Targeted, activity-dependent spinal stimulation produces long-lasting motor recovery in chronic cervical spinal cord injury

Abstract

Use-dependent movement therapies can lead to partial recovery of motor function after neurological injury. We attempted to improve recovery by developing a neuroprosthetic intervention that enhances movement therapy by directing spike timing-dependent plasticity in spared motor pathways. Using a recurrent neural-computer interface in rats with a cervical contusion of the spinal cord, we synchronized intraspinal microstimulation below the injury with the arrival of functionally related volitional motor commands signaled by muscle activity in the impaired forelimb. Stimulation was delivered during physical retraining of a forelimb behavior and throughout the day for 3 mo. Rats receiving this targeted, activity-dependent spinal stimulation (TADSS) exhibited markedly enhanced recovery compared with animals receiving targeted but open-loop spinal stimulation and rats receiving physical retraining alone. On a forelimb reach and grasp task, TADSS animals recovered 63% of their preinjury ability, more than two times the performance level achieved by the other therapy groups. Therapeutic gains were maintained for 3 additional wk without stimulation. The results suggest that activitydependent spinal stimulation can induce neural plasticity that improves behavioral recovery after spinal cord injury.spinal cord injury | spike timing-dependent plasticity | recurrent neural-computer interface | rehabilitation

Paired Stimulation for Spike-Timing-Dependent Plasticity in Primate Sensorimotor Cortex

“…Surprisingly, this effect was only produced in two of 15 site pairs (13%). Effects in the other 13 site pairs predominantly showed global increases in connectivity (50% of pairs) or depression of the targeted site pair (44% of pairs), likely resulting from changes in excitability or generalized plasticity (Pascual-Leone et al, 1998). These results are consistent with other studies, both in vitro (Bi and Poo, 1998) and in vivo (Jackson et al, 2006), showing that the expected effects of STDP were variable and occurred only in a subset of cases.…”

“…The "presynaptic" site was termed A, the "postsynaptic site" B, and the third site, C, was used as a control. For Monkey Q, conditioning stimulation was performed with the Neurochip2 (Zanos et al, 2011) in the home cage to assess the efficacy of STDP while the animal was freely behaving, similar to previous monkey and rodent studies (Jackson et al, 2006;Rebesco et al, 2010;Rebesco and Miller, 2011;Lucas and Fetz, 2013;Nishimura et al, 2013). Stimulation pulses were bipolar and biphasic as described during testing.…”

“…Typical in vitro STDP studies document connectivity changes using a direct measure of EPSPs (Markram et al, 1997;Bi and Poo, 1998;Sjöström et al, 2001;Froemke and Dan, 2002) sponses (Nishimura et al, 2013), motor evoked potentials (Wolters et al, 2003), network modeling (Rebesco et al, 2010;Rebesco andMiller, 2011), andothers (Feldman, 2012). This study is one of the first to show long-lasting STDP in evoked LFPs mediated by cortical connections.…”

“…Functional motor recovery facilitated by STDP paradigms has been demonstrated in animal models of stroke (Guggenmos et al, 2013) and SCI (McPherson et al, 2015), as well as in stroke (Buetefisch et al, 2011) and SCI (Bunday and Perez, 2012) patients.…”

“…Pairing of neural activity with electrical stimulation in primary motor cortex has also produced STDP-like changes in cortical connections in nonhuman primates (Jackson et al, 2006;Lucas and Fetz, 2013;Nishimura et al, 2013;Zanos, 2013) and rodents (Rebesco et al, 2010). In these studies, recorded spikes, muscle activity, or cortical field potentials were used to trigger stimulation repeatedly at a distant, but connected site.…”