**1. What is neuromodulation? Why is pain a challenge?**

Neuromodulation has been defined by the International Neuromodulation Society (INS) as "the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the body" [1, 2]. Neuromodulation has a wide range of possible clinical applications from the enhancement of vision, auditory function and the control of musculature, but the application to alleviate pain is perhaps one of the most challenging for the field. Whilst the efficacy of neuromodulation interventions, for instance for movement disorders, can be easily measured due to the many ways in which successful movement execution can be characterized, 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 experience.

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 aspects.

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 relief is an area that still requires development.
