Our research was initially inspired by the original article in Brain (Stefan et al. 2000), which proposed that plasticity induced by their paired associative stimulation (PAS) protocol, may represent mechanisms parallel to associative long-term potentiation (LTP) in the human cortex . Stefan et al. found that low-frequency stimulation of an afferent median nerve combined simultaneously with transcranial magnetic stimulation (TMS) of an appropriate area of the contralateral motor cortex, leads to plasticity, seen as an increase in amplitude of motor-evoked potentials (MEPs) in the somatosensory afferents. The plasticity was induced rapidly (within 30 min), was persistent (minimum duration 30-60 min) yet reversible, and was topographically specific.
Importantly, whether or not an increase in amplitude of MEPs was measured after PAS, was dependent on the interstimulus interval (ISI) between TMS and PNS: in this case, effects from both sources would be approximately synchronous at the motor cortex if median nerve stimulation at the wrist was followed by TMS at an interval of 25 ms. (See figure on the right).
Figure from Stefan et al. 2000, showing the experimental design (TOP) for PAS of the right abductor pollicis brevis (APB) muscle and associated part of motor cortex, with the measured amplitudes of motor-evoked potentials (MEPs) in response to TMS, before and after PAS intervention (BOTTOM). For more details please see the original article.
Our research has developed a modified version of PAS. This version utilizes high-frequency PNS trains and TMS pulses given at 100% of stimulator output and leads to a robust MEP potentiation, an indicator of LTP-like plasticity. This modified PAS is not as dependent on ISI as the conventional protocols, and is not highly sensitive to small inaccuracies in initial TMS target determination. Thus, it is feasible in challenging clinical conditions where measurements with millisecond precision are not always possible. Our pilot clinical studies have shown that patients with chronic incomplete traumatic and non-traumatic para- and tetraplegia can benefit from PAS and gain better motor function of upper or lower limbs, often leading to increased independence. For more details see our Publications.
Our current main project is a double-blind randomized sham-controlled trial in subacute tetraplegic patients, sponsored by Wings of Life. We also continue conducting research in chronic SCI patients and healthy subjects with the aim of optimizing the protocol, combining it with other stimulation modalities, and expanding its use to new patient groups.