Thomas E. Schlaepfer, MD

[[{"type":"media","view_mode":"media_crop","fid":"17812","attributes":{"alt":"","class":"media-image media-image-right","height":"172","id":"media_crop_9532435884001","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1121","media_crop_rotate":"0","media_crop_scale_h":"153","media_crop_scale_w":"160","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image","width":"180"}}]]In the past 15 years, there have been considerable advances in the research on and clinical use of neurostimulation for psychiatric disorders, especially mood disorders and MDD. These treatments offer hope to many, especially to patients with treatment-resistant disorders or those who cannot tolerate medication regimens. Current understanding of the optimal treatment methods, mechanism of action, and delivery of these treatments is evolving.

 (rTMS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS)-are reviewed in this article. An experimental new treatment-trigeminal nerve stimulation-is also briefly discussed.

. rTMS was the first noninvasive brain stimulation technique to receive FDA approval for the treatment of MDD. rTMS is typically delivered using an insulated magnetic coil placed on the scalp over the left dorsolateral prefrontal cortex. The coil induces a strong magnetic field (1.5 to 2.0 Tesla) that passes unimpeded through the skull into the brain and causes neuronal depolarization in a cortical area of approximately 2 to 3 cm2 and 2 cm in depth.

 Although depolarization is limited to the cortex, the stimulation is thought to exert its effects in more distant but functionally connected brain regions.

 rTMS is delivered in an outpatient setting, and a typical rTMS course delivers 3000 high-frequency (10 Hz) magnetic pulses 5 days a week for 4 to 6 weeks. Treatments are typically well tolerated; headaches and discomfort at the stimulation site are the most common adverse effects and the incidence of seizures is rare.

There have been more than 30 randomized controlled rTMS trials involving patients with MDD. Two large, multicenter, randomized controlled trials have shown superior antidepressant efficacy of rTMS over sham rTMS.

 In the study by O’Reardon and colleagues,

 rTMS antidepressant response rates were twice those of sham stimulation (23% response and 15% remission versus 12% and 5.5%, respectively, for sham after 6 weeks). A subsequent subanalysis of the trial concluded that the antidepressant effects were greater in MDD patients with less medication resistance, which led the FDA to approve rTMS for patients in whom only one antidepressant trial has failed.

. Since the FDA approval in 2008, there has been a considerable increase in the use of rTMS for MDD throughout the United States. However, similar to the reimbursement situation with VNS and despite FDA approval of rTMS, most health insurance plans do not cover rTMS treatment. Medicare coverage appears to depend on local coverage determination. Recently, a few private insurance carriers have started to include guidelines for TMS coverage and approval is granted on a case-by-case basis.

rTMS was used as an adjunct to medications in a study that comprised 100 patients with treatment-resistant major depression (TRMD).

 Response and remission rates were 50.7% and 24.7%, respectively, following up to 30 TMS treatments. The higher response and remission rates observed in this clinical trial were attributed to the higher rTMS doses used and the addition of concomitant low-frequency TMS applied over the right dorsolateral prefrontal cortex in select cases. The additive effects of coexisting medications were also thought to potentially account for the superior clinical response rates.

 have been used to optimize rTMS efficacy. These include high-dosing protocols that deliver up to 10,000 daily pulses; right-sided, low-frequency pulsing (1 Hz); and bilateral rTMS.

Findings from 2 large meta-analyses indicate that low-frequency rTMS, which is believed to inhibit cortical activity in the underlying right dorsolateral prefrontal cortex, is efficacious in reducing symptoms of MDD. Schutter

 (N = 252) calculated an effect size of 0.63 for low-frequency, right-sided rTMS compared with sham. 

 (N = 263) estimated that approximately 30% to 40% of patients with MDD who received low-frequency rTMS were responders or remitters compared with 10% of those who received sham rTMS. Both meta-analyses concluded that the efficacy of slow, right-sided stimulation is similar to that of high-frequency left-sided stimulation. Hence, this treatment modality could potentially be used as an alternative to or in addition to left-sided rTMS. Furthermore, clinical advantages to low-frequency TMS include better tolerability with fewer reports of headache and significantly fewer seizures.

