New research published in PLoS Biology They found that learning a new motor skill causes two different types of cellular changes in the human brain. This finding suggests that the brain experiences a temporary expansion of cell bodies, followed by long-term growth of cell expansions in specific regions. This dual response provides a deeper understanding of how the human brain physically adapts when learning something new.
Neuroplasticity refers to the brain’s ability to restructure its physical structure in response to new experiences. This biological process supports learning and memory and also influences a person’s vulnerability to neurological conditions.
Valeria Della Maggiore, an associate professor at the National University of San Martín and the University of Buenos Aires, led the study. She is also an adjunct professor at McGill University, where she heads the Behavioral Physiology Lab.
“Structural plasticity, the brain’s ability to restructure connections in response to experience, is the basis of learning and memory and shapes development and degenerative diseases,” she told PsyPost. She explained that most human studies over the past 20 years have used standard MRI protocols to detect changes in the brain’s microstructure and assumed that these changes are plastic in nature.
“However, animal studies have shown that cells can undergo structural changes that do not necessarily reflect synaptic remodeling,” Della Maggiore said. “To distinguish between plastic and non-plastic processes, we combined ultra-high gradient diffusion MRI with SANDI. SANDI is a biophysical model that allows inferences at the level of cellular compartments: the cell body and cellular processes.”
To measure structural changes in humans, scientists have commonly used a brain scanning technique called diffusion tensor imaging (DTI). This method measures how water molecules move and diffuse through brain tissue. By tracking this water movement, scientists can infer changes in the brain’s microstructure.
DTI blends signals from different parts of the brain tissue. “DTI captures a single global signal. We can see that changes in some regions last longer than others, but we don’t know what’s underlying them,” Dellamaggiore said. Because of this mixing, this technique cannot easily distinguish between permanent structural changes and transient biological responses.
To address this limitation, the authors utilized a combination of highly sensitive magnetic resonance imaging and a specialized mathematical model called Soma and Neurite Density Imaging (SANDI). Rather than grouping all tissue signals together, SANDI classifies scan signals into three different categories. These categories include the cell body, cell extensions called neurites, and the extracellular fluid that surrounds the cell.
“This research was only possible through a truly interdisciplinary effort in which neuroscientists, diffusion MRI experts, mathematicians and modeling experts, and engineers collaborated around a single scientific question,” Dellamaggiore said.
The collaboration includes her lab, the Athinoula A. Martinos Biomedical Imaging Center at Massachusetts General Hospital, and the Cardiff University Center for Brain Research and Imaging. “By bringing together these different forms of expertise, we are now able to derive biological insights from non-invasive measurements, something that no single discipline could have achieved alone,” she added.
Twenty-nine healthy adults (16 women and 13 men) between the ages of 18 and 36 participated in this study. All participants were right-handed and reported no history of neurological or psychiatric illness. They completed a motor sequence learning task in which they entered a specific sequence of five numbers on a keyboard using the four fingers of their non-dominant left hand. The exact order is 4-1-3-2-4, where the number 4 represents the index finger and the number 1 represents the little finger.
Participants were instructed to enter the sequence as quickly and accurately as possible. They completed 15 practice blocks of this finger tapping sequence. Each block consisted of 12 sequences, separated by 25-s breaks. The entire training session took approximately 15-20 minutes.
To assess how well participants retained their skills throughout the night, they were asked to complete an additional eight practice blocks 24 hours later. To track brain activity and physical changes, scientists used ultra-high gradient MRI scanners. This scanner offers excellent sensitivity for capturing microscopic tissue details. They collected functional MRI scans to measure which brain regions were active during the task. They also collected advanced diffusion MRI scans at three specific time points: before the start of the practice session, 30 minutes after practice ended, and 24 hours later.
Behavioral data showed that participants improved their typing speed and accuracy primarily during short rest periods between practice blocks. Functional brain scans are consistent with this observation, revealing increased activity in memory and motor areas of the brain during these short breaks. However, the most concrete findings came from the SANDI model, which is used to track cellular changes.
“When learning a new skill, two processes with different spatial and temporal dynamics occur in the brain at the cellular level,” Dellamaggiore says. “One is temporary, occurring at the level of the cell body and increases in size across all brain regions involved in the task; the other is persistent, specifically restricted to regions involved in learning, and occurring at the level of cellular processes consistent with structural plasticity.”
