Repeated motor cortex theta-burst stimulation produces persistent strengthening of corticospinal motor output and durable spinal cord structural changes in the rat

BACKGROUND: The strength of connections between motor cortex (MCX) and muscle can be augmented with a variety of stimulation protocols. Augmenting MCX-to-muscle connection strength by neuromodulation may be a way to enhance the intact motor system’s capacity for acquiring motor skills and promote function after injury to strengthen spared connections. But this enhancement must be maintained for functional improvements. OBJECTIVE: We determined if brief MCX muscle evoked potential (MEP) enhancement produced by single-block intermittent theta burst stimulation (iTBS) can be converted into a longer and structurally durable form of response enhancement with repeated daily and longer-term application. METHODS: Electrical iTBS was delivered through an implanted MCX epidural electrode and MEPs were recorded using implanted EMG electrodes in awake naïve rats. MCX activity was modulated further using chemogenetic (DREADDs) excitation and inhibition. Corticospinal tract (CST) axons were traced and immunochemistry used to measure CST synapses. RESULTS: A single MCX iTBS block (600 pulses) produced MEP LTP lasting ~30–45 min. Concatenating five iTBS blocks within a 30-min session produced MEP LTP lasting 24e48 h, which could be strengthened or weakened by bidirectional MCX activity modulation. Effect duration was not changed. Finally, daily induction of this persistent MEP LTP with daily iTBS for 10-days produced MEP enhancement outlasting the stimulation period by at least 10 days, and accompanied by CST axonal outgrowth and structural changes at the CST-spinal interneuron synapse. CONCLUSION: Our findings inform the mechanisms of iTBS and provide a framework for designing neuromodulatory strategies to promote durable enhancement of cortical motor actions.