Contingent negative variation as a dopaminergic biomarker: evidence from dose-related effects of methylphenidate

Abstract

Rationale: The basal ganglia play an important role in motor control, which is dependent on dopaminergic input. Preparation of a motor response has been associated with dopamine release in the basal ganglia, and response readiness may therefore serve as a pharmacodynamic marker of dopamine activity.

Methods: We measured response readiness using the amplitude of the contingent negative variation (CNV), a slow negative shift in the electroencephalogram. The CNV is evoked in a paradigm in which a warning stimulus (S1) signals the occurrence of the imperative stimulus (S2) 4 s later, to which the participant has to respond. CNV was assessed in healthy volunteers after administration of placebo or 10, 20 or 40 mg of methylphenidate, a catecholamine re-uptake blocker which primarily enhances the synaptic concentration of dopamine and to a lesser extent also noradrenaline. In addition, participants filled out two visual analogue scales measuring subjective ratings of mood and alertness: Profile of Mood States and Bond and Lader.

Results: Methylphenidate dose dependently increased CNV amplitude and decreased reaction times. Furthermore, participants reported improved mood, feeling more alert, vigorous and content and less angry and tired after methylphenidate.

Conclusions: These results indicate that dopamine availability increases response readiness as measured by the CNV paradigm. The CNV appears to be a good candidate biomarker for assessing changes in dopaminergic function by treatments that either directly or indirectly target the dopaminergic system.

Fig. 1

Grand average ERPs showing a clear CNV wave during the stoplight (a) and lines 2 (b) response preparation tasks. The ERPs depicted were recorded at Cz, at t240 relative to dosing

Fig. 2

Mean difference CNV amplitudes and reaction times relative to morning baseline at t30, 60, 120, 180, 240 and 300 min relative to dosing in the stoplight (amplitudes at Cz, a; reaction times, c) and lines 2 (amplitudes at Cz, b; reaction times, d) response preparation tasks. Error bars are only shown for PLA (placebo) and M40 (methylphenidate, 40 mg)