Researchers found that DTI scans alone lacked layers of detail. “Our approach reveals something that DTI cannot see: that in areas that show persistent changes, there are also transient responses,” Dellamaggiore explained. “In other words, beneath what DTI interprets as a single persistent effect are actually two distinct processes that unfold on different timescales.”
Specifically, the researchers found that the apparent density of cell bodies was temporarily increased across all brain regions engaged in this task. These regions include the hippocampus, primary motor cortex, posterior parietal cortex, and precuneus. This physical change was observed 30 minutes after the practice session. By the 24-hour mark, cell bodies in these regions had returned to their normal baseline size.
“The second (surprise) was the spatial pattern: transient changes at the level of the cell body appeared uniformly across all regions involved in learning, whereas sustained changes in cellular processes were confined to regions specific to the learned skill,” Della Maggiore said. “This dissociation in both space and time allowed us to infer different biological processes underlying these responses, namely homeostatic processes such as cell body swelling induced by increased neuronal activity and remodeling of cellular processes that mediate true structural plasticity.”
The authors propose that this short-lived cell proliferation is a temporary biological response to balance intense cellular activity. When brain cells become more active, an ionic imbalance occurs. To correct this imbalance, water flows into the cells, causing them to temporarily swell.
In addition to the temporary swelling, the SANDI model revealed a second long-lasting change in specific areas of the brain. The researchers observed a sustained increase in cell spread density in the precuneus and posterior parietal cortex. These cellular extensions include structures such as dendrites and axons that connect different brain cells to each other.
This increase in cell elongation persisted for a full day after the learning task. Researchers have noticed a direct relationship with task performance. “What’s remarkable is that the more a person improves, the more powerful this second change becomes,” Dellamaggiore said.
Interestingly, this long-term structural remodeling did not occur in the hippocampus. The hippocampus is a region of the brain known for helping encode new memories during the early stages of the learning process. The findings suggest that while the hippocampus is initially active, the long-term structural changes necessary to maintain motor performance occur in the outer layer of the brain, known as the cortex.
“The broader message is that changes in brain structure are not in themselves evidence of learning-related plasticity,” Dellamaggiore said. “The ability to non-invasively isolate these processes in the living brain provides something that has not previously existed in human neuroscience: a mechanistic window into brain plasticity, allowing us to begin to infer biological mechanisms directly in humans, rather than relying on animal models.”
To interpret these results, one must be aware of several limitations associated with the scanning technique. The SANDI model estimates the relative signal proportions of cellular components rather than providing a direct physical measurement of cell volume. This technique is based on certain mathematical assumptions about how water moves within the brain.
“Our approach does not directly quantify cells or cellular processes,” Della Maggiore explained. “This infers how much different cellular components contribute to the MRI signal based on a biophysical model that is interpreted based on animal and histological evidence.”
She added that when referring to changes in cell bodies or cellular processes, principled reasoning, rather than microscopic observations, is needed. “The strength of this method is that it tracks how these signals change over time compared to a person’s own baseline,” she said.
This study focused on a specific finger-tapping task in a small group of healthy young adults. Different types of learning, such as learning a new language or solving complex math problems, can involve different cellular mechanisms. “Our broader goal is to continue to refine this approach and investigate the biological mechanisms of plasticity directly in humans in greater detail than ever before,” Dellamaggiore said.
The researchers hope to apply this multicompartment imaging approach to other areas of neuroscience. “Beyond learning, distinguishing true adaptive remodeling from other processes may prove valuable in contexts such as development, aging, and disease, including conditions such as neurodegeneration and neuroinflammation. In these contexts, distinguishing between healthy and deleterious structural changes is difficult and clinically important,” she said.
“This result advances the field beyond descriptive diffusion changes and toward mechanistic reasoning, which is particularly valuable for the study of learning, development, and disease,” Dellamaggiore concluded.
The study, “Learning involves temporal and sustained cellular mechanisms in the human brain,” was authored by Guillermina Griffa, Marco Palombo, Abraham Yeffal, Hong-Hsi Lee, Agustin Solano, Susie Y. Huang, and Valeria Della-Maggiore.
