Substantia Nigra Integrity Correlates with Sequential Working Memory in Parkinson's Disease

Maintaining and manipulating sequences online is essential for daily activities such as scheduling a day. In Parkinson's disease (PD), sequential working memory deficits have been associated with altered regional activation and functional connectivity in the basal ganglia. This study demonstrates that the substantia nigra (SN) integrity correlated with basal ganglia function and sequencing performance in 29 patients with PD (17 women) and 29 healthy controls (HCs; 18 women). In neuromelanin-sensitive structural magnetic resonance imaging (MRI), PD patients showed smaller SNs than HCs. In a digit-ordering task with functional MRI (fMRI), participants either recalled sequential digits in the original order (pure recall) or rearranged the digits and recalled the new sequence (reorder and recall). PD patients performed less accurately than HCs, accompanied by the caudate and pallidal hypoactivation, subthalamic hyperactivation, and weakened functional connectivity between the bilateral SN and all three basal ganglia regions. PD patients with larger SNs tended to exhibit smaller ordering-related accuracy costs (reorder and recall vs pure recall). This effect was fully mediated by the ordering-related caudate activation. Unlike HCs, the ordering-related accuracy cost correlated with the ordering-related caudate activation but not subthalamic activation in PD patients. Moreover, the ordering-related caudate activation correlated with the SN area but not with the daily dose of D_2/3 receptor agonists. In PD patients, the daily dose of D_2/3 receptor agonists correlated with the ordering-related subthalamic activation, which was not related to the accuracy cost. The findings suggest that damage to the SN may lead to sequential working memory deficits in PD patients, mediated by basal ganglia dysfunction.SIGNIFICANCE STATEMENT We demonstrate that damage to the SN correlates with basal ganglia dysfunction and poor sequencing performance in PD patients. In neuromelanin-sensitive MRI, PD patients showed smaller SNs than healthy controls. In a digit-ordering task with fMRI, PD patients' lower task accuracy was accompanied by the caudate and pallidal hypoactivation, subthalamic hyperactivation, and weakened functional connectivity between the SN and basal ganglia. PD patients with larger SNs exhibited greater ordering-related caudate activation and lower ordering-related accuracy cost when sequencing digits. PD patients with more daily exposure to D_2/3 receptor agonists exhibited greater ordering-related subthalamic activation, which did not reduce accuracy cost. It suggests that the SN may affect sequencing performance by regulating the task-dependent caudate activation in PD patients.