Neuromodulation (medicine) | EPFL Graph Search

Neuromodulation is "the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the body". It is carried out to normalize – or modulate – nervous tissue function. Neuromodulation is an evolving therapy that can involve a range of electromagnetic stimuli such as a magnetic field (rTMS), an electric current, or a drug instilled directly in the subdural space (intrathecal drug delivery). Emerging applications involve targeted introduction of genes or gene regulators and light (optogenetics), and by 2014, these had been at minimum demonstrated in mammalian models, or first-in-human data had been acquired. The most clinical experience has been with electrical stimulation. Neuromodulation, whether electrical or magnetic, employs the body's natural biological response by stimulating nerve cell activity that can influence populations of nerves by releasing transmitters, such as dopamine, or oth

Personalizable computational models of electrical spinal cord stimulation to restore function after neurological disorders

Andreas Rowald

Spinal Cord Injury (SCI) disrupts the communication between the brain and spinal circuits below the lesion, leading to a plethora of neurological impairments, including the loss of motor function. At present, the only medical practices to enhance recovery after paralysis are activity-based therapies. In severe cases, SCI-patients fail to produce active movements voluntarily and are therefore unable to fully benefit from these therapies. Epidural Electrical Stimulation (EES) applied over the lumbosacral spinal cord has demonstrated to enable locomotion in preclinical animal models and humans with SCI. EES may therefore play a pivotal role in the recovery of locomotion after SCI.However, neither has EES reached the same level of efficacy in humans as in preclinical animal models, nor is there consensus on the definition of clinically meaningful stimulation protocols. In the absence of clear understanding on how EES promotes the formation of motor patterns, stimulation protocols have been largely based on empirical observations. Instead, hypothesis-driven definition of stimulation parameters has demonstrated superior efficacy in other neuromodulation therapies, such as deep brain stimulation.In this thesis, I outline a computational approach to inform EES strategies for the recovery of neurological function after SCI. For this purpose, I leveraged a combination of finite element methods, neurophysical and neuromusculoskeletal models to refine our understanding on how EES promotes locomotion after SCI, inform the design of neuromodulation technologies and develop personalized EES treatments in humans with SCI.In the first part of this thesis, I provide evidence that EES recruits proprioceptive and cutaneous afferents in the dorsal roots. I suggest that the recruitment of proprioceptive feedback circuits promotes the formation of motor patterns. In contrary, the continuous recruitment of cutaneous afferents may disrupt the production of locomotion. In the next chapter, I study interspecies difference of EES. I argue that these differences necessitate the adaption of stimulation protocols to enable translation of EES as a therapy from preclinical models to humans. I propose the application of spatiotemporal protocols with low-amplitude, high-frequency bursts to improve the efficacy of EES in humans. In the following chapter, I describe a technological framework that enables the implementation of such stimulation paradigms in people with SCI. I outline how personalized computational modeling can be used for treatment planning. I then summarize how I advanced this rudimentary computational tool into a computational framework for the rapid elaboration of highly realistic personalizable computational models. I explain how I leveraged this framework to inform the arrangements of electrodes on a paddle lead to enable locomotion in large and diversified patient-cohorts, perform preoperative treatment planning and validate the efficacy of both the lead and treatment planning protocol in individuals with severe, chronic SCI. Finally, I summarize how I translated my computational framework for other use-cases including the control of hemodynamics and the evaluation of an optoelectronic system to enable locomotion in preclinical models.

