Recently, the widespread use of magnetic resonance imaging (MRI) has called attention to the wide range of leukoencephalopathies that can be encountered clinically—these disorders highlight disconnection as a central theme of cognitive neuroscience.¹ In this article, the leukoencephalopathies will be discussed as common clinical problems that illuminate the role of white matter in both normal cognitive function and in the disconnection syndromes receiving increasing attention. This emphasis on white matter influences not only the care of many neurologic and psychiatric patients, but adds significantly to the research agenda of cognitive neuroscience.

Basic Science Aspects of White Matter
White matter occupies nearly half the volume of the adult cerebrum. Approximately 165,000km of myelinated fibers course within and between the hemispheres,4 linking cortical and subcortical gray matter areas into an extraordinarily complex web of interconnected structures. Of the three types of fiber systems—projection, association, and commissural—the latter two are devoted primarily to cognitive functions, whereas the projection fibers subserve elemental motor and sensory systems.At a microscopic level, the myelininvesting axons in the brain are a mixture of 70% lipid and 30% protein, which dramatically increases conduction velocity by the phenomenon of saltatory conduction. Mounting evidence supports the notion that damage to myelin, and particularly to axons, reduces the speed of cognition in association with the slowing of conduction velocity.³

In general, white matter in the brain can be envisioned as enabling information transfer, in contrast to the information processing subserved by gray matter. Normal cognition requires both of these features, permitting specific mental operations in such realms as memory, language, and visuospatial function, as well as the efficiency with which they are performed.A useful parallel distinction is that white matter provides macroconnectivity in the brain—between remote gray matter regions—as opposed to the microconnectivity occurring within gray matter via synaptic function. White matter tracts therefore connect widely dispersed gray matter regions into coherent neural ensembles— distributed neural networks—that are thought to mediate all aspects of higher function.⁵

The precise neuroanatomy of white matter is understood only at a rudimentary level, as most information has been gathered from tracing studies in non-human primates and limited investigations of postmortem human brains.The origin, termination, course, and interdigitation of white matter tracts remain largely obscure; therefore, the function of these tracts can only be inferred in tentative terms.The importance of white matter for human cognition is suggested by many lines of evidence, including a wealth of information on the role of myelinated systems in development, aging, and behavioral neurology.³ White matter may also be crucial in human evolution—a recent MRI study concluded that prefrontal white matter volume is the singular distinguishing feature between the brains of humans and non-human primates.6

Leukoencephalopathies
In clinical neurologic practice, disorders of white matter are commonly seen at all ages, and their prevalence is increasing as identification of new leukoencephalopathies with MRI is progressing continuously. Multiple sclerosis (MS) is the most familiar CNS white matter disease of adults, but is just one of more than 100 clinical entities in which white matter is prominently or exclusively affected.³ Genetic, demyelinative, infectious, inflammatory, toxic, metabolic, vascular, traumatic, neoplastic, and hydrocephalic disorders may all produce leukoencephalopathies, and, remarkably, some form of neurobehavioral impairment has been associated with every disorder previously described.³ In older individuals, leukoencephalopathy is extremely common, and usually manifests as MRI white matter lesions known as leukoaraiosis (LA). Although the origin and cognitive significance of these lesions have been controversial, it seems increasingly likely that LA typically results from cerebral ischemia and, when severe enough, has important consequences for cognitive function.⁷