According to the CDC, stroke is the most common cause of long-term severe disability in the United States and Veterans report a higher prevalence of stroke and stroke-related disability than non-Veterans (Kramarow & Pastor, 2012). Language deficits are among the most common and debilitating impairments caused by stroke. Rehabilitation of motor deficits after stroke requires extended treatment, and effectiveness is often limited, leaving patients with permanent functional deficits (phase III trials: EXCITE (Cramer, 2007), LEAPS (Duncan, 2011)). Rehabilitation of aphasia after stroke has not been tested in phase III trials but treatment efficacy appears to be even more limited. Most treatments focus on reestablishing functional connectivity between cortical regions processing semantic and phonological components of language. The success of this approach, however, is limited by the amount of preserved language eloquent cortex in the left hemisphere and by the potential of the right hemisphere to assume a greater role in language function. Therapeutically induced regeneration of infarcted cortex is unlikely to become a viable treatment strategy in the near future; however, mitigation of white matter injury or promotion of axonal regrowth following stroke may be feasible (Walmsley & Mir, 2007; Liu et al., 2012) and could significantly potentiate language recovery. There is a growing body of evidence of the importance of white matter in cognition, specifically language processing (Geschwind, 1965; Catani et al., 2005, 2007; Nadeau 2012). However, little is known about the contribution of specific white matter pathways to aphasia pathophysiology. The proposed study will initiate a line of research examining the structure of white matter pathways involved in language processing. Specifically, the study will examine pathways connecting Broca's area with ventral prefrontal cortex, a region implicated in pattern and feature processing of objects (Ungereider & Mishkin, 1982; Wilson et al., 1993; O'Scalaidhe et al., 1997; Romanski et al., 1999). In addition, this study will create an exemplar white matter atlas of these pathways in order to quantify the degree of damage to these pathways in individual stroke patients, to examine their contribution to manifestations of aphasia in subsequent studies (CDA-2), and eventually, to provide a biomarker in studies testing the efficacy of neurobiological treatments aimed at improving white matter recovery. To accomplish these goals, we will analyze existing data obtained from Dr. David FitzGerald's study, Diffusion Tensor Imaging of White Matter After Traumatic Brain Injury, which is a VA funded study (CDA-2, VA RR&D Grant # B6698W). We will select 20 healthy volunteers from this dataset (age matched, 10 males, 10 females). This sample size was determined based upon the feasibility of completion of data analyses during the two-year course of a CDA-1 award. We will first infer white matter pathways connecting Broca's area and ventral prefrontal cortex in each of these participants. After completion of this portion of data analysis, individual tractography results will be transformed to a common template to create a probabilistic population atlas.
According to the Centers for Disease Control, stroke is the most common cause of long-term disability in the United States and occurs more frequently among Veterans than non-Veterans. Language impairment (aphasia) is among the most common and debilitating consequences of stroke. Aphasia is caused by damage to the cerebral cortex and to connections between different regions of the cortex (white matter). Growing evidence suggests that white matter contributes importantly to aphasia pathophysiology, though these mechanisms are poorly understood. This clinical observation creates an urgent need for an atlas of connectivity underlying language function. The proposed study will initiate a line of research focused on development of such an atlas in normal subjects in order to apply the atlas to the clinical MR scans of stroke survivors in subsequent studies. The atlas will allow us to quantify the degree of damage to these pathways and to examine their contribution to aphasia pathophysiology as well as act as a biomarker for rehabilitation.
