Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide. The gold-standard PD treatment is oral administration of levodopa, which acutely ameliorates PD movement symptoms. However, chronic use of levodopa results in a side effect called levodopa-induced dyskinesia (LID), whereby patients develop involuntary excessive movements in response to subsequent levodopa treatments. LID develops over time: 40-50% of patients develop LID after five years and 50-80% develop LID after ten years. There is no treatment for LID and cessation of levodopa is not an option due to PD symptom resurgence. Therefore, further understanding of the mechanisms behind LID and developing better treatments are critical to improve patient outcomes for the millions of individuals with PD.
Dyskinesia is thought be the consequence of pulsatile dopamine (DA) receptor stimulation. LID is multifactorial, showing pathological changes in both cellular receptor expression and network activity throughout the movement pathway. Network research has focused on activity changes in the striatum and other basal ganglia (BG) nuclei including a BG output nucleus, the substantia nigra pars reticulata (SNpr). Previous research has identified direct pathway hyperactivity and decreased SNpr activity as critical in LID symptoms. However, little research has focused on downstream changes in the motor thalamus (Mthal), which receives monosynaptic inputs from the SNpr. The Mthal has been hypothesised to be an integration hub, receiving the movement plan from the BG and sensory inputs from the cerebellum and projecting a synthesised movement plan to the motor cortex. It is plausible that significant changes in the motor thalamus occur following LID onset.
This research explored SNpr and Mthal activity and investigated their interactions following LID onset. This expanded on LID research by pairing this novel structure to the SNpr, a well-understood nucleus. To achieve this, urethane anaesthetised extracellular electrophysiology was performed on four treatment groups: control, parkinsonian levodopa-naïve (PD), parkinsonian levodopa-dosed but non-dyskinetic (LID-), and parkinsonian levodopa-dosed and dyskinetic (LID+). Recordings were done in baseline, while a levodopa was being injected, and in the 25-80 minutes following. This permitted investigation of baseline activity, an acute levodopa response, and the relative effect of levodopa on the network. The LID- treatment group was novel and allowed the differentiation of activity changes of long-term levodopa use from LID onset.
Baseline SNpr activity was increased in PD compared to controls, aligning with historical findings. In addition, SNpr activity in LID+ was significantly increased with a higher firing rate, burst frequency, stronger bursts, and increased single spike oscillations compared to controls. However, levodopa greatly decreased SNpr output in LID+. Significant decreases were found in firing rate, burst number and strength. This drug-induced effect was not seen in any other treatment, suggesting SNpr inactivity is critical in LID.
Baseline Mthal activity did not change significantly in PD, aligning with previous papers, whereas LID+ showed significantly increased firing rate, general burst number, LTS burst number, single-cell oscillations and synchronisation compared to all other treatment groups. Following levodopa administration, significant changes occurred to LID+ Mthal activity where firing rate and general burst number increased further, while LTS burst number, single-cell oscillations, and synchronisation decreased. Interestingly, the opposite effects occurred in the LID- treatment following levodopa administration, where LTS bursts increased, firing rate decreased, and general burst number decreased.
Interactions between SNpr and Mthal activity were examined using simultaneous recordings. In baseline, SNpr-Mthal synchronisation was significantly increased in the PD and LID+ treatment groups but not in the LID- treatment group. Levodopa significantly decreased this interaction in the LID+ treatment but significantly increased it in the LID- treatment group. The different responses of these two groups possibly reflect the pathological and therapeutic effects of levodopa on network activity.
These results show that Mthal may be critical in LID symptom expression. This nucleus, once ignored in PD research, greatly changes in rate, pattern, synchronisation, and population activity following LID onset. Furthermore, SNpr-Mthal interactions may contribute to the pathology of LID onset. Normally SNpr modulates downstream Mthal activity, whereas these data show that levodopa-induced SNpr silencing results in hyperactive and disordered Mthal activity. Critically, this change only occurred in the LID+ treatment group, whereas effects were opposite in the LID- treatment group. This discrepancy between the levodopa-induced effects in the LID- and LID+ treatment groups reflects that there is a critical switch in the network’s response to levodopa that underlies LID onset. LID- proved to be useful as a novel treatment group in capturing the differences between therapeutic and pathological effects of levodopa. These findings add to the current understanding of network changes that underlie LID and application of these findings could improve health outcomes for millions of individuals living with LID worldwide.