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Featured Articles

The Promise of Targeted Neurostimulation in SCI Treatment


Last month, The National Institute of Neurological Disorders and Stroke (NINDS) — part of the National Institutes of Health (NIH) — awarded its prestigious R35 grant to Monica A. Perez, PT, PhD, to fund eight years of research into the long-term benefits and mechanisms of neurostimulation on patients with spinal cord injuries (SCI).

Read on to learn how Dr. Perez and her lab team — which joined Shirley Ryan AbilityLab from The Miami Project to Cure Paralysis in May 2019 — use precisely targeted neurostimulation to overcome damaged communication links between the brain and the body in patients with SCI.

How has the use of neurostimulation evolved?

The stimulation we use is not completely novel, but the way we’re using it is. Most protocols using paired associative stimulation in humans have targeted the motor cortex. For the first time, we are using paired associative stimulation to target spinal synapses in patients with SCI with the goal of enhancing motor output. In our protocol, we activate spinal motor neurons (via retrograde peripheral nerve stimulation) within a few milliseconds of the arrival of corticospinal action potentials (induced by magnetic and electrical stimulation of corticospinal axons). The key novelty of our approach is that we have found a way to target multiple upper- and lower-limb muscles simultaneously and combine this approach with physical therapy to achieve functional recovery. Neurostimulation is, by far, one of the most promising tools we have today to promote recovery in these patients — there is no doubt. As we enhance the efficacy of these protocols, improvements in recovery may continue to advance.

Tell us about your research.

Voluntary movement depends on synaptic connections between corticospinal axons — which encode the brain’s intent — and spinal motor neurons. Throughout life, synaptic connections are forged, in part, by activity-dependent plasticity. SCI eliminates spinal connections, resulting in devastating paralysis. Re-establishing these connections by inducing endogenous neural plasticity mechanisms could potentially restore voluntary movement. Our noninvasive paired associative stimulation protocol targets synaptic connections between corticospinal neurons and spinal motor neurons — a key site where descending commands influence motor output — to improve arm and leg function in patients with different levels of SCI.

The key breakthrough in using this protocol is that we can target multiple upper- and lower-limb muscles simultaneously by using the right timing. It is critical to ensure that the volleys elicited by stimulation of descending neurons reach the spinal cord in a precisely timed manner in relation to antidromic volleys elicited by stimulation of a peripheral nerve. This plasticity depends on the relative timing of pre- and postsynaptic action potentials. We do not just randomly stimulate the brain or the peripheral nerve. Instead, we use electrophysiology to measure the transmission times from the brain to the spinal cord, and the periphery to the spinal cord. These electrophysiological outcomes allow us to make these estimations.

This coordination effectively mimics a complete communication circuit between the brain and body based on fundamental principles of neuroplasticity.


What types of gains have your research subjects made?

To date, more than 60 subjects with chronic incomplete SCI have participated in our studies. They are randomized into two groups that receive either 30 minutes of targeted neurostimulation sessions followed by approximately 60 minutes of physical therapy, or sham neurostimulation followed by approximately 60 minutes of physical therapy. An additional experiment tests the effect of neurostimulation without physical therapy in a similar cohort. The targeted neurostimulation protocol has been customized to include patients with different levels of injury (cervical, thoracic or lumbar). We take measurements before the intervention, immediately following the intervention and then six months later. 

We’ve found that corticospinal excitability and the magnitude of maximal voluntary contractions in targeted muscles increase by 40%-50% after targeted neurostimulation with or without therapy, but that increase is not seen in the sham experiment. Individuals who also undergo physical therapy improve their walking speed and are able to grasp different objects more quickly. We’ve found that functional gains can last at least six months — a dramatic result for this patient population.

One of our research subjects, who initially was told she would never walk again following her SCI, was able to take more than 60 steps independently following 40 sessions of noninvasive neurostimulation and physical therapy. Following the same protocol, other research subjects experienced additional, significant, first-time gains, including using a manual wheelchair independently, dressing independently and gaining sensation where it had been lost. 

