Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task

Abstract

Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function) in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested.

Fig. 1.

MPH enhances fMRI anterior cingulate cortex activations and reduces commission errors on a cue-reactivity fMRI task. Variables are mean percent BOLD signal change from a fixation baseline as a function of drug vs. neutral words on the fMRI task in the (A) cdACC (x = −3, y = 9, z = 36) that showed medication × group (F_1,25 = 4.9, P < 0.05) and medication × group × word (F_1,25 = 7.7, P = 0.01) interactions, explained by hypoactivations in CUD compared with controls only during placebo (for drug words, t₂₅ = −2.1, P < 0.05) but not MPH (t₂₅ < 1.4, P > 0.2) and MPH- vs. placebo-enhanced signal in the CUD (for drug words, t₁₂ = 3.1, P = 0.01; mean percent increase in cdACC signal = 9.5 ± 3.2). (B) rvACC/mOFC (x = 0, y = 36, z = −3) showed a medication main effect (F_1,25 = 12.7, P = 0.001) and a trend to a medication × group interaction (F_1,25 = 3.8, P = 0.063), explained by MPH- vs. placebo-decreased hypoactivations in the CUD (for drug and neutral words, t₁₂ > 2.6, P < 0.05; mean percent increase in mOFC signal = 28.9 ± 11.7). (C) Errors of commission showed a medication main effect (F_1,25 = 5.6, P < 0.05; driven by MPH vs. placebo difference for drug words: Z = −2.3, P = 0.021; percent decrease = 4.7% ± 1.9%; driven by the CUD = 6.7 ± 3.2). (D) Correlation is between percent BOLD signal change (MPH − placebo) in the rvACC/mOFC (x = −9, y = 42, z = −6) with the respective change for accuracy during drug words. Error bars represent SEM. Midsagittal map on the bottom of the figure shows the cdACC and rvACC/mOFC ROIs. Subjects are 13 individuals with CUD and 14 healthy control. MPH, methylphenidate; PL, placebo.