Focused Deep Brain Stimulation of Parkinson’s Disease Patients can improve motor symptoms

Parkinson’s Disease (PD), characterized by the resting tremors, bradykinesia, rigidity and postural instability caused by the loss of dopamine cells, is the second most common neurodegenerative disorder due to aging and the most common movement disorder (Mhyre et al., 2012). Around 60,000 Americans are diagnosed with PD every year, and there are approximately 10 million individuals living with it. Though discovered in the 1800s by James Parkinson, the cause of this eponymous disease remains enigmatic; the same goes for the cure (Mhyre et al., 2012). Current treatments, however, are advancing daily and addressing a wide range of PD symptoms, including alleviating motor suppression.

One study, conducted on mice by University of Copenhagen neuroscientists, showed that Deep Brain Stimulation (DBS) treatment of locomotor problems in Parkinson’s could be advanced through the targeting of the caudal glutamatergic neurons in the pedunculopontine nucleus (PPN). 

The PPN, alongside the cuneiform (CnF), is a subregion of the mesencephalic locomotor region (MLR) crucial in the initiation and modulation of movement (Josset et al., 2018). Additionally, unlike the CnF, the PPN is under direct increased inhibition of the basal ganglia (BG) due to the loss of dopaminergic signals. Thus, the researchers believe that, by rescuing the PPN from the excessive BG inhibition, they can improve Parkinson’s locomotor symptoms. This focus is rather fruitful, especially when the previous treatments control mainly for the BG-induced tremors.

Instead of stimulating non-specific and diverse PPN neurons as previous studies have done, Masini and Keihn (2021) mainly focused on activating localized neurons in the caudal part of the PPN. “We use a technology to target specific group of cells in the PPN in order to close in on what areas are the best to stimulate… the result shows that the motor improvement is optimal, if we stimulate what we call excitatory neurons in the caudal area of the PPN,” Keihn suggested in an interview for the Science Daily. This approach is supported by Goetz et al. (2019) and Thevathasan et al. (2011) as they found motor facilitation might be restricted there.

To set this study in motion, they mimic the PD symptoms of motor suppression by antagonizing dopamine D1 and D2 receptors of two distinct mice models with haloperidol or SCH23390. After that, they use cell-type specific chemogenetic and optogenetic approaches to activate the caudal PPN neurons. In chemogenetic experiments, they injected a coding virus for excitatory DREADD (eD for short) in the caudal PPN of the treatment group (Vglut2) mice. With eD, Clozapine-N-oxide injection can be activated, increasing neuronal activity in said region. In optogenetic experiments, they injected a coding virus for channelrhodopsin-2 into the caudal PPN of the Vglut2 mice, which will activate and increase neuronal activity when exposed to light.

As expected, the activation of caudal PPN neurons promotes locomotor activities. The treatment group mice could walk for longer distances, with normal speed, and for a longer time compared to the control group. Additionally, the chemogenetic activation of glutamatergic PPN neurons rescued motor suppression from both the D1 and D2 receptor antagonism; this was shown both over prolonged periods as well as time-lock episodic events. This result was also found in a study by Caggiano (2018) where they stimulate the Vglut2 PPN neuronal activities with light activation. For GABAnergic neurons, however, locomotor abilities were only restored by D2-receptor antagonism, not D1. This suggests that the type of neurons stimulated can play a factor in whether or not motor suppression can be lessened.

Previous studies (Josset et al., 2018; Caggiano et al., 2018; Dautan et al., 2020) found that the CnF and PPN can work together to promote locomotor. Thus, Masini and Kiehn took an extra step to test whether the results they observed is mediated through the CnF neurons. They arrived at a unique result, one that enhances the findings from the studies mentioned above: locomotor promoting effects are independent of the CnF. Optogenetic activation of the glutamatergic PPN neurons promoted movement regardless of CnF engagement. In fact, the values of locomotor function after caudal PPN neuron activation between CnF and non-CnF inhibition mice were indistinguishable.

Finally, the Vglut2 mice could navigate a complex environment with obstacles and walk up an inclined ladder with the same proficiency as the control group, suggesting that the proficiency and adaptive locomotion in PD mice is rescued by the activation of caudal PPN activation. Put together, the results further solidify that the caudal part of the PPN is the key target region for movement loss recovery.

While DBS is a wonderful advance in the field of neuroscience, which brain region to target when performing the procedure is still one of the most crucial questions that burden clinicians (Lozano et al., 2019). Subsequently, these findings help narrow down the targeting site for Parkinson’s DBS to a single location: the caudal of the PPN. The results also help solidify and ensure patients of the effectiveness of DBS when other medications can no longer help with symptoms. 

Initiating movement and locomotion is one of the profound difficulties for PD patients. This study suggests that targeting the caudal glutamatergic PPN neurons can help release BG inhibition and restore movement. By shifting the focus away from the frequently seen cholinergic PPN neurons as the proposed target for this neuromodulatory approach, this study is a big step forward in the treatment as well as the search for PD etiology. Though their experiments have only been tested on mice, the researchers believe that the results merit is still the same. “Nearly everything we have learned in the beginning on how to treat Parkinson’s Disease comes from animal models, including the medication we use nowadays for patients. In this sense, it is a valid approach, and we hope our study can help provide better treatment for human patients,” says Debora Masini to Science Daily. For future studies, a closer look at GABAnergic neurons and CnF neurons and their contribution to DBS unreliable results is suggested. And finally, a direct translation of this study into a human setting would be a suitable next step in helping PD patients in restoring the fundamental function of movement.

References

Anon (2022) Treatment for parkinson’s could now get even better. ScienceDaily Available at: https://www.sciencedaily.com/releases/2022/02/220218100701.htm [Accessed May 10, 2022]. 

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