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

额纹状体回路中脑底物之间的动态相互作用在一定程度上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着关键作用。关于额纹状体回路的底物相互作用以影响认知灵活性的机制的知识已经积累起来。例如，多巴胺可能通过直接作用于额叶皮层和纹状体或通过前额叶皮层对纹状体的影响来调节这一回路。非侵入性脑刺激，如应用于额叶皮层的经颅直流电刺激（tDCS），已被证明可以增加皮层的兴奋性并改善认知。与目前大多数认知灵活性研究所追求的专注于任务/规则集之间切换或行为结果/奖励监测的额纹状体机制不同，该项目将研究该回路作为感知过滤和选择性注意的调节接口的较少探索的作用。具体来说，我们提出自上而下的注意控制和自下而上的知觉过滤之间的相互作用是由额纹状体电路的相互增益控制机制调节的。注意缺陷多动障碍（ADHD）患者灵活调节注意力的能力严重受损，并且在大脑不成熟或衰老等多种正常状态下也受到限制。因此，本项目拟将ADHD和衰老作为两种模型条件，这两种条件在额纹状体电路中具有一定的功能缺陷，但在听觉处理中表现出差异，以揭示额纹状体电路在调节选择性感知和选择性注意之间的相互作用中的相关性，并推进对这些条件下听觉感知问题的理解。鉴于多巴胺和膜电位调节的神经元增益控制机制已经在神经计算模型中提出，因此我们将要么通过哌甲酯增强(i)额纹状体多巴胺的药理学，要么通过阳极tDCS刺激增强（ii）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。通过对比ADHD和健康个体以及比较健康的青少年、年轻人和老年人，将分别研究与病理和寿命年龄相关的行为和大脑可塑性对药理学或tDCS调节的差异。该项目的预期结果将对额纹状体电路的交互增益控制机制产生新的见解，该机制是自上而下的注意控制和自下而上的选择感知之间灵活相互作用的基础。此外，该结果将与治疗多动症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.