Introduction

Closed-Loop Neuromodulation, also known as an intelligent neuromodulation, is a flexible neural device that sends a signal in response to a biomarker. This focused delivery of a stimulus to neural tissue whose intent is to affect neural or physiological processes helps researchers understand more about human physiology¹. A certain biomarker threshold has to be met in order for the closed-loop neuromodulation to be activated, meaning that this device acts as a Responsive Neurostimulation (RNS)². RNS differs from Deep Brain Stimulation (DBS) since DBS is created to reduce the frequency of brain malfunction while RNS targets specific malfunctions at the time of their occurrence. If you want to learn more about DBS, take a look at my other blog, Deep Brain Stimulation – A Neurorehabilitation Method for Parkinson’s Patients. Closed-loop neuromodulation encapsulates RNS, DBS, and Vagus Nerve Stimulation (VNS). An early example of closed-loop neuromodulation is its application in refractory epilepsy. Refractory epilepsy is when the seizures are unable to be controlled by medication or when the condition is too severe, warranting the therapeutic use of closed-loop neuromodulation. Once implanted, when a seizure begins in the patient, the electrodes stimulate certain areas of the brain to stop the episode³. In the beginning, an open-loop neuromodulation was used, a system whose response is dependent on a timed algorithm rather than in response to a neural stimulus. These systems are set by a neurologist and require multiple appointments. As can be presumed, the closed-loop neuromodulation is much more effective in its response since it is able to immediately respond to the biomarker stimulus instead of only being activated at scheduled times².

RNS and VNS

Responsive Neurostimulation (RNS) is a method that monitors electrical irregularities in the brain. It is an invasive method where a neurostimulator is implanted into the brain and is connected to wires that extend into areas of the brain where seizures occur. When triggered, it delivers a brief pulse of electrical stimulation through the leads. RNS is a great rehabilitative method, because it can be used to supplement epilepsy treatment and can be removed at any point⁵. How this device works as a treatment for epilepsy is that it disrupts the “electrical storm” that occurs in the brain when a seizure occurs. This intervention alleviates the amount of electrical stimulation and may even circumvent a seizure altogether⁶. Vagus Nerve Stimulation (VNS) intends to alter the activity of nerves by having an implanted device that sends mild pulses of electrical energy to the brainstem through the vagus nerve. Once it reaches the brainstem, the electrical charge disseminates across the brain and changes how brain cells work. VNS is believed to improve blood flow in critical areas of the brain, alter the electrical stimulations that occur when a person is having a seizure, and increase the level of neurotransmitters that control seizure development⁷.

Types of Neuromodulation

The algorithm within a closed-loop neuromodulation focuses on when a stimulation should be activated and how strong this stimulus should be. In current research, this device could be responsive to changes in neurochemical composition, such as potassium, sodium, calcium, or other neurotransmitters. As this can be adjusted, this system can be personalized for each individual. Neuromodulation can be separated into five different types of systems: scheduled intermittent, continuous, responsive, adaptive, and complete closed-loop. Scheduled intermittent is a form of an open-loop system, where the stimulation is sent at scheduled times as opposed to being sent in response to a biomarker⁴. A continuous neuromodulation is another open-loop system where the stimulus is continuously sent despite the physiological factors. A responsive neuromodulation is a partial closed-loop system where the stimulation is initiated when a certain physiological biomarker threshold is met. However, the device is still pre-set. An adaptive neuromodulation monitors only one biomarker and is a closed-loop system. This system is able to adjust its levels of stimulus according to the biomarker reaction. Lastly, a complete closed-loop neuromodulation is a system that monitors multiple biomarkers while also adapting to the biomarker reaction. In order for the adaptive and complete closed-loop neuromodulation to be able to operate autonomously, they must undergo training. This training can focus on biomarkers such as neurotransmitters and neurochemicals, which will then be analyzed by neuromodulation systems in order to create an appropriate reaction⁴.

