Effects of Ginkgo biloba extract EGb 761® on cognitive control functions, mental activity of the prefrontal cortex and stress reactivity in elderly adults with subjective memory impairment - a randomized double-blind placebo-controlled trial.

OBJECTIVE: Cognitive control as well as stress reactivity is assumed to depend on prefrontal dopamine and decline with age. Because Ginkgo biloba extract EGb761 increases prefrontal dopamine in animals, we assessed its effects on cognitive functions related to prefrontal dopamine. METHODS: Effects of 240-mg EGb761 daily on task-set-switching, response-inhibition, delayed response, prospective-memory, task-related fMRI-BOLD-signals and the Trier Social Stress-Test were explored in a randomized, placebo-controlled, double-blind pilot-trial in 61 elderly volunteers with subjective memory impairment. RESULTS: Baseline-FMRI-data showed BOLD-responses in regions commonly activated by the specific tasks. Task-switch-costs decreased with EGb761 compared to placebo (ANOVA-interaction: Group × Time × Switch-Costs p = 0.018, multiple tests uncorrected), indicating improved cognitive flexibility. Go-NoGo-task reaction-times corrected for error-rates indicated a trend for improved response inhibition. No treatment effects were found for the delayed response and prospective-memory tasks and fMRI-data. A non-significant trend indicated a potentially accelerated endocrine stress-recovery. EGb761 was safe and well tolerated. CONCLUSION: We observed indications for improved cognitive flexibility without changes in brain activation, suggesting increased processing efficiency with EGb761. Together with a trend for improved response inhibition results are compatible with mild enhancement of prefrontal dopamine. These conclusions on potential beneficial effect of EGb761 on prefrontal dopaminergic functions should be confirmed by direct measurements. © 2016 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons, Ltd.

The functional neuroanatomy of spontaneous retrieval and strategic monitoring of delayed intentions.

An intention stored in prospective memory (PM) for later execution can be retrieved either strategically through preparatory attentional processes such as active monitoring for PM targets or spontaneously through automatic retrieval processes when encountering a relevant cue. Using functional MRI to identify distinct brain areas involved in spontaneous retrieval of intentions and to dissociate them from monitoring-related processes, we compared brain activity in PM blocks in which subjects had to maintain and execute an intention in response to rarely occurring PM cues with blocks in which the previous intention had been completed. Although the PM task incurred performance costs in the ongoing task and was associated with increased block-related activation in the rostro-lateral prefrontal cortex (RLPFC), performance costs and RLPFC activation were no longer observed after the intention had been completed, providing further evidence for an involvement of RLPFC in strategic monitoring during PM tasks. By contrast, event-related activation induced by PM cues was observed in the ventral parietal cortex (VPC), precuneus and posterior cingulate cortex even after the intention was completed. These activations are consistent with the notion of spontaneous intention retrieval possibly mediated through a bottom-up driven re-activation of intention representations still persisting in a heightened state of activation in episodic memory. In conclusion, the results highlight the functional relevance of VPC and precuneus in prospective memory retrieval, possibly reflecting spontaneous, cue-based processes as opposed to top-down controlled strategic monitoring.

Dissociable neural routes to successful prospective memory.

Identifying the processes by which people remember to execute an intention at an appropriate moment (prospective memory) remains a fundamental theoretical challenge. According to one account, top-down attentional control is required to maintain activation of the intention, initiate intention retrieval, or support monitoring. A diverging account suggests that bottom-up, spontaneous retrieval can be triggered by cues that have been associated with the intention and that sustained attentional processes are not required. We used a specialized experimental design and functional MRI methods to selectively marshal and identify each process. Results revealed a clear dissociation. One prospective-memory task recruited sustained activity in attentional-control areas, such as the anterior prefrontal cortex; the other engaged purely transient activity in parietal and ventral brain regions associated with attentional capture, target detection, and episodic retrieval. These patterns provide critical evidence that there are two neural routes to prospective memory, with each route emerging under different circumstances.

Enhancement of cognitive control by approach and avoidance motivational states.

Affective variables have been shown to impact working memory and cognitive control. Theoretical arguments suggest that the functional impact of emotion on cognition might be mediated through shifting action dispositions related to changes in motivational orientation. The current study examined the effects of positive and negative affect on performance via direct manipulation of motivational state in tasks with high demands on cognitive control. Experiment 1 examined the effects of monetary reward on task-switching performance, while Experiment 2 examined the effects of both rewards and punishments on working memory, using primary (liquid) reinforcers. In both experiments, dissociable trial-by-trial and contextual (block-related) enhancements of cognitive control during task performance were observed in relationship to motivational incentive value. Performance enhancements were equivalent in the reward and punishment conditions, but were differentially impacted by individual difference measures of trait reward and punishment sensitivity. Together, the results suggest both common and specific mechanisms by which approach and avoidance motivational states influence cognitive control, via activation of reward and punishment processing systems.

Primary and secondary rewards differentially modulate neural activity dynamics during working memory.

BACKGROUND: Cognitive control and working memory processes have been found to be influenced by changes in motivational state. Nevertheless, the impact of different motivational variables on behavior and brain activity remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: The current study examined the impact of incentive category by varying on a within-subjects basis whether performance during a working memory task was reinforced with either secondary (monetary) or primary (liquid) rewards. The temporal dynamics of motivation-cognition interactions were investigated by employing an experimental design that enabled isolation of sustained and transient effects. Performance was dramatically and equivalently enhanced in each incentive condition, whereas neural activity dynamics differed between incentive categories. The monetary reward condition was associated with a tonic activation increase in primarily right-lateralized cognitive control regions including anterior prefrontal cortex (PFC), dorsolateral PFC, and parietal cortex. In the liquid condition, the identical regions instead showed a shift in transient activation from a reactive control pattern (primary probe-based activation) during no-incentive trials to proactive control (primary cue-based activation) during rewarded trials. Additionally, liquid-specific tonic activation increases were found in subcortical regions (amygdala, dorsal striatum, nucleus accumbens), indicating an anatomical double dissociation in the locus of sustained activation. CONCLUSIONS/SIGNIFICANCE: These different activation patterns suggest that primary and secondary rewards may produce similar behavioral changes through distinct neural mechanisms of reinforcement. Further, our results provide new evidence for the flexibility of cognitive control, in terms of the temporal dynamics of activation.