Where will your research go from here?

We’re not seeing any plateaus in our research subjects; every indication suggests that more promise lies ahead with this protocol.

For the next phase of research — for which we are now recruiting research subjects — we are applying stimulation to the brain and more than one peripheral nerve simultaneously, targeting sensory and motor fibers. Research subjects will undergo this treatment, combined with physical therapy, across 40 sessions.

In addition to researching subjects with chronic injuries, we have gained IRB approval to apply our protocol to patients who have recently experienced an SCI. So far, we have tested nearly 30 inpatients to gain an initial understanding of clinical and electrophysiological changes in this population. We have also used our paired associative stimulation protocol in one of them and seen pronounced improvements in physiological and clinical outcomes. Based on these results and the gains we’ve observed in the chronic population, it is possible that earlier intervention with this protocol could help to expedite recovery.

How might your research change the standard of care for patients with SCI — and what challenges remain before this change happens?

Right now, we are working on two aspects. One is optimization of the protocol to engage affected pathways: How can we strengthen these synaptic connections to elicit stronger and long-lasting changes in voluntary behaviors?

At the same time, we are seeking to determine the best time after injury to use paired associative stimulation for eliciting this plasticity. In this way, our neurostimulation protocol could be used as part of early treatments combined with conventional physical therapy.

Our neurostimulation protocol requires medical personnel with specialized training. The protocol is customized to each patient depending on how pathways are affected. Its use requires someone with knowledge of neurophysiological assessments. Not every physician has this training, but a neurologist or physician trained in physiological outcomes would. We are looking for ways to make the protocol more accessible and standardized so that it can be available in every facility.

Does your research into neurostimulation have potential application in other patient populations?

Theoretically. Because we target and regulate activity in the spinal cord, this kind of neurostimulation could work in people with multiple sclerosis or other disorders that lead to imbalances in excitability in the spinal cord. However, we haven’t tested it and don’t have any data to support that hypothesis. There’s still so much work to be done to make this protocol accessible to patients with SCI, but, yes, the promise exists.

What is your hope for patients with SCI 10 years from now? How might their outcomes and prognoses be different?

I have been working in this field for more than 15 years, and we need to make patient improvements happen faster. We need to shift the timeline for making our protocols stronger and more readily available to different types of patients. We need to expedite the transition from laboratory to use — and effectiveness — in the clinical environment.

My hope is that paired associative stimulation will become accessible to patients all over the world as the standard of care. We have data that these protocols are working. The key will be to do the intervention earlier in the rehabilitation process.


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Reversing Osteoarthritis: A Systemic Solution to Regrowing Cartilage


In a 2021 study published in Aging and Disease, Mitra Lavasani, PhD, Director, Translational Cell Therapy Lab at Shirley Ryan AbilityLab, and Seth Thompson, researcher in Dr. Lavasani’s lab and PhD candidate in Northwestern University’s Interdepartmental Neuroscience (NUIN) program, described the results of a novel stem cell treatment on naturally aged mice.

Instead of injecting stem cells locally, the team injected them intraperitoneally, enabling these cells to circulate systemically. The result: inflammation was reduced, regenerative cells flourished and cartilage was regrown — lending hope that osteoarthritis can be reversed.


What inspired this research?

Mitra Lavasani: This research was a continuation of work I published in Nature Communications (2012). In that work, we used stem cells to double the lifespan of artificially aged progeroid mice and delay the onset of certain common diseases. For this new study, we wanted to translate our findings to naturally aged 2-year-old mice — equivalent to an approximately 70-year-old human. We intraperitoneally injected adult progenitor cells that we had isolated from skeletal muscle of young mice — equivalent to a preteen human. We found that this systemic transplantation rejuvenated aged cartilage and increased its regeneration. This breakthrough was exciting because cartilage is one of the toughest tissues to regenerate and repair.

