Treating Parkinson’s Disease Symptoms Using Optogenic Deep Brain Stimulation in the Subthalamic Nucleus

Adam Vanderlaan

Deep brain stimulation has been proven to be effective, however some of the mechanisms for its success are unclear. A patient who has experienced Parkinson’s symptoms for over 4 years may undergo this procedure which involves doctors using a thin wire to send electrical impulses into the brain. This stimulation alleviates Parkinson’s symptoms like muscle stiffness, slowness to movement, and muscle tremors. However, there are other symptoms associated with Parkinson’s that it does not treat and may even worsen issues involving memory and thinking (Michael J. Fox Foundation, 2020). DBS targets the subthalamic nucleus, a node that is critical to motor control from the basal ganglia. In animal models, inhibiting the function of the subthalamic nucleus using DBS has been demonstrated to be an effective method of treatment for Parkinson’s motor symptoms. It is similarly effective in humans but requires high frequency chronic stimulation from an implanted device (Benabid, 2003). The study by Yu et al. further investigated the mechanisms behind this form of treatment and concluded that a higher stimulation rate contributed to reduced abnormal oscillatory activity in the subthalamic nucleus, therefore treating Parkinson’s motor symptoms better than low frequency optogenic treatment. Their main findings stipulated that the kinetic properties of the opsins used are very important to the results of the optogenic deep brain stimulation treatment.

turning after high rate DBS, but no change in behaviour after low rate stimulation. The other opsin that was tested was ChR2, which had no change to behaviour after both high rate and low rate stimulation. These results were significant as a measurable improvement in forelimb stepping was observed after high rate optogenic DBS to the STN using the opsin Chronos.

Major Results

The main discovery of the study by Yu et al. was that using an opsin that could keep up with the high rates of stimulation required for DBS effectively reduced the forelimb motor ChR2 was unable to elicit a response in both high rate and low rate stimulation, which confirms that the kinetics of the opsin

Background and Introduction

Optogenic DBS therapy has many clinical benefits, but the mechanisms behind its effect remain somewhat of a mystery. Further research into the subject could potentially optimize treatment, and a broader understanding of its function may lead to its use in the treatment of other neurological disorders. Deep brain stimulation was first introduced in 1997 and was a vast improvement to the treatment of Parkinson’s symptoms over previous ablative methods like thalamotomy (Benabid et al., 2003). DBS is a safer alternative as it is reversible, and the high frequency electrical pulses at 100khz were very effective at inhibiting activity that produces movement from Parkinson’s disease. Benabid et al. found that DBS of the subthalamic nucleus in particular greatly improved the daily activities of patients even after a 12-month period and remarked that potential uses for the treatment were “far from fully explored at this time”. This treatment also allowed them to decrease other dopaminergic treatments by 50%. As this technique is so proficient at getting meaningful results in patients and comes at a relatively lower risk than previous treatments, it is justifiable to dedicate further resources to enhance our knowledge of the underlying processes in DBS. In the paper by Yu et al., optogenic deep brain stimulation was used to treat mouse models with induced HemiParkinson’s disease. Optogenic therapy involves genetically modifying the neurons in the subthalamic nucleus to produce a type of protein called an opsin. When specific ranges of light are received by the opsin, the neuron will activate. In this way, researchers can specifically target certain neurons in the brain and activate them at will (Frontiers for Young Minds, 2020). Yu et al. compared two different opsins in their approach. A low frequency, commonly used opsin called ChR2, and an opsin All of the rats were injected with 6-OHDA to induce HemiParkinson’s and implanted with optical fibers in the subthalamic nucleus. A circling test and adjusted step test were performed to demonstrate the effects of DBS, where the ratio of steps with the contralateral forelimb to the ipsilateral forelimb was measured over the course of the tests. They found that rats injected with Chronos exhibited suppressed ipsilateral degradation caused by Parkinson’s. The kinetically slower opsin

that responded to high frequency stimulation called Chronos. are just as important as the rate by which it is stimulated.

The above graphics from Yu et al. visually demonstrate the main findings of the paper. On the left in dark blue, Chronos is seen to reduce the turns per minute of the rats under testing, but only at stimulation rates of 75pps to 130pps. Conversely, the ChR2 is unable to mitigate the effects of Parkinson’s motor control symptoms at all stimulation rates. These results are in line with other studies which concur that DBS at the STN is an effective treatment for Parkinson’s motor symptoms, however there is still debate around the actual reason as to why this is the case. A study by Lüscher et al. proposes that this type of treatment works due to the inhibition of an overactive striatal output pathway, and that the DBS is correcting a pathway that is malfunctioning as a result of dopamine absence, without actually restoring dopamine levels.

Conclusion/Discussions

The key takeaway from this paper is that the kinetic properties of the selected opsin play a large role in its effectiveness in treatment, and as such may be an important avenue of research for further discoveries. If we can better understand how exactly the treatment works, then perhaps it can be applied more efficiently or used as treatment in other scenarios. With deep brain stimulation it is hard to identify exactly what is

affected by the treatment, and even harder to specifically activate neurons without affecting many of the adjacent neuronal regions. For this reason, DBS via optogenics may not be feasible as a treatment in humans since our brains are vastly more complex than the genetically modified ones found in rats currently being used for optogenics (Lüscher et al.). There is also a discussion to be had as to why the subthalamic nucleus is the preferred target for the therapy, as the internal pallidum may be just as effective (Krack et al.). This illustrates another area where there is still much left to investigate.

Critical Analysis

The study by Yu et al. sets out to explore an area of science where there are many questions left to be answered, but exactly how much they achieved to further the research is questionable. It has long been established that deep brain stimulation is able to achieve treatment to Parkinson’s motor symptoms since its discovery in 1997 (Benabid et al., 2003). The researcher’s use of optogenics to implement the DBS is compelling, but the likelihood that that technology will ever be safely utilized in human patients is uncertain. However, they were able to conclude that only ultrafast opsins like Chronos would be effective in treatment, and this is progress nonetheless. It is always hard to see where the next breakthrough will come from, so studies like these are important to fully explore all aspects of a topic that are available to researchers with today’s technology. An example of where this new information may be implemented could be as a follow up to a study by Chiang et al. where the opsin ChR2 was used to treat epileptic symptoms. In this case, they used high frequency stimulation while using ChR2 and achieved a response to the treatment. It would be interesting to see the same experimental procedure carried out using the ultrafast opsin Chronos now that we know that the kinetics of the opsin can play a large role in the outcome of the procedure. There is certainly a lot to learn about DBS and its applications to treat neurological diseases. Since we don’t quite understand exactly how it treats these parkinsonian symptoms, I think it would be beneficial to use it on a plethora of different rats with various induced neurological diseases. Using the results from the study by Yu et al., we know that high frequency stimulation using ultrafast opsins has a pronounced effect on the brains of the test subjects, so maybe it would have as of yet unknown effects on rats with induced Alzheimer’s, epilepsy, or other neurodegenerative diseases. Knowing that depression relates to dopaminergic imbalances, DBS may even be a method of treatment to explore. It was speculated by Lüscher et al. that DBS treatment corrected a similarly malfunctioning pathway in the case of Parkinson’s. In a field of science where there is still so much to learn, doing as much research as possible into the unknown is sure to yield some fascinating results.

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