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  • Periodic Report Summary 1 - NEUROPLAST (Implementation of a Novel Brain Machine Interface to Restore Limb Movement and Promote Recovery from Partial Spinal Cord Injury: Basic Studies and Clinical Application)

Periodic Report Summary 1 - NEUROPLAST (Implementation of a Novel Brain Machine Interface to Restore Limb Movement and Promote Recovery from Partial Spinal Cord Injury: Basic Studies and Clinical Application)

Spinal cord injury (SCI) causes alterations in the brain, as well as the sensorimotor and autonomic systems below the injury, and has devastating personal and socioeconomic costs. Although there is currently no cure, new research opportunities offer the prospect of accelerating both our understanding of the disorder, and the design of therapies to promote recovery. In this project I am investigating, in both animal models and patients, novel rehabilitation techniques that consist of activating the paralyzed muscles electrically, driven by the subject’s own movement intent. I expect long-term use of this type of motor neuroprostheses will lead to unprecedented levels of restored movement, while the subject uses the system, and to maintained functional gain even without the neuroprosthesis, after therapy is complete.

There is mounting evidence that the nervous system has an important ability to reorganize and heal itself, a mechanism referred to as “neural plasticity.” This evidence comes from studies in cell culture, animals and, in more limited number, humans. Most of these observations are based on Donald Hebb’s principle that “neurons that fire together wire together.” The idea of Hebbian plasticity is central to the project: I am exploring how neuroprostheses that associate movement intent and restored function with neurostimulation may induce adaptive plasticity and lead to movement restoration. Unfortunately, the postulate of Hebbian plasticity is deceivingly simple. In reality, much is yet to be discovered about the mechanisms of neural plasticity, how they are altered by a specific disease or injury, and how neural plasticity can be “guided” to promote recovery.

In the first phase of the project, carried out at Prof. Lee Miller’s lab in Northwestern University (Chicago, USA), I set out to do basic studies in animal models to: 1) understand better how the brain forms motor commands and causes movement, and 2) illuminate the neural changes underlying adaptation to long-term neuroprosthesis use, and assess their therapeutic potential. These goals are both relevant basic science questions and key for the development of novel rehabilitation techniques using motor neuroprostheses.

Historically, to understand how the brain causes movement, neuroscientists searched for a lawful relationship between the firing patterns of single neurons and behavioral parameters. Although these studies were very informative, it soon became apparent that there is not a single, robust lawful relationship between single neuron activity and behavior. Recent and accelerating technical developments provide the experimental tools for monitoring the activity of large numbers of neurons. Thanks to these tools, a number of groups are investigating movement planning and execution at the population level. I am especially interested in the “neural manifold” framework, which proposes that brain function is based on specific patterns of correlated activity that are determined by network connectivity, the neural modes (Fig. 1A,B).

My collaborators and I investigated, for the first time, the similarities between neural modes from different tasks in primary motor cortex (M1), the main motor area of the brain. We found that the structure of the neural modes is largely preserved for different arm and hand tasks (Fig. 1C), providing further support for the neural manifold framework. Moreover, some neural modes are activated following very similar temporal dynamics, despite the differences in motor output across tasks. A subset of these modes seems to capture a constant mapping between cortical activity and commands to muscles. These findings, elusive when examining single neuron activity, provide insight into how the brain controls movement. They also suggest that movement intent estimated using neural modes may provide the most appropriate control signal for a motor neuroprosthesis.

I also collaborated in a study where we applied this conceptual framework to study how the brain quickly adapts movement (short-term learning). By recording neural population activity from upstream premotor cortex (PMd) and M1, we found that fast behavioral adaptation is not mediated by changes in the firing properties of individual neurons. Instead, during movement adaptation, planning-related activity in premotor cortex explores new patterns within the region of the PMd manifold that does not effect on M1. These new PMd patterns recruit M1 in novel ways, thus driving the adapted movement. Critically, there are no plastic changes within any of these cortical areas, or in the functional connections (the mapping) between them. This study identified a new population mechanism that mediates short-term learning. It also has implications for neuroprosthetics, as it indicates that a neuroprosthesis should rely on activity patterns that lie in the existing manifold and that are “transmitted” through an existing mapping, so as to maximize ease of learning.

During this phase, I also integrated the first fully wireless cortically-controlled neuroprosthesis to restore movement. This neuroprosthesis comprises a wireless “neurosensor” that transmits neural data in real-time, a computer that maps them onto stimulation commands, and a wireless, fully controllable multichannel muscle stimulator (Fig. 2A). The neuroprosthesis also permits recording muscle activity during free behavior with another wireless transmitter. During pilot experiments with the neuroprosthesis in the laboratory, we could restore hand use to non-human primates (macaca mulatta) that had received a temporary nerve block. The final objective is to study long-term adaptation to neuroprosthesis use. To this end, I developed a month-long, reversible paralysis model using an implanted mini-pump that delivered the nerve blocking agent tetrodotoxin. Our group has also begun to record neural and muscle activity while the primates move freely in a purposely built plastic cage routinely (Fig. 2B,C). With this unique setup, we are beginning to investigate the basic mechanisms of motor control during free behavior using the neural manifold framework. In the next phase, we will study neural adaptation to long-term use of a neuroprosthesis to restore hand use. This ongoing project has tremendous potential to impact both rehabilitation and neuroscience.

The paralysis model has obvious ethical and practical advantages, but does not replicate some of the complications that follow an SCI, like spasticity or hyperreflexia. For this reason, I also worked with colleagues in the lab to implement a similar cortically-controlled neuroprosthesis to restore movement using muscle stimulation in rats (rattus norvegicus). The final goal of this ongoing project is to show that assisted movement that accurately replicates the motor intent induces neural plasticity and drives motor recovery after a real SCI. During this last year of my Marie Curie Fellowship, I will implement and evaluate clinically a non-invasive version of this neuroprosthesis to restore hand function in SCI patients. In this translational study, I will not detect motor intent with intracortical electrodes, but through recordings of residual muscle activity. I will then use this activity to activate the paralyzed muscles with preprogrammed muscle stimulation patterns. I expect this association of motor intent and assisted movement will induce associative plasticity and drive lasting recovery, even after therapy is complete. I anticipate that this study will provide evidence of this appealing rehabilitation approach for SCI, and contribute to elucidate how critical the timing and fidelity of the evoked movement are for this type of interventions.

By the end of the project, I expect to have advanced our current understanding of how the brain controls movement, and to have shown that neuroprostheses that assist intended movement with muscle stimulation can help restore movement after an SCI. The intertwined progress in neuroscience and rehabilitation, as in this project, has great potential to improve the quality of life of people who have suffered an injury to the nervous system. Understanding the brain is perhaps the greatest scientific challenge of our time; many basic neuroscience discoveries will likely have an impact of proportions that we cannot foresee.

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