Neuromodulation Approaches to Depressive Disorders

sean/AdobeStock

CATEGORY 1 CME

Premiere Date: March 20, 2024

Expiration Date: September 20, 2025

This activity offers CE credits for:

1. Physicians (CME)

2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

ACTIVITY GOAL

To explain the principles and applications of both invasive and noninvasive neuromodulation techniques for the treatment of mood disorders.

LEARNING OBJECTIVES

Understand the principles and applications of noninvasive neuromodulation techniques, particularly transcranial magnetic stimulation (TMS), including its benefits, risks, and future directions, as a potential treatment for mood disorders.

Examine the invasive neuromodulation methods, such as vagus nerve stimulation (VNS) and deep brain stimulation (DBS), evaluating their efficacy, associated benefits, risks, and potential future advancements, in the context of treatment-resistant depression.

TARGET AUDIENCE

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

ACCREDITATION/CREDIT DESIGNATION/FINANCIAL SUPPORT

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Physicians’ Education Resource,® LLC, and Psychiatric Times.® Physicians’ Education Resource, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

Physicians’ Education Resource, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits.™ Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians’ Education Resource, LLC. No commercial support was received.

OFF-LABEL DISCLOSURE/DISCLAIMER

This accredited CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this accredited CE activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource, LLC.

FACULTY, STAFF, AND PLANNERS’ DISCLOSURES AND CONFLICT OF INTEREST (COI) MITIGATION

Dr Widge reports that he receives grant/research support from Boston Scientific and Medtronic. Otherwise, none of the staff of Physicians’ Education Resource, LLC, or Psychiatric Times or the planners or the authors of this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing health care products used by or on patients.

For content-related questions, email us at PTEditor@mmhgroup.com; for questions concerning the accreditation of this CME activity or how to claim credit, please contact info@gotoper.com and include "Neuromodulation Approaches to Depressive Disorders" in the subject line.

HOW TO CLAIM CREDIT

Once you have read the article, please use the following URL to evaluate and request credit: https://education.gotoper.com/activity/ptcme24mar. If you do not already have an account with PER,® you will be prompted to create one. You must have an account to evaluate and request credit for this activity.

Since the introduction of the first antidepressant in the 1950s, biological treatments for unipolar depressive disorders have largely focused on altering monoaminergic neurotransmission, with varying degrees of success. In the landmark STAR*D trial, about 30% of patients did not achieve remission over the course of all 4 treatment levels.¹

Two recently approved antidepressants target the glutamate system, including the 2019 US Food & Drug Administration (FDA) approval of intranasal esketamine and the 2022 FDA approval of the oral combination drug dextromethorphan/bupropion.^2,3 Neuromodulation therapies take an alternative approach by directly altering the brain’s electrical activity through electromagnetic stimulation and electrical impulses.

Selecting an Intervention

Neuromodulation (Table) can be divided into invasive and noninvasive methods. Both methods are primarily indicated for depressive symptoms, generally as an adjunct to pharmacotherapy and psychotherapy, and usually in patients with treatment resistance, which is commonly defined as a lack of response to 2 medications with adequate doses and duration.⁴ Treatment resistance usually includes a lack of response to multiple medication classes and evidence-based psychotherapy.

Table. Choosing a Neuromodulation Intervention

However, a careful examination of a patient’s psychosocial structure is necessary, as their mood is unlikely to show lasting change if severe, persistent stressors are present. Similarly, a comorbid personality disorder may contribute to depressive symptoms or alter the response to neuromodulation, just as it can for antidepressant trials. Additionally, reassessing the patient for other causes of their depression—such as a medical disorder, substance use disorder, or medication adverse effect—as well as evaluating for a comorbid psychiatric disorder that may be the primary cause of the depressive symptoms, should be part of the evaluation of any patient who presents with treatment resistance.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is a hospital-based treatment that uses an electrical current to induce a tonic-clonic seizure under general anesthesia. An acute series consists of 3 weekly treatments for up to 4 weeks, with each session requiring at least 1 hour from pre-op to recovery.

