Regina McGlinchey - US grants

DESCRIPTION: This project renewal proposal requests continued support for studies in three aspects of alcoholic Korsakoffs' and chronic alcoholics' cognitive processing impairments. The first component extends our search for the cognitive factors identifying alcoholic Korsakoffs' and non-Korsakoff chronic alcoholics' memory disorders. Our prior research has shown that alcoholic Korsakoff patients' amnesia stems largely from an inability to utilize features of verbal and/or visual information to store and retrieve information. We have shown that this is largely a problem on tasks involving explicit retrieval and less so on implicit retrieval. However, even on these latter tasks, difficulties exist when conceptual processes are evoked. Chronic alcoholics have been shown to suffer from a different pattern of difficulties less tied to initial processing and more linked to task difficulty. Our future research is designed to pursue these areas of analytic deficiency in the domains of an explicit and implicit conceptual memory. The second component seeks to pursue our exploration of the factors contributing to chronic alcoholics' deficits on delayed-classical conditioning acquisition. Converging evidence from animal and human literature implicates cerebellar involvement in this type of learning, so we intend to explore this possibility by also testing learning on a trace conditioning paradigm that relies more strongly on hippocampal involvement. In addition, heart-rate and GSR conditioning and extinction will be explored. Finally, we shall extend our thesis of possible cerebellar dysfunction in chronic alcoholics by exploring the status of brain functioning in this area utilizing an fMRI procedure. Both uptake during a contrast fMRI and a structural analysis of the cerebellum will be performed to determine the extent to which any dysfunction in this area might contribute to the patients' impaired acquisition during conditioning. Then, an fMRI targeting frontal activity during an encoding and a retrieval task will be performed to determine the extent to which these behavioral deficits can be visualized on-line.

ESCRIPTION (provided by applicant): The primary aim of this proposal is to evaluate the ability of abstinent chronic alcoholics to acquire, express and retain conditioned responses during complex classical eyeblink associative learning tasks. We have conducted several investigations of associative learning using relatively simple eyeblink classical conditioning tasks with abstaining alcoholics in prior studies and propose to expand this line of investigation using more challenging and informative eyeblink associative learning tasks. In our past investigations, we have found impairments in the learning and timing of conditioned responses that we attributed to cerebellar atrophy that is typical following chronic misuse of alcohol. However, it is in fact unclear to what extent their deficits are attributable solely to cerebellar atrophy because the neural circuit that supports various forms of eyeblink classical conditioning involves additional regions of the forebrain such as the hippocampal system and frontal cortex, and these regions are also impacted by the effects of alcohol. We further propose to relate these findings to underlying neuropathology (as indexed by MRI) and neuropsychological function. Of particular interest will be to relate eyeblink conditioning performance to underlying white matter using diffusion tensor imaging to examine whether possible changes in neural connectivity are related to impaired learning. We will also investigate whether possible deficits in alcoholics' ability to become explicitly aware of stimulus contingencies contributes to their impairment. The proposed investigation, using classical eyeblink conditioning tasks that are well understood at the level of neural networks in nonhuman animals, will help us to further define the extent of associative learning impairment in alcoholics and begin to uncover the human neuropathology that is responsible for impaired and preserved learning. Gaining a comprehensive understanding of the underlying nature of the proposed learning deficit in the formation of new associative memories may be critical to understanding why the behavioral changes needed to control abusive drinking may be particularly difficult for these individuals.