PROJECT SUMMARY

Brain connectivity plays a fundamental role in neural activity and the way the brain processes information. Yet
there is limited understanding of how connectivity varies in relation to genetic factors, environmental stressors,
and cognitive traits - in normal individuals or in neurological and neuro-psychiatric conditions. Improving this
understanding is of critical importance in obtaining mechanistic insight into factors underlying substance misuse,
neurological and neuro-psychiatric disorders. Is there something about the “wiring” or circuitry of an individual’s
brain that pre-disposes them to substance misuse, depression, anxiety and other disorders? What roles do
genetic factors play in the development of such risky, or vulnerable circuitry? Is it possible to target medication
and therapy to an individual’s specific circuitry? This project develops fundamental statistical tools needed to
address questions of this type.

The structural connectome corresponds to a dense network of interconnected neurons, linked by white matter
fiber bundles. These fibers act as highways for neural activity and communication across the brain. Diffusion
tensor and structural MRI provide indirect information on locations, and strength of connections between neigh-
boring or remote cortical domains. Current statistical pipelines consist of (1) tractography - pre-processing of
MRI data to infer fiber bundles; (2) connectome representation – each individual’s connectome is summarized
via an adjacency matrix with each cell summarizing connections between a pair of brain regions of interest
(ROIs); and (3) statistical analysis relating adjacency matrices to other variables. This project develops trans-
formative statistical tools to fundamentally improve these steps to reduce measurement errors in connectome
reconstruction, systematic differences across studies and platforms, and sensitivity to the chosen ROIs. A key
advance is a surface-based connectome extraction and integration (SBCI) approach that exploits the geometric
structure of the brain. We develop the pre-processing, data harmonization and statistical analysis tools neces-
sary to implement this new framework routinely in neuroscience studies. The statistical tools developed in this
project will have a fundamental impact on the interpretation of data from brain connectivity studies, providing
insights into how brain structure and function vary with genetic and patient factors and impact cognitive and
neuro-psychiatric outcomes. Work will proceed via the Aims: (1) Development of accurate high-resolution
representations of human brain networks using surface-based connectome extraction and integration
(SBCI). (2) Development of statistical methods for studying relationships between connectomes and
other factors, ranging from cognitive traits to genetics. (3) Development of batch-correction, outlier de-
tection and robust statistical analysis methods for connectomes. (4) Software development and data
sharing: resources developed in Aims 1-3 will be made easily accessible through an SBCI repository.