The research, published in the Journal of Neurology by a team at the Mayo Clinic led by Purnashree Chowdhury and B. Mark Keegan, retrospectively reviewed patients seen at the Mayo MS Clinic between 2002 and 2025. The investigators searched for people with progressive central nervous system demyelinating disease and at least one year of progressive upper motor neuron weakness that could be anatomically linked to a presumed demyelinating lesion of the cerebral white matter, the internal capsule, or the upper brainstem. Crucially, they excluded patients whose progressive weakness could be explained by lesions in the spinal cord or at the cervicomedullary junction, ensuring that the brain lesions themselves were the plausible culprit.

Out of more than two decades of clinical records, the team identified just seventeen patients who met these strict criteria. The lesions were located in the cerebral white matter in twelve cases, roughly seventy percent, in the internal capsule in three cases, about eighteen percent, and in the upper brainstem in two cases, twelve percent. Ten of the seventeen patients were female, and all were white. In thirteen patients, or seventy-six percent, the progressive course began from disease onset, while in four patients, twenty-four percent, progression emerged after an initial relapsing course. The median age at the onset of progressive motor impairment was forty-six years, with an interquartile range of thirty-eight to fifty-two.

The clinical picture that emerged was strikingly consistent. Sixteen of the seventeen patients, ninety-four percent, developed progressive spastic hemiparesis, a gradual stiffening and weakening of one side of the body, while a single patient developed monoparesis, weakness confined to one limb. This pattern makes anatomical sense: the corticospinal fibers that serve the arm and leg on one side of the body travel together in a compact bundle as they descend through the subcortical white matter, the posterior limb of the internal capsule, and the cerebral peduncles of the midbrain. A demyelinating lesion that strikes this narrow corridor disrupts a large volume of motor output despite occupying a relatively small amount of tissue.

Disability at the last evaluation was substantial. The median Expanded Disability Status Scale score, the standard metric used in multiple sclerosis research, was 5.5, with an interquartile range of 4.0 to 5.5. A score of 5.5 typically corresponds to difficulty walking without aid or rest over limited distances, underscoring how much functional impact a single, well-placed brain lesion can exert when it sits astride the corticospinal tract. The findings reinforce a concept the Mayo group has been developing for years: that in some patients with progressive demyelinating disease, disability accrues not diffusely but through a small number of lesions in anatomically critical locations.

Beyond the motor system, the study documented additional neurological consequences in patients whose critical lesions lay in the cerebral white matter. Cognitive impairment occurred in six of twelve such patients, fifty percent, and seizures occurred in three of twelve, twenty-five percent. These associations suggest that large or strategically placed subcortical demyelinating lesions can affect cortical and network function beyond pure motor control, a reminder that white matter lesions are rarely as silent as their location in non-eloquent-appearing regions might imply.

Supporting laboratory and pathological data added further weight to the diagnosis. Abnormal intrathecal production of immunoglobulin G, the hallmark oligoclonal band pattern consistent with multiple sclerosis, was present in ten of fifteen patients in whom cerebrospinal fluid markers were assessed, sixty-six percent. When tissue was available, the evidence was even more direct: neuropathology confirmed demyelination in four of six biopsy specimens. These findings help distinguish the syndrome from mimics such as primary lateral sclerosis, motor neuron disease, or slow-growing gliomas, which can present with similarly gradual, one-sided spastic weakness.

The study builds on a lineage of Mayo Clinic work that has progressively mapped the anatomy of critical demyelination. Earlier investigations described progressive motor impairment arising from critical lesions of the spinal cord and the cervicomedullary junction, and a prior study identified unilateral motor progression in multiple sclerosis associated with a critical corticospinal tract lesion. Related work on progressive solitary sclerosis, in which gradual motor impairment stems from a single central nervous system demyelinating lesion, and on tumefactive demyelination, where large lesion-like areas of demyelination can trigger Wallerian degeneration of the corticospinal tract, laid the conceptual groundwork. The present study extends this framework into the intracerebral white matter itself, completing a picture in which nearly any segment of the motor pathway, from the subcortical radiations to the cord, can host a lesion capable of driving relentless progression.

