Whereas the cerebral cortex has long been regarded by neuroscientists as the major locus of cognitive function, the white matter of the brain is increasingly recognized as equally critical for cognition. White matter comprises half of the brain, has expanded more that gray matter in evolution, and forms an indispensable component of distributed neural networks that subserve neurobehavioral operations. White matter tracts mediate the essential connectivity by which human behavior is organized, working in concert with gray matter to enable the extraordinary repertoire of human cognitive capacities. In this review, we present evidence from behavioral neurology that white matter lesions regularly disturb cognition, consider the role of white matter in the physiology of distributed neural networks, discuss emerging concepts regarding the prevention and treatment of cognitive dysfunction associated with white matter disorders, and develop the hypothesis that white matter dysfunction is relevant to neurodegenerative disorders, including Alzheimer's Disease and the newly-described entity chronic traumatic encephalopathy. Further investigation of the role of white matter in cognition promises to expand understanding of normal brain structure and function, improve the treatment of many neurobehavioral disorders, and disclose new opportunities for research on many challenging problems facing medicine and society.
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