DEEP BRAIN STIMULATION AND PARKINSON’S DISEASE

Written By: Jefrin Joseph, Claire Rowley, Abhi Misra

Parkinson’s is a neurodegenerative disease that is characterized by the loss or death of neurons in the brain, causing symptoms such as tremors, stiffness, and difficulty walking among others that affect over 10 million people worldwide. These neurons are essential to performing vital functions and producing neurotransmitters such as dopamine and norepinephrine. As time goes on, these symptoms become more extreme in Parkinson’s patients. These symptoms do not directly cause death, but the disease weakens patients and causes them to become more susceptible to other illnesses that are more deadly, such as pneumonia.

Source: https://www.a4clinics.com/single-post/2018/04/11/Early-Intense-Exercise-Delays-Parkinsons-Disease-Progression

Parkinson’s treatments vary heavily based on the progression of the disease and the specific symptoms that a patient may feel. In the case of patients who suffer from degenerated motor symptoms, it is common for dopamine agonists to be prescribed as dopamine usually decreases as Parkinson’s develops. Monoamine Oxidase inhibitors are also prescribed to allow for the levels of dopamine to be present for a longer period of time by inhibiting the enzyme that breaks down dopamine. Non-motor symptoms of Parkinson’s are also quite diverse as they range from depression, constipation, psychosis, to sleep problems. As much of dementia treatment primarily targets the alleviation of a symptom rather than expelling the cause, several forms of symptom-specific medication are diagnosed based upon the specific case of a dementia patient. A non-invasive treatment that seeks to alleviate multiple symptoms at a time is focused ultrasound therapy. In this treatment, different targets in the brain (thalamus, globus pallidus, pallidothalamic tract) are hit with beams of ultrasonic energy to disrupt tissue. While not perfect, this treatment can result in the restoration of some ability as well as the slowed progression of Parkinson’s. One drawback with ultrasonic treatment is that it is irreversible.

DEEP BRAIN STIMULATION

Deep brain stimulation (DBS) is a procedure designed to be done in correlation to typical Parkinson’s medication treatments. Unlike other procedures it is reversible and its impact can be modified. The goal of the procedure is to help combat the dyskinesia (uncontrolled pauses or outbursts in movement) resulting from medication. As with any form of brain surgery, there is always the risk of complications arising so there are several criteria doctors look at when evaluating patients for DBS. This is why it is typically reserved for those with worsening symptoms and severe dyskinesia. Other key criteria looked at before prescribing the procedure are already responsiveness to dopaminergic medication like levodopa and the absence of dementia or severe depression (since the procedure could worsen those conditions). It is also worth noting that younger candidates tend to handle the procedure better as well. DBS does not cure Parkinson’s, instead, it is meant to complement medical treatment and can help reduce dosage levels of proper medication. According to the Cleveland Clinic, “after DBS, patients on average improve their daily ‘on time’ — when they are at their best, without troublesome dyskinesia — by half a day.” (clevelandclinic.org)

Source: https://www.aiphc.com/methods-to-treat-parkinsons-disease/

Though the effectiveness of DBS is no longer questioned, it is still unknown how exactly it works. One proposed explanation is ‘Rate Hypothesis’. As mentioned before Parkinson’s is the result of dopamine-producing neuron degeneration in the substantia nigra compacta. The lack of dopamine production leads to the suppression of the globus pallidus (a portion of the basal ganglia involved in the regulation of voluntary movement) ability to inhibit subthalamic nucleus (STN) activity. The STN is an important modulator of basal ganglia activity. The lack of dopamine also interferes with the functions of the striatum which is a dopaminergic input dependent region of the basal ganglia which serves as its primary input relay and is an inhibitor of the globular pallidus. This results in excessive GPi activity and suppression of thalamic activity to the cortex. This was first seen in the increased rate of action potentials in the brains of monkeys with Parkinson’s compared to those with healthy brains. The electric stimulation of the electrodes used during DBS is thought to induce micro strokes that help combat the hyperstimulation of the globus pallidus.

The components involved in DBS include:

  • Electrodes placed in the brain at sites of stimulation (roughly the size of a spaghetti strain).
Source: https://www.nejm.org/doi/full/10.1056/NEJMct1208070

The surgery typically is done while the patient is awake with the use of scalp numbing anesthesia. Before the procedure, the scalp is numbered and metal pins are inserted into the head to install a metal frame to stabilize it and help align the equipment used during the procedure. The patient’s brain is then mapped with an MRI and using x-rays the electrode is installed at the thalamus, STN, or the globus pallidus internus. Advancements in 21st-century technology now allow for this procedure to be done while the patient is asleep using an MRI adjusted aiming device. The choice of being awake or asleep is typically up to the patient’s preference, but asleep surgery is used for patients who can’t tolerate being off their Parkinson’s medications for the duration of the surgery.

