Modulating frontostriatal regulations of attentional control and selective perception: enhancing dopamine signaling and frontal cortical excitability in attentional deficit hyperactivity disorder and aging

额纹状体回路中大脑底物之间的动态相互作用部分地由多巴胺能系统调节，在认知灵活性和自上而下的注意力调节中起关键作用。关于额纹状体回路底物相互作用以影响认知灵活性的机制的知识一直在积累。例如，多巴胺可以通过直接作用于额叶皮层和纹状体，或者通过前额叶皮层对纹状体的影响来调节这个回路。非侵入性脑刺激，例如在额叶皮层上施加的经颅直流电刺激（tDCS），已被证明可以增加皮层兴奋性并改善认知。而不是专注于任务/规则集之间的切换或监控的动作结果/奖励的额叶纹状体机制，目前大多数认知灵活性的研究追求，这个项目将调查较少探索的作用，这个电路的监管界面的知觉过滤和选择性注意。 具体来说，我们建议，自上而下的注意力控制和自下而上的感知过滤之间的相互作用调节的额纹状体电路的交互式增益控制机制。灵活调节注意力的能力在注意缺陷多动障碍（ADHD）患者中严重受损，并且在各种正常状态下也受到限制，例如大脑不成熟或老化。因此，拟议的项目将使用ADHD和老化作为两个模型条件，这两种疾病在额纹状体回路中存在一定的功能缺陷，但在听觉处理方面表现出差异，从而为额纹状体回路在调节选择性知觉和选择性注意之间的相互作用方面的相关性提供了新的线索，并促进了对这些疾病中听觉知觉问题的理解。调节的神经元增益控制机制已经在神经计算模型中提出，因此，我们将通过哌甲酯增强（i）额纹状体多巴胺释放或（ii）经由阳极tDCS刺激的皮质兴奋性。这两种方法在调节神经元增益控制方面的潜在相互作用也将在健康年轻人的样本中进行研究。病理学和寿命年龄相关的行为和大脑可塑性的差异，药理学或tDCS调制将分别进行调查，通过对比ADHD和健康的个人，并通过比较健康的青少年，年轻人和老年人。这个项目的预期成果将产生新的见解互动增益控制机制的额纹状体电路，自上而下的注意力控制和自下而上的选择性知觉之间的灵活的相互作用的基础。此外，这些结果将与治疗ADHD和缓冲老年认知能力下降直接相关。

Dynamic interactions between brain substrates in the frontostriatal circuit that are, in part, modulated by the dopaminergic system, play key roles in cognitive flexibility and top-down attentional regulation. Knowledge about mechanisms through which substrates of the frontostriatal circuit interact to implicate cognitive flexibility has been accumulating. For instance, dopamine may modulate this circuit by acting directly in the frontal cortex and the striatum or through influences from the prefrontal cortex on the striatum. Non-invasive brain stimulations, such as transcraninal direct current stimulation (tDCS) applied over the frontal cortex, have been shown to increase cortical excitability and improve cognition. Instead of focusing on frontostriatal mechanisms for switching between task-/rule-sets or monitoring of action outcomes/rewards as most current research on cognitive flexibility pursues, this project will investigate the less explored role of this circuitry as the regulatory interface of perceptual filtering and selective attention. Specifically, we propose that interactions between top-down attentional control and bottom-up perceptual filtering are regulated by interactive gain control mechanisms of the frontostriatal circuitry. The abilities to flexibly regulate attention are critically impaired in individuals with attention deficit hyperactivity disorder (ADHD) and are also constrained in a variety of normal states, such as brain immaturity or aging. Therefore, the proposed project will use ADHD and aging as two model conditions, which share certain functional deficits in the frontostriatal circuitry but exhibit differences in auditory processing to shed new lights on the relevance of frontostriatal circuitry in regulating interactions between selective perception and selective attention as well as advance understandings about problems of auditory perception in these conditions.Given that dopamine and membrane potential regulated neuronal gain control mechanisms have been proposed in neurocomputational models, we will therefore either enhance (i) frontostriatal dopamine pharmacologically by methylphenidate or (ii) cortical excitability via anodal tDCS stimulation. Potential interactive effects of these two approaches in regulating neuronal gain control will also be investigated in a sample of healthy young adults. Pathology- and lifespan age-related differences in behavioral and brain plasticity to pharmacological or tDCS modulations will be investigated, respectively, by contrasting ADHD and healthy individuals and by comparing healthy adolescents, young and older adults. Expected outcomes of this project will yield new insights into interactive gain control mechanisms of the frontostriatal circuitry that underlie flexible interplays between top-down attention control and bottom-up selective perception. Furthermore, the results will be of direct relevance for treating ADHD and for buffering cognitive declines in old age.