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

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.

Effects of tyrosine/phenylalanine depletion on electrophysiological correlates of memory in healthy volunteers.

Dopamine is well known for involvement in reinforcement, motor control and frontal lobe functions, such as attention and memory. Tyrosine/phenylalanine depletion (TPD) lowers dopamine synthesis and can therefore be used as a model to study the effects of low dopamine levels. This is the first study to assess the effect of TPD on memory performance and its electrophysiological correlates. In a double blind placebo (PLA)-controlled crossover design, 17 healthy volunteers (six males, 11 females) aged between 18 and 25 were tested after TPD and PLA. Working memory was assessed using a Sternberg memory scanning task (SMS) and episodic memory using the Visual Verbal Learning Test (VVLT). Simultaneously, event-related potentials (ERPs) were measured. The tyrosine and phenylalanine ratio was significantly reduced after TPD and increased after PLA. Working memory performance was not affected by TPD. However, ERP measures were affected by the treatment, indicating that TPD impaired stimulus processing during working memory performance. Episodic memory was not impaired after TPD. Again, alterations in ERP measures suggested adverse effects of TPD on memory-related processing. These results suggest that dopamine is involved in both working memory and episodic memory-related processing, although the effects are too small to be detected by performance measures.