Why would a single demyelinating lesion produce progressive rather than static disability? Several mechanisms are plausible and are actively debated in the progression literature. Demyelination impairs saltatory conduction, forcing action potentials to travel slowly and unreliably along denuded axons. Over time, chronic demyelination can lead to axonal degeneration, and injury to axons at one level can trigger Wallerian degeneration of the fibers downstream, so that the functional deficit grows even if the visible lesion does not. There is also the concept of functional reserve: as long as enough parallel fibers remain intact, the nervous system compensates, but progressive loss of a critical tract gradually exhausts that reserve and clinical worsening becomes apparent. The clinico-radiological paradox, the well-known mismatch between lesion burden on magnetic resonance imaging and disability, is in part resolved by recognizing that location matters as much as load.

For clinicians, the practical message is one of vigilance. A patient with a demyelinating disease who develops slowly progressive, one-sided spastic weakness deserves careful scrutiny of the entire corticospinal pathway, not only the spinal cord. Advanced magnetic resonance imaging, including tract-specific sequences, can help identify lesions along the intracerebral corticospinal tracts, and cerebrospinal fluid studies and, in selected diagnostic uncertainty, biopsy can confirm the demyelinating nature of the process. Recognizing these rare intracerebral critical lesions may spare patients unnecessary treatments for misdiagnosed motor neuron disease and may sharpen the anatomical reasoning that guides prognosis. As the Mayo team concludes, intracerebral critical demyelinating lesions associated with progressive motor impairment can rarely occur along the corticospinal tracts of the brain, and knowing where to look is the first step toward seeing them.

Subject of Research: Intracerebral critical demyelinating lesions of the corticospinal tract causing progressive motor impairment in multiple sclerosis

Article Title: Progressive motor impairment from intracerebral critical demyelinating lesions

Article References: Chowdhury, P., Flanagan, E. P., Guo, Y., Tobin, W. O., Coen, B. A., Lucchinetti, C. F., Weinshenker, B. G., Kantarci, O. H., & Keegan, B. M. (2026). Progressive motor impairment from intracerebral critical demyelinating lesions. Journal of Neurology, 273(10), Article 629. https://doi.org/10.1007/s00415-026-14168-3

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14168-3

Keywords: multiple sclerosis, demyelinating disease, corticospinal tract, critical lesion, progressive motor impairment, spastic hemiparesis, internal capsule, cerebral white matter, Expanded Disability Status Scale, cervicomedullary junction, neurology, Wallerian degeneration

The biology underlying peripheral nerve repair is intricate. After a nerve is transected, the segment downstream of the cut undergoes Wallerian degeneration, a process in which the axoplasm and axolemma break down and myelin debris accumulates in the injured stump. This debris must be cleared before new axons can grow. Schwann cells, the glial cells of the peripheral nervous system, respond by rapidly de-differentiating into repair-mode cells that secrete pro-regenerative factors, digest myelin through autophagy, recruit macrophages, and form regeneration tracks, known as bands of Büngner, that guide growing axons from the proximal stump back toward their original targets. Macrophages, meanwhile, perform the dual tasks of removing debris and supporting axon elongation. Coordinating all of these players takes time; axons may need up to ten months to reach their target tissues, which is why clinicians have long sought drugs that can safely speed the process.

Neurotrophic factors, the signaling proteins that nurture neuronal survival and growth, have been an obvious place to look. Molecules such as nerve growth factor, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, VEGF and IGF-1 have all shown promise in experimental settings. Yet their clinical translation has been hampered by poor pharmacokinetics, high costs and significant side effects. Basic fibroblast growth factor, or bFGF, is one of the most powerful of these agents, secreted by Schwann cells and neuronal populations, and it stimulates the proliferation of neurons, Schwann cells and fibroblasts while playing a pivotal role in nerve and spinal cord repair. But native bFGF has a troubled clinical record. A trial in acute stroke patients failed to demonstrate efficacy and revealed fever, lowered blood pressure, elevated leukocyte counts and potential carcinogenic effects, largely because the growth factor also drives cell proliferation.

SUN11602 was designed to sidestep that problem. It is a small aniline-derivative molecule that mimics the neuroprotective effects of bFGF by engaging the same receptor, FGFR1, a transmembrane tyrosine kinase receptor to which bFGF binds with high affinity. Crucially, SUN11602 activates FGFR1 to induce expression of calbindin-D28k, a calcium-binding protein that helps maintain intracellular calcium homeostasis, without triggering the proliferative activity that makes native bFGF risky. The compound also boasts pharmacokinetics that make it a plausible drug candidate: oral bioavailability above 65 percent in rodents and dogs. Previous studies have suggested neuroprotective effects in models of Alzheimer’s disease, depression, Parkinson’s disease and traumatic spinal cord injury, but its role in peripheral nerve regeneration had not been tested.

