 Spinal cord stimulation offers long-term relief to patients managing chronic pain without the need for opioids. This winning combination has spurred incredible growth in the industry, with approximately 50,000 spinal cord stimulators being implanted each year and an estimated market of $7 billion by 2020. But despite this progress, exactly how the technology works remains unclear, especially with regard to potential changes in brain activity. A new review article in the journal Anesthesiology takes a closer look at these potential supra-spinal pathways and actions. Covering both pre-clinical and clinical articles, the review starts with the 1960s, when an idea known as gate control theory was proposed to explain how conventional tonic stimulation works. The theory suggests that a combination of presynaptic inhibition and inhibitory interneuronal communication occurs in the spinal cord following the electrical activation of large-diameter afferent fibers. The result is inhibition of signal processing from small-diameter fibers, dulling pain. Although foundational to the development of spinal cord stimulation, gate control theory doesn't fully explain how stimulation works. To fill this gap, researchers began investigating supra-spinal involvement. Human EEG studies conducted in the 1970s suggested that spinal cord stimulation selectively masks neuropathic but not nososceptive pain as a result of processing at the cerebral level, diencephalon, or brainstem. Follow-up studies in animals largely supported this conclusion, although the exact details of which brain regions were affected and how remained a matter of debate. The 1990s brought much discussion regarding the effects of spinal cord stimulation on blood flow, including cerebral blood flow. Coupling of cerebral blood flow to the sensory motor regions, activated by stimulation, was proposed as a mechanism for the treatment's effectiveness. Neuroimaging helped pinpoint specific regional cerebral blood flow changes following stimulation, and researchers also investigated the neurochemical mechanisms linked to supra-spinal activity. Although enlightening, much of the work produced mixed results, potentially due to variations in stimulation intensities and methodology. The 2000s brought new tools for elucidating the supra-spinal mechanisms and biological basis beyond the gate control theory of stimulation. Neurophysiologic studies revealed that stimulation attenuates somatosensory evoked potential signals in both the primary and secondary somatosensory cortices. Neuroimaging identified the thalamus and anterior cingulate cortex as key structures responsible for supra-spinal effects. The use of novel waveforms such as burst simulation has also given the technology a use beyond managing pain. One particularly exciting new avenue is the treatment of movement disorders such as dystonia, multiple sclerosis, and Parkinson's disease.