Over the past two decades, neuromodulation therapies have transformed from niche interventions to evidence-based tools for treating serious psychiatric and neurologic conditions. Once considered “last resort” measures, transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS) are now increasingly integrated into multidisciplinary care pathways for treatment-resistant depression (TRD), obsessive-compulsive disorder (OCD), epilepsy and more.
Yet where these therapies fit in the broader medical continuum is still evolving. As the science behind circuit-based psychiatry advances, neuromodulation is poised to play a central role in shaping the next era of personalized, neurobiologically informed mental health treatment.
From Experimental to Essential: A Brief History
The concept of using electricity to influence brain activity has deep roots, with the earliest experiments in electroconvulsive therapy (ECT) dating back to the 1930s. However, modern neuromodulation emerged in the 1990s and early 2000s with more targeted technologies that reflected an improved understanding of brain circuitry.
- VNS was approved in 1997 for epilepsy, then in 2005 for treatment-resistant depression. It marked the beginning of implantable neuromodulation in psychiatry, targeting mood regulation via afferent vagus nerve pathways.
- DBS, originally pioneered in Parkinson’s disease, began to show psychiatric potential in the early 2000s, with trials exploring targets such as the subgenual cingulate and nucleus accumbens in severe depression and OCD.
- TMS, approved by the FDA in 2008 for depression, was the first non-invasive neuromodulation tool to gain wide adoption, enabling outpatient treatment of major depressive disorder without systemic side effects.
Each of these interventions represents a paradigm shift from chemical to circuit-level targeting in psychiatric disorders.
Clinical Applications Today
Transcranial Magnetic Stimulation (TMS)
TMS is FDA-cleared for:
- Treatment-resistant depression
- Obsessive-compulsive disorder
- Smoking cessation
- Migraines
Additionally, it has been granted breakthrough-device designation for bipolar depression. It is widely used off-label for conditions such as post-traumatic stress disorder (PTSD), generalized anxiety disorder, schizophrenia, attention deficit hyperactivity disorder, chronic pain and cognitive decline.
In most treatment algorithms, TMS is introduced after the failure of at least one antidepressant. It is especially appealing for patients who are prone to side effects when taking medications or those who prefer drug-free treatment options. Because it is non-invasive and well-tolerated, TMS has become a common bridge between pharmacotherapy and more invasive approaches such as ECT or neurosurgical procedures.
Vagus Nerve Stimulation (VNS)
VNS remains a valuable option for chronic, refractory depression, especially for individuals who have failed four or more antidepressant trials. While its use is limited by its invasiveness and inconsistent insurance coverage, data from long-term observational studies, such as the D-21 registry, support its efficacy in achieving sustained symptom relief and functional improvement.
Some insurers now cover VNS for TRD, albeit with strict criteria. Despite being underutilized, VNS may represent a vital tool in cases where both pharmacologic and non-invasive interventions have failed.
Deep Brain Stimulation (DBS)
DBS is approved under a Humanitarian Device Exemption for severe OCD but remains investigational for depression and other psychiatric conditions. Clinical use is generally restricted to patients with highly refractory illness who have exhausted all other options.
DBS for depression has yielded mixed results in clinical trials, but when targeted precisely — especially in the subcallosal cingulate — it shows promise in restoring functional connectivity in dysregulated circuits leading to symptomatic improvement.
Persistent Challenges
While neuromodulation is steadily gaining ground, several systemic, scientific and logistical hurdles remain:
Access and Cost
TMS, VNS, and DBS procedures are expensive and time intensive. Insurance coverage varies widely, and treatment is often only offered at major academic centers. TMS, while more widely available, still presents a barrier for rural patients or those with transportation challenges due to its daily commitment over weeks.
Limited Personalization
One of the biggest obstacles in psychiatry is the relative inability to classify heterogenous disorders to allow for individualized treatment recommendations. For example, current TMS protocols typically use a standardized protocol to identify patients’ stimulation targets, which do not take into consideration unique neural circuit abnormalities between patients. Efforts to guide treatment using imaging biomarkers, such as functional MRI connectivity maps, are ongoing but not yet standard practice.
