Rethinking Stroke Recovery: New Insights into Neuronal Remapping and Rehabilitation Potential
Dan Lewis Foundation

Stroke is a common neurological condition that damages brain cells (neurons) in the affected area, leading to a loss of the functions controlled by that region. A hopeful aspect of stroke recovery is that, over time and with rehabilitation, many individuals regain some abilities. This recovery has been linked to a process called “remapping,” where neurons in unaffected areas of the brain adapt to take over the functions of the damaged areas. Although many studies have explored this remapping phenomenon, most evidence has been indirect, based on changes in brain activation patterns or neuron connections after stroke in animal models. Direct proof that neurons change functionality after stroke has been lacking, partly because measuring neuron activity in the brain over time, especially at the necessary scale and duration, is challenging.

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With advances in neuroscience and microscopy, we set out to test the remapping hypothesis and obtain direct evidence. We induced precise strokes in the part of a mouse’s brain responsible for processing sensory information from whiskers—the somatosensory whisker barrel cortex. While humans don’t have whiskers, the whisker barrel cortex in mice has key features that make it ideal for studying fundamental neuroscience questions. Mice use their whiskers as a primary sensory tool, and the whisker barrel cortex has a precise anatomy where each whisker’s sensory data is processed in distinct columns (or barrels) in the cortex, arranged just as whiskers are on the snout. This setup allows us to pinpoint brain areas activated by specific whisker stimulation.


Using specialized microscopy to observe hundreds of neurons in real-time, we tested remapping by targeting a stroke to a specific barrel of neurons, the “C1” barrel. Before the stroke, only a few neurons in neighboring barrels responded to the C1 whisker. Based on the remapping theory, we anticipated that after the stroke, these nearby neurons would take on the C1 barrel’s function. Surprisingly, we found the opposite: fewer neurons responded to the C1 whisker, and this low response rate persisted for up to two months. When we stimulated other whiskers, these same neurons responded normally, indicating they weren’t damaged but had lost responsiveness specifically to the C1 whisker.


We then applied a rehabilitation technique known as forced use therapy, trimming all whiskers except the C1 whisker, akin to encouraging stroke patients to use a weaker limb during physical therapy. This approach didn’t increase the number of neurons responding to the C1 whisker, but the few neurons that did respond showed more reliable responses with forced use therapy. Our

findings indicate that remapping doesn’t occur naturally after stroke; instead, rehabilitation may work by enhancing the function of existing neurons rather than promoting remapping.


Our study has some limitations. Humans don’t have whiskers, so our results might not translate directly. Additionally, we focused on the sensory system, and other brain areas, like the motor cortex, might recover differently. However, our work adds to evidence suggesting that adaptive plasticity and remapping in brain areas spared by stroke are limited, not enhanced. While this might seem discouraging, it opens new avenues for brain recovery. We may be able to restore function by targeting spared neurons that are dysfunctional but not irreversibly damaged, creating a critical window for post-stroke interventions like optimized physical therapy.


In future work, instead of assuming spontaneous brain remapping, we aim to investigate the specific circuits and molecular mechanisms that limit adaptive plasticity after brain injury. We’re expanding our whisker barrel cortex model and using genetic tools to examine how different types of neurons are affected by stroke. We are studying interactions between neuron populations to understand how these relationships affect remapping potential. Additionally, by analyzing changes in gene expression within neuron populations, we hope to identify new molecular targets that could lead to therapies promoting plasticity, remapping, and recovery for stroke and other brain injuries.

