“We need to be more innovative about what we combine and how – that’s the key. It’s not just about combining one intervention with another: there has to be a real neurophysiological mechanism linking them.
That’s what makes the difference between stacking treatments and actually building recovery”.
Ahead of her talk at the IFESS annual congress in Lecco, Monica Perez – Scientific Chair of the Arms + Hands Lab at Shirley Ryan AbilityLab – explains why restoring movement after spinal cord injury depends on combining neurostimulation, exercise, and pharmacology through a shared neurophysiological mechanism, and why the future of rehabilitation is inherently multidisciplinary.
Monica Perez, PT, PhD, MBA, is Scientific Chair of the Arms + Hands Lab at Shirley Ryan AbilityLab, Professor in the Department of Physical Medicine and Rehabilitation at Northwestern University, and a Research Scientist at Edward Hines Jr. VA Hospital. For more than 20 years, her work has focused on the neural mechanisms underlying voluntary movement control, in both healthy individuals and people with spinal cord injury — with the goal of translating these mechanistic insights into more effective rehabilitation therapies. Ahead of her talk at the IFESS annual congress, Perez spoke about her laboratory’s combinatorial approach to restoring upper limb function after spinal cord injury.
Professor Perez, your research combines transcranial magnetic stimulation, electrical stimulation, neuroimaging and behavioral techniques to investigate voluntary movement after spinal cord injury. Could you elaborate a little bit on that?
This is a way to access and target the spinal cord without stimulating it directly. Different groups use different methodologies, but our approach targets the descending inputs to the motor neurons, the motor neurons themselves by stimulating peripheral nerves — the signals meet in the spinal cord. This gives us another way to reach the spinal cord and strengthen its connections after a spinal cord injury.
We’ve published several clinical trials using this approach to strengthen the connection between the motor cortex and different muscle groups, which has enhanced voluntary motor output. We were the first group to apply this approach in people with spinal cord injury, in 2012, when we published the first proof-of-principle protocol in people with chronic cervical spinal cord injury. Since then, we’ve continued to optimize and refine it — it’s a protocol our laboratory has followed for many years now.
And what did this kind of approach teach you?
I think it’s an important approach because it’s grounded in principles of neuroscience and mechanisms of plasticity. Over the years we’ve learned that, depending on the severity of the injury, combinatorial approaches are extremely important — we’ve seen more success in patients with more severe paralysis specifically when we combine this protocol with exercise training and pharmacology.
These approaches need a mechanistic link between them to be successful. The deficits in spinal cord injury are very complex, especially in people with severe paralysis, so we need more combinatorial approaches. What we’ve learned is that you must understand the underlying mechanisms, and also how to make the protocol stronger given how severe the paralysis can be. We’ve had great success so far, but at the IFESS annual congress in Lecco I’ll present our new avenues — the future of these combinatorial approaches, and our vision for advancing neurostimulation.
And is this necessarily limited to the upper limbs, given that you’re Chair of the Arms + Hands Lab at Shirley Ryan AbilityLab?
No, this approach has also been expanded to the legs. We target leg muscles as well, and we do so bilaterally. We’ve even been able to target the arms and legs simultaneously in people with high cervical injuries.
Many rehabilitation interventions aim to enhance corticospinal plasticity, but clinical outcomes remain highly variable across patients. What do you think are the main biological factors limiting recovery after spinal cord injury?
I think it’s a combination of factors. We have to start by combining clinical outcomes with more sensitive assessments of patients’ underlying pathology.
Clinical outcomes are extremely important, but because most of them use nominal scales, they are less informative on their own, less intrinsically sensitive. If we combine clinical outcomes with more sensitive assessment measurements, we can get a better understanding of the patient’s initial state. There are techniques we can use for this, and they aren’t complicated.
These techniques help us characterize the patient better, and that’s fundamental for designing the intervention. We have to start from a good assessment of our patients, combining sensitive outcome measures with clinical outcomes, to better understand recovery, because every patient with spinal cord injury is different.
The pathophysiology differs because most spinal cord injuries are due to a contusion injury, with different areas of the spinal cord affected and different degrees of severity. So, we need proper characterization of patients. If you don’t characterize patients well before applying an intervention, it’s harder to understand whether the intervention had an effect, and in which areas. It’s a complex process, it’s not only about having a good intervention, but also about having good assessments to detect changes and inform how to improve it.
So, based on what you’re saying, rehabilitation protocols will become increasingly individualized and tailored to each patient?
