A systematic review of the proposed mechanisms underpinning pain relief by primary motor cortex stimulation in animals.

• Mechanisms involved in alleviating pain by use of TMS and iMCS have considerable amount of overlap. • Key regions which were impacted by TMS and/or iMCS consisted of the thalamus, striatum, PAG, RVM and dorsal horn. • Both functional and structural changes were observed to occur within these key regions after TMS and iMCS. • All key regions are known to be interconnected anatomically, providing a rational for further investigation. Experimental treatments for treating neuropathic pain include transcranial magnetic stimulation (TMS) and invasive electric motor cortex stimulation (iMCS) of the primary motor cortex (M1). Mechanisms of action of both methods, however, remain largely elusive. Within this paper, we focus on animal-based experiments in order to investigate the biological mechanisms that are involved in alleviating pain by use of TMS and/or iMCS. Therefore, this paper systematically reviewed the animal-based evidence on these mechanisms. Multiple online databases were systematically searched and retrieved articles were assessed using predefined inclusion and exclusion criteria. Twenty-three suitable articles were included; six on TMS and seventeen on iMCS. In general, iMCS and TMS were found to impact the primary motor cortex structure and function in animals. Furthermore, structural and functional changes within the thalamus, striatum, periaqueductal grey, rostral ventromedial medulla and dorsal horn were reported to occur. Although widespread, all areas in which structural and functional changes occurred after TMS and iMCS have been found to be interconnected anatomically. This could provide a rationale for future investigations of treating neuropathic pain by use of neuromodulation. [ABSTRACT FROM AUTHOR]