After the procedure, patients should expect a hospital stay of 1–2 days and should not engage in light activity for 2 weeks and heavy activity for 4 to 6 weeks. It can take up to 3–6 months to design optimal programming and medication modifications.

HISTORY OF DBS

Physicians have been experimenting with electrode stimulation to treat medical conditions since the 1930s. Wilder Penfield, a pioneer in brain surgery, used electricity to stimulate patients’ brains and watch for their reactions, hoping to locate and burn off the area of the brain causing seizures. Most experts agree that the first version of DBS comparable to the modern version was first developed by a team in 1987 in France. They worked on treating patients with essential tremor and Parkinson’s. This technology established the foundation for stereotactic neurosurgery. Physicians began to use a combination of electrical stimulation and imaging, such as CT or MRI scanning to obtain the most accuracy and precision during surgery. This led directly to the modern DBS technology that is continually being used and improved upon today.

Modern DBS was first approved for use by the FDA in 2002. Since then, over 40,000 people have used DBS to treat symptoms of Parkinson’s. Despite being rather invasive and riskier than other treatments, there are many success stories. Patients are able to regain many aspects of normal life after previously being confined to their home or bed due to debilitating symptoms. The impact of patients reclaiming their lives after Parkinson’s diagnosis is exciting and hopeful to the neuroscience and medical community.

THE FUTURE OF DBS

A modern implementation of DBS involves active feedback and adjustments caused by the implementation of biomarkers. The existence of these biomarkers such as electrophysical surrogates of Parkinson’s diseases’ motor signs allows for the implementation of adaptive algorithms. An expected increase in the recognition of biomarkers will allow for the efficacy of a closed-loop system of deep brain stimulation. Rather than be constantly reprogrammed based upon novel symptoms, a closed-loop system can actively slow and potentially prevent future symptoms through the recognition of faulty signaling. The applications of such a process can also be reactive such as triggering thalamic deep brain stimulation in the instances of epilepsy, seizures, or tremors. Current investigations such as the pattern hypothesis further expand research areas for potential breakthroughs to arise. It was found that movement disorders often stemmed from a variance in patterns of neuronal activity rather than changes in the rate. This opens up the potential for different ways in which stimulation is targeted within the brain as well as varying targets to utilize.

Source: https://www.ccjm.org/content/ccjom/75/3_suppl_2/S59.full.pdf

From a hardware perspective, DBS can be improved through the creation of flexible multi-contact electrodes. Such electrodes would be able to accurately provide a model of neural circuitry which would provide increased accuracy of where stimulation and treatment are needed. Additionally, such electrodes have better accuracy in terms of where the actual stimulation is directed as thinner and more flexible electrodes can target more specific and smaller regions of the brain.

Currently, research is being done towards the efficacy of non-invasive deep brain stimulation. Non-invasive methods such as transcranial magnetic stimulation have been experimented with to see the accuracy of targeting as well as the effectiveness of stimulation. Further research and development into non-invasive methods would allow for the costs of the process to reduce and the number of people able to conduct such an operation to increase. Although medication paired with deep brain stimulation stands as the most effective combatant of Parkinson’s disease as of today, the development of deep brain stimulation and other technologies such as gene therapy provides a positive outlook for the treatment of Parkinson’s Disease.

REFERENCES

Lee, D., Lozano, A., (2018) The Future of Surgical Treatments for Parkinson’s Disease. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311380/

Deep Brain Stimulation for Parkinson’s Disease Patients: Recovery and Outlook. (n.d.). Retrieved November 13, 2020, from https://my.clevelandclinic.org/health/treatments/4080-deep-brain-stimulation-for-parkinsons-disease-patients/recovery-and-outlook

Fang, J., Tolleson, C. (2017) The Role of Deep Brain Stimulation in Parkinson’s Disease: an overview and update on new developments. National Center for Biotechnology Information. PMID: 28331322 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349504/

Gardner J. (2013). A history of deep brain stimulation: Technological innovation and the role of clinical assessment tools. Social Studies of Science, 43(5), 707–728. https://doi.org/10.1177/0306312713483678

Hitti, F. L., Ramayya, A. G., McShane, B. J., Yang, A. I., Vaughan, K. A., & Baltuch, G. H. (2019). Long-term outcomes following deep brain stimulation for Parkinson’s disease. Journal of neurosurgery, 1–6. Advance online publication. https://doi.org/10.3171/2018.8.JNS182081

Michigan Medicine (Oct 17, 2016) Deep Brain Stimulation (DBS) for Parkinson’s Disease: Dr. Emily Levin[Video]. Youtube: https://www.youtube.com/watch?v=p2UgCT0o07I

Vitek, J. L. (2008). Deep brain stimulation: How does it work?. Cleveland Clinic Journal of Medicine, 75, Online ISSN: 1939–2869