In a study published in Journal of Neuroscience, the researchers from Dr. YE Zheng’s Lab at the Institute of Neuroscience, Center for Excellence in Brain Sciences and Intelligence Technology of the Chinese Academy of Sciences, and Prof. JIN Lirong’s team from Zhongshan Hospital of the Fudan University, demonstrated that damage to the substantia nigra (SN) correlates with basal ganglia dysfunction and poor sequencing performance in Parkinson’s disease (PD).  

Cognitive impairment is one of the most common non-motor symptoms in PD, significantly affecting patients’ quality of life and functional independence. There is no cure for PD. Anti-parkinsonian drugs such as levodopa and dopamine receptor agonists are used to alleviate motor symptoms.  

The ability to process sequential information online is essential for a broad spectrum of daily activities, from making a conversation (what to say first) to scheduling a day (what to do first). In healthy brains, a neural system for sequential working memory comprises the prefrontal cortex and basal ganglia, which include the striatum, globus pallidus, and subthalamic nucleus. Previous work by the researchers showed that PD patients’ poor sequencing performance correlates with hyper-activation of the subthalamic nucleus and weakened functional connectivity between the subthalamic nucleus and striatum.  

To better understand the neurobiology of sequential working memory deficits in PD, the researchers measured the area of the SN pars compacta with high neuromelanin signals in 29 patients with PD and 29 healthy control participants, using neuromelanin-sensitive structural magnetic resonance imaging (MRI). They also measured participants’ behavioral performance and brain activity when they conducted a digit ordering task during functional MRI scanning.

In the digit ordering task, participants were asked to remember a sequence of four digits and recall the digits in ascending order. In half of the trials, the digits appeared in ascending order, and participants only had to remember the original sequence. In the other half of the trials, the digits were fully randomized, and participants had to reorder the digits. Sequencing performance was measured by contrasting the two conditions.  

The researchers found that the SN areas with high neuromelanin signals were significantly smaller in patients with PD than healthy participants, indicating disease-related damage to the SN pars compacta.

In the digit ordering task, the striatum and globus pallidus were hypo-activated, the subthalamic nucleus was hyper-activated, and the functional connectivity between the bilateral SN and basal ganglia regions was significantly weakened in patients with PD than healthy participants. Moreover, PD patients with smaller SN areas tended to exhibit weaker ordering-related striatal activation and worse sequencing performance.

Anti-parkinsonian drugs such as dopamine receptor agonists could modulate ordering-related subthalamic activation but could not improve the sequencing performance of patients with PD. The findings of this study suggest that damage to the SN pars compacta may lead to sequential working memory deficits in PD, mediated by basal ganglia dysfunction.

Idiopathic PD is the second most common age-related neurodegenerative disease. It is characterized by the progressive death of dopaminergic neurons in the substantia nigra pars compacta. PD's primary motor symptoms include resting tremor, rigidity, and slowness of movement. Patients with PD also develop a series of non-motor symptoms such as cognitive decline, sleep disorders, and autonomic nervous system dysfunction.