The Different Effects of Deep Brain Stimulation in Parkinsonian and Essential Tremor

Nearly one million people in the United States alone suffer from Parkinson’s disease (PD), an astounding number and one expected to double by 2040. Being the second most common neurodegenerative disease, understanding Parkinson’s disease and developing new treatments is critical [1].  One of the most noticeable disruptions to motor functions in Parkinson’s is the presence of tremors, with essential tremors being the most common source of tremors associated with voluntary movement [2]. One of the most common PD treatments is the prescription levodopa, a drug aiding in motor function. 

However, recent research has nominated a new PD treatment for cases where medication fails: deep brain stimulation (DBS). DBS is a surgical procedure to implant a pulse generator (IPG) to deliver electrical stimulation to an area of the brain, such as the subthalamic nucleus or globus pallidus internus,  that helps control movement. In PD, the target area is the ventral intermediate nucleus of the thalamus (VIM) and the posterior subthalamic area. This device functions to block abnormal nerve signals in the respective areas of the brain, allowing correct transmission of nerve signals [3]. The ventral intermediate nucleus of the thalamus is targeted because it is part of the cerebello-thalamo-cortical network which connects the primary cortex to the dentate nucleus, in simpler words it connects the cerebellum to the cortex [4][5]. This connection is essential as the cerebellum regulates motor movement and balance control whilst the motor cortex (located in the cerebral cortex) generates the signals to direct the movement. Malfunctions between these pathways may be the basis of tremors [6][7].

DBS can provide combinations of stimulation with varying pulse width, frequency, and voltage [8]. Researchers need to optimize these parameters to develop the best treatments for each patient or disease. At the University of Hamburg, researchers are testing one such treatment combination using short pulse and directional stimulation patterns in the VIM/PSA region of the brain. This treatment is exciting because it differs from past DBS studies, as the electrode implanted in the patient’s brain can deliver more precise and versatile stimulation. Past studies used omnidirectional stimulation where the electrodes consist of 4-8 contacts arranged vertically that are activated together to provide stimulation in a vertical fashion. On the other hand, directional stimulation is arranged in a very similar way however the two central contacts are split into 3 segments which can be activated together or separately allowing omnidirectional or individual stimulation respectively [10].  

To test their new approach, researchers recruited six PD patients and seven patients with essential tremors (different from PD) to receive a VIM/PSA-DBS implant [8]. DBS electrodes were surgically implanted, targeting specific brain regions, and their placement was verified using imaging techniques. To evaluate the ideal placement and stipulation settings of DBS, researchers used the assessment of essential tremors (ET) and recorded tremor severity and ataxia (lack of muscle coordination that leads to awkward movements ). The patients were split into four experimental conditions as follows: DBS switched off, longer omnidirectional stimulation at a higher pulse width of 60µs, shorter omnidirectional stimulation at a lower pulse width of 30µs, and longer directional stimulation with a higher pulse width of 60µs. Patients and evaluators were blinded to the stimulation settings, which were randomized to reduce bias. Statistical analyses were performed to identify differences between the PD and ET groups and to determine how changes in stimulation settings affected symptoms [8].

The researcher found that the varying stimulation patterns had differential effects on Essential Tremor patients and Parkinson’s Disease patients [8]. Short pulse and omnidirectional 60µs stimulation (30µs) have similar results in suppressing tremors and were both more effective than stim off, oDBS60 and oDBS30. Short pulse stimulation also had significant effects of short pulse stimulation on hand tremor scores and ataxia.  Directional and omnidirectional DBS stimulation patterns were both effective in suppressing tremor hands. Tremor reductions were also seen to be more pronounced in PD patients than ET patients in the conventional setting. The predominant tremor and postural tremor in PD patients were suppressed completely by DBS in both regions whilst intentional, action tremor which is seen more in ET patients was less impacted by VIM/PSA DBS. This also indicates that omnidirectional and directional stimulation improved the resting tremors in PD patients whilst ET patients had improved postural and intention tremors but a lack of improvement in predominant drawing tremors in both stimulation modes [8]. 

