Diving Deep into White Matter to Improve Our Understanding of the Pathophysiology of Schizophrenia

Abstract

Innovations in our capacity to image the fine structure of the human brain are urgently needed because after more than a century of research into the biology of schizophrenia, we still find ourselves far from understanding the neurobiological mechanisms responsible for the disorder. Without such an understanding, we are unlikely to discover more effective ways of preventing or reversing the underlying pathology. In this issue of Biological Psychiatry, Du et al. (1) describe the use of two in magnetic resonance (MR)-based technologies that, when used in combination, allowed them to make specific references about the nature of white matter abnormalities in patients with schizophrenia. The idea that schizophrenia is not caused by a disturbance in a single brain structure but rather by the way that distant brain regions communicate with one another is not new. In 1906, Carl Wernicke hypothesized that the disorder might emerge from a process that damages association fiber tracts running beneath the cortex (2). Nancy Andreasen further enriched this concept by drawing attention to the timing of information transfer among involved brain structures, coining the term “cognitive dysmetria” (3). Although there have been a host of reports of disease-related abnormalities in individual brain structures, the evidence for disrupted interstructural connectivity is now also growing rapidly (4). But hypothesizing disruptions in the mechanisms of connectivity leaves open the question of whether the problem is localized to the axon or to the structural elements that support it (5). Subcortical axons form the infrastructure of intercortical connectivity. Some of these fibers link cortical regions with one another, and others serve as projection fibers linking the cortex to the gray matter structures below. Although it has been long known that disorders of myelination can disrupt motor and sensory functions, evidence has emerged in the past 2 decades suggesting that such disruptions can similarly affect higher-order cognition functions, including executive function, attention and processing speed (6). For example, white matter changes have been recently associated with cognitive dysfunction following the onset of traumatic brain injury, Alzheimer disease, and even the effects of oncologic chemotherapy (7). If axonal integrity is intrinsically compromised, then one would expect to see changes in neuroimaging measures that represent the integrity of the neurons themselves, such as the movement of N-acetylaspartate (NAA) molecules. In addition, because white matter axons are surrounded by myelin sheaths produced by glial cells that allow impulses to propagate quickly across neurons and