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Brain Stimulation Treatments for Depression

Abstract and Keywords

The use of brain stimulation for the treatment and investigation of mood disorders is rapidly expanding. Mood disorders are common, but so are treatment-refractory or intolerant patients, explaining increasing interest in alternatives to medications and talk therapy. Additionally, depressive episodes are periodic or temporary states and are thus amenable to pulsatile, non-systemic treatments. The oldest brain stimulation method, electroconvulsive therapy (ECT), remains the most effective acute antidepressant available. The newer brain stimulation methods, in particular repetitive transcranial magnetic stimulation (rTMS), also show that non-invasive stimulation of key brain regions not only effectively treats depression, but also causes quantifiable changes in brain biomarkers. More research is needed, though, to better understand how these treatments work, for whom they work, and how to optimize their use.

Keywords: electroconvulsive therapy, magnetic seizure therapy, focal electrically administered seizure therapy, transcranial magnetic stimulation, transcranial direct current stimulation, transcranial alternating current stimulation

Background and Definitions

Brain stimulation” refers to a wide variety of neuropsychiatric treatments in which electricity (or something that induces electricity) is used to modulate neuronal activity. Procedures range from invasive surgical implantation of electrodes into deep regions of the brain, to barely perceptible, non-invasive transcutaneous stimulation. The most focal devices use a direct electrical charge to stimulate very specific areas; others rely on a more generalized spread of electricity through conduction or triggered action potentials; while still others utilize electromagnetic induction to achieve desired effects. Within individual devices, differing parameters may be used to create wholly different physiological and clinical outcomes.

Electricity applied to the head has been used as a treatment for illness for thousands of years. Prior to the development of generators, electric eels were used to treat a variety of ailments, from headaches to demonic possession (Endler, 1988). The first documented use of electricity in the treatment of mood disorders is attributed to physics professor Giovanni Aldini of Bologna in 1801 (Endler, 1988). Following this, the relationship between electricity, seizures, and mood was explored intermittently throughout the 19th century, but the next major breakthrough was with the advent of electroconvulsive therapy (ECT) by Ugo Cerletti and Lucio Bini in 1938. Since that time, not only has ECT improved in both its safety and its efficacy, but a host of other neuromodulatory devices have also been developed. Current US Food and Drug Administration (FDA)–approved brain stimulation modalities for the indication of major depressive disorder are limited to ECT, transcranial magnetic stimulation (TMS), and vagus nerve stimulation (VNS), but many more devices are being researched.

(p. 399) There have been numerous advances in understanding the neuroanatomy of mood and emotion regulation that provide the groundwork on which brain stimulation technologies are being developed and used. There is a general consensus that healthy mood and emotion regulation involves a balance of activity between ventral and medial prefrontal cortical regions, and deeper structures such as the cingulate cortex, insula, amygdala, and hippocampus (George, Ketter, & Post, 1994; George, 1994). If the cortex serves to regulate deeper limbic regions, then repeated superficial stimulation might serve to strengthen and reset this governing relationship and restore health. Supporting this theory is the pioneering work of Robinson with the discovery that individuals with a prefrontal cortex stroke, particularly on the left side, are more vulnerable to developing a post-stroke depression than are patients with strokes in other brain regions (Jorge et al., 2004; Robinson et al., 1988).

Work in the learned helplessness model of depression also supports the important role of prefrontal regulation, and it may explain how TMS and other prefrontal cortical stimulation methods could work as antidepressants. In 1975 Seligman developed the learned helplessness model in rats, an analogue to depression or post-traumatic stress in humans. Maier and colleagues have shown that animals with a “sense of control” do not develop depression or PTSD-like behavior after exposure to learned helplessness models, and that this “sense of control” is actually a signal from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DRN). Interestingly, pharmacologic activation of the mPFC is also protective against learned helplessness in these scenarios, even if animals are given no “sense of control” over their situation.

Brain stimulation modalities to be reviewed in this chapter are: electroconvulsive therapy (ECT), magnetic seizure therapy (MST), focal electrically administered seizure therapy (FEAST), repetitive transcranial magnetic stimulation (rTMS), vagus nerve stimulation (VNS), deep brain stimulation (DBS), and subdural or epidural (EpCS) Any definition will find some exceptions, and this chapter is no different. Additionally, this chapter will not discuss other experimental brain stimulation methods such as transcranial direct current stimulation (tDCS), transcranial electrical stimulation, light therapy or chronotherapy, sound therapy or music therapy, optogenetics, or transcranial pulsed ultrasound.

