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Director’s Blog: Tracing the Brain’s Connections

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It has become our mantra at NIMH that mental disorders can be addressed as disorders of brain circuits.  We frequently use an analogy with heart disease:  mental disorders can be thought of as conduction problems or arrhythmias, in contrast to neurodegenerative disorders (Parkinsons, Huntingtons, Alzheimers) which involve loss of tissue similar to the infarctions of ischemic heart disease. 

But can we identify the dysfunctional circuits of brain disorders?  Only partly.  In 2010, we still lack a comprehensive connectional map of the human brain.  The wiring of the mouse and monkey brain are more complete because in experimental animals, scientists have been able to inject tracers into the brain and then map their distribution with great precision, ex vivo.  But the human brain has not been amenable to such techniques. 

Remarkably we know relatively little about the projections to and from various parts of the prefrontal cortex, a complex region implicated in virtually all mental disorders and yet not well developed in experimental animals.  How do these regions link to each other and to other parts of the cortex?  How do connections develop to subcortical targets, such as the amygdala and basal ganglia?  How do genes and experience shape these connections?  And most important, how do these connections vary between individuals?

This critical gap in our knowledge about the human brain is being met with a series of studies that are just beginning to be reported.   Milham and his colleagues in the advanced publication of PNAS (Bhiswal et al, PNAS, 2010) report on a “1000 Functional Connectomes Project,” similar to the 1000 Genomes project which  mapped the landscape of variation in the human genome.  In this “discovery science” project, fMRI was used to chart the pattern of activation in the resting brain, sometimes called the default state, from 1,414 volunteers at 35 centers across the world.  A universal, intrinsic,  functional architecture was observed, with variations related to sex and age.   This project discovered pathways with high individual variation, reminiscent of hotspots for variation in the human genome.   But perhaps most important, all of the data are now in a public repository (www.nitrc.org/projects/fcon_1000/ ) which can form the basis of a reference atlas for future work.

This project is only the first of several that should yield a much-needed picture of brain connections and how they vary.  The NIH Blueprint, a collaboration of 16 institutes and centers at NIH, plans to support an effort to collect both structural and functional connectivity from hundreds of subjects, and make those data accessible to the research community as part of a grand challenge on the human connectome.  Current projects supported by NIMH include the development of technologies to collect connectivity data in humans, such as diffusion spectrum imaging -- a novel quantitative approach to mapping white matter tracts -- that provides higher resolution than current diffusion tensor imaging (see below), as well as comprehensive connectional maps in experimental animals.

How these circuits develop is one of the great questions NIMH hopes to answer in the next 2-3 years.  John Gilmore and his colleagues at University of North Carolina are using longitudinal neuroimaging studies of twins, beginning 2 weeks postnatal.  Using a different approach, with funding from the Recovery Act, NIMH is supporting an effort to map gene expression in the developing human brain – providing the first picture of molecular anatomy across hundreds of brain regions during fetal and post-natal development.  As with the imaging data, the gene expression maps will be available as part of a collaboration with the Allen Brain Institute.  We expect these and related projects to identify the fundamental principles by which genes and experience shape the developing circuitry.

Just as discovery science in genomics has yielded targets for understanding the risk architecture of complex disease, discovery science in connectomics and brain development should provide insights into the mechanisms of individual differences in basic cognitive and behavioral functions, such as executive function and mood regulation, that form the basis of mental disorders.  In the future, when we describe mental disorders as circuit disorders, we can expect the same precision with which we distinguish conduction defects or arrhythmias in the heart, based on clinical features, physiology, and imaging.

 

Diffusion spectrum imaging picture of the human brain

Diffusion spectrum imaging of the human brain.
Source: Van J. Wedeen, M.D., Harvard Medical School