Severe upper limb impairment in chronic stroke patients does not respond to standard rehabilitation strategies; for this reason there is the need of new treatments that might be effective in patients with drastically limited residual movement capacity. In patients with moderate to severe upper-limb impairment, a slight improvement have been reported using robot-assisted rehabilitative treatment, even years after a stroke (Lo et al., 2010). Another innovative approach for the enhancement of motor recovery is represented by non-invasive human brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). These techniques can induce long-lasting changes in the excitability of central motor circuits via long-term potentiation/depression (LTP/LTD)-like phenomena (Di Pino et al., 2014b). A recent study reported a mild motor improvement after 10 sessions of rTMS in a group of severe chronic stroke patients (Demirtas-Tatlidedea et al., 2015).
Aim of present study was to explore whether the combination of these two approaches might enhance their positive effects on motor recovery. To the end of assessing safety and potential efficacy of the combination of robot-assisted rehabilitation and non-invasive brain stimulation in a group of chronic stroke patients with severe upper limb impairment, we designed a proof-of-principle double blinded semi-randomized sham-controlled trial. We used continuous theta burst stimulation (cTBS), a robust form of inhibitory rTMS inducing LTD-like changes lasting for about 1 h . The choice of employing cTBS on the affected hemisphere was based on the findings of our recent study, which suggested that this inhibitory protocol can improve the response to physical therapy (Di Lazzaro et al., 2013). Moreover, rTMS protocols suppressing cortical excitability have been shown to strongly facilitate motor learning in normal subjects (Jung and Ziemann, 2009). Jung and Ziemann suggested that such enhancement might involve the phenomenon of “homeostatic” plasticity, which can be induced in the human brain using a variety of brain stimulation protocols (Karabanov et al., 2015). Considering the close link between LTP and mammalian learning and memory (Malenka and Bear, 2004), an enhancement of learning after LTD induction might appear a paradox. However, the experimental studies by Rioult-Pedotti et al. demonstrated the existence of a homeostatic balance between learning and the induction of LTP/LTD (Rioult-Pedotti et al., 2000), thus showing that the ease of producing synaptic LTP/LTD depends on the prior history of neural activity. In the context of stroke, this predicts that by delivering a rTMS protocol that induces LTD-like effects on the stroke-affected hemisphere before performing rehabilitation, would luckily result in better relearning (Di Pino et al., 2014a).