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By Dan Lewis Foundation April 2, 2025
For the third consecutive year, the Dan Lewis Foundation for Brain Regeneration is proud to announce the DLF Prize competition. The 2025 DLF Prize, a $20,000 award, will recognize an outstanding early career scientist (2 to 5 years post-doc) conducting innovative research in neuroscience, pharmacology, or biotechnology. This prestigious prize honors researchers whose work aligns with the DLF mission to drive breakthroughs in neural regeneration and repair. The current research priorities of the DLF are: Pharmacological Reactivation of Neural Repair: Research into pharmacological methods of reactivating or augmenting synaptogenesis, neurogenesis or axonal repair. Cell-Based Cortical Repair: Investigating the potential of derived cortical neurons to restore function in damaged cortical regions. Transcriptomics of Neural Recovery: Characterizing transcriptomic profiles of cortical neurons in the recovery phase following brain injury to identify pathways that drive repair. Molecular Inhibitor Targeting: Advancing anti-sense oligonucleotides (ASO’s) or small-molecule therapeutics designed to downregulate inhibitors of neural regeneration in the cortex or spinal cord. Application for the 2025 DLF Prize can be made by going to our website— danlewisfoundation.org —and clicking on the Tab “ 2025 DLF Prize ”. This will bring you into the application portal. The application portal opened in March, 2025 and will remain open through May 31st. Once in the portal, you will find complete information about the DLF prize, eligibility requirements, and an application form which can be filled in and submitted online. The winner of the 2023 DLF Prize, Dr. Roy Maimon, continues his research indicating that downregulation of PTBP1, an RNA-binding protein, can convert glial cells into neurons in the adult brain (Maimon et al. 2024) .* Dr. Maimon, currently a post-doc at the University of California, San Diego is currently interviewing for a faculty position at several prominent neuroscience departments. The winner of the 2024 DLF Prize, Dr. William Zeiger is a physician-scientist in the Department of Neurology, Movement Disorders Division, at UCLA. Dr. Zeiger has expertise in interrogating neural circuits using a classic “lesional neurology” approach. He states, “Our lab remains focused on understanding how neural circuits become dysfunctional after lesions to the cortex and on investigating novel circuit-based approaches to reactivate and restore damaged cortex”. * Maimon, Roy, Carlos Chillon-Marinas, Sonia Vazquez-Sanchez, Colin Kern, Kresna Jenie, Kseniya Malukhina, Stephen Moore, et al. 2024. “Re-Activation of Neurogenic Niches in Aging Brain.” BioRxiv. https://doi.org/10.1101/2024.01.27.575940.
By Dan Lewis Foundation April 2, 2025
Alan was injured in 2021, at age 42. An art teacher in Lakewood, Colorado, Alan was riding his bicycle after school and was crossing at an intersection when a truck turned into the crosswalk area and hit him. Alan reports no memory of the event but has been told this is what happened. Alan says “My frontal lobe took the brunt of the impact, particularly the left frontal lobe”. Alan had a 2 ½ week stay at a nearby hospital where he, “re-learned to talk, to walk, and drink”-- although again he reports no memory of his stay there. Alan was then transferred to Craig Rehabilitation Hospital, in Englewood, Colorado. Alan says, “The only reason I knew I was at Craig is that I rolled over in bed and saw “Welcome to Craig” on the dry erase board.” During this stage of recovering, Alan repeatedly denied that he had been in an accident. Twice he tried to leave Craig on his own accord despite his wife’s and his therapists’ assurances that it was important for him to stay to recuperate from his injuries. Alan’s wife was 8 months pregnant at the time of his accident and gave birth to their son while Alan was an inpatient at Craig. Alan’s wife brought his newborn son to visit him days after the birth and Alan held him while sitting in his wheelchair, but Alan wistfully reports this is another thing he can’t remember. Alan reports that he still has significant difficulties with memory. Alan has also experienced several other neuropsychological difficulties. He states that for months after his injury, he could not experience emotion. “I could not laugh, I couldn’t cry.” Even after three years, his emotional experience is constricted. However, an emotion that is sometimes elevated is irritation and anger. Sometimes, dealing with people can be difficult because he may have temper flare-ups with little reason. This is something that Alan regrets and he is working hard with his neuropsychologist to improve the regulation of his emotions. Alan also has difficulty with organization, motivation, and distractibility. Earlier in his recovery, he had trouble sequencing and had difficulty carrying out personal and household routines. Alan has benefited greatly from therapy and his own hard work to make improvements in these areas. A chief reason that Alan works so hard in his recovery is so that he can be a good father to his son who is now almost 3 years old. He recognizes that it is important not to get frustrated when it seems that he can’t provide what his son wants or needs at a given moment. “I’m trying to raise my son the best I can…he’s at such a pivotal time in his life.” Alan’s financial situation was helped for a time by Social Security Disability Insurance payments but these payments ended. He is trying to get SSDI reinstated but the process of doing so is confusing and is taking a lot of time. Alan returned to work about 11 months ago at a liquor store (after about 2 years of not being able to work), the same store where he previously worked part time while teaching. He works in the wine department. “I sell wine and make recommendations.” When asked for advice to other brain injury survivors, Alan’s words were: “No matter how confused or upset you are or how frustrated you get, keep pressing on and moving forward because there is light at the end of the tunnel even though it may seem long. Keep moving forward and don’t give up no matter what anyone says to you”. Alan added that supports for individuals with brain injury are very important. He has found support groups, retreats, and seminars/events where brain injury survivors can share their experience to be very helpful. The volunteer work he does at Craig Hospital has been valuable for him. Alan is an inspiring individual. Despite having scarce memory of his accident and some confusion about the functional losses he has experienced, Alan has worked hard to make his recovery as complete as possible. He continues to work hard to progress and to express gratitude for those who have assisted him along the way.
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