EPFL2021

Neuroprosthetic system to restore locomotion after neuromotor disorder

Nikolaus Wenger

Neuromodulation of spinal sensorimotor circuits improves motor control in animal models and humans with Spinal Cord Injury (SCI) and Parkinson disease. Stimulation parameters are tuned manually and remain constant during motor execution which is suboptimal to mediate maximum therapeutic effects. Here, I present a novel neuroprosthetic system that enabled adaptive changes of neuromodulation parameters during locomotion and allowed to restore high-fidelity control over leg movements in paralyzed rats. Beyond the therapeutic potential, these findings provide a conceptual and technical framework to personalize neuromodulation treatments for other neurological disorders. Several limitations have restricted the development of neuroprosthetic systems for closed loop neuromodulation. (1) First, it required a mechanistic understanding of the relationships between stimulation features and the recruitment of specific sensorimotor circuits. I found that electrical neuromodulation primarily recruits afferent reflex pathways that lead to coordinated activity of leg muscles during stepping. Moreover, the specific electrode location on the spinal cord could activate distinct reflex pathways and activate specific leg muscle groups of paralyzed rats. These results have been leveraged for the design of flexible and stretchable multi-electrode arrays for electrical and chemical spinal cord stimulation. (2) Second, it was necessary to perform comprehensive mapping experiments to characterize the effect of neuromodulation parameters on hind limb kinematics in order to establish stable and robust feedback signals for real time control. Step height and ground reaction forces emerged as the primary targets for the control of closed loop neuromodulation after spinal cord injury. (3) Third, implementation and optimization of closed-loop neuromodulation strategies necessitated the development of an advanced technological platform that combined feedback and feed-forward loops that match the natural flow of information in the modulated neural systems. These integrated developments allowed animals with complete spinal cord injury to perform over 1000 successive steps without failure, and to climb staircases of various heights and lengths with precision and fluidity. Moreover, the neuroprosthetic system was able to alleviate locomotor deficits in an alpha-synuclein rodent model of Parkinsonâs disease. Current knowledge of human spinal cord properties in response to electrical neuromodulation suggests that the developed control policies can translate into clinical applications to improve neurorehabilitation therapies. Moreover, the developed neuroprosthetic system can readily be interfaced with control signals from the brain to establish cortico-spinal neuroprostheses that are intended to promote activity-dependent plasticity during recovery from spinal cord injury.

EPFL2014

The role of sensorimotor afferent feedback in mediating functional recovery after spinal cord injury

Kay Alexander Bartholdi

Spinal cord injury (SCI) leads to permanent deficits in sensory and motor function due to the physical disruption of descending and ascending pathways. As a consequence, spinal circuits below the level of lesion remain in an intact, but inactive state. A number of studies have shown that epidural electrical stimulation (EES) of the lumbar spinal cord can reactivate these spinal circuits after SCI. EES reversed paralysis of lower limbs in rodent and primate models of SCI as well as in a number of clinical case studies. However, although the positive effects of EES have been documented, little is known about the neural circuits through which EES enables motor pattern formation after SCI. In the first part of this thesis, we examined the neural circuits activated by EES. In the past, modeling experiments highlighted a pivotal role for large-diameter, myelinated afferent circuits in mediating the facilitating effects of EES after SCI. Using calcium imaging and chemogenetic inactivation experiments, we confirmed that EES primarily recruits proprioceptive and low-threshold mechanoreceptor feedback circuits. We next sought to exploit this knowledge to specifically enhance the effects of EES. We found that alpha2a receptors are prominently expressed on proprioceptive afferent neurons in DRGs, whereas alpha2c receptors are located on low-threshold mechanoreceptor interneurons in the dorsal spinal horn. Based on this knowledge, we built a computational model that identified beneficial and detrimental interactions between EES and noradrenergic circuits. This understanding guided the design of a circuit-specific, electrochemical neuromodulation that specifically gated the effects of EES towards proprioceptive feedback circuits and re-established locomotion in paralyzed mice and rats. The second part of this thesis uncovers the impact of movement on sensory afferent pathways. For this, mice were exposed to environmental enrichment (EE) or standard housing (SH). We found that EE primed sensory dorsal root ganglia neurons, inducing a lasting increase in their regenerative potential after SCI. This EE-mediated increase in regenerative potential was confined to proprioceptive afferent neurons and characterized through increased calcium signalling and CBP-dependent histone acetylation which is associated with enhanced gene expression. In a next step, we mimicked the exposure to EE using pharmacology. The pharmacological activation of CBP after injury enhanced axonal growth of proprioceptive afferent fibers and enhanced the recovery of sensory and motor functions. Here, we provide direct and conclusive experimental evidence for the mechanistic understanding of EES and EE and how they mediate functional recovery after SCI. Based on this knowledge, we identified specific receptors and epigenetic mechanisms for pharmacological modulation. Our findings demonstrate the importance of large-diameter afferent fibers in mediating functional recovery and will be important in establishing a framework for the design of targeted neuromodulation therapies after SCI in human patients.

EPFL2019