Nods of Neuromod: Neuromodulation Techniques
Game changers for the nervous system
Imagine a time and place where the boundaries of health and neurological care stretch far beyond the confines of traditional pharmaceuticals. Picture a world where side effects are minimized, unpredictable outcomes are reduced, and the specter of addiction fades into the background. In this world, when humans think of treatments, the first thought isn't about a pill nor an injection but about bioelectronic medicine.
Bioelectronic medicine has made tremendous gains in cardiology with the widespread use of pacemakers. While all cells in the body respond in to electricity, the nervous system’s language has strong reliance on electrical signals to propagate information with speed and efficiency. This means the nervous system has good potential to benefit from bioelectronic medicine to treat an array of conditions. Bioelectronic medicine as applied to the nervous system even has its own term: neuromodulation.
Neuromodulation devices, with their myriad forms of energy—electrical, magnetic, optical, mechanical, or acoustic—dive directly into the intricate dance of nerve activity. This approach offers a rapid, precise, and highly personalized treatment method that feels like it was tailor-made just for you. In the journey ahead, we will explore the dazzling array of neuromodulation techniques, uncover the vast potential applications, and confront the challenges that lie in wait.
All of this paints a vivid picture of how these pioneering devices are reshaping the landscape of neurological care, offering a glimpse into a future that seems both extraordinary and inevitable.
Mechanical Stimulation
Mechanical stimulation involves the application of physical pressure or vibration to nerve tissue, commonly used in rehabilitation therapies for motor recovery post-stroke or to manage musculoskeletal pain. This non-invasive and safe method utilizes specific frequencies to achieve therapeutic effects, though its efficacy can vary significantly among individuals and conditions. Pain Care Labs is advancing this approach by using harmonic frequencies with a thermal stimulus to reduce pain.
Electrical Stimulation encompasses techniques that can be done in different modalities and with different parts of the body
Transcutaneous Electrical Nerve Stimulation (TENS)
Transcutaneous Electrical Nerve Stimulation (TENS) is a widely used non-invasive therapy that involves applying low-voltage electrical currents to alleviate pain. By placing electrodes on the skin near the area of discomfort, TENS devices deliver electrical impulses that interfere with pain signals while simultaneously stimulating the release of endorphins, the body's natural painkillers. This method is often employed to manage chronic conditions such as back pain, arthritis, and fibromyalgia.
Victor Pikov, PhD, CEO of Medipace Inc., emphasizes the prominence of TENS in the field of commercial neurostimulation, describing it as the "gold standard." He notes that approximately one million TENS devices are sold annually, underscoring the therapy's widespread adoption. However, he also sees potential for further advancement, stating, “There is a fundamental limit [to how selectively we can stimulate], but we are not there yet.”
Several companies are actively involved in the development and sale of TENS devices. These include well-known brands such as Omron Healthcare, which offers a variety of portable TENS units, and Bio Medical Life Systems, which manufactures a range of TENS devices for both professional and home use. Another key player is iReliev, known for its combination TENS and EMS (Electrical Muscle Stimulation) units, which provide users with dual therapeutic options.
Transcutaneous Afferent Patterned Stimulation (TAPS)
A treatment developed by Cala Health that uses gentle electrical pulses to improve symptoms in people with hand tremors caused by essential tremor. It's a non-invasive method where the electrical impulses are delivered directly to the skin to help manage the condition. This approach offers a convenient and potentially effective way to reduce tremors without the need for more invasive procedures.
Transcranial Direct Current Stimulation (tDCS)
Transcranial direct current stimulation is a non-invasive therapy that involves delivering a constant, low electrical current to the brain through electrodes placed on the scalp. This technique is primarily used to enhance cognitive functions, such as memory and attention, and to help treat conditions like depression.