Bilateral rTMS has also been proposed as a treatment optimization strategy. This approach combines sequential application of high-frequency left-sided stimulation with low-frequency right-sided rTMS. This approach is thought to produce synergistic effects, thereby maximizing treatment response. However, despite promising results from a randomized controlled trial that demonstrated greater response (44%) and remission (36%) with bilateral rTMS than with sham, a recent study found no significant differences between unilateral stimulation and bilateral rTMS.

 Note that these rTMS treatment optimization strategies remain off-label.

. The future for rTMS is promising. Technological advances in coil design allow stimulation of deeper brain structures-deep rTMS. Deep rTMS uses a special H coil that modulates cortical excitability up to 6 cm in depth. This allows for stimulation of the orbito-medial, cingulate, and insular cortical regions.

Although the number of treated patients is small, the preliminary results for deep 

 In addition, the adverse effects of deep rTMS are similar to those of standard rTMS. Although rapid steps in technological advances and research are allowing for enhancement of TMS, a significant barrier to treatment is that the health insurance coverage remains low.

. VNS has been widely used in the United States and Europe for persistent treatmentrefractory seizure conditions. In 2005, the FDA approved VNS for TRMD.

A small electrical current is applied to the left vagus nerve using an implanted electrical generator (typically implanted in the chest region). The lead from the device is attached to the cervical region of the vagus. The patient receives around-the-clock stimulation, typically with stimulation periods, or “trains,” lasting 30 seconds, with 5 minutes of rest between trains. The electrical parameters (pulse width, frequency, duration of stimulation, and duty cycle) can be modified transcutaneously (as with cardiac pacemakers) using a “wand” that is attached to a small handheld programming computer. To date, there have been 5 large clinical trials that have shown the efficacy of VNS in TRMD.

. Until recently, the optimal electrical treatment parameters for VNS in TRMD had not been studied. To clarify this issue, Aaronson and colleagues

 conducted a large, prospective, double-blind trial that used VNS applied at different electrical parameters. Patients with TRMD were randomized to 3 target stimulation settings: low (output current 0.25 mA, pulse width 130 microseconds); medium (0.5 to 1.0 mA, 250 microseconds); or high (1.25 to 1.5 mA, 250 microseconds). All treatment groups used the same duty cycles (30 seconds on and 5 minutes off) and pulse frequencies (20 Hz). The study was divided into a 22-week double-blind acute phase and a 28-week long-term phase. Unlike the acute phase, the long-term phase allowed dose titration.

Several relevant findings emerged from this study:

• There were no statistically significant differences in antidepressant efficacy among the 3 dosing groups in the acute, blinded phase (22 weeks)

• Statistically significant improvement in the primary measure of depression over the acute phase and long-term phase was seen in all 3 groups

• Continued antidepressant improvement was seen in all 3 groups in the long-term phase

The study demonstrated a relationship between the initial dosing and sustained antidepressant effect at the end of the long-term phase, ie, there was a statistically significant difference between the percentage of low-dose cohort responders (end of the acute phase) who maintained their response to the end of the long-term phase (44%) and the percentage of similarly sustained responders in the medium- and high-dose cohorts (88% and 82%, respectively). These findings suggest that higher-current dosing may be clinically superior to lower dosing in maintaining antidepressant benefits.

. Clinical studies, as well as brain imaging studies, have demonstrated that the effects of VNS occur slowly. For example, in a 1-year extension of the 

 in TRMD, the frequency of antidepressant response increased over many months of stimulation: 15% at 3 months, 18% at 6 months, 23% at 9 months, and 30% at 12 months.

 This cumulative increase in response in patients with TRMD closely tracks the response patterns observed in patients with epilepsy.

