Disinhibition of intracortical networks to augment crossed and uncrossed corticospinal pathways

Abstract

Multi-modal neurorehabilitation models for stroke patients recommend an approach based on severity of hemisphere damage. If the ipsilesional primary motor cortex (M1) is still intact, the crossed corticospinal tract (CST) can be targeted. However, severely affected patients rely on contralesional motor cortices and therefore the uncrossed CST. Disinhibition of intracortical networks can facilitate plasticity induction in the CST and therefore recovery. Motor execution or imagery (MI) results in an endogenous disinhibition. Exogenous modulation of inhibitory intracortical networks is achieved by a repetitive paired-pulse transcranial magnetic stimulation (TMS) protocol, referred to as DIS, or electrical stimulation (ES). A combination of the different disinhibition protocols has not been tested yet. Furthermore, the efficacy of targeting the uncrossed CST from contralesional M1 remains unclear. As the presence of ipsilateral motor evoked potentials (MEPs) from the uncrossed CST in hand muscles has escaped recognition, limited data is available. We hypothesized that lasting corticospinal excitability (CSE) changes could be achieved by associatively pairing endogenous modulation with exogenous stimulation of the same intracortical circuits. Furthermore, we investigated in detail the uncrossed CST. In this line of work, we combined MI of finger extension with DIS to modulate uncrossed CST in healthy subjects. For uncrossed CST, we tested different stimulation protocols for optimal detection of MEPs and combined DIS with active motor execution for CSE enhancement. Furthermore, modulation of ipsilateral CST was investigated in healthy subjects and severely affected stroke patients. MI combined with DIS resulted in a significant and persistent increase of contralateral CSE, e.g. of the crossed CST. A longer intervention duration further enhanced sustainability of CSE changes. MI alone, DIS alone, or MI/DIS in combination with ES did not result in changes of CSE. Ipsilateral MEPs from the uncrossed CST were reliably measured after TMS during biceps brachii (BB) contraction with a coil orientation of 45° to the sagittal line. Furthermore, paired-pulse TMS facilitated ipsilateral MEPs. DIS alone, but not in combination with MI, resulted in plasticity induction of ipsilateral CST. Additionally, DIS in combination with motor execution resulted in CSE increases in both healthy subjects and severely affected stroke patients. Taken together, we designed and improved two effective associative stimulation protocols combining endogenous and exogenous disinhibition of intracortical circuits. Each protocol was optimized to augment plasticity induction in contralateral or ipsilateral CSE, respectively. Both represent new, efficient interventions targeting either crossed or uncrossed CST and can be applied according to intactness of ipsilesional CST. This thesis may help in developing new therapeutic approaches in stroke rehabilitation, especially for severely affected stroke patients with no residual control of their paretic hand.