Several companies are at the forefront of developing and selling tDCS devices. These include Neuroelectrics, known for their Starstim tDCS system, which is used in both research and clinical settings. Another prominent company is Flow Neuroscience, which offers a wearable headset and is available to purchase in the European Union. Samphire Neuroscience has created the Nettle as a for use in premenstrual syndrome and menstrual pain, available in the United Kingdom and European Union. Additionally, Fisher Wallace Laboratories produces the Fisher Wallace Stimulator, which is designed to treat depression, anxiety, and insomnia. Fisher Wallace is developing their next generation device, the OAK, which uses transcranial alternating current stimulation (tACS) with a human voice assistant for depression and anxiety.
Spinal Cord Stimulation (SCS)
Spinal cord stimulation is an invasive therapy used to manage chronic pain by implanting a device that sends low levels of electrical impulses directly to the spinal cord. These electrical signals interfere with the pain messages sent to the brain, offering relief to patients with conditions that haven't responded well to other treatments. While the effectiveness of SCS can vary from person to person, the procedures for implanting these devices are becoming less invasive, making the therapy more accessible.
Several companies are leading the development and sale of spinal cord stimulation devices. Medtronic, a pioneer in medical technology, offers the Inceptiv SCS system, which is designed to provide long-lasting pain relief. Boston Scientific is another major player with its Spectra WaveWriter SCS system, known for its customizable therapy options. Additionally, Abbott produces the Proclaim XR SCS system, which is notable for its ability to deliver relief with low-dose stimulation, potentially extending the life of the device's battery.
Electroconvulsive Therapy (ECT)
ECT is a powerful treatment used primarily for severe depression and other serious mental health conditions, particularly when other treatments have not been effective (Cleveland Clinic, 2022). ECT involves delivering controlled electric currents to the brain, intentionally triggering a brief seizure. This process can provide significant relief from symptoms, making it a valuable option for patients with treatment-resistant conditions. Somatics, LLC, known for their Thymatron System IV, a device designed to deliver precise and customizable ECT treatments. SigmaStim has a wide range of parameter settings with their Σigma ECT Device. ECT is also associated with side effects, including memory loss, which makes it a treatment that is carefully considered and monitored by healthcare professionals.
Vagus Nerve Stimulation (VNS)
Vagus nerve stimulation is a therapeutic technique that uses electrical impulses to stimulate the vagus nerve, which plays a significant role in regulating various bodily functions. This method is used to treat conditions such as epilepsy and depression by influencing brain activity. VNS is increasingly gaining traction.
Pikov highlights the broad therapeutic possibilities of VNS, stating, “There are 10-20 different organs with diseases that can be treated by stimulating the vagus nerve.” This statement underscores the versatility of VNS as a treatment option.
Several companies are at the forefront of developing VNS devices. SetPoint Medical focuses on using VNS to treat chronic inflammatory diseases, while MicroTransponder is known for its Vivistim® Paired VNS System, which aids stroke recovery by enhancing neuroplasticity.
LivaNova is another key player in the VNS market, particularly known for its VNS Therapy® System, which is one of the most widely used devices for treating drug-resistant epilepsy and depression. LivaNova’s extensive experience in the field has made it a leader in developing reliable and effective VNS solutions.
Non-invasive VNS, while less intrusive, requires about ten times more current than invasive methods to achieve similar results. This challenge is being actively addressed by these companies through ongoing innovation, aiming to improve the efficiency and effectiveness of non-invasive VNS therapies. In the non-invasive VNS space, companies like electroCore and Parasym are making notable advancements. electroCore’s gammaCore device is used to treat migraines and cluster headaches, while Parasym is exploring non-invasive VNS for conditions such as heart failure and gastrointestinal disorders.
Additionally, Hoolest Performance Technologies is focusing on non-invasive VNS for enhancing mental performance and reducing stress. Their portable VNS devices are designed to help individuals manage anxiety and improve focus, catering to both clinical and consumer markets. IST LLC has been approaching the vagus nerve through the ear: they are working on transdermal auricular vagus nerve stimulation to treat insomnia, augment cognition, and optimize human performance.