ECT remains one of our most rapid and effective treatments for unipolar, bipolar, psychotic, and peripartum depression. Even in treatment resistance, response rates can exceed 60% to 80%.⁵ For those who respond but then relapse, maintenance ECT (weekly to monthly) is possible. In cases of depression with severe suicidal ideation, psychosis, or life-threatening catatonia, ECT should strongly be considered even in the absence of multiple medication trials.

There are no absolute contraindications to ECT. However, ECT can increase intracranial pressure. Also, underlying cardiovascular disease should be considered before prescribing ECT because induced seizure causes a surge in blood pressure and heart rate.

Patients can experience mild or moderate cognitive adverse effects, which usually resolve within days to weeks after the completion of the ECT course. Ultrabrief right unilateral ECT has less cognitive adverse effects compared with bilateral ECT.⁶

This highly effective treatment is often seen as a last resort, with patients wasting months to years of their lives on ineffective treatments. Discussing and delivering ECT earlier in the treatment algorithm would likely be beneficial.

Noninvasive Neuromodulation

Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) is an office-based treatment for unipolar depression, although it is used off-label for bipolar depression. Conventional TMS is given Monday through Friday for 4 to 8 weeks, with treatments usually lasting 20 to 30 minutes. TMS uses a magnetic coil to induce electric currents in the prefrontal cortex (PFC). The usual target of TMS in depression is the dorsolateral prefrontal cortex (DLPFC).

The size and shape of coils vary, and multiple parameters can be adjusted, including frequency (eg, excitatory [10 Hz] vs inhibitory [1 Hz]), treatment duration, and target brain region.⁷ Some coils allow for deeper stimulation of cortical tissue (deep TMS),⁸ but current literature does not show deep TMS to be superior to regular TMS when adjusting for placebo rates.⁹

There are some benefits to TMS; treatment does not cause cognitive impairment, so patients can continue driving and working. Depression response rates in naturalistic studies are good, showing response in 30% to 60% of patients.^10-12 The effects appear to be durable, with 1 study showing a 60% sustained response at 1 year.¹³ Patients who do relapse usually respond to another TMS series.¹⁴

However, TMS also has some risks and disadvantages. Seizure is the primary, but very rare risk (< 0.003% per treatment exposure) of TMS.¹⁰ The risk is higher for patients who have had seizures, brain injuries, or intracranial pathology, and who have taken substances or medications that reduce the seizure threshold.⁷

With careful monitoring and dose titration, TMS may still be utilized in patients with increased risk. For example, we routinely adjust treatment energy based on changes in brain excitability (motor threshold), which correlates with seizure threshold. Regular dose adjustment also reduces headache—the most common adverse effect of TMS.

Compared with ECT, TMS works more slowly, with response usually at 4 to 6 weeks into treatment, and it is difficult to predict a patient’s response in advance. Therefore, in a clinical setting that requires rapid and definitive treatment, such as active suicidality, psychotic depression, or catatonic symptoms, ECT should be preferred over TMS.

Overall, TMS is less efficacious than ECT, but its safety and office-based nature promote continuous, rapid innovation. For instance, recent studies suggest that intermittent theta burst stimulation (iTBS), a modified TMS that takes 10 minutes or less per treatment, is as effective as longer sessions, potentially allowing for the treatment of many more patients with a single machine.¹⁵

Furthermore, the SAINT TMS protocol, a recent intermittent theta burst stimulation (iTBS) protocol that has been approved by the FDA, allows accelerated TMS treatment within a week by delivering 10 TMS sessions per day for 5 days. The formally studied SAINT protocols use a neuroimaging-guided, individualized TMS targeting strategy that is believed to maximize engagement of a depression-related circuit.¹⁵ The response rate of this protocol was comparable to or better than that of conventional TMS,¹⁶ which allows for the possibility of short, inpatient-based TMS therapy.