Electroconvulsive Therapy (ECT)

ECT is a well-studied, non-invasive form of brain stimulation. It is the most effective acute antidepressant treatment available, but it is generally reserved for severely treatment-resistant patients, or patients at high risk of suicide. In these “treatment-resistant” patients, ECT remains the most effective option, but the results are not as robust as those found using ECT in treatment-naïve patients. Since the 1950s, estimates of remission rates with ECT have ranged from 60% to 90%. More recent estimates in “treatment-resistant” patients are significantly lower, ranging between 50% to 60%, and the reasons for this are not well understood. Worldwide, roughly 1 million patients receive ECT annually (Prudic et al., 2001). However, data on ECT utilization are out of date, and with recent improvements in ECT methods, changing public opinion, and the growing number of ECTs provided on an outpatient basis, Prudic et al. estimate that current utilization rates are probably at least 25% higher than published estimates.

Of all the modern brain stimulation methods, ECT has the largest body of literature regarding its use. In 2001, the American Psychiatric Association (APA) convened a task force that conducted a thorough review of the literature on the efficacy of ECT. Below is the summary of their conclusions regarding the indications for the use of ECT:

Major Depression—Numerous randomized controlled trials (RCTs) have been conducted with ECT in depressed patients. The most remarkable were the trials comparing ECT with sham ECT—a study design that is no longer considered ethical. In the 1940’s and 1950’s when ECT was the primary treatment for depression, response rates of 80% to 90% were typically reported. Following the advent of antidepressant medications, numerous trials have been conducted comparing ECT with medications and placebo. In a meta-analysis of studies comparing ECT with antidepressants, ECT was found to have a 20% greater response rate compared to TCAs and a 45% greater response rate compared to MAOIs [monoamine oxidase inhibitors] (Janicak et al., 1985).

ECT was found to be effective for bipolar depression, catatonia and psychotic depression, but may be less effective for patients with a long duration of current symptoms, depression secondary to medical conditions or patients with personality disorders.

In summary, ECT is, to date, the most efficacious acute treatment for unipolar and bipolar (p. 400) depression. ECT is particularly useful in patients in urgent need of symptom resolution (e.g., catatonic and suicidal patients; Sackeim et al., 2009).

ECT Theory

There are multiple theories on the mechanism behind ECT’s therapeutic efficacy (Sackeim et al., 1987). Currently, the three main hypotheses of ECT mechanisms are based on (1) direct and indirect effects of the seizure, (2) neuro-endocrine changes, and (3) alteration of brain structure or connectivity. The seizure hypothesis is supported by evidence that real ECT outperforms sham, chemically induced seizures can have similar antidepressant effects to ECT, and brain stimulation modalities such as TMS and tDCS that do not invoke seizure activity are not as effective as ECT. However, differences in outcomes with modified seizures reveal that not all seizures are equal, and that the seizure alone is not sufficient for an antidepressant effect. Several studies have found much improved treatment efficacy by treating at roughly six times the seizure threshold in right unilateral ECT, and at roughly two times the seizure threshold in bilateral ECT. Reinforcing the neuroendocrine theory are findings that ECT seizures induce a variety of endocrine responses related to the hypothalamic pituitary axis (HPA), which is known to be dysregulated in depression. Finally, in support of the anatomical hypothesis, ECT has been shown to increase hippocampal and amygdala volume in both animals and humans (possibly through increased production of brain-derived neurotrophic factor [BDNF]); reduce corticostriatal white matter hyper-connectivity associated with the depressions; and regulate regional brain metabolic abnormalities. Given the complexity and heterogeneity of the depressions, though, none of the above hypotheses stands independently, and all probably overlap in both their direct and downstream effects.

ECT Procedural Variables

For decades, the efficacy of ECT was believed to depend only on the induced generalized seizure and total charge delivered, while its cognitive side effects were determined largely by the intensity of electrical stimulation. However, it is now evident that electrode placement (EP), stimulus parameters (wave form, pulse width, pulse frequency, pulse amplitude, pulse train duration), and dosage relative to seizure threshold (ST) all play critical roles in both efficacy and side effects.

