Project Summary Emerging research has suggested that chronic stroke induced motor impairments exhibit a dependence on heighted brainstem mediated monoaminergic drive. Explicitly, an increase in descending monoamines is believed to increase spinal motoneuron excitability and thus (1) generate spasticity and (2) amplify the diffuse commands that are responsible for flexion synergy expression. Though modulating this descending monoaminergic drive yields tremendous potential in affecting both impairments, current pharmacological approaches prove inadequate and require lengthy titration schedules and elicit burdensome side effects. Thus, I propose the novel application of transcutaneous electrical ophthalmic trigeminal nerve stimulation (TNS). This non-invasive stimulus has been shown to attenuate systemic measures of monoamines and is believed to modulate monoaminergic brainstem areas such as the locus coeruleus. Such an ability to non-invasively reduce monoamines represents the possibility for substantial improvements in stroke induced movement impairments. To investigate this potential, the goal of the proposed project is to elucidate the effects of TNS on (1) upper limb spinal motoneuron excitability and (2) flexion synergy expression in chronic stroke survivors. Highly quantitative metrics will be employed for both aims. Spinal motoneuron excitability will be quantified through the tonic vibration reflex and deep tendon reflex and flexion synergy expression will be quantified with precise robotic measures of upper extremity work area. These measures will be conducted before, during and after either a real or sham TNS stimulus condition, with stimulus induced changes in the metrics compared between conditions and against a quantitative metric of systemic monoamines (salivary α-amylase). Preliminary work has highlighted the feasibility of the proposed measures and supported the posited rationale. Specifically, initial efforts have shown a reduction of motor impairments during TNS in individuals with chronic hemiparetic stroke. Findings from this study will act to inform an understanding of the functional role of monoaminergic contributions to human motor control. This will deepen our understanding of human motor control and could facilitate substantive efforts in the development of neurorehabilitation paradigms. Specifically, through the application of TNS detailed here, this project will supply initial evidence for a neuromodulatory probe with the potential to alter monoaminergic drive and reduce chronic stroke induced motor impairments. This will provide insight into the magnitude of monoaminergic contributions to upper extremity motoneuron excitability and flexion synergy expression and their susceptibility to changes in monoaminergic drive.