Even beyond SAINT, personalized targeting of TMS is under extensive investigation. The most common approach is based on connectivity between the TMS target region (eg, a specific part of the DLPFC) and another subcortical region (eg, the subgenual anterior cingulate cortex [sgACC], a “negative mood center”).¹⁷ This downstream region could also be individualized for patients based on their symptom profiles or biological phenotypes.¹⁸

Controlling the context (and thus, the brain state) under which TMS is given may also improve outcomes. For example, delivering TMS with cognitive training or psychotherapy could engage the circuit being stimulated, leading to greater clinical change.^19,20 In fact, concomitant psychotherapy is a required component of TMS for obsessive-compulsive disorder (OCD).²¹

Treatment parameters might also be tailored to a patient’s brain activity. For example, TMS could be delivered at either the positive or the negative peak of the ongoing cortical rhythms to increase brain plasticity.^22,23

All of these parameters and approaches require substantial further development, but may improve outcomes. Finally, although there is minimal literature on the use of TMS in pregnancy, a small clinical trial recently showed safety and efficacy, which is an exciting prospect for an understudied population.²⁴

Invasive Neuromodulation

Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) is an implanted device that repeatedly stimulates the left cervical vagus nerve. VNS was FDA-approved in 2005 for adjunctive treatment of severe unipolar and bipolar depression. VNS leverages the vagus nerve’s afferent projections to brainstem nuclei. It is theorized to augment norepinephrine and dopamine signaling throughout the brain through those projections, in turn enhancing the effects of monoaminergic medication.^25,26 VNS also helps regulate the balance between sympathetic and parasympathetic tones.

The implant procedure takes approximately 2 hours and can be completed under local or general anesthesia. Patients then return for office-based stimulator programming by a trained clinician. Programming is typically repeated biweekly to monthly over the first 6 months of treatment. It often takes a year for most VNS patients to be responsive.²⁷ VNS is usually reserved for patients who have not responded to medications or noninvasive forms of neuromodulation such as TMS and ECT.

Although VNS is FDA-approved, it is rarely covered by commercial insurance due to a limited evidence base. The published large, randomized, controlled trial failed to show a separation between active and sham stimulation after 10 weeks.²⁸ However, many criticize that short comparison period.

The FDA approval was based on data from a 1-year, open-label, follow-up study, which showed increasing response rates with time. A 5-year, open-label study of 795 patients replicated this result, with significantly higher VNS response rates compared with treatment as usual (67.6% vs 40.9%).²⁸ This study has brightened the prospects for VNS. Medicare currently covers VNS as part of a large randomized trial,²⁹ and commercial insurers are slowly following.

VNS offers long-term benefits, even for treatment-resistant depression (TRD). A subanalysis in the 5-year study showed a significantly higher response rate to VNS compared with treatment as usual (59.6% vs 34.1%). The response rate was even higher in patients who previously responded to ECT (71.3% vs 56.9%). In addition, patients who remitted remained in remission longer with VNS compared with treatment as usual (40 months vs 19 months), although remission rates did not reach statistical significance. VNS works for both unipolar and bipolar depression with a comparable response rate.²⁷

Furthermore, VNS can be beneficial for patients who respond but require extensive maintenance with costly and burdensome treatments such as ECT, ketamine, and TMS. Adjunctive VNS reduces the use of all of these interventions.³⁰

However, VNS also has some risks and disadvantages. Like any surgical procedure, VNS carries a risk for pain and infection. The vagus nerve innervates muscles involved in swallowing and speech, and surgical damage can result in dysphagia or vocal cord paralysis. The risk of these complications is less than 1% with a well-trained surgeon. The stimulation also frequently switches on and off, and many patients note throat sensations or voice changes, both of which remit over time.

The primary limitations of VNS are logistical. Because the effects take months to be noticeable, patients may prefer a more rapid-acting treatment. Most payors still do not cover VNS, limiting patients’ access.

Regarding the efficacy of VNS, a recently completed large, multisite, randomized, double-blind, controlled study (RECOVER, NCT03887715)²⁹ should provide some clarity. Noninvasive VNS devices may greatly expand the reach of VNS while reducing its cost. A transcutaneous stimulation device (tVNS) was FDA-approved in 2018 for the treatment of migraines and cluster headaches.³¹ Similar systems may be very useful for mood disorders.

VNS could also be useful for depression that is comorbid with other disorders by reducing sympathetic overdrive. For example, rodent studies suggest that VNS enhances the extinction of aversive memory and enhances distress tolerance,^32,33 and VNS for posttraumatic stress disorder (PTSD) recently received FDA Breakthrough Device Designation. Therefore, VNS is potentially useful for patients whose TRD arises from comorbid PTSD or other trauma-related disorders.