To fill that gap, the Messina team used sixteen female Wistar rats and a surgically precise injury model. Under an operative microscope, the median nerve of the left upper limb was exposed at the middle third of the brachium and transected, then repaired with an end-to-end suture using two to three epineurial stitches of 9-0 monofilament nylon, replicating the standard clinical repair technique. Beginning 24 hours after surgery, one group of injured rats received SUN11602 at 2.5 milligrams per kilogram by oral gavage once daily for seven consecutive days, while injured controls received only saline. A sham group underwent incision without nerve section. The dose and route were grounded in earlier in vivo work by the same laboratory, and the study was conducted under Italian and European animal research regulations with approval from the Ministry of Health.

Seven days after suture, the differences between groups were visible under the microscope. Haematoxylin and eosin staining revealed that the injured, untreated nerves had the expected hallmarks of acute Wallerian degeneration: structural disorganization, oedema, vacuolization and early myelin and axonal degeneration. Nerves from the SUN11602-treated animals, by contrast, showed comparatively preserved architecture, with reduced vacuolization and less tissue disarray. In other words, the drug appeared to blunt the secondary damage that typically accompanies the degenerative phase, without abolishing degeneration itself, which the authors emphasize is a physiologically required step for successful regeneration.

The anti-inflammatory effects were equally striking. Toluidine blue staining, which highlights mast cells, showed that injured control nerves accumulated large numbers of these cells in the connective tissue and along axon fibres with irregular morphology and degenerating myelin sheaths. Mast cells congregate near peripheral nerves and are considered key orchestrators of neurogenic inflammation and neuropathic pain. In the SUN11602-treated group, mast cell accumulation was suppressed and axon fibre density was higher. Immunostaining for IBA-1, a marker of activated resident macrophages, and CD68, a marker of pro-inflammatory M1 macrophages that infiltrate the injury site and release cytokines, both showed intense upregulation after nerve transection. SUN11602 treatment significantly attenuated both, suggesting the drug restrains the inflammatory response that can otherwise impede repair in the critical first days after injury.

The compound also appeared to support the rebuilding side of the ledger. Immunofluorescence labeling for S100, a Schwann cell marker, showed more consistent and interconnected stained areas in treated nerves, indicating enhanced Schwann cell proliferation and myelinization. Quantification of myelin basic protein by ELISA confirmed the histological picture: concentrations of MBP were significantly higher in the SUN11602 group than in injured controls, evidence of increased myelin production at the molecular level. MCOLL staining, a histochemical method that distinguishes myelin in blue from collagen fibers in red, allowed the researchers to visualize the nodes of Ranvier and the organization of connective tissue around nerve fibers. Injured control nerves showed marked demyelination and disorganized collagen deposition consistent with fibrosis, whereas treated nerves displayed axonal remyelination and reorganized collagen architecture.

The authors are careful about what these findings do and do not mean. All evaluations were performed at a single early time point, seven days after suture, when axonal regeneration and remyelination are only beginning. The observed attenuation of myelin degradation, they write, should not be read as a global inhibition of Wallerian degeneration; rather, they hypothesize that SUN11602 may selectively reduce secondary or excessive demyelination in spared fibers, a distinction that will require ultrastructural analysis and time-course studies of myelin clearance to confirm. The histological improvements also remain unlinked to functional recovery, since no electrophysiological or behavioral testing was included. Future work, the team notes, should incorporate extended follow-up periods, functional and electrophysiological assessments, and combination strategies such as nerve conduits and biomaterials to better mimic complex clinical conditions.

Even with those caveats, the study adds SUN11602 to a short list of candidates that could reshape how peripheral nerve injuries are treated. Because it is orally bioavailable and lacks the proliferative liabilities of native bFGF, the compound addresses the two biggest obstacles that have kept neurotrophic therapies out of the clinic: delivery and safety. If the early histological benefits observed here translate into sustained axonal regrowth, remyelination and functional recovery in longer studies, an oral pill taken in the days and weeks after nerve repair surgery could become a genuine adjunct to the operating microscope. For now, the message from Messina is a proof of principle: the molecular machinery of nerve regeneration can be pharmacologically tuned, and the earliest, most inflammatory phase of repair may be the best place to intervene.