Why is it so difficult to repair cartilage?

Seth Thompson: The stem cells in cartilage — chondrocyte progenitors — are present throughout the lifespan. However, once cartilage starts to age and deteriorate, stem cell signals deteriorate, too. In other types of tissue that have circulation, like skeletal muscles, new stem cells or growth factors can enter the area and bring positive signaling. Cartilage is avascular, however, and is essentially a closed microenvironment.

As people age, they tend to generate elevated levels of inflammation in their knee joints. The knee’s synovial tissue contains inflammatory cells, which, in the case of an injury, clear away debris. However, when knee injuries occur later in life, the increased number of inflammatory cells actually can harm cartilage — leading to more debris, more inflammation and more damage. It becomes a continuous loop of elevated inflammation.

How did you discover that this stem cell treatment was actually regrowing cartilage?

Mitra Lavasani: Our goal with this experiment was not to regenerate cartilage; it was to increase the healthspan of naturally aged mice. Function is our number-one goal. Just as a physiatrist or therapist measures functional outcomes for patients, we use mobility and gait as our main functional metrics for mice. As our lab team increased treadmill speed, only the cell-transplanted mice could keep up, and even run — the subjects without cell transplantation could not. When we saw this result, we said, “Wow, what’s causing that?” Then, we went back and examined everything — neuromuscular tissues and cartilage — to see why this was happening. We discovered that the cartilage had experienced a huge change and regeneration.

What was behind the cartilage regeneration?

Mitra Lavasani: Following the stem cell injection, certain pro-inflammatory factors and senescent-associated secretory phenotype (SASP) factors that accumulate in the body — such as tumor necrosis factor (TNF) and Interleukin-1 alpha (IL-1a) — had decreased.  

Seth Thompson: Then, with inflammation down, the chondrocytes could return to being pro-regenerative, regenerating the lost collagen and proteoglycans that make up cartilage. By shutting down inflammation, the negative loop stopped: pro-regenerative signals increased, allowing cartilage regeneration to occur.

Mitra Lavasani: The really fascinating part of this experiment is that the transplanted cells were not found in the area of the cartilage, but the rejuvenating factors they secrete were able to change the microenvironment of the cartilage, activate dormant chondrocytes, repair damage and increase regeneration of cartilage — all far from the injection site. Basically, we tricked aged cells to regenerate cartilage by making the microenvironment seem more youthful. For example, we observed an increase in Pot1b, known as a pro-longevity gene, in addition to genes responsible for healthy collagens and proteoglycans.

How might this research translate to patients?

Mitra Lavasani: Ultimately, we hope to translate this approach in humans by first evaluating chondrocyte progenitor cells in patients before and after treatments. Then, we can better understand how the treatments affect the cells and their microenvironment. We can evaluate differences between males and females, and between young and elderly patients. By looking at what gene signatures are expressed, we can optimize and individualize treatments. Further into the future, we hope to identify the factors secreted by our stem cells that are critical for rejuvenating articular cartilage effected by osteoarthritis and begin human trials.

You’re not clinicians, you’re researchers — how does conducting your experiments in Shirley Ryan AbilityLab’s translational medicine environment affect your scientific production?

Mitra Lavasani: One major advantage of working here is the opportunity for collaboration. For another project I’m working on, we have direct access to 200 synovial fluid samples collected pre- and post-exercise by Dr. Prakash Jayabalan [Shirley Ryan AbilityLab’s Physician-Scientist Director of the Nancy W. Knowles Strength + Endurance Lab] from the knees of patients with osteoarthritis. Anywhere else, it would have been very difficult to acquire so many samples. I always say Shirley Ryan AbilityLab is a goldmine for stem cell biologists like me.

Seth Thompson: It’s also different to work in a building where you’re surrounded by patients, doctors and clinicians. You start to think more about the people who will benefit from your research.