Regulatory and Reimbursement Bottlenecks
Lengthy approval processes, variable insurance criteria, and ambiguous definitions of “treatment resistance” hinder timely access. Many payers require three to four failed antidepressants before approving TMS or VNS, despite growing evidence that early intervention with neuromodulation may be more effective.
Stigma and Awareness
Despite their growing legitimacy, neuromodulation interventions are still misunderstood. Many patients associate electrical brain stimulation with outdated stereotypes or invasive brain surgery. Provider familiarity with newer protocols — especially outside academic institutions — is also limited.
What’s Next: The Future of Neuromodulation
As the field matures, the next chapter of neuromodulation will center on precision, accessibility, and discovering new indications.
Precision-Guided Stimulation
- MRI-guided/accelerated TMS. As of 2022, the FDA has approved the first biomarker-guided treatment for depression — Stanford Neuromodulation Therapy. This unique protocol uses individual brain MRI data to target the particular sub-region of the dorsolateral prefrontal cortex that is most functionally anticorrelated with the subgenual cingulate cortex. Additionally, it condenses the typical 6-week course of TMS into 5 days, making it more attractive for those who desire a shorter treatment course.
- Closed-loop DBS systems under development can adjust stimulation based on real-time brain activity, enhancing efficacy and minimizing side effects. Additionally, advancements are being made in the field of connectomic DBS, which allows for stimulation of specific neural circuits corresponding to individual patient symptom profiles.
- EEG-synchronized TMS explores the use of brainwave patterns to time stimulation pulses for maximum effect.
Home-Based Options
Portable neuromodulation — such as home-based transcranial direct current stimulation or wearable TMS — could democratize access and reduce costs.
Broader Indications
Research is expanding into:
- Addiction – Modulating craving-related circuits
- Alzheimer’s disease – Enhancing memory circuits with TMS
- Eating disorders – DBS and TMS trials under way for anorexia and binge eating
- Anxiety and PTSD – Targeting fear circuits in the amygdala and medial prefrontal cortex
Combinatorial approaches that pair neuromodulation with psychotherapies (CBT, mindfulness-based therapies) or pharmacogenomics may soon become the standard of care.
Conclusion: Toward Circuit-Based Psychiatry
Neuromodulation therapies represent a shift in how we understand and treat psychiatric illness — from one-size-fits-all pharmacology to tailored circuit modulation. TMS, VNS and DBS each offer unique advantages, and their growing role in the treatment continuum is supported by strong efficacy data, improved safety, and increasing accessibility. Yet barriers remain — from insurance delays and infrastructure gaps to a need for improved patient and provider education.
Moving forward, a combination of research, policy advocacy, and training will be necessary to embed these interventions more fully into mental healthcare. As we continue to unlock the mechanistic secrets of neural networks, neuromodulation will not just supplement psychiatric care — it will redefine it.
References
- Cole, E. J., et al. (2022). Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. Am J Psychiatry, 179(2), 132-141.
- Aaronson, S. T., et al. (2017). Five-Year Observational Study of VNS Therapy in Treatment-Resistant Depression. J Clin Psychiatry, 78(6), e742–e750.
- Holtzheimer, P. E., & Mayberg, H. S. (2011). Deep Brain Stimulation for Psychiatric Disorders. Annu Rev Neurosci, 34, 289–307.
- Scangos, K. W., et al. (2021). Closed-Loop Neuromodulation in Depression. Nature Med, 27(10), 1696–1700.
- Luber, B., & Lisanby, S. H. (2014). Cognitive Enhancement with TMS. NeuroImage, 85, 961–970.
- U.S. Food and Drug Administration. (1997). Premarket Approval (PMA) – P970003: VNS Therapy System. FDA Center for Devices and Radiological Health.
Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P970003 - U.S. Food and Drug Administration. (2005). PMA Supplement – P970003/S050: VNS Therapy System for Treatment-Resistant Depression. FDA Center for Devices and Radiological Health.
Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=p970003s050