Bilateral (BL) electrode placement is the original ECT method and remains a first-line choice for patients who require extremely acute care such as in catatonia, and for patients with severe psychotic disorders, as it works more quickly than right unilateral (RUL) electrode placement. However, direct current through medial temporal lobe (MTL) regions probably contributes to BL ECT’s increased cognitive side effects in comparison to RUL ECT. RUL electrode placement was designed as an alternative to BL placement, and has resulted in a reduction of cognitive side effects, not only by avoiding direct stimulation through MTL regions, but also by avoiding stimulation over dominant language centers (Goldman, 1949; d’Elia, 1970; Sackeim et al., 2009; Sackeim et al., 2007). Other electrode placements include bifrontal (BF), left unilateral (LUL), and left anterior right temporal (LART), but thus far, none has proven safer or more effective than RUL or BL electrode placements.

As noted above, total ECT stimulus dose is a product of multiple variables that both interplay to produce a net charge, and independently affect treatment outcomes. Pulse width is one of these variables. Traditional wide pulse (WP) stimuli of greater than 1 millisecond are about 10 times the estimated chronaxie (optimal pulse duration) needed for mammalian central nervous system (CNS) neuronal depolarization and hence are nonphysiological. To that purpose, the greatest treatment benefit with the least severe cognitive side effect profile has been found using ultra brief pulse (UBP) (0.3 msec) RUL ECT and brief pulse (BP) (0.5 msec–1 msec) bilateral (BL) ECT. It remains unclear why UBP BL ECT is not as effective. Nonetheless, these advantages have not always been demonstrated, and newer evidence points towards BP RUL ECT being just as safe and effective as UBP ECT, highlighting the need for further research into this parameter. The ECT stimulus waveform is another important variable. Traditionally delivered as a sine wave, as ECT practice developed, trains of rectangular, constant-current pulses with alternating polarity were instituted as a way to maximize treatment efficacy while minimizing total charge received, and thus, minimizing adverse effects. Pulse train duration is defined as the total amount of time (seconds) over which the stimulus is administered, and the magnitude of this stimulus parameter correlates positively with cognitive side effects. Pulse amplitude (current) is locked at a maximum of 800 mAmp on most modern ECT devices (Lee et al., 2013). Finally, pulse pair frequency, defined as the number of pairs of positive and negative pulses per second (hertz), can impact seizure production if too (p. 401) high or too low, but little is known about its influence on efficacy.

Adverse Effects of ECT

ECT is safe when practiced appropriately and can often be more advantageous than aggressive pharmacotherapy in that it may help limit the adverse effects associated with polypharmacy and escalating dosages. ECT also works more quickly than most medications, making it a gold standard treatment for suicidal patients who are at an acutely high risk to themselves. The mortality rate per treatment session is roughly that of general anesthesia, about one or two per 100,000. Common side effects from the ECT procedure are easily treated and include headache, musculoskeletal aches and pains, nausea, and transient (minutes to hours) post-ictal confusion. Uncommon side effects include cardiovascular compromise, respiratory collapse, malignant hyperthermia, musculoskeletal injury, stroke, and post-ictal delirium. These can be usually avoided through careful history-taking and an appropriate pre-procedural medical screen.

The most common side effect of ECT is cognitive impairment, but although almost all patients experience cognitive impairment to some degree, it is highly variable in quality, severity, and duration between patients. Cognitive impairment may occur as both retrograde and anterograde amnesia, involving memories from the weeks prior to ECT and persisting for weeks after the last treatment. Retrograde amnesia is especially difficult to study, as autobiographical memories fade or change with the passage of time, are they more difficult to validate given their individualized nature, and depressed patients who have not received ECT also experience impairments in autobiographical memory that can persist into times of remission. Dense, remote, retrograde amnesia of important biographical events or persistent anterograde amnesia is uncommon with modern ECT, but it has been observed. Many characteristics, both of patients and of procedures, affect the level of risk of cognitive impairment with ECT. Younger age and higher premorbid cognitive ability appear to be protective. Increased number of treatments, high dosage, sine wave form, BL and BF as opposed to RUL, increased pulse width, and certain medications all increase the risk of cognitive side effects with ECT (Sackeim et al., 2009). Conversely, the use of acetylcholinesterase inhibitors in certain populations, namely geriatric patients with cognitive impairment at baseline, may be protective.

Continuance or Maintenance ECT

Despite the remarkable acute efficacy of ECT, long-term benefits are difficult to sustain. With no treatment following ECT, over 90% of patients relapse by three months. Studies show that regardless of randomization to maintenance ECT, pharmacotherapy, or a combination of both, about 50% of patients who remit with an acute series of ECT relapse within six months (Sackeim et al., 2001a; Kellner et al., 2006). There are small studies to suggest that maintenance ECT may be more effective than, and as tolerable as, pharmacotherapy alone in specific populations; namely, elderly unipolar psychotically depressed patients. However, it is apparent that, for the vast majority of patients, better approaches to maintenance treatment are needed.