Deep Brain Stimulation

Deep brain stimulation (DBS) is an experimental treatment for unipolar and bipolar depression that involves MRI-assisted electrode implantation directly into brain regions associated with mood. Because it is highly invasive, DBS has only been tested in patients who no longer respond to any other therapy. The implantation surgery takes 6 to 8 hours and is done under a combination of local and general anesthesia.

Major target regions of DBS are the subgenual anterior cingulate cortex and ventral capsule/ventral striatum,³⁴ and in a smaller series of studies, the medial forebrain bundle.³⁵ Overall, those 3 regions have shown similar effects in clinical trials.³⁶ After surgery, patients return to the clinic for office-based stimulator programming by a trained clinician.

Given multiple parameters, including a selection of electrodes to stimulate and pulse parameters, DBS programming is very flexible; it is continued until optimal parameters are found, which usually takes 1 to 3 months.

Some benefits of DBS include that its acute stimulation effect ranges from increased positive mood and energy to reduction of anxiety and reduction of psychological pain.³⁷ These subjective changes usually last for minutes to hours, and then more gradual improvement happens with continued stimulation over weeks to months.

Initial open-label studies of DBS for TRD showed promising results with response rates of 40% to 66%.^38,39 Evidence from the subsequent randomized, well-controlled studies is less clear. For example, 2 US industry-funded trials (BROADEN [NCT01801319] and RECLAIM [NCT00837486]) failed to show a separation between DBS and sham stimulation,^40,41 while 1 European trial using a different design did show a separation.⁴²

A new approach, termed “connectomic” DBS, attempts to target stimulation to white matter bundles passing through/near the subgenual cingulate cortex, rather than targeting the subgenual gray matter itself. Although preliminary, 1 open-label trial of this connectomic approach had encouraging results, with a response rate of 82%.⁴³

The time to achieve DBS response is variable across patients and, like VNS, DBS may require several years to demonstrate its effect.⁴⁴ For those who respond to DBS, the benefits appear to last for a long time. A recent study reported a more than 50% response rate at 8 years post DBS.⁴⁵

However, DBS also comes with some risks and disadvantages. Risks include intracranial bleeding, stroke, seizure, and infection. The risk of serious neurologic or other damage is rare (under 1%). For instance, if infections occur, they tend to be superficial and to resolve with appropriately aggressive treatment. Adverse psychological effects are more common—up to 50% of patients may experience worsened mood, anxiety, or hypomania while their clinicians search for optimal stimulation settings.

Furthermore, patients often see DBS as a last resort. If a response is delayed or difficult to achieve, they can lose hope. This is life-threatening, as evidenced by a suicide rate near 10% in DBS clinical trials.^40,41

The largest challenge of DBS is the wide range of stimulation parameters that can be applied, with no clear guidance on how to search for the best settings. Neuroimaging research seeks to better define the target mood circuits and to use advanced electric field modeling to optimally activate the desired neural pathways.⁴³ Closed-loop approaches seek a reliable biomarker of patients’ symptoms, such as brain activity or behavior, in real time and allow the device to self-adjust until a desired biomarker pattern is achieved.³⁶ Either strategy may lead to higher and more durable clinical response rates.

Emerging Forms of Neuromodulation

Although ECT, TMS, VNS, and DBS represent some of the best-studied tools for mood disorders, the landscape of neuromodulation is rapidly changing, and several emerging interventions are actively being studied. These encompass a variety of techniques including direct electrical stimulation at subthreshold energy levels with transcranial direct current stimulation (tDCS) or transcranial alternating current stimulation (tACS) as well as other forms of seizure therapy such as magnetic seizure therapy (MST). Further evidence is needed to support their clinical use at this time.

Accessing Neuromodulation

Most academic institutions now employ at least 1 neuromodulation specialist, and TMS is usually available from multiple interventional practices in most metropolitan areas. Referral to such specialists is often the first step in helping patients access these next-generation treatments. A critical aspect of referral is a detailed treatment history, especially medications tried and reasons for nonresponse. That history often influences treatment selection and is critical for obtaining payor approval.

Lack of reimbursement remains the single largest barrier to offering patients these circuit-based treatments. As the evidence base grows and patients continue to demand better options, this barrier will fall, and neuromodulation will occupy a larger role in the psychiatric toolbox.

