Principal Investigator:
Aaron Warren, PhD
Instructor in Neurosurgery
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
Project Summary
The need: Essential tremor (ET) research faces a fundamental infrastructure gap. Most imaging studies map the brains of people with ET onto generic anatomical templates derived from healthy young adults. This mismatch introduces systematic spatial error and misaligns disease-altered anatomy, blurring the very circuits researchers aim to localize and clinicians aim to treat. In parallel, ET is often analyzed as a single condition, which can mask biological signals that explain variability in symptoms, progression, and treatment response.
The overall goal of this project is to move ET research beyond group-averaged description toward a biologically grounded, circuit-resolved stratification that supports etiologic discovery and individualized care. Our objective is to deliver the core infrastructure the field lacks: an ET-specific anatomical and connectomic reference space and a flexible imaging framework for defining biological subtypes.
The central hypothesis is that ET reflects multiple separable circuit-level perturbations that become measurable when patients are mapped to a disease-appropriate reference space and heterogeneity is modeled explicitly. We will test this hypothesis using our uniquely large, deeply characterized clinical–MRI repository of 650+ individuals with ET, one of the largest such datasets available.
Specific Aim 1 will develop and openly release the first population-level ET template and connectome, with harmonized reference distributions that define an ET-specific coordinate system and typical ranges for anatomy and connectivity. This will allow alignment of multimodal data—including electrophysiology, molecular findings, neuromodulation targets, and more—within a common, disease-relevant space and enable quantification of patient-specific deviations relative to the ET reference.
Specific Aim 2 will identify and characterize ET subtypes by integrating patterns of brain atrophy with fiber-specific diffusion MRI metrics that resolve crossing white-matter architecture, then linking these subtypes to motor and non-motor phenotypes to test whether ET heterogeneity reflects distinct disease trajectories.
The innovation is twofold: a disease-specific framework built at scale to replace one-size-fits-all reference anatomy, and subtype-resolved modeling that captures heterogeneity rather than averaging it away. The impact will be an openly shared ET research platform, with the template/connectome and initial subtyping delivered in Year 1, followed by validation, expansion, and steps toward clinical translation in Years 2–3.
The team brings complementary strengths in computational neuroscience and clinical translation at Brigham and Women’s Hospital. The PI, Dr Aaron Warren, is an early-career investigator specializing in neuroimaging and neuromodulation, mentored by ET clinical and surgical leaders Drs John Rolston and Rees Cosgrove. This award will accelerate Dr Warren’s path to research independence in tremor by producing field-defining resources and the preliminary data needed to compete for larger, longer-term funding and build a sustainable program in ET biology and circuit therapeutics.
Read the full proposal here.