Transcranial Magnetic Stimulation (TMS)
A non-invasive therapy that uses magnetic fields to stimulate nerve cells in the brain. It is approved for treating depression and holds promise for addressing other conditions like anxiety and schizophrenia. However, TMS, particularly in its traditional form known as repetitive TMS (rTMS), has some limitations—it cannot penetrate much deeper than the brain's cortex, and it typically requires multiple sessions to achieve significant clinical benefits.
Joshua Cain, PhD, Senior Research Scientist at the Institute for Advanced Consciousness Studies, explains, “TMS is arguably the best treatment for depression if you can manage to go to all the sessions. The way it works is that you stimulate the outside of the brain, which indirectly inhibits a deep region that TMS cannot target, thereby suppressing depressive symptoms.” This emphasizes the need for consistency in treatment to see effective results.
Danielle DeSouza, PhD, VP of Research at Acacia Clinics, highlights the role of insurance in making TMS accessible, stating, “Insurance mostly covers conventional TMS approaches – once per day, in the left prefrontal dorsolateral cortex for depression.” This points to the current standard practices and limitations in TMS therapy coverage.
Several companies are at the forefront of producing TMS devices. These include BrainsWay, known for their Deep TMS system; Magstim, which offers the Horizon Performance system; MagVenture, known for their MagVita TMS Therapy system; NeuroStar, which produces the NeuroStar Advanced Therapy system; and Magnus Medical, which is pioneering innovative rTMS treatments to expedite the effectiveness of TMS therapy. Ampa Health is producing a portable TMS system.
With advancements in TMS technology, particularly with companies like Magnus Medical pushing the boundaries of rTMS, the potential for more effective and accessible treatments is growing. These developments could expand the use of TMS beyond depression, offering new hope for patients with a variety of mental health challenges.
To learn more about the TMS Market, see Neurotech Futures’ Teardown:
Focused Ultrasound Neuromodulation
Focused ultrasound is an innovative technique that uses high-frequency, low-intensity sound waves to stimulate deep brain regions non-invasively. This approach shows great promise in treating conditions like essential tremor and Parkinson's disease, as it allows for the precise targeting of deep brain structures without impacting the surrounding tissues.
Cain states that focused ultrasound is “the only way to selectively, and in a very spatially precise way, stimulate … any specific neural tissue in the brain or the peripheral nervous system.” This underscores the unique ability of focused ultrasound to reach specific areas of the brain with high accuracy.
Several companies are leading the way in creating focused ultrasound neuromodulation technologies. These include: Sanmai Technologies PBC*, which is developing Lotus, a medical device to help with mental health, Nudge, which is creating a device for brain health, Openwater, which builds open-source software and hardware which can be used to advance research studies and device development in focused ultrasound, Attune Neurosciences, which is investigating their device for sleep disorders, human improvement, depression, pain, movement disorders, and tinnitus, and Prophetic, which is studying how focused ultrasound can aid in lucid dreaming.
* Disclosure: Sharena Rice is employed by Sanmai Technologies PBC.
Pulsed Electromagnetic Field (PEMF) Therapy
Pulsed electromagnetic field therapy is a non-invasive treatment that uses electromagnetic fields to promote healing in conditions such as bone fractures and depression. This technology is known for its minimal side effects, making it a gentle and appealing option for many patients. However, while PEMF therapy shows promise, more research is needed to fully understand its mechanisms and to optimize treatment protocols for different conditions.
Several companies are leading the development and sale of PEMF devices. Orthofix, for example, offers the Physio-Stim and Spinal-Stim systems, which are FDA-approved for promoting bone healing. BEMER Group is another key player, producing PEMF devices designed to improve circulation and enhance overall well-being. BioBalance also markets a range of PEMF devices aimed at both professional and home use, focusing on wellness and recovery. FluxWear is making strides in the Shift, a hat that delivers PEMF.
Photobiomodulation
Uses light, typically near-infrared, to target tissues in order to reduce pain, decrease inflammation, and promote healing. This treatment is particularly used for conditions like brain injuries and neurodegenerative diseases. While photobiomodulation holds significant promise, its effectiveness can vary, and there is a growing need for more standardized treatment guidelines to ensure consistent outcomes.