How VNS brings about an antidepressant effect in TRMD is not known; however, brain imaging studies demonstrate that changes occur with sustained VNS. Nahas and colleagues

 had previously shown changes in functional MRI scans that occurred over many months of stimulation-at approximately 7 months of stimulation. More recently, PET was used to study the changes in regional metabolic activity in the brains of 14 patients with TRMD who had a VNS implant.

Brain PET scans were obtained at baseline and at 3 and 12 months of stimulation. Interestingly, subacute (3 months) stimulation was associated with very profound decreases in right-sided regional cerebral metabolic activity in the dorsolateral prefrontal cortex and medial prefrontal cortex, regions known to be associated with depression. In contrast, 12-month regional metabolic activity in these regions did not differ from baseline. There was a large increase in brainstem (midbrain region, localized to the ventral tegmental area) regional cerebral metabolic activity at 12 months in responders, but not in nonresponders. Although these findings are preliminary, they suggest that brainstem regions associated with response in VNS may be activating dopaminergic brainstem regions, because the ventral tegmental area is a primary region of dopaminergic cell bodies.

. Despite multiple clinical trials that have shown the antidepressant efficacy of VNS in TRMD, and FDA approval for this indication, the Centers for Medicare and Medicaid Services (CMS) will not reconsider their noncoverage of TRMD, which has been in effect since 2007. This will continue to limit patients’ access to this treatment, because many private insurance companies fall in step with CMS decisions regarding coverage. Under Medicare, some TRMD patients who have had sustained response to VNS will not be eligible to have their devices replaced when the battery runs out. Without insurance coverage, they will not be able to afford a new device.

Given the poor prognosis of TRMD (11.6% response to treatment as usual at 1 year) along with new and compelling evidence regarding VNS efficacy in TRMD, we believe that 

 We have experienced considerably higher success rates with VNS in carefully selected TRMD patients (screening out for personality disorders and concomitant substance abuse or dependence). Additional studies are needed to ascertain the mechanism of VNS in TRMD and which patients are most likely to respond to this novel treatment.

. DBS is being evaluated as an option for TRMD.

 DBS uses stereotactically implanted intracerebral electrodes connected to a neurostimulator (implanted in the chest wall) to interfere continuously (though reversibly) with the functions of neurons surrounding the electrodes. High-frequency stimulation has become the first-choice surgical alternative to the medical treatment of idiopathic Parkinson disease. Findings from long-term studies of treatment for Parkinson disease indicate that DBS is highly effective in reducing severe motor complications (mainly tremor), although the overall process of degeneration cannot be slowed down.

. Wound infection after surgery or battery exchange, lead migration, and device-related infections are important surgical complications in DBS. Lead migration (2.5% of patients), erosion, and infection (4.5% to 8.9% of patients) have been reported.

 So far, there is only one report of hemorrhage, although statistically, DBS surgery has a substantial risk (0.9%) for hemorrhage.

Adverse effects (eg, erythema, increased anxiety, agitation, elevation of mood) of stimulation are typically transient and occur within minutes to hours after new treatment parameters have been introduced. The exact mechanism leading to adverse effects is not fully understood; however, in some cases (eg, oculomotor adverse effects), a modulation of neighboring neuronal tissue to the target region may explain the effect. If adverse effects persist and are judged to be troublesome, a change in stimulation settings is required.

. Several brain structures play a role in the development and maintenance of depression. TRMD studies are targeting the anterior cingulate cortex (Cg25), the anterior limb of the capsula interna (ALIC), the nucleus accumbens (NAcc), and the medial forebrain bundle (MFB).

 on Cg25, ALIC, and NAcc are available from studies with small sample sizes (N < 30). These targets are in close anatomical or functional relationship (neural networks), and an overlap of effect is seen.

 The superolateral branch of the MFB has also been proposed as a target.

 Higher stimulation intensities have been used in DBS for depression than in DBS for neurological indications; the generated large electric fields thus stimulate structures beyond the intended target sites. Electric field stimulation and probabilistic fiber tracking have shown that the superolateral branch of the MFB is anatomically and functionally connected with other DBS targets (Cg25, ALIC, and NAcc).

