In this study, dFNC analysis was used to explore the differences of dynamic functional network connectivity in PD patients with or without LID and on/off levodopa treatments, focusing on temporal properties (fractional windows, dwell time and number of transitions). Five states were identified across the entire sliding time windows. State 1–4 were less frequent but had strong within-network and between-network connections; State 5 was the most frequent characterized by relatively weak within-network connections and lack of strong between-network connections. Specifically, LID group occurred more frequently and dwelled longer in State 1 compared with No-LID group in ON phase. When switching from OFF to ON phase, frequency of occurrence of LID group increased in State 2 and decreased in State 3, correspondingly, dwell time of State 2 was longer and that of State 3 was shorter. While in No-LID group, only State 5 occurred more frequently and dwelled longer when levodopa medications worked. Further, correlation analysis indicated that the severity of dyskinesia in LID group was associated with frequency of occurrence and dwell time in State 2.
In this work, we did not focus on definite brain areas of interest as in previous LID studies , but examined FC of whole brain at the network level. Importantly, considering potential influence of dopaminergic medications on fMRI, we explored dFNC both in OFF and ON phases. Traditional static FC is used to analyze the average connectivity, implicitly assuming that FC remains constant throughout MRI scans. However, it is widely known that FC in human brain is dynamic. And spontaneous brain activity of LID patients, characterized by levodopa medications triggering involuntary movement, is considered as changing over scanning time. The dFNC can capture time fluctuations in network interactions and gain a deeper understanding of basic properties of brain networks [9, 12]. Emerging data suggested the important utility of dFNC for exploring underlying nerve damaged mechanisms such as migraine , epilepsy , schizophrenia , and Alzheimer’s disease . In particular, for PD, Kim et al. proposed for the first time that PD patients occurred more frequently and dwelled longer in strongly between-network connected state compared to healthy controls . Subsequently, they reported that increased dwell time in weak within-network connected state was associated with the presence of dementia in PD . These findings implied that dFNC was a promising approach for clinical neuroimaging, and might provide greater insights into the neural mechanism of LID.
In this study, no significant differences of temporal properties were found between PD subgroups in OFF phase. In ON phase, compared to No-LID group, LID group occurred more frequently and dwelled longer in State 1. For State 1, interconnections were found between the VIS and other networks (strong positive connectivity between VIS and SMN, and negative connectivity of VIS with DMN). This indicated that LID may be related to the superexcitation of VIS. VIS is one of the most important sensory perception networks in humans. Since the aberrant processing of visual information has precise influences on motor impairments via sensory guidance [36, 37], the visual cortex is expected to be superexcitable in LID. However, the exact mechanism needs to be confirmed by further research.
The pathogenesis of LID is still not clear, but it is believed that aberrant dopaminergic modulation of basal ganglia-cortical motor loops in the direct and indirect pathways lead to overactivity of frontal cortical areas and the occurrence of peak-dose LID [5, 38, 39]. Our results showed that after controlling for associated covariates, the severity of dyskinesia was only closely linked with frequency of occurrence and dwell time in State 2, dominated by the IFC in CEN, strongly connecting with SMN and VIS. In general, the IFC has been included in a critical component of CEN, defined as the motor inhibition network, which has been shown to be connected with inhibitory control over motor responses, such as performance monitoring and implementing executive control [40, 41]. Long time levodopa treatment may pathologically alter the ability of IFC to monitor motor response and enhance the neural activity in motor cortex (the SMN in this study) either via cortico-basal ganglia pathway, or via cortico-cortical pathway . Our results further confirmed the above hypothesis in terms of network level and dynamics of brain activity. CEN primarily comprising fronto-parietal regions is involved in key interactive functional networks for coordinating motor function . It was reported that patients with LID was profoundly relevant to the dysfunction of cognition and execution (i.e. CEN) . The SMN is involved in sensory perception and motor process [45, 46]. Studies identified that the disinhibition of cortical-subcortical circuits in the SMN may contribute to the abnormal involuntary movements . It is conceivable that abnormal interconnections between CEN and SMN, VIS may have impact on inhibition of motor circuits, closely relating to the occurrence of LID [47, 48].
In agreement with previous studies [9, 12], our results revealed that State 5 was the highest frequency of occurrence, characterized by weak within-network connections and lack of strong between-network connections. The frequency of this more common state is thought to be related to the number of self-focused thoughts , while other states are considered to reflect cognitive, physiological or motion-related processes . When switching from OFF to ON phase, the frequency of occurrence and dwell time of State 5 increased significantly in patients without LID, correspondingly resulting in the shortage of time spent in other four strongly connected states. Thus, we speculated that when levodopa worked, PD patients without LID might prefer to remain in a calm state, which could be the reason for the absence of LID.
However, a few limitations have to be noted. First, head movements can have a bad effect on resting-state FC. To alleviate this influence, we performed a series of procedures, but the influence of head movements may not be completely ruled out. Second, similar to previous studies , the disease duration did not match well in our study, so we have considered this as one of covariates in further analysis to mitigate its effect. Third, to ensure the security of patients and avoid the impact of head movements on image quality, we begun fMRI scanning for those patients with LID before levodopa reached its peak in ON phase, which may not fully reflect the functional state of brain during the peak of dose.