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EPI_nanoSTIM Report Summary

Project ID: 661452
Funded under: H2020-EU.1.3.2.

Periodic Reporting for period 1 - EPI_nanoSTIM (Enabling motor control after a spinal cord injury through nanoscaled electrical)

Reporting period: 2015-10-01 to 2017-09-30

Summary of the context and overall objectives of the project

A spinal cord injury causes motor paralysis, sensory deficit, autonomic dysfunctions and a series of life threatening complications that, as of today, can rarely be ameliorated. In case of a complete paralysis, the chances of recovering volitional motor control below injury after two years is negligible.
Electrical stimulation of the spinal cord, already used to alleviate chronic pain, has been recently reported to elicit volitional motor control in paraplegics. Nevertheless, no detailed analysis was ever performed to establish the characteristics of the protocols adopted to facilitate recovery. In fact, only stereotyped trains of pulses have been employed as a standard in experimental research and clinics, and are sometimes associated with debilitating side effects related to the high intensity used.
Moreover, current technology hinders the potentials of electrostimulation, as well as the safe delivery of customized signals and the possibility to simultaneously stimulate and record electrical signals to target electrical stimulation on the most effective sites.
Finally, persons with a spinal cord injury cannot count on any pharmaceutical interventions aimed at sustaining the recovery of volitional motor control.

The results of this study might support the introduction of a novel generation of epidural electrostimulators to improve the recovery of functions after a spinal cord injury. Furthermore, new technologies and original pharmacology could take part in highly promising clinical trials for potential new medical devices and protocols of neurorehabilitation. Considering the relatively high incidence of spinal cord injuries, the promising goals of this research might soon contribute to reducing the overall financial costs related to health care and welfare of persons with spinal cord injury, improving their quality of life and in turn increasing their productivity and participation to society.
Considering the basic mechanisms shared between a spinal cord injury and other neurodegenerative disturbances affecting the neuromotor system (such as stroke), the findings of this research might bring to even greater benefits for a wider audience of beneficiaries.

This study aims at testing on in vivo preclinical models some promising innovative hardware and software tools for a new generation of electrostimulators, thus providing a very promising basis for future clinical trials to improve volitional motor recovery after spinal cord injury.
In detail, the aims are as follows:
- to refine a multielectrode array interface recently designed by Prof. Wentai Liu’s group at UCLA (Chang et al., 2014), exploiting the properties of innovative materials to improve the performance of stimulation;
- to develop and identify new variable patterns of stimulation to restore descending motor control after spinal cord injury;
- to validate the use of the planar and flexible interface also for recording electrical potentials from the surface of the dorsal cord in order to find the most effective sites of stimulation and assess the functionality of ascending and descending white matter tracts pre- and post- an experimental spinal lesion;
- to test, for the first time, new pharmacological agents to improve the impact of spinal electrical stimulation to restore motor control of paralyzed limbs;
- to assess the best protocols and technology both in an acute setting (pre and post lesion) and in a chronic condition;
- to explore at cellular level the mechanisms behind the effects of this innovative neuromodulation.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

While obtaining my certifications and training to perform in vivo animal research, I studied the current literature in the field, which was finalized into an extensive review paper about the neurophysiological mechanisms of spinal neuromodulation.
Afterwards, I designed new protocols of electrical stimulation using terminal experiments to evaluate the impact of an acute stimulation in modulating and restoring spinally-induced motor responses from lower limbs. These innovative paradigms of stimulation were designed starting from hind-limb electromyographic traces or from recordings from neonate and adult spinal cords, at rest or during stepping.
I delivered these complex patterns of stimulation (Dynamic Stimulation, DS) through a sophisticated planar multi-electrode epidural array recently devised in Prof. Liu’s lab at UCLA Department of Bioengineering. Then, the close collaboration with his team further improved the device with new electrode materials and coatings, which improved the quality and features of signals and allowed simultaneous epidural electrophysiological recordings from the dorsum of the cord.
DS was continuously delivered to multiple segments at very low intensity and in opposite directions, and was compared to the delivery of a train of impulses at 40 Hz, considered as a standard in experimental research and clinics.
In fully-anesthetized neurologically-intact animals, DS modulated motor responses and induced a short-lasting increase in spinal network excitability.
DS also demonstrated to potentiate weak input from the brain to the cord. Then, when this descending control was reduced, such as after a severe compression of the spinal cord, the acute delivery of DS through the innovative epidural interface restored some electromyographic responses from hindlimbs. The efficacy of DS delivery in animals with a chronic spinal cord injury provided insights on the intrinsic mechanisms of motor output modulation by neuronal circuits in the spinal cord and on the pathophysiology of an acute spinal cord injury. For the first time, we proposed electrostimulation across the acutely lesioned cord as a first surgical tool to limit the loss of functions following a spinal cord injury, opening a new vision for the early management of spinal cord injuries.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The main findings of the research pursued in these two years are that:
- a new protocol of electrical stimulation (DS) composed of noisy waves, applied to in vivo anesthetized animals, was more effective than current stimulating protocols to facilitate motor control. Indeed, DS seems to recruit a wider propriospinal network and increase the level of baseline excitability of spinal circuits, as well as their reconfiguration post-lesion, thus making exiguous descending axons, spared by the lesion, physiologically able to recruit sublesional motoneuronal pools;
- DS limits the loss of functions in the acute phase of injury;
- The refinement of an innovative array for a more efficient and independent epidural stimulation along multiple segments, as well as simultaneous recordings from the spinal surface.
In the third year, these discoveries will be shared with European experts in the field, in particular to further refine the resolution of signal delivered.
Then, the study will identify the mechanisms of recovery of volitional motor control using in vivo electrophysiological recordings from terminal experiments and in freely moving adult rats.
The results of this study can potentially bring to the patenting of a new array and an electrical stimulation protocol, as well as possible further preclinical studies to support the introduction of this neurorehabilitation method in clinical practice. If this happens, it will likely improve the quality of life and participation to society of the vast majority of persons that currently live with a spinal cord injury, while also reducing health care expenses.

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