PROJECT SUMMARY
When a new route is learned, what happens in the hippocampus? How fast do these changes occur? Are
all hippocampal subfields involved in memory encoding? Decades of research have shown that the hippocampus
is necessary for spatial memory. However, the neural foundation of spatial learning and memory and its link to
hippocampal architecture remain major study topics. According to animal research, learning alters the functional,
chemical, and structural properties of hippocampal cells. Unfortunately, we know considerably less about
humans' microstructural basis of learning and memory. An accurate assessment of learning-induced
hippocampal neuroplasticity —the ability of the hippocampus to modify its function and structure in response to
information—would significantly enhance human memory research. For decades, we have lacked the
noninvasive technology necessary to evaluate neuroplasticity with the same biological precision as animals.
Diffusion Magnetic Resonance imaging (dMRI) holds the most promise among non-invasive technology to reveal
the microstructural substrate of learning and memory in humans. Initial studies in healthy humans have shown
that dMRI can be sensitive to changes during learning. But technological limitations in gradient technology have
diminished the expectations of what the diffusion MRI signal can reveal in term of specificity to the different
cellular processes that are thought to be involved in neuroplasticity.
This K99/R00 proposal takes advantage of newly available ultra-high gradient strength dMRI at the MGH
Martinos Center to create a noninvasive marker of learning-induced neuroplasticity in the human hippocampus
subfields during human navigation with a high level of biological specificity. I will combine behavioral testing,
high-resolution functional MRI, state-of-the-art multi-compartment gray matter dMRI models, and ultra-high
gradient strength (500 mT/m) high-resolution dMRI data acquired with our center's BRAIN Initiative-funded
Connectome 2.0 MRI scanner to achieve a unified view of the structural-functional response of the human
hippocampus in spatial memory. The in vivo neuroplasticity marker developed in this proposal might be used as
a diagnostic tool in Alzheimer's disease to detect early indications of pathological hippocampus remodeling or to
assess the efficacy of deep brain stimulation (DBS) techniques for memory impairment repair. The project makes
use of the vast expertise of my mentors and collaborators in cognitive neuroscience, high-gradient strength
dMRI, hippocampal anatomy, and high-resolution functional MRI. The candidate aims to get the necessary skills
to begin an independent long-term research program focused on developing the next generation of in vivo
functional and diffusion MRI technologies to connect cellular-specific information with cognition and brain
functioning. The training component of the K99/R00 award will enrich the candidate's prior strong expertise in
mathematical modeling, diffusion image acquisition, and reconstruction, with complementary skills in behavioral
testing, fMRI analysis, hippocampus anatomy, and the validation of dMRI biomarkers of brain microstructure.