A new study published in PLoS Biology has found that learning a new motor skill sets off two different types of cellular changes in the human brain. The findings suggest that the brain experiences a temporary swelling of cell bodies followed by a long-lasting growth of cellular extensions in specific regions. This dual response offers a deeper understanding of how the human brain physically adapts when we learn something new.
Neuroplasticity refers to the brain’s ability to remodel its physical structure in response to new experiences. This biological process supports learning and memory, and it also influences a person’s vulnerability to neurological conditions.
Valeria Della-Maggiore, an associate professor at the National University of San Martin and the University of Buenos Aires, led the research. She also serves as an adjunct professor at McGill University and directs the Physiology of Action Lab.
“Structural plasticity, the brain’s ability to remodel its connections in response to experience, is fundamental to learning and memory and shapes development and degenerative disorders,” she told PsyPost. She explained that most human studies over the past two decades have used standard MRI protocols to detect changes in brain microstructure, assuming these changes were always plastic in nature.
“Yet animal studies show that cells may undergo structural changes that do not always reflect synapse remodeling,” Della-Maggiore said. “To disambiguate plastic from non-plastic processes, we combined ultra-high-gradient diffusion MRI with SANDI, a biophysical model that allows making inferences at the level of cellular compartments, that is, cell bodies and cell processes.”
To measure structural changes in humans, scientists have typically relied on a brain scanning technique called diffusion tensor imaging, or 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 microscopic structure.
DTI blends the signals from various parts of the brain tissue together. “DTI captures a single, global signal: it can tell you that a change in one region lasts longer than in another, but not what underlies it,” Della-Maggiore said. Because of this blending, the technique cannot easily distinguish between a permanent structural change and a temporary biological reaction.
To address this limitation, the authors utilized highly sensitive magnetic resonance imaging paired with the specialized mathematical model called Soma and Neurite Density Imaging, or SANDI. Rather than grouping all tissue signals together, SANDI separates the scanning signals into three distinct categories. These categories include the cell bodies, the cellular extensions called neurites, and the extracellular fluid surrounding the cells.
“This study was only possible through a genuinely multidisciplinary effort, in which neuroscientists, experts in diffusion MRI, mathematicians and modeling specialists, and engineers worked together around a single scientific question,” Della-Maggiore said.
The collaboration included her lab along with the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, and the Cardiff University Brain Research Imaging Centre. “Bringing these different forms of expertise into alignment is what made it possible to extract biological insight from a non-invasive measurement, something no single discipline could have achieved on its own,” she added.
The study included 29 healthy adults between the ages of 18 and 36, consisting of 16 females and 13 males. All participants were right-handed and reported no history of neurological or psychiatric conditions. They completed a motor sequence learning task involving typing a specific five-number sequence on a keyboard using the four fingers of their left, non-dominant hand. The exact sequence was 4-1-3-2-4, with the number 4 representing the index finger and the number 1 representing the pinky finger.
Participants were instructed to type the sequence as quickly and accurately as possible. They completed 15 practice blocks of this finger-tapping sequence. Each block consisted of 12 sequences and was separated by 25 seconds of rest. The entire training session took about 15 to 20 minutes.
To assess how well the participants retained the skill overnight, they were asked to complete eight additional practice blocks 24 hours later. To track brain activity and physical changes, the scientists used an ultra-high-gradient MRI scanner, which offers exceptional sensitivity for capturing microscopic tissue details. They collected functional MRI scans to measure active brain regions during the task. They also collected advanced diffusion MRI scans at three specific points: before the practice session began, 30 minutes after the practice ended, and 24 hours later.
The behavioral data showed that participants improved their typing speed and accuracy primarily during the short rest periods between practice blocks. The functional brain scans aligned with this observation, revealing increased activity in the brain’s memory and motor regions during these brief breaks. However, the most specific discoveries emerged from the SANDI model used to track cellular changes.
