Commentary on Schmitz et al . (2017): Advancing medication development for addiction-behavioral and neuroimaging outcomes as indirect biomarkers of target engagement : Commentary on Schmitz et al. (2017): Advancing medication development for addiction: behavioral and neuroimaging outcomes as indirect biomarkers of ta

White matter is the brain region underlying the gray matter cortex, composed of neuronal fibers coated with electrical insulation called myelin. Previously of interest in demyelinating diseases such as multiple sclerosis, myelin is attracting new interest as an unexpected contributor to a wide range of psychiatric disorders, including depression and schizophrenia. This is stimulating research into myelin involvement in normal cognitive function, learning and IQ. Myelination continues for decades in the human brain; it is modifiable by experience, and it affects information processing by regulating the velocity and synchrony of impulse conduction between distant cortical regions. Cell-culture studies have identified molecular mechanisms regulating myelination by electrical activity, and myelin also limits the critical period for learning through inhibitory proteins that suppress axon sprouting and synaptogenesis.

Advances in the neurosciences have placed the field in the position where it is poised to significantly reduce the burden of nervous system disorders. However, drug discovery, development, and translation for nervous system disorders still pose many unique challenges. The key scientific challenges can be summarized as follows: mechanisms of disease, target identification and validation, predictive models, biomarkers for patient stratification and as endpoints for clinical trials, clear regulatory pathways, reliability and reproducibility of published data, and data sharing and collaboration. To accelerate nervous system drug development, the Institute of Medicine's Forum on Neuroscience and Nervous System Disorders has hosted a series of public workshops that brought together representatives of industry, government (including both research funding and regulatory agencies), academia, and patient groups to discuss these challenges and offer potential strategies to improve the translational neuroscience.

It is vitally important to identify the genetic determinants of complex brain-related disorders such as autism, dementia, mood disorders, and schizophrenia. However, the search for genes predisposing individuals to these illnesses has been hampered by their genetic and phenotypic complexity and by reliance upon phenomenologically based qualitative diagnostic systems. Neuroimaging endophenotypes are quantitative indicators of brain structure or function that index genetic liability for an illness. These indices will significantly improve gene discovery and help us to understand the functional consequences of specific genes at the level of systems neuroscience. Here, we review the feasibility of using neuroanatomic and neuropsychological measures as endophenotypes for brain-related disorders. Specifically, we examine specific indices of brain structure or function that are genetically influenced and associated with neurological and psychiatric illness. In addition, we review genetic approaches that capitalize on the use of quantitative traits, including those derived from brain images. (c) 2007 Wiley-Liss, Inc.