Dr Kim is a resident in the Department of Psychiatry & Behavioral Sciences at the University of Minnesota in Minneapolis. Dr Widge is an associate professor in the Department of Psychiatry & Behavioral Sciences at the University of Minnesota in Minneapolis.

References

1. Questions and answers about the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study—all medication levels. National Institute of Mental Health. Accessed March 15, 2023. https://www.nimh.nih.gov/funding/clinical-research/practical/stard/allmedicationlevels

2. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. US Food & Drug Administration. News release. March 5, 2019. Accessed March 15, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified

3. Salib V. FDA approved Auvelity for major depressive disorder in adults. PharmaNews Intelligence. August 30, 2022. Accessed March 15, 2023. https://pharmanewsintel.com/news/fda-approved-auvelity-for-major-depressive-disorder-in-adults

4. Sackeim HA, Aaronson ST, Bunker MT, et al. The assessment of resistance to antidepressant treatment: rationale for the Antidepressant Treatment History Form: Short Form (ATHF-SF). J Psychiatr Res. 2019;113:125-136.

5. Mutz J, Vipulananthan V, Carter B, et al. Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis. BMJ. 2019;364:l1079.

6. Espinoza RT, Kellner CH. Electroconvulsive therapy. N Engl J Med. 2022;386(7):667-672.

7. McClintock SM, Reti IM, Carpenter LL, et al. Consensus recommendations for the clinical application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. J Clin Psychiatry. 2018;79(1):16cs10905.

8. Levkovitz Y, Isserles M, Padberg F, et al. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial. World Psychiatry. 2015;14(1):64-73.

9. Filipčić I, Šimunović Filipčić I, Milovac Ž, et al. Efficacy of repetitive transcranial magnetic stimulation using a figure-8-coil or an H1-Coil in treatment of major depressive disorder; a randomized clinical trial. J Psychiatr Res. 2019;114:113-119.

10. Carpenter LL, Janicak PG, Aaronson ST, et al. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety. 2012;29(7):587-596.

11. Connolly KR, Helmer A, Cristancho MA, et al. Effectiveness of transcranial magnetic stimulation in clinical practice post-FDA approval in the United States: results observed with the first 100 consecutive cases of depression at an academic medical center. J Clin Psychiatry. 2012;73(04):e567-573.

12. Taylor SF, Bhati MT, Dubin MJ, et al. A naturalistic, multi-site study of repetitive transcranial magnetic stimulation therapy for depression. J Affect Disord. 2017;208:284-290.

13. Dunner DL, Aaronson ST, Sackeim HA, et al. A multisite, naturalistic, observational study of transcranial magnetic stimulation for patients with pharmacoresistant major depressive disorder: durability of benefit over a 1-year follow-up period. J Clin Psychiatry. 2014;75(12):1394-1401.

14. Janicak PG, Nahas Z, Lisanby SH, et al. Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant major depression: assessment of relapse during a 6-month, multisite, open-label study. Brain Stimul. 2010;3(4):187-199.

15. Cole EJ, Stimpson KH, Bentzley BS, et al. Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. Am J Psychiatry. 2020;177(8):716-726.

16. Cole EJ, Phillips AL, Bentzley BS, et al. Stanford neuromodulation therapy (SNT): a double-blind randomized controlled trial. Am J Psychiatry. 2022;179(2):132-141.

17. Siddiqi SH, Taylor SF, Cooke D, et al. Distinct symptom-specific treatment targets for circuit-based neuromodulation. Am J Psychiatry. 2020;177(5):435-446.

18. Goldstein-Piekarski AN, Ball TM, Samara Z, et al. Mapping neural circuit biotypes to symptoms and behavioral dimensions of depression and anxiety. Biol Psychiatry. 2022;91(6):561-571.

19. Webler RD, Fox J, McTeague LM, et al. DLPFC stimulation alters working memory related activations and performance: an interleaved TMS-fMRI study. Brain Stimul. 2022;15(3):823-832.

20. Neacsiu AD, Luber BM, Davis SW, et al. On the concurrent use of self-system therapy and functional magnetic resonance imaging-guided transcranial magnetic stimulation as treatment for depression. J ECT. 2018;34(4):266.

