Brain-spine interface technologies to alleviate gait deficits after Parkinson's disease

Gait and balance deficits are motor disabilities that typically develop late in the progression of Parkinson's disease (PD). These deficits are thought to be the result of dysregulated neural activity in the cortico-basal ganglia-thalamic-cortical motor loop, caused by the depletion of dopaminergic and cholinergic circuits. PD patients exhibit gait abnormalities characterized by postural instability and reduced locomotor control, which diminish their functional independence and strongly affect their quality of life. This is further aggravated by the onset of falling events. These deficits represent a therapeutic challenge as they typically respond poorly or not at all to standard therapies, such as dopaminergic medication and deep brain stimulation (DBS). Whereas the efficacy of DBS in treating cardinal symptoms of PD, such as tremor, rigidity and bradykinesia is well established, effects on gait and balance deficits are still controversial. With disease progression the majority of PD patients develop a resistance to DBS treatment, which results in a significant worsening of gait and postural stability, while cardinal symptoms remain partially stable. In the last decade, Epidural Electrical Stimulation (EES) of the spinal cord has been proposed as a possible solution for improving locomotor performance in people with PD. Initial results on rodent and marmoset models of PD were promising. In these studies, EES was delivered continuously at the thoracic level of the spinal cord, without taking into consideration the locomotor state. However, translation to human patients led to conflicting results. In parallel, studies in spinal cord injury (SCI), in both animal models and patients, have drawn attention to the use of spatially and temporally specific stimulation protocols that independently engage flexion and extension muscles synergies. This strategy has allowed unprecedented progress, enabling full weight-bearing and restoration of locomotion after only a few days of application. In order to promote voluntary control of locomotion after SCI, a first brain-spine interface (BSI) was engineered to link the intended motor state to the EES protocols, re-establishing the altered communication between the brain and the spinal cord. In this thesis, I show that gait and balance deficits developed in the non-human primate (NHP) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD are similar to those observed in PD patients. Next, I describe the design of spatiotemporal EES protocols using the activation of the spinal motor neurons. I subsequently show that, although MPTP treatment drastically reduces the number of dopaminergic neurons in the substantia nigra, it has no detectable impact on the cortical dynamics underlying locomotion. Furthermore, I demonstrate that a BSI immediately alleviates gait and balance deficits in an NHP MPTP model of PD. Finally, I investigate the interaction between DBS and BSI in a MPTP-treated NHP. Although DBS incr