Instead our goal was an “annotated” genome, including the locations of regulatory elements and descriptions of the impact of mutations and epigenomics on

developmental biology, disease, and aging. From this perspective, the BRAIN project is not harder than the genome project—indeed, it is an unfinished subset. Lesson four: Lack of prior “understanding” should not impede innovation. Vaccines were amazing well before Inhibitors,research,lifescience,medical we understood the immune system. Did we know “THE genetic code” before HGP? That code only applied to 1% of the genome (the part encoding proteins) and, even there, did not reveal function. The role of innovative imaging technologies We can leverage exponentially advancing technologies (optical, electronic, imaging, nanotechnology, Inhibitors,research,lifescience,medical and synthetic biology) to radically improve the accuracy, cost, and comprehensiveness of neurotechnologies capable of measurement and alteration of brain development and functioning in animal models and clinical settings. Especially valuable would be applying and integrating a variety of such methods in a single (“Rosetta”) brain sample. This would include an initial behavioral phase including MRI, ultrasound, and electrical/optical stimulation/recording, followed by a serial section phase exploiting fluorescent in Inhibitors,research,lifescience,medical situ sequencing (FISSEQ) to assess RNA transcriptomes,

barcoded connectomes, and time series data (ranging from developmental lineage to biochemical changes in cell membranes and nuclei). The physical limits and work-arounds for a variety of imaging modalities and Inhibitors,research,lifescience,medical means of transducing the data on potential neurons in a brain to an external device have been recently reviewed.1 Magnetic resonance imaging The NIH Human Connectome Project (HCP, 2009-2014) Inhibitors,research,lifescience,medical is ongoing at Washington University, University

of Minnesota, Harvard University, GS-7340 in vivo Massachusetts General Hospital, and UCLA. HCP is largely focused on imaging methods, which include structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), almost high-angular-resolution diffusion imaging (HARDI), functional MRI (fMRI), and diffusion spectrum imaging (DSI). To connect imaging to behavior, the HCP includes the NIH Toolbox for Assessment of Neurological and Behavioral function. The highest practical field gradients, so far, 300 mT/m (with slewing at 200 T/m/s), has resulted in temporal and spatial resolutions of 0.62 msec and 1.5 mm respectively. (One mm3 contains roughly 50 000 neurons). Some of the above limits are set by unwanted peripheral nervous system and retinal stimulation.2Proton MRI is limited to 100 ms temporal resolution by water T1 relaxation time, and limited to spatial resolutions of 40 μm by the self-diffusion of water. T1 premapping could allow T2 contrast on a 10-msec timescale.