Potential of Neuromodulation

In recent years, the development of the closed-loop neuromodulation system has taken precedence over the open-loop systems due to developments in response to physiological biomarkers and its ability to be personalized. However, open-looped systems continue to demonstrate its efficacy as a rehabilitative device. A research paper published in 2016 provided data showing that, when an intermittent open-looped neuromodulation device was implanted in the thalamus of patients, it reduces tics in patients with Tourette Syndrome⁸. Another benefit of neuromodulation is that they act as an alternative treatment to epilepsy when patients are drug-resistant. Because neuromodulation is able to either increase or decrease nerve activity, the device regulates neural activity. With this being said, it can alleviate persistent pain, spasticity, movement disorders, bowel/bladder dysfunction, spinal injury, ischaemia, and other impairments. Neuromodulation has the potential to regulate many ailments pertaining to the nervous system, making it one of the more effective treatments¹⁰. I believe that as studies progress, it will be a definitive intervention for epilepsy, movement disorders such as Parkinson’s Disease, and may even have the ability to counter the prominent symptoms of dementia-related illnesses like short-term memory loss and brain atrophy. Although the illnesses that neuromodulation could resolve are vast, there are still both ethical and clinical issues that still need to be addressed.

Issues of Applying Closed-Loop Neuromodulation in the Clinical Setting

As closed-loop neuromodulation is a recently-developed neurorehabilitative measure, there are still many factors to be studied when applying this device in the clinical setting. Namely, knowing where to place the electrodes, the effects of adjusting the detector and stimulation parameters, and the overall lack of knowledge of the long-term effects of using this advice. Additionally, electroclinical correlation and dissociation, patient concerns about device capabilities, clinician opportunities and burdens, and data ownership and access are other notable issues that need to be addressed. Electroclinical correlation and dissociation refers to the device’s limited spatial sampling and limited storage capacity. These limitations have resulted in recordings of epileptic episodes being deleted or the device is unable to detect the origination of a seizure. This leads to a conflict as to how much freedom an epileptic patient may have, as they may be restricted from driving from faulty recordings of seizures. Patients also are not trustworthy of the data it records due to these malfunctions. To add on, with open-loop systems, specialists are required to modify the device weekly, placing a strain on their time. Lastly, the data recorded can be accessed by other institutions, which could be perceived as a breach in privacy⁹.

Cited Sources

1. Stavros, Z. (2019, November 1). Closed-loop neuromodulation in physiological and Translational Research. Closed-Loop Neuromodulation in Physiological and Translational Research. Retrieved May 10, 2022, from https://pubmed.ncbi.nlm.nih.gov/30559253/

2. Parastarfeizabadi, M., & Kouzani, A. (2017, August). Overview of open-loop DBS. Advances in Closed-Loop Deep Brain Stimulation Devices. Retrieved May 11, 2022, from https://www.researchgate.net/figure/Overview-of-open-loop-DBS-a-versus-closed-loop-DBS-b-In-open-loop-DBS-a-neurologist_fig3_319068029

3. Kam, K. (2021, April 28). Help When Epilepsy Treatment Doesn’t Work. Refractory epilepsy: Causes, symptoms, treatment, and more. Retrieved May 11, 2022, from https://www.webmd.com/epilepsy/refractory-epilepsy

4. Mirza, K. B., Golden, C. T., Nikolic, K., & Toumazou, C. (2019, August 20). Closed-loop implantable therapeutic neuromodulation systems based on neurochemical monitoring. Frontiersin. Retrieved May 10, 2022, from https://www.frontiersin.org/articles/10.3389/fnins.2019.00808/

5. Unknown. (2020, October 7). Responsive neurostimulation. ucsfhealth.org. Retrieved May 10, 2022, from https://www.ucsfhealth.org/treatments/responsive-neurostimulation

6. Unknown. (n.d.). Responsive neurostimulation. Responsive Neurostimulation | Neurological Surgery | University of Pittsburgh. Retrieved May 14, 2022, from https://www.neurosurgery.pitt.edu/centers/epilepsy/responsive-neurostimulation

7. Unknown. (n.d.). Vagus nerve stimulation (VNS): What it is, uses & side effects. ClevelandClinic.org. Retrieved May 14, 2022, from https://my.clevelandclinic.org/health/treatments/17598-vagus-nerve-stimulation-vns

8. Rossi, J. P., Opri, E., Shute, J. B., Molina, R., Bowers, D., Ward, H., Foote, K. D., Gunduz, A., & Okun, M. S. (2016, August). Scheduled, intermittent stimulation of the thalamus reduces tics in tourette syndrome. Parkinsonism & related disorders. Retrieved May 12, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969169/

9. Hegde, M., Chiong, W., & Rao, V. R. (2021, April 27). New ethical and clinical challenges in “closed-loop” neuromodulation. Neurology. Retrieved May 12, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166428/
10. Neuromodulation frequently asked questions – faqs. International Neuromodulation Society. (2013, July). Retrieved May 12, 2022, from https://www.neuromodulation.com/neuromodulation-faqs#