Subject of Research: Pharmacological enhancement of early peripheral nerve regeneration using the oral FGFR1 agonist SUN11602 in a rat median nerve transection model

Article Title: SUN11602 Accelerates Early Peripheral Nerve Regeneration in an Experimental Median Nerve Transection Model

Article References: Casili, G., Papalia, I., Ardizzone, A., Basilotta, R., Costa, A. L., Titolo, P., Esposito, E., Colonna, M. R., & Galeano, M. (2026). SUN 11602 Accelerates Early Peripheral Nerve Regeneration in an Experimental Median Nerve Transection Model. Journal of Cellular and Molecular Medicine, 30(19), Article e71375. https://doi.org/10.1111/jcmm.71375

Image Credits: AI Generated

DOI: 10.1111/jcmm.71375

Keywords: peripheral nerve injury, SUN11602, FGFR1, bFGF, Schwann cells, Wallerian degeneration, mast cells, macrophages, myelination, median nerve transection, neuroprotection, rat model

The central obstacle has long been mechanical. Optical windows implanted through the skull have transformed neuroscience by letting researchers image the living brain over months, but those implants are stabilized by bone. Peripheral nerves have no such anchor. They are wrapped in soft, mobile muscle and connective tissue, and they stretch and shift with every step. Earlier attempts at chronic nerve windows relied on rigid frames that were prone to instability, misalignment, and tissue damage, and were easily dislodged by the animals’ grooming. The new approach solves the anchoring problem with a flexible implant cast from polydimethylsiloxane, or PDMS, a silicone elastomer whose elastic properties closely match those of soft tissue.

Surgeons split the biceps femoris muscle overlying the sciatic nerve, displace it with fine sutures, and slide the folded PDMS window into a subcutaneous pocket. Skin tension holds the implant’s outer brim in a circumferential groove, while regenerating fascia grows through holes in the subdermal brim to anchor the device long-term. The result is a fluid-filled optical port with an injection septum through which dyes can be delivered and debris can be cleared. The numbers are striking: the soft windows remained embedded for a median of about seven weeks, with 90 percent lasting at least 18 days and some exceeding 80 days. Rigid 3D-printed acrylic implants of comparable size, tested as a control, lasted a median of only about nine days.

Crucially, the implant does not appear to interfere with the nerve it exposes. Mice with windows walked without asymmetry on a grid-walking test, and muscle force and electromyography measurements of sciatic-innervated muscles three months after implantation showed no deficits, with compound muscle action potentials in the normal range. Histological sections of windowed nerves roughly 90 days after surgery revealed axon densities and calibers indistinguishable from the opposite, unoperated leg. The researchers report that fluorescent signals from the transgenic labels did not photobleach appreciably, allowing the same individual axons, identified by fiducial features such as bends and swellings, to be tracked repeatedly over at least 24 days.

The imaging itself combines multiple modalities. Confocal and two-photon microscopy captured fluorescently labeled axons and Schwann cells within roughly 30 to 100 micrometers of the nerve surface, while second-harmonic generation imaging revealed the collagen and elastin of the extracellular matrix without any label at all. Genetically encoded reporters did much of the heavy lifting: Thy1-YFP and Thy1-GCaMP mice label neurons, and S100-GFP mice label Schwann cells. A topical dye called Nile Red stains myelin sheaths and lipid droplets, and an injected tomato lectin conjugate outlines blood vessels, even allowing the team to film individual blood cells streaming through intraneural capillaries. Axon diameters measured through the window averaged about 4 micrometers, consistent with large myelinated fibers in the mouse sciatic nerve.

Then came the injuries, and the window delivered a front-row view. Within minutes of a partial crush injury, Schwann cells near the damage site swelled, retracted, and shifted position, while myelin and collagen outside the injury zone remained stationary. Within 20 to 30 minutes, the fluorescent signal from affected Schwann cells dropped sharply, and over the following hour the cells beaded up and pulled back their membranes, behavior consistent with conversion to the mobile repair phenotype that Schwann cells adopt to clear debris and guide regrowth. In axon-labeled mice, the distal portions of damaged fibers lost their fluorescence over one to two days as Wallerian degeneration set in, with visible fragmentation by day two.