Several companies are leading the development and sale of photobiomodulation devices. Vielight is known for its innovative products designed for brain health, including the Vielight Neuro, which uses near-infrared light to target the brain. Thor Photomedicine is another major player, offering a devices for both clinical and home use, focusing on pain relief and tissue repair. Neuronic also creates devices aimed at enhancing overall wellness and supporting recovery from various conditions.
Emerging Modalities in Neuromodulation
Combination techniques
There is growing evidence that combining multiple therapeutic techniques can enhance their effectiveness, particularly in the field of neurostimulation. Cognito Therapeutics is at the forefront of this approach with their innovative platform, which uses synchronized light and sound stimulation at 40 Hz—a frequency that aligns with the brain's gamma waves. This dual stimulation method is designed to support people with Alzheimer's disease. By targeting brain activity in this way, Cognito Therapeutics aims to slow the progression of and potentially improve cognitive function.
Elemind is another company exploring the benefits of multi-modal stimulation, focusing on phase-locked acoustic and bone conduction stimulation. Their technology is designed to help people fall asleep more easily and maintain deep, restful sleep by tuning the stimulation to match the phase of the brain's natural waves. This precise synchronization helps to regulate sleep patterns and improve overall sleep quality. Beyond its applications in sleep, Elemind is currently studying the potential of this technology for treating essential tremor, a neurological condition characterized by involuntary shaking. By fine-tuning brain activity, Elemind's approach holds promise for managing and potentially reducing the symptoms of essential tremor.
Neuromodulation can also be used to facilitate drug delivery. Cordance Medical uses focused ultrasound to temporarily open the blood brain barrier and help in delivering drugs to the brain.
Genetic Techniques
Some of the most exciting advancements in neuromodulation involve the use of genetic techniques, which have the potential to revolutionize how we treat neurological disorders. One such technique is optogenetics, which uses light to control specific cells—usually neurons—that have been genetically modified to respond to light. This approach has been primarily used in laboratory settings to study neural circuits, but it also holds promise for highly targeted interventions in neurological disorders. For instance, Science Corp is working on applying optogenetics to restore sight, with plans for human trials starting in 2025.
Another emerging technology is sonogenetics, which is similar to optogenetics but instead uses ultrasound waves to influence neurons that have been genetically modified to be particularly sensitive to these waves. While sonogenetics is still in the experimental stage, primarily being tested in animals, it offers the potential for non-invasive neuromodulation, which could be a game-changer for treating a variety of neurological conditions.
In addition to Science Corp, other companies are also exploring genetic techniques for neuromodulation. For example, GenSight Biologics is another company in this space, focusing on gene therapy techniques that could complement optogenetic approaches, particularly in restoring vision and treating retinal diseases.
Considerations in Neuromodulation Developments
Neuromodulation is revolutionizing our approach to treating neurological disorders. By harnessing the power of various energy forms to influence nerve activity, these devices offer a game-changing solution for many patients. The precision and personalization of neuromodulation treatments lead to quick results with fewer side effects, making them an attractive option for those struggling with chronic pain, mental health challenges, movement disorders, epilepsy, and even cognitive decline.
As we continue to understand the mechanisms of neuroplasticity, neuromodulation techniques are becoming more refined and effective. Take tinnitus treatment, for example. By using spike timing dependent plasticity and ensuring that precisely timed stimulations are sent to the somatosensory and auditory system, companies such as Neuromod Devices and Neosensory have been able to stop those phantom ringing sounds. Another example is Nia Therapeutics’s preclinical work in preparation for precision brain stimulation for memory loss in traumatic brain injury.
While promising, riding neuromodulation’s potentials are not all smooth sailing. The field faces challenges such as technological hurdles, the lengthy time horizons of clinical trials, and complex landscapes surrounding regulatory and reimbursement. Despite these obstacles, the future of neuromodulation looks bright. Emerging technologies in optogenetics and combination techniques, in conjunction with advances in materials science, AI, and machine learning, are set to push the boundaries of what's possible in caring for the nervous system.