Overall the results of this study show that the conventional, short pulse, and directional stimulation techniques have variable effects on PD patients and ET patients [8]. The overall improvement in tremor hands subscores was seen significantly in the conventional stimulation (omnidirectional DBS 60µs), short pulse (omnidirectional DBS 30µs), and directional (directional DBS 60µs) in both PD and ET patients at the dorsal contact region, with the best conditional effect being the short pulse stimulation in comparison to directional and conventional [8]. These results allow us to recognize new treatment plans that may better suit the signs shown by different conditions. Both short pulse and directional seem to show better improvements in symptoms of both disorders, however this effect is better seen in PD patients due to the fundamental difference in brain physiology from ET. If the study is better tailored to the physiology of ET by conducting further research on the anatomy of the brain that causes ET, and placing electrodes there, perhaps a more pronounced effect can be seen in ET patients. While DBS unfortunately, does not slow down the progression or treat PD, this research may change the way both ET and PD symptoms, such as tremor, are currently treated with DBS and allow a deeper understanding of the neurodegenerative care we provide.

References: 

[1] Office of Communications and Public Liaison. (2023, January 30). Parkinson’s disease: Challenges, progress, and promise. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/current-research/focus-disorders/parkinsons-disease-research/parkinsons-disease-challenges-progress-and-promise 

[2] Agarwal, S. (2023, July 10). Essential tremor. Essential Tremor. https://www.ncbi.nlm.nih.gov/books/NBK499986/#:~:text=Tremors%20are%20the%20most%20common,Hz%20tremor%20of%20the%20hands. 

[3] Volkmann MD, J., Moro, E., & Pahwa, R. (2006, June 29). Basic algorithms for the programming of deep brain stimulation in parkinson’s disease. Movement disorders : official journal of the Movement Disorder Society. https://pubmed.ncbi.nlm.nih.gov/16810675/ 

[4] T.Barbe, M. (2017, October 26). DBS of the PSA and the vim in essential tremor. DBS of the PSA and the VIM in essential tremor. https://www.neurology.org/doi/10.1212/WNL.0000000000005956 

[5] Harith Akram, Viswas Dayal, Philipp Mahlknecht, Dejan Georgiev, Jonathan Hyam, Thomas Foltynie, Patricia Limousin, Enrico De Vita, Marjan Jahanshahi, John Ashburner, Tim Behrens, Marwan Hariz, Ludvic Zrinzo, Connectivity derived thalamic segmentation in deep brain stimulation for tremor, NeuroImage: Clinical, Volume 18, 2018, Pages 130-142, ISSN 2213-1582, https://doi.org/10.1016/j.nicl.2018.01.008. 

[6]Jimsheleishvili, S. (2023, July 24). Neuroanatomy, cerebellum. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK538167/ 

[7]F;, Y. D. (2022, September 12). Physiology, motor cortical. National Center for Biotechnology Information. https://pubmed.ncbi.nlm.nih.gov/31194345/#:~:text=Excerpt,cortex%2C%20and%20supplementary%20motor%20area. 

[8] Hidding, U., Schaper, M., Gulberti, A., Buhmann, C., Gerloff, C., Moll, C. K. E., Hamel, W., Choe, C., & Pötter-Nerger, M. (2022, May 4). Short pulse and directional thalamic deep brain stimulation have differential effects in Parkinsonian and essential tremor. Nature News. https://www.nature.com/articles/s41598-022-11291-9 

[9] Fahn, S., Tolosa, E., & Marin, C. (1988). Fahn S, tolosa E, Marín C. Clinical Rating Scale for tremor. in. Tremor Rating Scale for Tremor. https://www.researchgate.net/profile/Eduard-Tolosa/publication/307538277_Clinical_Rating_Scale_for_Tremor/links/5832e79508ae004f74c57ae1/Clinical-Rating-Scale-for-Tremor.pdf 

[10] Blandini, F., Temel, Y., Benabid, A. L., Steigerwald, F., Baizabal-Carvallo, J. F., Schnitzler, A., Rebelo, P., Butson, C. R., Deli, G., Steffen, J. K., Shukla, L. C., Kouli, A., Vitek, J. L., Okun, [11] M. S., Shenai, M. B., Horn, A., Anderson, D. N., & Sterne, J. A. C. (2022, November 23). Directional Deep Brain Stimulation–a step in the right direction? A systematic review of the clinical and therapeutic efficacy of directional deep brain stimulation in parkinson disease. World Neurosurgery. https://www.sciencedirect.com/science/article/pii/S1878875022016370?via%3Dihub