Abstract:
Stroke is a leading cause of permanent disabilities worldwide. One third of the patients show only poor recovery of upper-extremity motor functions when reaching the chronic stage of stroke. To improve motor functions in chronic stroke patients, high-dose motor training interventions have been developed. However, the potential has not yet been investigated in patients with severe motor impairment. Additionally, neurostimulation is a widely used tool to facilitate motor recovery. The aim of this thesis was to (1) investigate the potential of a high-dose hand motor training intervention combined with associative neurostimulation in severely affected chronic stroke patients; (2) evaluate and adapt mapping methods for the presented patient cohort; (3) study clinical and neurophysiological effects following the intervention; and (4) evaluate the contributions of the two hemispheres in the recovery process and get insights in underlying recovery mechanisms. 21 severely impaired chronic stroke patients with hand paralysis took part in a within-subject, standard-of-care controlled clinical trial with high-dose upper limb training. The intervention consisted of two blocks of intensive daily upper-limb training lasting 3 weeks each, and two follow-up periods lasting 3 month each. During the training blocks, concurrent neuromuscular electrical stimulation (NMES) was applied to the paretic arm. In parallel, patients received ipsi- and contralesional cortical transcranial alternating current stimulation (tACS) during the training, which was applied in double-blind, randomised, cross-over order. The Fugl-Meyer Upper Extremity score (FMUE) was the primary outcome and assessed at all visits, while determining the minimal clinically important difference (MCID) with anchor- and distribution-based methods. Furthermore, contra- and ipsilateral corticospinal excitability (CSE) was assessed using transcranial magnetic stimulation (TMS) at the motor hotspot as well as by extended motor maps. The FMUE showed no significant changes during the control period. For the intervention period, there was a significant, clinically relevant FMUE improvement, with twelve patients showing a MCID. CSE and motor maps changed in both hemispheres following different patterns, i.e., the excitability of contra- and ipsilateral corticospinal pathways peaked after the first and second training block, respectively. Moreover, both FMUE and CSE of ipsilateral pathways improved significantly more, when tACS was applied to the lesioned hemisphere in the first block, and to the non-lesioned hemisphere in the second block. Finally, the excitability of the contralesional motor map predicted the amount of hand motor recovery independent of the clinical baseline status. This study provides evidence that clinically relevant motor recovery is possible when chronic stroke patients with severe motor impairment undergo high-dose motor training with NMES and tACS. The cortical hemispheres seem to play a complementary role during the recovery process. While contralateral pathways from the lesioned hemisphere are recruited first, ipsilateral pathways from in the non-lesioned hemisphere contribute gradually and peak in parallel to the clinical follow-up effects. Neuromodulation protocols that target both hemispheres in sequential order may enhance the recovery process in severely impaired stroke patients with hand paralysis.
Stroke