Regeneration followed with cinematic clarity. By four days after injury, thin new axonal sprouts tipped with growth cones had emerged from the proximal nerve segments and pushed through the injury zone, often retracing the paths of the degenerated fibers. The researchers estimate regeneration rates of at least one millimeter per day, matching published values for the mouse sciatic nerve. Growth cones of this kind had previously been filmed only in zebrafish and in very superficial mouse nerves, never in a major mammalian nerve trunk. In compression injuries that preserved the endoneurial channels, the delicate collagenous tubes left behind by degenerated axons, regrowing fibers closely aligned with those residual channels, supporting the long-standing idea that the extracellular matrix provides physical guidance cues for pathfinding. In one striking case, an axon encountering a surgically deformed channel deviated from it and sprouted multiple growth tips into a small defect in the epineurial collagen.

The platform also captured the slowest process of all: repair across a complete transection. The team cut the sciatic nerve entirely and bridged the 2.5-millimeter gap with a hemitubular PDMS conduit, chosen over a closed tube to permit optical access and nutrient exchange. Over days, mobile fluorescent cells, likely immune and stromal cells, populated the saline-filled gap, peaking in density around day eleven. By day 25, bundled axonal sprouts had crossed the conduit along its axis, and their density and organization continued to increase through day 35, accompanied by the return of grasping ability and sensation. Histology at day 59 confirmed small, myelinated regenerative axons at the distal end. In most of the conduit-repair mice followed, tissue cables formed, fluorescent regrowth appeared, and functional recovery was observed.

The authors are candid about limitations. Tissue scattering restricted imaging largely to the outermost portion of the nerve, an estimated 5 to 30 percent of its volume, and a fibrotic membrane inevitably formed against the implant within two to three weeks, degrading image quality, though it could often be mechanically cleared through the injection port. Whether that clearing itself disturbs regeneration remains untested, and the functional assessments in the uninjured window model involved small sample sizes. The transgenic reporters, too, are not perfectly cell-type-specific, labeling some non-neuronal and non-Schwann cell populations. Future refinements may include anti-fibrotic coatings, adaptive optics, three-photon excitation, and wearable or implantable cameras that could image awake, moving animals.

Even so, the implications are broad. By imaging the same nerve region repeatedly within the same animal, the technique eliminates inter-animal variability as a confound and makes it possible to link early injury events to later regenerative outcomes, something discrete histological sampling cannot do. On timescales of days to weeks, researchers can now track angiogenesis, Schwann cell migration, formation of the regenerative bands of Büngner, and extracellular matrix remodeling; on timescales of milliseconds to minutes, calcium transients, neuropeptide release, mitochondrial transport, and immune cell trafficking come within reach. The method is particularly suited to evaluating biofabricated nerve grafts, and could allow surgeons and scientists to see early whether a repair conduit is filling with regenerative tissue or failing. Combined in the future with genetically encoded calcium indicators or optogenetic actuators, the nerve window could enable both sensing and control of peripheral nerve activity, opening a new chapter in the study and treatment of peripheral nerve disorders.

Subject of Research: Longitudinal in vivo imaging of peripheral nerve injury and regeneration in mice using a soft PDMS optical window implant

Article Title: Longitudinal Single‐Axon‐Resolution Imaging of Peripheral Nerve Injury Response in Mice Using an Optical Window Implant

Article References: Luzhansky, I. D., Anisman, E., Perez, R., Zhang, S., Hoffman, M., Hunter, D., Cherian, A., Bonner, J., Feria, E., Ahmed, A., Malik, M., Du, J., Sudlow, L. C., Brogan, D. M., Wood, M. D., & Berezin, M. Y. (2026). Longitudinal Single‐Axon‐Resolution Imaging of Peripheral Nerve Injury Response in Mice Using an Optical Window Implant. Advanced Science, 13(53), Article e76375. https://doi.org/10.1002/advs.76375

Image Credits: AI Generated

DOI: 10.1002/advs.76375

Keywords: peripheral nerve injury, sciatic nerve, PDMS optical window, axon regeneration, Schwann cells, two-photon microscopy, Wallerian degeneration, growth cones, nerve conduit repair, endoneurial channels, intravital imaging, Thy1-YFP mice