Mitra Lavasani: Exactly. If I were isolated in a university building, I’d only be thinking about basic research. Here, I’m constantly thinking about how my research translates to making patients better. If we come up with something that won’t help them, we quickly tweak it based on what we learned, or pivot and pursue another direction.


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Redefining Pelvic Health Rehabilitation


Founded in the 1990s, the Women’s Health Rehabilitation program at Shirley Ryan AbilityLab (formerly known as RIC) initially focused on serving women experiencing pain after giving birth. The specialty was needed then because women were not being provided adequate care.

According to Sarah Hwang, MD, current program director, three decades later, that problem remains distressingly common.

“Unfortunately, when women bring up issues with their doctors, often they are told that problems like urinary incontinence are normal after having a baby — that they’re part of being a woman and something they must learn to live with,” said Dr. Hwang. “However, there’s so much that we can do to help with pelvic pain, bowel and bladder issues, and pain during and after pregnancy. People don’t have to suffer through it.”

During medical school, Dr. Hwang was passionate about both gynecology and PM&R. As a resident at RIC, working in the Women’s Health Rehabilitation program combined what she liked best in both fields. Specializing in PM&R enabled her to focus on function and quality of life for her patients.

After completing her residency, Dr. Hwang worked at University of Missouri Health Care, where she founded a new women’s health rehabilitation practice. After five years, she returned to Shirley Ryan AbilityLab with the goal of growing the program in the rehabilitation hospital where she began her career.

“Anyone Can Have Pelvic Pain”

Today, the Women’s Health Rehabilitation program continues in its founding mission of treating women with childbirth-related medical issues, while also expanding treatment to include pelvic floor dysfunction, nerve injuries and bowel/bladder issues. In addition, the program now also treats men, nonbinary and transgender individuals with pelvic floor challenges.

“Anyone can have pelvic pain,” said Dr. Hwang. “Over the last couple of years, we have had more and more referrals for transgender patients who experience pain, are undergoing hormonal treatments or require pelvic floor physical therapy before and after gender-affirming surgery.”

With this patient population in particular, Dr. Hwang emphasized that providing a safe space is key.

“It’s important to remember that a lot of transgender people have a history of poor experiences in healthcare,” she said. “As physicians, we must take extra care to engage and empower them in their healthcare decisions.”

Treatment Options

Today, patients with pelvic floor dysfunction generally have good results with a combination of physical therapy and medications. In fact, most patients require an average of just 12 therapy sessions. Those with chronic pain also can benefit from intravaginal injections in the muscles of the pelvic floor (including levator ani, bulbospongiosus, obturator internus and coccygeus).

“When physical therapy alone isn’t making adequate progress, I perform trigger-point injections with Lidocaine to aid in the treatment of trigger points and taut bands,” said Dr. Hwang. “These injections can result in better progress in physical therapy. In patients who have high-tone throughout levator ani that isn’t improving with physical therapy alone, I perform botulinum toxin injections, which can help to improve the tone of the muscles.”

For those with pelvic floor pain, dyspareunia or constipation, Dr. Hwang said she prescribes therapy to focus on decreasing tone through myofascial release, and strengthening other muscle groups to support the pelvic floor. Additionally, strengthening of the pelvic floor becomes a focus for those who have fecal and urinary incontinence.

Identifying and Addressing Patients’ Needs

Although some of these treatments are highly specialized and performed by a scant number of physiatrists in the U.S., Dr. Hwang stressed that the majority of patients with pelvic floor, bowel and bladder issues, and pregnancy-related pain will benefit from physical therapy. The biggest hurdle is that so many of these potential patients do not realize a physiatry team can help them. They key, said Dr. Hwang, is for medical providers to break the ice.

“A recent study looked at women with low back pain and pelvic girdle pain, assessing for pelvic floor problems. Researchers found that 95.3% had some form of pelvic floor dysfunction,” said Dr. Hwang. “Even if you are a musculoskeletal physiatrist who is only treating a patient for back pain, you should at least consider that the pelvic floor could be involved.”

