Then and Now: Annina Schmid Uncovers Neuropathic Pain Signatures

A physiotherapist by training, Annina Schmid never thought she would pursue a research path that was not fully clinical. During her graduate studies, though, she met neurophysiologist Elspeth McLachlan, who showed her the wonders of how a more mechanistic approach to research could help Schmid explore the biology behind chronic pain.

Back then, Schmid’s work in a rat model suggested that neuroinflammation could help explain why patients with mild nerve compression, also known as entrapment neuropathy, reported pain beyond the injured site.¹ Schmid also drew on her clinical experience in patients with chronic pain when she turned her attention to those affected by carpal tunnel syndrome (CTS), a common nerve pain condition that affects people’s wrists. By analyzing patient skin biopsies, she described morphological changes that extended far away from the site of compression.²

The Scientist featured Schmid’s early research in 2018. Since then, the physiotherapist and pain neuroscience researcher at the University of Oxford has pulled out all of the scientific stops, applying her basic neuroscience and clinical expertise to show that entrapment neuropathies go beyond mechanical compression and tension on the peripheral nerves, leading to neuroimmune changes that make pain last.

Looking at Human Wrists to Understand Chronic Neuropathies

Schmid and her team have used CTS as a model to understand the cellular and molecular underpinnings of neuropathic pain. According to Schmid, this condition is an excellent model for several reasons. First, it is common, making it easy for researchers to find participants for studies. It is a very localized injury, meaning that scientists can isolate injured and intact nerves from the same patient for comparison. Additionally, patients with CTS often do not exhibit comorbidities, making pinpointing the biological consequences of the syndrome easier. Lastly, surgery is a very effective intervention to treat the condition, which provides researchers with a unique opportunity to evaluate patients before and after surgery to assess injury- and recovery-related factors.

Using the CTS model, Schmid’s team investigated how sensory nerves regenerate after injury, assessing patients before and six months after surgical intervention.³ The team found that, following surgery, patients showed improvement in their pain, numbness, and tingling symptoms, as well as hand function, even though nerve regeneration was incomplete at the six-month timepoint. A closer look at skin biopsies revealed gene expression signatures associated with nerve fiber recovery, including upregulation of the gene adenylate cyclase activating polypeptide 1 (ADCYAP1), which encodes the pituitary adenylate cyclase-activating peptide (PACAP). This is a multifaceted molecule that acts as a neuromodulator and neurotrophic factor, altering the intrinsic properties of neurons and supporting their growth, maintenance, and survival.⁴ In vitro experiments using human induced pluripotent stem cell-derived sensory neurons revealed that exposure to PACAP facilitated outgrowth of neuronal projections.³ “[This] is obviously quite interesting because it suggests that there is potentially a therapeutic target for nerve regeneration,” Schmid said.

The researchers also used CTS to study neuroimmune interactions in neuropathic pain. Schmid and her team performed a comprehensive analysis of blood samples from patients in search of inflammatory markers associated with nerve injury and recovery.⁵ They observed upregulation of pro-inflammatory cytokines before surgery. In contrast, the recovery stage showed pro-resolution markers, including interleukin (IL) 9 which was associated with patients’ recovery from pain. “Carpal Tunnel Syndrome is a relatively mild focal nerve injury, so we were quite surprised that we could still find signatures in the blood [of] these patients,” Schmid said.

Beyond Carpal Tunnel Syndrome

While looking at blood may uncover systemic biomarkers associated with neuropathic pain, Schmid’s team also wanted to explore the changes occurring at the injury site. The researchers used biopsies obtained from patients with Morton’s neuroma, a form of entrapment neuropathy that affects the forefoot and can lead to sudden bursts or spasms of intense pain combined with a pins-and-needles sensation. For some patients, treatment of the condition includes removal of the injured nerve, providing researchers with nerve tissue to study local changes associated with the injury. Morton’s neuroma tissues showed demyelination and infiltration of immune cells, particularly of a type of macrophage that was associated with the condition’s sudden bursts of pain.⁶ Schmid’s team is currently studying sensory neurons in vitro to explore whether these macrophages increase the neurons’ excitability directly or indirectly through the release of modulatory molecules.

Schmid and her team have also started to generalize some of their CTS findings to other conditions, including nerve injuries after motor vehicle accidents, whiplash injuries, and spine-related leg pain, uncovering neuroinflammation and nerve fiber density changes in some of these conditions.^7,8 “We have started to go to the kind of conditions that we believe have similarities with carpal tunnel syndrome but are more complex to treat clinically,” she explained.

For Schmid, working with both patients and translational models makes her research feel like it has come “full circle,” in a scientific journey that, according to her, took an unexpected turn when she decided to enter the world of basic science. “That has opened so many doors for me and made me have a repertoire that spans from clinical trials to molecular work in a dish, which is very exciting to do in pain research,” she explained. “A lot of the things that happened, I just took the opportunities, and I have learned to just be open to opportunities even though these might sometimes be a bit daunting or scary to take. In my experience, it has always been incredibly worthwhile.”