Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Brain. 2022 Nov 21;145(11):4042-4055. doi: 10.1093/brain/awac007.
Dopaminergic medication is widely used to alleviate motor symptoms of Parkinson's disease, but these medications also impact cognition with significant variability across patients. It is hypothesized that dopaminergic medication impacts cognition and working memory in Parkinson's disease by modulating frontoparietal-basal ganglia cognitive control circuits, but little is known about the underlying causal signalling mechanisms and their relation to individual differences in response to dopaminergic medication. Here we use a novel state-space computational model with ultra-fast (490 ms resolution) functional MRI to investigate dynamic causal signalling in frontoparietal-basal ganglia circuits associated with working memory in 44 Parkinson's disease patients ON and OFF dopaminergic medication, as well as matched 36 healthy controls. Our analysis revealed aberrant causal signalling in frontoparietal-basal ganglia circuits in Parkinson's disease patients OFF medication. Importantly, aberrant signalling was normalized by dopaminergic medication and a novel quantitative distance measure predicted individual differences in cognitive change associated with medication in Parkinson's disease patients. These findings were specific to causal signalling measures, as no such effects were detected with conventional non-causal connectivity measures. Our analysis also identified a specific frontoparietal causal signalling pathway from right middle frontal gyrus to right posterior parietal cortex that is impaired in Parkinson's disease. Unlike in healthy controls, the strength of causal interactions in this pathway did not increase with working memory load and the strength of load-dependent causal weights was not related to individual differences in working memory task performance in Parkinson's disease patients OFF medication. However, dopaminergic medication in Parkinson's disease patients reinstated the relation with working memory performance. Our findings provide new insights into aberrant causal brain circuit dynamics during working memory and identify mechanisms by which dopaminergic medication normalizes cognitive control circuits.
多巴胺能药物被广泛用于缓解帕金森病的运动症状，但这些药物也会对认知产生影响，不同患者之间存在显著差异。据推测，多巴胺能药物通过调节额顶叶-基底神经节认知控制回路来影响帕金森病的认知和工作记忆，但对其潜在的因果信号机制及其与对多巴胺能药物反应的个体差异的关系知之甚少。在这里，我们使用一种新的状态空间计算模型，结合超快（490 ms 分辨率）功能磁共振成像，研究了与工作记忆相关的额顶叶-基底神经节回路中的动态因果信号，研究对象包括 44 名帕金森病患者在使用和不使用多巴胺能药物时，以及 36 名匹配的健康对照者。我们的分析揭示了帕金森病患者在不使用药物时额顶叶-基底神经节回路中的异常因果信号。重要的是，多巴胺能药物使异常信号正常化，一种新的定量距离测量方法预测了帕金森病患者药物相关认知变化的个体差异。这些发现是针对因果信号测量的，因为使用传统的非因果连通性测量方法没有检测到这种影响。我们的分析还确定了一个特定的额顶叶因果信号通路，从右额中回到右顶后回，该通路在帕金森病患者中受损。与健康对照组不同的是，在这个通路中，因果相互作用的强度并没有随着工作记忆负荷的增加而增加，并且在帕金森病患者停药时，依赖负荷的因果权重的强度与工作记忆任务表现的个体差异无关。然而，帕金森病患者的多巴胺能药物恢复了与工作记忆表现的关系。我们的研究结果为工作记忆期间异常因果大脑回路动力学提供了新的见解，并确定了多巴胺能药物使认知控制回路正常化的机制。