To catch many patients who are suffering and would benefit from treatment, Dr. Hwang recommended including questions on intake forms such as, “Do you have pelvic pain? Do you have pain with intercourse? Do you have incontinence of bowel or bladder? Do you have chronic constipation?”

The next step is finding a physical therapist with specialized training in pelvic floor issues, either through the American Physical Therapy Association or the Herman & Wallace Pelvic Rehabilitation Institute. According to Dr. Hwang, finding a specially trained PT can be easier than one might assume.

“When I was at Mizzou, we were in a fairly rural area, but I still was able to connect patients with PTs qualified to do pelvic floor therapy. They were usually no more than an hour’s drive away,” she said. “Finding a therapist to whom you can send patients is the key to treating them effectively.”

Many physical therapists can teach patients the skills they need, such as how to use a dilator and TheraWand, and continue therapy at home on their own. Physicians who are unable to locate a pelvic floor physical therapist who is convenient for the patient may also consider telehealth.

“One does not need to specialize in pelvic floor rehabilitation to support these patients in their recoveries,” said Dr. Hwang. “As physiatrists, we’re uniquely equipped to help them recover and thrive.”


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COVID Peripheral Nerve Damage & Diaphragm Muscle Dysfunction: What We’ve Learned


In March 2020, Shirley Ryan AbilityLab neuromuscular researcher Colin Franz, MD, PhD, began noticing the significant debilitation of patients who had survived severe cases of COVID-19. This awareness motivated him to shift the focus of his research.

Six months later, Dr. Franz and his team published a paper in the British Journal of Anaesthesia that identified permanent nerve damage in patients with COVID-19 who had been on ventilators and placed in a prone position. This discovery has led to improvements in patient care.

How does an expert in nerves — who, by his own admission, “doesn’t know about virology or immunology” — contribute to the fight against COVID-19? What vital role do physiatrists play in the care of COVID-19 patients? How did Shirley Ryan AbilityLab’s unique medical residency research track set up Dr. Franz for success?

Read the conversation with Dr. Franz.

What was the catalyst for your research?

I’m an outpatient physician and scientist, and I run the Electrodiagnostic Lab at Shirley Ryan AbilityLab. In the early days of COVID-19, when we were all in the “fog of war,” all outpatient services largely came to a halt, and I was the only person left running my research lab and performing EMG tests. Dr. Rydberg and Dr. Soriano, who were working on our COVID Care Unit, told me about a patient who they thought had a nerve injury, and asked me to do an EMG. Within a few days, there was a second patient with nerve injury. Then, a third. For a few months, these tests and consultations on COVID patients with neuromuscular complications consumed my clinical work.

In the process, I found that approximately 15% of the most severely ill COVID patients — those who were placed in the prone position in the ICU — have permanent nerve damage. I had some patients who had up to nine distinct neuromuscular diagnoses by the end of a test. Injuries to arms and legs outside of the central nervous system are devastating and underappreciated, as nerve regeneration is so slow and inefficient in the peripheral nervous system. Because of the nature of the nerve and muscle damage, these survivors of severe COVID will be the ultimate long-haulers and will continue to need extensive rehabilitation for months, if not years.

I wasn’t the first physiatrist on campus to be asked to step up to the challenge of COVID-19, but I found a role in which I was uniquely suited to make a contribution. I’m grateful for the opportunity to help these patients.

How can physiatrists identify this COVID-related nerve damage? What are the warning signs?

The biggest warning sign in recognizing acquired nerve injuries in COVID-19 patients is asymmetrical weakness that is way out of proportion with the opposite side of the body. Of course, in rehabilitation medicine, we’re used to symmetrical weakness patterns from myopathy and neuropathy after critical illness. The situation with COVID patients is different, however; when we frequently see asymmetry — like wrists, ankles or shoulders paralyzed on just one side of the body — it’s a clue that we need to investigate more.

