STUDYING BRAIN BIOLOGY IN LIVING PEOPLE

Abstract

A goal of biomedical research is to advance knowledge of the molecular basis of human brain function. One way to achieve this goal is through studies of cells and molecules in samples of human brain tissue. As brain samples from living people (“LIV samples”) are largely unavailable for research, most such studies are conducted using brain samples from postmortem donors (“PM samples”). This practice, while necessary, is subject to four key limitations. First, the extent to which PM samples faithfully represent LIV samples at the molecular level has not been rigorously investigated. Second, in contrast to the living brain, the postmortem brain is by definition not capable of any meaningful function – therefore, the molecular basis of human brain functions like perception, mood, and memory cannot be fully established using PM samples. Third, the postmortem state is unsuitable for studying the molecular relationship between the brain and more readily accessible tissues - most importantly, the blood - and this hinders biomarker discovery. Fourth, valuable information about PM sample donors (e.g., neuroimaging data, deep clinical phenotyping information) is often not available to researchers, thus precluding comprehensive understanding of how functions emerge from the biological, electrophysiological, and anatomical features of the human brain.

The Living Brain Project (LBP) was designed to help address these limitations. The LBP is a translational research framework predicated upon the deep brain stimulation (DBS) procedure. From each LBP study participant the following is obtained: samples of the prefrontal cortex (PFC), peripheral blood samples obtained simultaneously with the PFC, intracranial electrical recordings, neuroimaging, and deep clinical phenotyping. To date, analyses of LBP data have identified (1) the safety of the PFC biopsy approach, (2) widespread biological differences between LIV samples and PM samples, (3) biological signatures of neurotransmission, (4) complex patterns of molecular communication between the brain and the blood, and (5) relationships between brain biology and structure. Overall, the LBP framework provides a blueprint for the safe, ethical, and scalable study of brain biology in living people and enables the investigation of fundamental questions about the brain that were previously unable to be studied.