Many of these implantable neurostimulation devices were adapted from the design of cardiac pacemakers, and their design and stimulation parameters have not changed substantially since their initial introduction. However, differences do exist among SCSs; for instance, some are based on tonic stimulation, whereas others on burst stimulation,

Other invasive stimulators have targeted pain pathways in the brain to alleviate pain, often utilizing the knowledge of role of the thalamus as having a critical role in sensory processing. Deep brain stimulation (DBS) has been applied to different thalamic nuclei, including the ventral posteromedial sensory nuclei and ventral posterolateral sensory nuclei and the centromedian-parafascicular intralaminar region. There is widely varying reports of the effectiveness of DBS of the thalamus but with the strongest response believed to be in patients with neuropathic pain [22]. DBS has also included stimulation of the ACC, with the aim of reducing the affective component of chronic pain, and this has been shown to be effective

The primary motor cortex (M1) was the first cortical target that was proven to be efficacious in chronic pain treatment [24]. Motor Cortex Stimulation (MCS), where epidural electrodes are implanted has been shown to be a particularly useful intervention for neuropathic pain that is not responsive to pharmacological interventions [25, 26]. The primary motor cortex (M1) is somatotopically arranged and receives inputs from three main sources. These are [1] the peripheral body via the thalamic relay nuclei-somatosensory cortex system, from the premotor cortex and from the sensory association areas of the cortex; [2] the basal ganglia; and [3] from the cerebellum. Therefore, there is considerably overlap with motor processing areas and those associated with the pain neuromatrix. It is believed that cathodal MCS is associated with an indirect stimulation of pyramidal neurons via interneurons, whereas anodal MCS is

that pain can arise from a vast range of different underlying pathologies.

**3. Neurostimulation for pain modulation**

106 Transcranial Magnetic Stimulation in Neuropsychiatry

and the stimulation frequency can be varied.

within small studies [23].

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 or experiencing acute pain.