A second hidden neuromuscular complication involves the diaphragm. At the recent AAPM&R meeting, I presented unpublished data  in which we used ultrasound and found an incredibly surprising amount of diaphragm muscle weakness in the vast majority — 80% — of COVID patients who have survived critical care. This weakness is in addition to the shortness of breath from pneumonia-related lung damage caused by COVID infection. However, the substantial weakness in the diaphragm muscles is expected to make recovery slower as it represents an acquired neuromuscular respiratory disease.

Another telltale sign with these patients is when shortness of breath affects sleep — they're not getting good oxygenation, and they can't lie flat. As a result, they wake up throughout the night, or they have a headache in the morning. You can even see metabolic disturbances on basic laboratory tests, such as an elevated bicarbonate level related to hypercapnia. If anyone comes into rehabilitation after COVID, I’d suggest screening through a neuromuscular diaphragm ultrasound examination.

Most physicians trained in internal medicine are not going to pick up on this kind of shortness of breath, so it’s up to physiatrists — those of us who think about nerves and muscles — to be on the lookout for these issues and be prepared to address them creatively.

Is there anything about COVID patients as a group that is different from other PM&R patients?

They never seem to complain! Severe COVID-19 survivors have been through such a terrible illness, and they have every reason to complain, but they don’t. I’d ask patients what their issues were, and they would say, “You know, Doc, I’m doing pretty well, actually” — even when they couldn’t lift an arm or move a leg. As a result, nerve injuries are no doubt overlooked and underreported. It’s up to us to identify and address these issues.

What’s next with your work with COVID-19 patients?

COVID-19 has presented us with an opportunity to accelerate some of the research on nerve damage that we were already leading. In terms of diagnostics, we’ve been really interested in identifying better ways to characterize and locate nerve problems. Our ability to do so has been improving through use of better techniques, including advanced imaging options such as MRIs and high-resolution neuromuscular ultrasound. The benefit of our field is that we can analyze living, breathing, rehabbing COVID survivors — and learn much in the process.

One major problem to solve relates to positioning. For prevention and quality improvement, prone positioning for respiratory symptoms is potentially life-saving. However, sustaining that position over time is associated with significant nerve damage. To address this central issue, we’ve developed a pressure map of hot spots for nerve sensitivity and suggested modifications to the ICU protocol. We’re also developing sensors for new applications to identify nerves under distress before they get damaged.

Nerve Damage Illustration

Most COVID patients won’t need surgery, but their nerves do need to heal. On the therapeutics front, we are ready to roll out a precise, non-invasive, low-frequency stimulation to the nerve that is just proximal to point of injury. We’re developing a protocol out of our bench work to guide us in understanding the best dosage so that we can optimize it accordingly and make the data available.

With so many people infected with COVID-19, it’s a race to get our insights out there and to help as many patients as possible. Every article we’ve published is available on open access. I also welcome connections and discourse through Twitter.

You were Shirley Ryan AbilityLab’s first resident in the research track — what was that experience like and how was it unique?

Shirley Ryan AbilityLab initially committed time and resources to develop this first-of-its kind program more than a decade ago. When I first met with [Chief Medical Officer] Dr. Jim Sliwa before I started my residency, he laid out the research track for me. It was exciting to give my input to make the program even better, because no one had done it before. In time, a lot of doors opened up for me to do high-powered science. Now, the program’s offered to every single resident who sets foot in the building. Every time I interview applicants, they ask me about it.

What impact did the research track have in shaping your approach to practice and your COVID research?

My research looked at using activity to augment or enhance nerve repair and regeneration. Looking back, I benefited from the unique insights gleaned from working with patients, identifying problems and finding ways my research could help address those problems — it was a kind of reverse translation. By having better insights, I was able to ask even better questions and be more creative in my thinking and approach.


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