Measuring success in treating mental health conditions and pain isn't always straightforward. It used to be thought that biomarkers would be used to objectively diagnose people and to determine clinical endpoints. This quest has been harder than originally imagined. The nervous system is complex, people who experience mental health challenges or pain frequently have co-morbidities and confounds from medications, and the human experience is inherently subjective. Some recent advances in the space include the findings of six clinically distinct biotypes of depression and anxiety (Tozzi et al., 2024), the findings of cingulate dynamics in tracking the progression of depression recovery with deep brain stimulation (Alagapan et al., 2023), and intracranial chronic pain state predictors using biomarkers (Shirvalkar et al., 2023).
It's crucial to remember that neuromodulation isn't a magic fix-all. Simply "zapping" away depression not address the whole picture. People who have lived with these conditions for years may find benefits from their treatment, yet need support in adjusting to life without depression. It is important to pair neuromodulation with therapy or community support. Further, family members are important motivators and decision collaborators for enrolling in clinical trials for psychiatric deep brain stimulation (Boulicault et al., 2023). The effects extend beyond the person who receives the treatment.
As neuromodulation becomes more mainstream, its potential to improve lives is skyrocketing. From TMS treatments giving people a reason to get out of bed in the morning to deep brain stimulation helping people to stay moving (but not shaking) in their everyday lives, the impact is real and significant. Keep in mind, though, that effects can vary and may require ongoing maintenance.
In a nutshell, neuromodulation is a rapidly evolving field that's set to transform how we treat neurological and psychiatric conditions. As research and technology advance, we're moving towards a future of more precise, effective, and personalized interventions. It's an exciting time for neuroscience and for patients who stand to benefit from these groundbreaking treatments.
References
Pikov, V. (2024). Personal communication.
DeSouza, D. (2024). Personal communication.
Cain, J. (2024). Personal communication.
Cleveland Clinic. (2022). *Electroconvulsive therapy (ECT)*. Cleveland Clinic. Retrieved September 2, 2024, from https://my.clevelandclinic.org/health/treatments/9302-ect-electroconvulsive-therapy
Tozzi, L., Zhang, X., Pines, A., Olmsted, A. M., Zhai, E. S., Anene, E. T., Chesnut, M., Holt-Gosselin, B., Chang, S., Stetz, P. C., Ramirez, C. A., Hack, L. M., Korgaonkar, M. S., Wintermark, M., Gotlib, I. H., Ma, J., & Williams, L. M. (2024). Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety. Nature medicine, 30(7), 2076–2087. https://doi.org/10.1038/s41591-024-03057-9
Boulicault, M., Goering, S., Klein, E., Dougherty, D., & Widge, A. S. (2023). The Role of Family Members in Psychiatric Deep Brain Stimulation Trials: More Than Psychosocial Support. Neuroethics, 16(2), 14. https://doi.org/10.1007/s12152-023-09520-7
Alagapan, S., Choi, K. S., Heisig, S., Riva-Posse, P., Crowell, A., Tiruvadi, V., Obatusin, M., Veerakumar, A., Waters, A. C., Gross, R. E., Quinn, S., Denison, L., O'Shaughnessy, M., Connor, M., Canal, G., Cha, J., Hershenberg, R., Nauvel, T., Isbaine, F., Afzal, M. F., … Rozell, C. J. (2023). Cingulate dynamics track depression recovery with deep brain stimulation. Nature, 622(7981), 130–138. https://doi.org/10.1038/s41586-023-06541-3
Shirvalkar, P., Prosky, J., Chin, G., Ahmadipour, P., Sani, O. G., Desai, M., Schmitgen, A., Dawes, H., Shanechi, M. M., Starr, P. A., & Chang, E. F. (2023). First-in-human prediction of chronic pain state using intracranial neural biomarkers. Nature neuroscience, 26(6), 1090–1099. https://doi.org/10.1038/s41593-023-01338-z
Author contributions
Steven Veld conducted the personal communication interviews.
Sharena Rice compiled the background research.
Steven Veld and Sharena Rice wrote this piece.
Naveen Rao contributed light editing and images.
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