Our laboratory has consistently observed significantly lower amplitudes of Event-Related Potential (ERP) components, particularly the visual P3(00) in abstinent alcoholics. More recently, we focused on Event- Related Oscillations (EROs) that underlie sensory and cognitive events and serve as measures of neuronal network status; we found that alcoholics had decreased theta, delta and gamma band responses during cognitive tasks, particularly deficits in theta oscillations in frontal regions during response inhibition, trget detection and reward evaluation. Similar to P3, frontal theta power was inversely correlated with impulsivity, and alcoholics with low frontal theta power had high impulsivity and were more likely to relapse. Using a new measure developed in this grant cycle-synchrony during cognitive processing-we find impairments in frontal synchrony in alcoholics that indicate deficits in coupling in brain networks; these synchrony deficits significantly correlated with deficits in medial frontal activations on functional Magnetic Resonance (fMRI). We also found a lack of differentiation in neural responses (ERP/ERO characteristics, topography) in alcoholics, who utilize similar/identical neural networks regardless of cognitive demands, rather than specific networks to optimize performance. Based on these preliminary findings and the current literature, the proposed project will study specific circuit-based hypotheses of brain dysfunction in alcoholics during resting state and during specific cognitive tasks (response inhibition, reward processing, conflict monitoring and emotional interference) with complementary neurophysiological and functional/structural neuroimaging methods, benefiting from the advantages of each. Neuroimaging methods will localize impairments in specific circuits associated with task- related and resting states in alcoholics, using tasks homologous to electrophysiological tasks to examine response inhibition (Go/NoGo), reward evaluation and risk taking (Monetary Gambling Task), and affective interference on frontal executive processes in a Cognitive/Motivational/Emotional Stroop, and correlations between these measures of frontal lobe function to clinical/behavioral factors. We will investigate neural oscillations and their synchrony during cognitive processing and resting state (EEG); with synchrony measures and rsfMRI we will examine patterns of connectivity, and with DTI examine white matter integrity, and will derive more meaningful structural/functional relationships combining all of these measures. Using the best discriminators between alcoholics and controls from electrophysiology, MRI and clinical/behavioral factors, we will create an objective method to identify subgroups more/less likely to relapse and determine the processes of recovery/decline with abstinence/relapse by retesting a subset of our sample (abstainers, relapsers and controls) 1 year after their initial test on the same protocols. Thus, our renewal project will have importan implications for cognitive, behavioral, and neural liabilities involved in alcoholism and the tendency to relapse, and the transition to recovery with abstinence, with utility in treatment and prevention protocols.
The project will address important clinical challenges and basic science questions regarding the pathophysiology of structural/functional deficits in alcoholics that cause them to repeatedly drink despite adverse outcomes, recovery of brain function with abstinence, and adverse effects with continued drinking. It is of utmost importance to elucidate the underlying predisposition for the overwhelming urge to drink (craving) resulting in recidivism to inform prevention strategies. Our findings will have important implications for cognitive, behavioral and pharmacological treatment protocols.
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