ECT Variants: Focal Electrically Administered Seizure Therapy (FEAST) and Magnetic Seizure Therapy (MST)

Unfortunately, traditional ECT methods with alternating current offer limited control over intracerebral current paths and current density (Sackeim et al., 1994). However, basic research has shown that more focal transcranial electrical stimulation can be achieved when a unidirectional waveform is applied (Cracco et al., 1987; Amassian et al., 1989; Brasil-Neto et al., 1993; Amassian et al., 1993). Adapting this approach to electrocortical stimulation (ECS) in nonhuman primates, one can reliably elicit seizures at remarkably low dosage (3 millicoulombs [mC]) that are predominantly expressed in frontal electroencephalogram (EEG), propagate to motor cortex only at higher stimulus intensity, are asymmetrical in motor seizure expression, and are profoundly asymmetrical in EEG. These phenomena are not seen with traditional RUL ECT (Spellman et al., 2009). This novel unidirectional ECS, known as focal electrically administered seizure therapy (FEAST), may spatially direct seizure activity to the prefrontal cortex (PFC) and reduce involvement of temporal lobe regions, with preliminary results suggesting that FEAST may preserve treatment efficacy while reducing the amnestic side effects of traditional ECT.

FEAST differs from traditional ECT in three respects. First, instead of a bidirectional stimulus, FEAST uses a positive and a negative electrode (anode and cathode) to create current flow in one direction. Second, instead of identical electrodes, FEAST uses a small anode (anterior) and a large cathode (posterior) to produce highly focal and efficient stimulation (Amassian et al., 1993). Third, (p. 402) FEAST electrode placement differs slightly from RUL ECT in that the smaller electrode is placed anteriorly, with the lower boundary just above the center of the right eyebrow to concentrate stimulation in the ventromedial PFC and away from the temporal lobe, as demonstrated in e-field modeling studies (Spellman et al., 2009).

In a recent human clinical trial, 17 unmedicated depressed adults received open-label acute series FEAST (median 10 sessions; Nahas et al., 2013). Subjects showed clinically significant improvement in Hamilton Rating Scale for Depression (HRSD24) scores compared to baseline, and five out of 17 patients met remission criteria (HRSD24 ≤ 10). Times to full reorientation following treatments were favorable, averaging around 7 minutes, and cognitive scores at two- and six-month follow-ups showed no worsening from baseline. This proof-of-principle trial found that FEAST produced clinically meaningful antidepressant improvement, with limited cognitive side effects, although additional work is needed to refine the FEAST technique. In a followup cohort, 16 unmedicated and 4 unmedicated depressed adults received open-labeled acute series FEAST (median 9.3; Sahlem et al., 2016). Eleven of twenty patients met remission criteria (HRSD24 ≤ 10). Time to orientation averaged 4.4 minutes, while the autobiographical memory index short form (AMI-SF) was 97.5% suggesting minimal, if any, cognitive side effect burden with FEAST treatment.

Magnetic seizure therapy (MST) is another neurostimulation technique developed with the goal of reducing cognitive side effects through enhanced focality. With traditional ECT, 80% to 95% of the electrical stimulus never reaches the brain due to shunting from skull impedance (Sackeim et al., 1994). This impedance can result in regional variability in current density, and variable treatment effects, even when electrode placement is consistent (Sackeim et al., 1996). MST theoretically avoids these limitations by generating magnetic fields that pass through tissue without impedance, resulting in more precise control over the site of seizure initiation and, perhaps, the capacity to limit seizure spread.

With current devices, the electrical field induced by MST is capable of neural depolarization at a depth of about 2 cm below the scalp, so direct effects of stimulation are limited to the superficial cortex. Human clinical studies have demonstrated that MST is feasible in the clinical setting (Lisanby et al., 2001), although it has been difficult to induce MST seizures in the PFC, which has a higher seizure threshold than motor cortex or hippocampus. Research trials are underway to test if there is antidepressant efficacy and if the side effect burden is less than with conventional ECT.

Transcranial Magnetic Stimulation (TMS)

The initial use of daily prefrontal TMS to treat depression was based on the theory that clinical depression involves an imbalance in the relationship between prefrontal (cortical) and limbic regions involved in mood regulation. Detection of hypometabolism in the PFC, a region involved in emotional control, suggested a target for stimulation. Early investigators of TMS theorized that repeated subconvulsive stimulation of the superficial PFC could promote health in regulatory pathways involving deeper limbic structures, which are also involved in mood regulation. These areas were and still are inaccessible by non-invasive means (George, 1994).

