The Contribution of Endogenous Modulatory Systems to TMS- and tDCS-Induced Analgesia: Evidence from PET Studies

Chronic pain is an important public health issue. Moreover, its adequate management is still considered a major clinical problem, mainly due to its incredible complexity and still poorly understood pathophysiology. Recent scientific evidence coming from neuroimaging research, particularly functional magnetic resonance (fMRI) and positron emission tomography (PET) studies, indicates that chronic pain is associated with structural and functional changes in several brain structures that integrate antinociceptive pathways and endogenous modulatory systems. Furthermore, the last two decades have witnessed a huge increase in the number of studies evaluating the clinical effects of noninvasive neuromodulatory methods, especially transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), which have been proved to effectively modulate the cortical excitability, resulting in satisfactory analgesic effects with minimal adverse events. Nevertheless, the precise neuromechanisms whereby such methods provide pain control are still largely unexplored. Recent studies have brought valuable information regarding the recruitment of different modulatory systems and related neurotransmitters, including glutamate, dopamine, and endogenous opioids. However, the specific neurocircuits involved in the analgesia produced by those therapies have not been fully elucidated. This review focuses on the current literature correlating the clinical effects of noninvasive methods of brain stimulation to the changes in the activity of endogenous modulatory systems.