“When you learn a new skill, two processes of different spatial and temporal dynamics take place in your brain at the cellular level,” Della-Maggiore said. “One is transient and occurs at the level of cell bodies, which increase in size across all brain regions engaged by the task. The other is persistent, confined to the regions specifically involved in learning, and occurs at the level of cell processes, compatible with structural plasticity.”
The researchers found that DTI scans alone missed a layer of detail. “Our approach revealed something DTI cannot see, that the regions showing lasting changes also carry a transient response,” Della-Maggiore explained. “In other words, beneath what DTI reads as a single persistent effect, there are in fact two distinct processes unfolding on different timescales.”
Specifically, the researchers found a temporary increase in the apparent density of cell bodies across all the brain areas engaged by the task. These areas included the hippocampus, the primary motor cortex, the posterior parietal cortex, and the precuneus. This physical change was observed 30 minutes after the practice session. By the 24-hour mark, the cell bodies in these regions had returned to their normal baseline size.
“The second [surprise] was the spatial pattern: a transient change at the level of the cell body appeared uniformly across all regions engaged by learning, whereas the sustained change in cellular processes was confined to those regions specific to the learned skill,” Della-Maggiore said. “It was this dissociation, in both space and time, that let us infer different biological processes underlying these responses: a homeostatic process such as swelling of cell bodies induced by increased neuronal activity, and cell-process remodeling mediating genuine structural plasticity.”
The authors propose that this short-lived cell expansion is a temporary biological reaction to balance out intense cellular activity. When brain cells are highly active, they experience an imbalance of ions. 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, longer-lasting change in specific areas of the brain. The researchers observed a sustained increase in the density of cellular extensions in the precuneus and the posterior parietal cortex. These cellular extensions include structures like dendrites and axons, which connect different brain cells to one another.
This increase in cellular extensions persisted a full day after the learning task. The researchers noticed a direct link to task performance. “Notably, the more a person improved, the stronger this second change was,” Della-Maggiore said.
Interestingly, this long-lasting structural remodeling did not occur in the hippocampus. The hippocampus is a brain region known for helping encode new memories early in the learning process. The findings suggest that while the hippocampus is engaged initially, the long-term structural changes required to retain a motor skill happen in the outer layers of the brain, known as the cortex.
“The broader message is that a change in brain structure is not, in itself, evidence of learning-related plasticity,” Della-Maggiore said. “Being able to separate these processes in a living brain, non-invasively, provides something that did not exist before in human neuroscience: a mechanistic window onto brain plasticity, allowing us to begin inferring biological mechanisms directly in humans rather than relying on animal models.”
Interpreting these findings requires acknowledging a few limitations related to the scanning technology. The SANDI model estimates relative signal fractions of cell components rather than providing a direct physical measurement of cellular volume. The technique relies on specific mathematical assumptions about how water moves in the brain.
“Our approach does not quantify cells or cell processes directly,” Della-Maggiore explained. “It infers how much different cellular components contribute to the MRI signal, based on a biophysical model whose interpretation is grounded in animal and histological evidence.”
She added that referring to changes in cell bodies or cell processes involves principled inferences, not microscopic observations. “The strength of the method lies in tracking how these signals evolve over time, compared against the person’s own baseline,” she said.
The study focused on a specific finger-tapping task in a small group of healthy young adults. Different types of learning, such as studying a new language or solving complex math problems, might engage different cellular mechanisms. “Our broader aim is to keep refining this approach to probe the biological mechanisms of plasticity in ever greater detail, directly in humans,” Della-Maggiore said.
The researchers hope to apply this multi-compartment imaging approach to other areas of neuroscience. “Beyond learning, distinguishing genuine, adaptive remodeling from other processes could prove valuable in contexts such as development, aging, and disease, including conditions like neurodegeneration or neuroinflammation, where telling apart healthy from harmful structural change is both difficult and clinically important,” she said.
“The results move the field beyond descriptive diffusion changes toward mechanistic inference, which is particularly valuable for studies of learning, development, and disease,” Della-Maggiore concluded.
The study, “Learning engages transient 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.
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