This has led to the hypothesis that these targets are all clinically effective because of their common relationship to the MFB, leading to rapid (within days) and substantial antidepressant effects.

 A study using optogenetic neuromodulation together with DBS has recently shown that activation and modulation of afferent fiber tracts are a plausible mechanism of action in DBS.

. Four general hypotheses exist concerning the mechanism of action of DBS: depolarization blockade, synaptic inhibition, synaptic depression, and stimulation-induced modulation of pathological network activity.

 However, the therapeutic mechanism is likely a combination of several of these phenomena. DBS at specific stimulation parameters induces a functional lesion that is a reversible and controlled modification/inhibition of the function of a given neuronal circuit. DBS can thus be seen as an improved alternative to ablative neurosurgical procedures, which are used for well-defined groups of patients with extremely severe treatment-refractory mental disorders.

. After a decade of DBS research in TRMD, there is consensus about its efficacy: this neurostimulation modality holds considerable promise in lessening the suffering of patients who hitherto have had little or no hope of having MDD symptom remission. Nonetheless, substantial surgical risks and high costs are associated with DBS.

DBS has the additional potential to be used as a research tool, informing us about the underlying neurobiology of MDD. Thus far, existing studies have contributed to a novel view of depression that moves away from a synaptocentric view toward a conceptualization of disordered brain networks, ie, networks processing responses to 

 Future DBS studies may reveal that several psychiatric disorders are correlated with similar network dysfunctions.

Transcutaneous trigeminal stimulation for TRMD

. Transcutaneous, high-frequency stimulation of the V1 branch of the trigeminal nerve has been successfully used in medication-resistant epilepsy.

 Currently, very limited and only open-label data exist regarding its use for TRMD.

Two open-label studies describe the application of this treatment modality in 11 patients with TRMD.

 Study participants received nightly (approximately 8 hours per night) bilateral transcutaneous electrical stimulation of the V1 trigeminal branch for 8 weeks. Stimulation was delivered at a 120-Hz repetition frequency, with 250-microsecond pulse width, and with a duty cycle of 30 seconds on and 30 seconds off. A statistically significant reduction in depressive symptoms (both rater- and patient-rated) was seen after 8 weeks of stimulation: 6 patients had treatment response (50% or greater reduction in depressive symptoms) and 4 patients had symptom remission. These positive findings suggest that larger, prospective, double-blind studies are warranted.

Dr Conway is Associate Professor of Psychiatry at Washington University in St Louis. Dr Cristancho is Assistant Professor of Psychiatry at Washington University. Dr Schlaepfer is Vice Chair and Professor of Psychiatry and Psychotherapy at University Hospital Bonn, Dean of Medical Education at the University of Bonn in Germany, and Associate Professor of Psychiatry and Mental Health at The Johns Hopkins University School of Medicine in Baltimore. The authors report no conflicts of interest concerning the subject matter of this article.

 George MS, Bohning DE, Loberbaum JP. Overview of transcranial magnetic stimulation. In: George MS, Belmaker RH, eds. 

Transcranial Magnetic Stimulation in Clinical Psychiatry.

 Arlington, VA: American Psychiatric Publishing, Inc; 2006:1-20.

 Nahas Z, Lomarev M, Roberts DR, et al. Unilateral left prefrontal transcranial magnetic stimulation (TMS) produces intensity-dependent bilateral effects as measured by interleaved BOLD fMRI. 

 O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. 

 George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. 

 Reti IM. A rational insurance coverage policy for repetitive transcranial magnetic stimulation for major depression. 

 Hadley D, Anderson BS, Borckardt JJ, et al. Safety, tolerability, and effectiveness of high doses of adjunctive daily left prefrontal repetitive transcranial magnetic stimulation for treatment-resistant depression in a clinical setting. 

 Schutter DJ. Quantitative review of the efficacy of slow-frequency magnetic brain stimulation in major depressive disorder. 