Yes. The stimulation approach we use isn’t one-size-fits-all. We individualize it. The underlying principle stays the same, but we adjust the stimulation according to each patient’s specific deficit. If someone has greater impairment in the upper limb, in the flexor muscles, or in proximal versus distal muscles, we account for those differences to make the protocol stronger.
We’ve shown, and I’ll present data on this at the IFESS congress, that using the same stimulation protocol with the same parameters in a proximal and a distal muscle can produce good plasticity in one but not the other. This suggests different muscles may need different doses, because the central nervous system is complex and its connections to different muscles vary. So, we have to factor that into the treatment to make it more effective.
From a neurophysiological perspective, what is the rationale for integrating these different forms of neuromodulation?
Exercise is part of be the standard of care. We know it’s essential for strengthening those connections, but we also know it’s not sufficient on its own. So, we combine exercise-based rehabilitation with different forms of stimulation, or with other treatments such as pharmacology. I think the key is to combine interventions that target different aspects of the pathophysiology of spinal cord injury. That’s one approach, and it makes the interventions synergistic, helping produce a stronger effect.
There has to be a link based on an actual neurophysiological or biological mechanism for this to make sense. You could combine one stimulation approach with another without that link, but the outcome is much better when the interventions are connected through a shared mechanism. In my view, exercise should be the standard for everyone. It’s the base needed to strengthen those connections, but it’s not sufficient on its own. So, we enhance the effectiveness of exercise by combining it with these other targeted, synergistic approaches, with the goal of achieving greater recovery.
And within this scenario, what is the role of pharmacology?
I’ll show some data from our laboratory. We use a pharmacological agent that enhances the conduction of action potentials and synaptic plasticity, which complements the role of our neurostimulation protocol, since that’s also aimed at enhancing synaptic plasticity. So, the two are synergistic: they work together, targeting different aspects, but toward the same goal.
We’ve seen great success, and we keep pushing forward because more severe paralysis is much harder to target. Those patients have much more severe deficits, so we need to keep improving. I’ll walk through some of the history of how we make decisions in designing the next protocol. It’s a process of building, step by step, to make the protocol stronger.
Looking ahead, what do you think will be the next major breakthrough in restoring upper limb function after spinal cord injury?
I think the future lies in making this combinatorial process stronger. It could involve combining a repair agent or repair molecule – cells, peptides, or other molecules that repair the central nervous system – with approaches that strengthen those connections. Ultimately there may be other areas involved too, but I’m convinced it will be a combinatorial approach. We have extensive evidence that combining interventions leads to better outcomes, depending on the protocol. We need to be more innovative about what we combine and how we do it.
Patients with more severe outcomes present more difficulties; they’re more challenging for us as scientists to target, but we’re working on it. After 20 years in the field, I don’t see one single answer, but I do think we’re getting there and we need to push harder on clinical translation, by using and discussing these protocols much more. How do we make it better? It turns out to be a multidisciplinary question: one person, or even one team, can’t do everything alone.
You need to work in multiple teams, right?
Exactly. Even within one team, you need to look at multiple ways of targeting the approach to restoration. Multiple approaches mean you can combine efforts — collaborating with another team or having more than one treatment or strategy within your own. It’s difficult to know which combinations are best, but there are many ongoing efforts and groups working at that intersection right now.
We used to be more conservative, relying on a single treatment plus exercise, but this is evolving rapidly, which is good for our patients, because the evidence tells us we have to move in this direction. That’s why forums like the IFESS congress are so important: they bring different disciplines to the table, and that’s often where new ideas emerge to make these approaches stronger.
Is there anything you’d like to add to this discussion?
I’d say integration is extremely important and multidisciplinarity, too, both in assessments and in treatments. That means people with different roles and different expertise within the team, and multidisciplinary treatments as well. So: a multidisciplinary team, and a multidisciplinary approach, to reach the target.
I think we’re in a good moment right now, but we have to work together with different stakeholders. It’s not only about science if we want to move translation forward. To bring these protocols to patients, to the standard of care, we need much more than good science. Science is essential, but we also need to work with other stakeholders — the FDA, companies, universities, funders to get there faster. This is one of the reasons I recently completed and Executive MBA at the Kellogg School of Management at Northwestern University.
It’s an ecosystem.
Exactly. And I’m very grateful to IFESS for providing this forum to discuss these approaches, especially given that IFESS’s core expertise is in electrical stimulation — one of the best therapies we have. If you think about spinal cord injury, some of the most important improvements in performance come from neurostimulation approaches, regardless of which one you use. It’s an important forum, and I’m really looking forward to being there for these discussions with more people.