Early work showed that single sessions of prefrontal rTMS in healthy adults produced no side effects, but there was evidence of HPA interaction (serum thyroid) and slight mood changes (George et al., 1996a), clearing the way for later clinical trials (George et al., 1995; George et al., 1997). There is now accumulating support, primarily from brain imaging studies (Large et al., 2009; Li et al., 2004c; Li et al., 2004b), that prefrontal TMS in depressed patients does indeed change cortical and limbic activity and regulatory circuits. No one has yet linked these changes directly to the antidepressant effects, although an important study using a serotonin positron emission tomography (PET) ligand in depressed patients undergoing TMS found that a prefrontal serotonin deficiency at baseline recovered after several weeks of treatment (Baeken et al., 2011).

Acute major depression has been the most widely studied condition with TMS, with initial studies using TMS over the vertex of the head (Hoflich et al., 1993; Kolbinger et al., 1995; Grisaru et al., 1994; George et al., 1997; George, 1997). More recent meta-analyses have shown better antidepressant effects with coil placement over the left prefrontal cortex, with this form of TMS proving statistically superior to sham treatment. The clinical features that appear to be associated with greater response include younger age, lack of major refractoriness to antidepressants, and no psychotic features (Avery et al., 2008).

There have now been four large multi-site trials of TMS for depression, three of which were with (p. 403) more traditional figure-8 coils. A European trial used TMS as an adjunctive treatment to new medications in 127 patients and failed to find benefit over sham TMS plus the new medications (Herwig et al., 2007). A TMS manufacturer (Neuronetics) conducted the largest multi-site randomized control trial to date, with 301 medication-free depressed patients, which resulted in FDA approval (O’Reardon et al., 2007). The FDA agreed to approve the treatment only after reviewing response data on subgroups (Anderson et al., 2009; Avery et al., 2008). Because there was a large effect seen in those who were less treatment-resistant, FDA labeling is for the treatment of unipolar major depressive disorder (MDD) in adult patients who have failed an adequate antidepressant trial in the current depressive episode (Oquendo et al., 2003; Dew et al., 2005; Joo et al., 2005). More recently, a large multi-site trial in depression called Optimization of TMS (OPT-TMS) used an improved sham technique and found that, after three weeks, there was a statistically significant difference in remission rates between sham (5%) and real TMS (15%; Borckardt et al., 2008; Borckardt et al., 2009). In an open-label extension for another three weeks, another 15% (30% total) of patients remitted (George et al., 2010). McDonald et al. (2011) then reported on an extended open-label extension phase, finding that 30.5% of patients who enrolled in this phase of the study eventually met criteria for remission, with some patients taking up to six weeks to remit fully (McDonald et al., 2011). In regard to durability, Mantovani et al. (2012) reported on the three-month outcomes of OPT-TMS. Of the 50 patients who remitted and agreed to participate in follow-up, 58% were classified as in remission, 4% as partial responders, and 2% met criteria for relapse (Mantovani et al., 2012; Speer et al., 2000; Kimbrell et al., 1999).

The fourth large (n = 212), multi-site TMS trial utilized a fundamentally different device labeled “deep TMS” (Brainsway H Coil; see Levkovitz et al., 2015). Patients received daily weekday treatments over the PFC for four weeks acutely, and then biweekly for an additional 12 weeks. Positive findings resulted in FDA approval, as response and remission rates were significantly higher with active deep TMS compared to sham treatment (response: 38.4% and 21.4%, respectively; remission: 32.6% and 14.6%, respectively). These differences between active and sham treatment were stable during the 12-week maintenance treatment phase and were also observed in patients with higher degrees of treatment resistance. Though deep TMS did generally show few side effects, one seizure occurred in a patient (who did not follow the protocol) in the active group. Most recently, the Magstim company has received FDA approval for their TMS device for treating depression. More recently, two other manufacturers, MagVenture and NeuroSoft, have received FDA clearance for their figure-8 coil devices. There are now 5 different TMS machines that are FDA-approved for treating depression.