21. Carmi L, Tendler A, Bystritsky A, et al. Efficacy and safety of deep transcranial magnetic stimulation for obsessive-compulsive disorder: a prospective multicenter randomized double-blind placebo-controlled trial. Am J Psychiatry. 2019;176(11):931-938.

22. Wendt K, Denison T, Foster G, et al. Physiologically informed neuromodulation. J Neurol Sci. 2022;434:120121.

23. Zrenner B, Zrenner C, Gordon PC, et al. Brain oscillation-synchronized stimulation of the left dorsolateral prefrontal cortex in depression using real-time EEG-triggered TMS. Brain Stimul. 2020;13(1):197-205.

24. Duprat R, Desmyter S, Rudi DR, et al. Accelerated intermittent theta burst stimulation treatment in medication-resistant major depression: a fast road to remission? J Affect Disord. 2016;200:6-14.

25. George MS, Sackeim HA, Rush AJ, et al. Vagus nerve stimulation: a new tool for brain research and therapy. Biol Psychiatry. 2000;47(4):287-295.

26. Rush AJ, Marangell LB, Sackeim HA, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry. 2005;58(5):347-354.

27. Aaronson ST, Sears P, Ruvuna F, et al. A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: comparison of response, remission, and suicidality. Am J Psychiatry. 2017;174(7):640-648.

28. Rush AJ, Marangell LB, Sackeim HA, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry. 2005;58(5):347-354.

29. Conway CR, Olin B, Aaronson ST, et al. A prospective, multi-center randomized, controlled, blinded trial of vagus nerve stimulation for difficult to treat depression: a novel design for a novel treatment. Contemp Clin Trials. 2020;95:106066.

30. Aaronson ST, Goldwaser EL, Kutzer DJ, et al. Vagus nerve stimulation in patients receiving maintenance therapy with electroconvulsive therapy: a series of 10 cases. J ECT. 2021;37(2):84.

31. Redgrave J, Day D, Leung H, et al. Safety and tolerability of transcutaneous vagus nerve stimulation in humans; a systematic review. Brain Stimul. 2018;11(6):1225-1238.

32. Noble LJ, Souza RR, McIntyre CK. Vagus nerve stimulation as a tool for enhancing extinction in exposure-based therapies. Psychopharmacology (Berl). 2019;236(1):355-367.

33. Noble LJ, Chuah A, Callahan KK, et al. Peripheral effects of vagus nerve stimulation on anxiety and extinction of conditioned fear in rats. Learn Mem. 2019;26(7):245-251.

34. Drobisz D, Damborská A. Deep brain stimulation targets for treating depression. Behav Brain Res. 2019;359:266-273.

35. Schlaepfer TE, Bewernick BH, Kayser S, et al. Rapid effects of deep brain stimulation for treatment-resistant major depression. Biol Psychiatry. 2013;73(12):1204-1212.

36. Widge AS, Malone DAJ, Dougherty DD. Closing the loop on deep brain stimulation for treatment-resistant depression. Front Neurosci. 2018;12:175.

37. Sheth SA, Mayberg HS. Deep brain stimulation for obsessive-compulsive disorder and depression. Ann Rev Neurosci. 2023;46:341-358.

38. Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45(5):651-660.

39. Malone DA, Dougherty DD, Rezai AR, et al. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry. 2009;65(4):267-275.

40. Holtzheimer PE, Husain MM, Lisanby SH, et al. Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lancet. 2017;4:839-849.

41. Dougherty DD, Rezai AR, Carpenter LL, et al. A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol Psychiatry. 2015;78(4):240-248.

42. Bergfeld IO, Mantione M, Hoogendorn ML, et al. Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2016;73(5):456-464.

43. Riva-Posse P, Choi KS, Holtzheimer PE, et al. A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression. Mol Psychiatry. 2018;23(4):843-849.

44. Holtzheimer PE, Kelley ME, Gross RE, et al. Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen Psychiatry. 2012;69(2):150-158.

45. Crowell AL, Riva-Posse P, Holtzheimer PE, et al. Long-term outcomes of subcallosal cingulate deep brain stimulation for treatment-resistant depression. Am J Psychiatry. 2019;176(11):949-956.