Carpal tunnel syndrome (CTS), the most common entrapment neuropathy, is exceeded only by low back pain as a cause of employee absenteeism. Maladaptive neuroplasticity in the brain of CTS patients has been noted by several neuroimaging studies, and includes altered primary somatosensory cortex (SI) somatotopy and SI hyperactivation, which may be due to cortical disinhibition. We hypothesize that the disability and pain associated with CTS is not only a consequence of the peripheral nerve lesion but also relates to the observed, altered cortical sensory processing. Acupuncture has shown potential as a conservative treatment option for CTS, but its mechanisms of action are unknown. CTS is an excellent model for studying acupuncture mechanisms as clinical improvement can be evaluated by several objective outcome measures in addition to subjective symptom assessments. We propose that acupuncture, a somatosensory conditioning stimulus, can reverse CTS-associated maladaptive neuroplasticity including cortical disinhibition via use-dependent plasticity. Furthermore, it is known that repetitive stimulation - in the healthy brain - results in temporally defined changes of cortical activity, the most prominent of which is a reduction in cortical response with extended stimulus duration. This is referred to as adaptation. Cortical disinhibition is known to modulate adaptation metrics. We propose that a biobehavioral assessment of cortical disinhibition quantified by maladaptive change in adaptation metrics will be sensitive to brain abnormalities in CTS. Thus, these metrics complement our fMRI data, potentially providing important cross-validation via an independent testing protocol. CTS patients randomized to verum acupuncture (forearm acupoints) and placebo acupuncture groups will be evaluated with adaptation metrics. We hypothesize that verum, but not sham acupuncture will alleviate CTS pathology and increase cortical inhibition, leading to normalization in adaptation metrics. Improvement in adaptation metrics will correlate with fMRI biomarkers and median nerve dysfunction. Hence, we will combine biobehavioral testing with fMRI neuroimaging to better delineate the central mechanisms by which acupuncture ameliorates CTS pathology. By understanding the neural mechanisms of different forms of acupuncture therapy, we hope to refine acupuncture utility for CTS and advance rehabilitation options in CTS care. PUBLIC HEALTH RELEVANCE: Carpal tunnel syndrome (CTS) is a very common ailment resulting from excessive compression of the median nerve in the wrist and consistently leads in lost work time among major disabling injuries. Acupuncture has shown potential as a conservative treatment option for CTS, but its mechanisms of action are not known. This grant will assess changes in brain activity and cortical disinhibition that accompany the dysfunction in the wrist, as well as how acupuncture might modify both local nerve health and brain function to help treat CTS patients.