 Berlim MT, Van den Eynde F, Daskalakis ZJ. Clinically meaningful efficacy and acceptability of low-frequency repetitive transcranial magnetic stimulation (rTMS) for treating primary major depression: a meta-analysis of randomized, double-blind and sham-controlled trials. 

Repetitive Transcranial Magnetic Stimulation Treatment for Depressive Disorders: A Practical Guide

 Fitzgerald PB, Benitez J, de Castella A, et al. A randomized, controlled trial of sequential bilateral repetitive transcranial magnetic stimulation for treatment-resistant depression. 

 Fitzgerald PB, Hoy KE, Singh A, et al. Equivalent beneficial effects of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in a large randomized trial in treatment-resistant major depression. 

 Bersani FS, Minichino A, Enticott PG, et al. Deep transcranial magnetic stimulation as a treatment for psychiatric disorders: a comprehensive review. 

 Aaronson ST, Carpenter LL, Conway CR, et al. Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: acute and chronic effects. 

 Rush AJ, Sackeim HA, Marangell LB, et al. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. 

 Morris GL 3rd, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05 [published correction appears in Neurology. 2000;54:1712]. 

 Nahas Z, Teneback C, Chae JH, et al. Serial va-gus nerve stimulation functional MRI in treatment-resistant depression. 

 Conway CR, Chibnall JT, Gebara MA, et al. Association of cerebral metabolic activity changes with vagus nerve stimulation antidepressant response in treatment-resistant depression. 

 Dunner DL, Rush AJ, Russell JM, et al. Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. 

 SchlÃ¤pfer TE, Bewernick BH. Deep brain stimulation for psychiatric disorders-state of the art. 

 Hilker R, Portman AT, Voges J, et al. Disease progression continues in patients with advanced Parkinson’s disease and effective subthalamic nucleus stimulation. 

 Doshi PK. Long-term surgical and hardwarerelated complications of deep brain stimulation. 

 Fily F, Haegelen C, Tattevin P, et al. Deep brain stimulation hardware-related infections: a report of 12 cases and review of the literature. 

 Zrinzo L, Foltynie T, Limousin P, Hariz MI. Reducing hemorrhagic complications in functional neurosurgery: a large case series and systematic literature review. 

 Coenen VA, Schlaepfer TE, Maedler B, Panksepp J. Cross-species affective functions of the medial forebrain bundle-implications for the treatment of affective pain and depression in humans. 

 Coenen VA, Schlaepfer TE, Allert N, MÃ¤dler B. Diffusion tensor imaging and neuromodulation: DTI as key technology for deep brain stimulation. 

 Schlaepfer TE, Bewernick BH, Kayser S, et al. Rapid effects of deep brain stimulation for treatment-resistant major depression. 

 Gradinaru V, Mogri M, Thompson KR, et al. Opti-cal deconstruction of parkinsonian neural circuitry. 

 McIntyre CC, Savasta M, Walter BL, Vitek JL. How does deep brain stimulation work? Present understanding and future questions. 

 Krishnan V, Nestler EJ. The molecular neurobiology of depression. 

 DeGiorgio CM, Murray D, Markovic D, Whitehurst T. Trigeminal nerve stimulation for epilepsy: long-term feasibility and efficacy. 

 DeGiorgio CM, Soss J, Cook IA, et al. Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy. 

 Cook IA, Schrader LM, Degiorgio CM, et al. Trigeminal nerve stimulation in major depressive disorder: acute outcomes in an open pilot study. 

 Schrader LM, Cook IA, Miller PR, et al. Trigeminal nerve stimulation in major depressive disorder: first proof of concept in an open pilot trial. 

Articles

There have been considerable advances in the research on and clinical use of neurostimulation for psychiatric disorders, especially mood disorders and MDD. Three of the most recognized are reviewed here. An experimental new treatment-- trigeminal nerve stimulation-- is also briefly discussed.

Thomas E. Schlaepfer, MD

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Neurostimulation Treatments in Psychiatry: An Overview and Recent Advances