Chapter

Methods for identifying and understanding brain structure–function relations have evolved over the past century, from astute observations of selective impairments associated with focal brain damage to dissociations measured by combining quantitative neuropsychologic assessment and brain imaging. Enhanced spatial and temporal resolution in brain imaging modalities has led to refined visualization and quantification of the brain’s substructures, microstructural integrity, and functional connectivity of neural networks. The double dissociation model has been a gold standard used to demonstrate that a particular cognitive, emotional, sensory, or motor process is selectively related to a particular brain region or neural network and not to others. This model has provided a fruitful means for testing hypotheses of functional localization and enabled examination and establishment of component processes contributing to complex cognitive and motor functions, parsing multifactorial behaviors and identifying brain regions, and networks subserving these complex abilities. In this chapter we discuss the evolution of the dissociation model and highlight how the modifications of this model are used presently to establish selective brain–behavior relationships in disorders such as chronic alcoholism with a neuropathologic signature but no localizable, space-occupying lesion.

Oxidative stress is associated with numerous neurological disorders. Mitochondrial malfunction contributes to generation of reactive oxygen species (ROS) in proximity to mitochondrial membranes rich in polyunsaturated fatty acids (PUFAs). ROS initiate PUFA autoxidation, a chain reaction that alters membrane fluidity and promotes toxic reactive carbonyl products (RCP) that damage proteins and DNA. Due to the stochastic nature of ROS generation, increased antioxidants cannot prevent such injury. However, deuterium-for-hydrogen substitution at bis-allylic sites reduces the rate-limiting step of autoxidation and results in inhibition of the subsequent PUFA oxidation chain reaction, decreasing toxic RCP levels. We propose a novel approach, using such isotopic reinforcement, to alleviate oxidative injury and have pre-clinical evidence demonstrating neuroprotection in an oxidative stress model of Parkinson’s disease. We hypothesize that site-specific PUFA deuteration will mitigate progression of degeneration in other disorders that manifest oxidative injury either as a primary or secondary insult.