Animal testing on non-human primates

Experiments involving non-human primates (NHPs) include toxicity testing for medical and non-medical substances; studies of infectious disease, such as HIV and hepatitis; neurological studies; behavior and cognition; reproduction; genetics; and xenotransplantation. Around 65,000 NHPs are used every year in the United States, and around 7,000 across the European Union. Most are purpose-bred, while some are caught in the wild. Their use is controversial. According to the Nuffield Council on Bioethics, NHPs are used because their brains share structural and functional features with human brains, but "while this similarity has scientific advantages, it poses some difficult ethical problems, because of an increased likelihood that primates experience pain and suffering in ways that are similar to humans." Some of the most publicized attacks on animal research facilities by animal rights groups have occurred because of primate research. Some primate researchers have abandoned their studi

Electrical spinal cord stimulation protocols to regulate neurological functions after spinal cord injury

Salif Axel Komi

Spinal cord injury (SCI) is a life-changing event. People who suffer from it lose their abilityto move normally and are subject to life-threatening symptoms. When the insult is not toosevere, partial recovery is possible. Otherwise, for severely affected people, the perspectives toever retrieve normal functions is almost non-existent. A critically important window to promoteplasticity is in the acute phase after the trauma (weeks to months). However, at this stage,people cannot take active part in rehabilitation programs due to their incapacity to activate theirlimbs and to the apparition of severe autonomic symptoms such as orthostatic hypotension.Hence, current activity-based treatments are of little help for this population. Consequently, SCIdramatically affects their autonomy and quality of life on the life-long term.Continuous Epidural Electrical Stimulation (EES) of the spinal cord has been proposed as amethod to reactivate dormant neural networks innervated below the site of injury. It enablesrobust control over locomotion and autonomic functions. In animal models of severe lesion,continuous EES promoted long lasting recovery of motor abilities when coupled with an intensivetraining. In human, its recent application indeed supported overground walking in chronicallyand severely injured people, but only showed limited plastic effects when compared to animals.Why? Recent advances support that continuous EES abolishes proprioceptive feedback thatis essential to promote recovery. Moreover, late treatment of severe injuries consistently fail apromoting recuperation of functions. Alternatively, over the last decade, our laboratory developeda spatio-temporally patterned approach to EES. In addition to restore fine control over motorfunctions, this technique avoids the caveats of continuous EES, and hypothetically opens a windowof opportunity for plasticity to happen. In this thesis, we propose a translation of this concept tohumans. We first demonstrate that spatio-temporal EES restores robust and versatile locomotorcontrol in people with chronic incomplete, though severe, SCI. Furthermore, the results supportan aptitude of this approach to promote long lasting recovery of functions without stimulationafter 5 months of intensive training. We then report on a patient-tailored technology, thatincludes personalized computational models enabling precise pre-operative planning strategies, anew electrode-lead and control softwares. This technology enables restoration of various motorfunctions in people with chronic and motor-complete injuries within few hours after beginningof therapy. Finally, we transfer this targeted approach to the control of blood pressure. Wedemonstrate that closed-loop stimulation protocols support a precise control over arterial bloodpressure in rodents, non-humane primates and humans with severe SCI submitted to challengingcardiovascular conditions. Combined, the results presented in this manuscript open a clinicallyrealistic perspective for the application of EES acutely after injury and to potentially promoterobust recovery in severe SCI.

EPFL2021

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

Flavio Raschella

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 increases the alertness and locomotor activity of the NHP, it has no effect on kinematic parameters during gait. The BSI, instead, alone or in combination with DBS, improves locomotor performance such that it approaches healthy locomotion. Therefore, I demonstrate that the BSI and DBS can be simultaneously applied, opening up the possibility of a combined therapeutic approach in human patients. As such, the subsequent step should be to test the efficacy of the BSI in treating PD patients.

EPFL2019

Electrical spinal cord stimulation protocols to regulate neurological functions after spinal cord injury

Salif Axel Komi

EPFL2021

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

Flavio Raschella

EPFL2019

Animal testing on non-human primates

Electrical spinal cord stimulation protocols to regulate neurological functions after spinal cord injury

Low-Dimensional Motor Cortex Dynamics Preserve Kinematics Information During Unconstrained Locomotion in Nonhuman Primates (vol

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

Electrical spinal cord stimulation protocols to regulate neurological functions after spinal cord injury

Low-Dimensional Motor Cortex Dynamics Preserve Kinematics Information During Unconstrained Locomotion in Nonhuman Primates (vol

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