Modafinil, Inhibitory Control, and Alcoholism

Abstract

A lcohol is implicated as a causal factor in numerous diseases and injuries; its harmful use accounts for approximately 2.5 million deaths worldwide each year, according to the World Health Organization’s Global Status Report on Alcohol and Health, 2011. Alcohol dependence is by definition a heterogenous disorder, characterized by the past 12-month occurrence of at least three of seven DSM criteria (Fourth Revision, American Psychiatric Association). Examples of these criteria include tolerance, withdrawal symptoms, and continued use despite knowledge of physical/psychologic alcohol-related harm. Despite some success from psychosocial and pharmacologic interventions, there is an ongoing search for more effective treatments. People with alcohol dependence manifest cognitive deficits that likely contribute to persistence of addiction and interfere with the ability to engage with and successfully deploy psychologic techniques. Response inhibition involves the suppression of a habitual or prepotent response that would ordinarily be made, when an unpredictable change occurs in the external environment. This ability is important in day-to-day life and is often impaired in attention-deficit/hyperactivity disorder and in substance addiction including alcohol (1). In heavy alcohol drinkers, relative baseline deficits in response inhibition were significantly predictive of the subsequent development of alcohol dependence (1). In addition, neural abnormalities during inhibitory control have been identified in alcohol-dependent patients, even during the early phases of abstinence (2). Response inhibition thus represents a candidate therapeutic target for people with alcohol dependence, and, theoretically, for people at risk of alcohol dependence. Modafinil is a wake-promoting agent with cognitive-enhancing potential (3). Schmaal et al. (4) in the current issue of Biological Psychiatry explored the effects of modafinil on response inhibition and its neurobiologic substrates in people with alcohol dependence and in healthy volunteers, using functional magnetic resonance imaging in a double-blind, placebo-controlled design (4). Response inhibition was measured using a stop-signal task, in which participants observed a series of stimuli appearing one per time and made speeded responses (a left button in response to a left-facing stimulus; and vice versa). On a subset of trials, a stop signal occurred (a visual cross), indicating to the participant that they had to attempt to suppress the response. By adjusting the time interval between the go and stop signal, stop-signal tasks such as these yield the stop-signal reaction time: an estimate of the time taken by the brain to stop a response that would normally be undertaken. Longer stop-signal reaction times equate to worse motor inhibition. Several tiers of research have indicated that response inhibition, thus operationalized, is dependent on a distributed neural network including the inferior