Deficits in response inhibition associated with chronic methamphetamine abuse

Abstract

Chronic methamphetamine (MA) abuse is associated with cerebral deficits, involving frontal/basal-ganglia regions that are important for inhibitory control. We used the Stop-Signal Task to measure response inhibition in 11 MA abusers (5–7 days abstinent) and two groups of control subjects who did not use MA (14 tobacco smokers and 29 non-smokers). Stop-signal reaction time (SSRT), which indicates the latency to inhibit an initiated motor response, was significantly longer for MA abusers than for either control group (p's < .01). In contrast, the MA abusers did not differ from either group on Go trial reaction time (RT) or number of discrimination errors, which reflect motor speed and decision-processes, respectively. MA abuse in this study was therefore associated with a specific deficit in inhibiting a pre-potent response. Future research could examine whether SSRT is different for MA abusers who respond to treatment compared to those who do not. If such differences are established then response inhibition may serve as a marker for investigating MA abuse in basic science and clinical trials.

Introduction

Response inhibition can be defined as the intentional prevention of a behavior that is underway or that is otherwise automatically evoked (i.e., “pre-potent”). Experimentally, it can be studied with stop-signal, Go/No-Go and other inhibitory tasks. It has been hypothesized that response inhibition is relevant to the cessation of drug use because the suppression of rapid conditioned drug-seeking responses may occur by a similar mechanism as the suppression of a motor response (Fillmore, 2003; Jentsch and Taylor, 1999; Lyvers, 2000). Response inhibition has been consistently related to functional activation and structural integrity of the right inferior frontal cortex, and fairly consistently with the basal-ganglia (for review, see Aron et al., 2004; Aron and Poldrack, in press). Response inhibition may be particularly relevant to methamphetamine (MA) dependence given the range of frontal/basal-ganglia abnormalities observed in MA abusers, including low levels of dopamine transporter (McCann et al., 1998; Sekine et al., 2001, Sekine et al., 2003; Volkow et al., 2001b), low concentrations of cortical serotonin (Wilson et al., 1996), low concentrations of N-acetylaspartate (a marker for neuronal integrity) (Ernst et al., 2000), abnormalities in glucose metabolism (Volkow et al., 2001a; London et al., 2004), and deficits in gray matter relative to controls (Thompson et al., 2004).

The handful of neuropsychological reports on chronic MA abusers (Chang et al., 2002; Kalechstein et al., 2003; Paulus et al., 2003; Rogers et al., 1999; Salo et al., 2002; Simon et al., 2000) indicate impairment on measures associated with frontal cortical functioning, including verbal and non-verbal fluency (see Kalechstein et al., 2003) and working memory (Chang et al., 2002; Simon et al., 2000). Response inhibition among MA abusers has primarily been assessed in past studies using paper or computer versions of the Stroop Color-Word Task (Perret, 1974), which requires inhibition of reading color names. Both Simon et al. (2000) and Salo et al. (2002) reported impairment on Stroop performance among MA users, while Kalechstein et al. (2003) and Chang et al. (2002) did not find significant deficits among MA abusers on the task. The discrepancy between these studies may reflect variability given an underlying modest effect, or may be related to methodological differences; only Salo et al. (2002) used a voice-sensitive trial-based computerized version of the task, and only Simon et al. included MA abusers who tested positive for MA on the day of testing.

Compared with the Stroop Task, the Stop-Signal Task is a more direct means of assessing response inhibition (Logan et al., 1984, Logan et al., 1997; Nigg, 2000; Quay, 1997). Through a method described below, the Stop-Signal Task measures the amount of time (typically on the order of 200 ms) required to inhibit a motor response already initiated. Several lines of evidence suggest that this measure may relate to clinically relevant behavior and pathology. First, individuals with attention deficit hyperactivity disorder do poorly on the task (see Nigg, 2000 for review), and their performance improves following administration of methylphenidate (Tannock et al., 1995). Second, poor performance on the task is correlated with greater ratings of impulsivity on a personality scale (Tannock et al., 1995). And third, cocaine abusers perform poorly on the task relative to controls (Fillmore and Rush, 2002). Consistent with the notion that Stroop Task performance is mediated by a variety of factors other than response inhibition (for review, see MacLeod, 1991) performance on the Stop-Signal Task does not appear to be well correlated with performance on the Stroop Task (in Friedman and Miyake (2004) r = .15; in Avila et al. (2004), r = −.11).

The purpose of this study was to assess whether MA abusers would demonstrate slower stop-signal response inhibition than control subjects and whether individual differences among MA abusers in response inhibition would be correlated with duration and extent of MA abuse.