As is often true, treatment outcomes differ between rigorous scientific trials and clinical settings. With a combined total of 407 real-world patients receiving TMS in clinical practice settings, response rates averaged about 55%, and remission rates averaged about 31% (Carpenter et al., 2012; Connolly et al., 2012). Outcomes further stratified by level of treatment resistance (<2 vs. ≥2 treatment failures) showed that response and remission rates were similar between groups. Out of 42 patients entering six months of maintenance TMS treatment, 62% maintained their responder status at the last assessment (Connolly et al., 2012). These data from care-seeking patients suggest that TMS, unlike many therapies in medicine, does not suffer from an efficacy/effectiveness gap between clinical trials and clinical treatments.

Where to place the coil?

The early National Institutes of Mental Health (NIMH) studies used a rough measurement technique known as the five-centimeter rule to place the TMS coil roughly over the prefrontal cortex (George et al., 1995; George et al., 1996b; George et al., 1997). Researchers would determine the optimum position on the scalp to produce movement in the right thumb, and then would measure anterior from this location in a parasagittal line to locate the device over what was thought to be the PFC. Because the location of the motor strip and skull size vary between individuals, this simple rule results in large variations of treatment location between patients. One study suggested that the 5-cm rule resulted in 30% of patients’ being treated over their supplementary motor area (SMA) rather than their PFC (Herwig et al., 2001). Two retrospective analyses of clinical trials where brain imaging was performed to document the coil location have independently confirmed that a coil position that is more anterior and lateral than that found with the 5-cm rule is associated with a better clinical response (Herbsman et al., 2009; Fitzgerald et al., 2009). These findings suggest that the location of the coil matters, even within broad boundaries of a specific lobe. It is not (p. 404) clear whether individualized location will be needed or used, or whether general algorithms (such as a newly suggested “7 cm anterior to thumb” location, or AF3-EEG positioning; Beam et al., 2009) are sufficient.

How intense to make the stimulus?

In several of the early TMS depression studies, researchers noted that TMS did not work well for older patients (Figiel et al., 1998), and it is now thought that this is likely to be the consequence of older patients’ having more prefrontal atrophy and thus needing a higher magnetic field in order to overcome the greater distance from the coil (Nahas et al., 2001; McConnell et al., 2001). An open-label study (Nahas et al., 2004) and, later, a randomized trial (Jorge et al., 2008) in geriatric depression showed more robust responses using doses above motor threshold.

How many stimuli?

A meta-analysis (Gershon et al., 2003) and prospective clinical trial (Jorge et al., 2008; Epstein et al., 2007; Holtzheimer et al., 2010) suggest that increasing the number of stimuli per day, above the FDA-recommended dose of 3,000, may be more effective, yet both tolerable and safe (George et al., 1997; George et al., 2000b; O’Reardon et al., 2007; Epstein et al., 2007; Anderson et al., 2006; Hadley et al., 2011). The largest known dose of TMS given within a week (38,880 stimuli) was reported by Anderson and colleagues (Anderson et al., 2006). In healthy adult men participating in a sleep-deprivation study, there were no side effects or adverse effects, including no TMS-related changes in cognition. Finally, a recent study tested high-dose (nine sessions, total 54,000 pulses, over three days) rTMS in suicidal inpatients and found that it was feasible and safe. Suicide rating scores declined rapidly over the three days for both TMS and sham groups, with a trend for more rapid decline on the first day with active rTMS (George et al., 2014).

Is there a need for maintenance TMS?

Two large trials studying TMS durability found that, at six months, only 12% to 14% of patients had relapsed. These are encouraging data compared to over 50% of ECT patients relapsing within the first six to 12 months, but such a comparison across different patient populations remains tenuous. It seems that most patients with recurrent depression do appear to need maintenance interventions, but if rTMS is used for maintenance purposes, how should it be delivered? Several groups have performed maintenance TMS, but there have been no controlled clinical trials, and optimal ways of using TMS to prevent relapse remain to be defined (O’Reardon et al., 2005; Li et al., 2004a). In the same vein, another interesting concept is whether TMS might be used as a maintenance strategy following ECT, given that TMS is less invasive and does not disrupt effective medication strategies such as the use of lithium. There is as yet little research to support this, but in a recent small case series, four of six patients maintained remission at between seven and 24 months, and the remaining two patients maintained remission to eight and nine months, respectively (Simpson et al., 2009; Kozel et al., 2004; Kozel & George, 2002).

Vagus Nerve Stimulation (VNS)

“Vagus nerve stimulation” refers to a technique where a unidirectional wire is wrapped around the vagus nerve in the neck and connected to a subcutaneous, battery-operated generator, which is implanted subcutaneously in the left chest wall. The generator intermittently sends an electrical current through the wire and into the nerve, which then conveys a signal via neural impulses into the brainstem (George et al., 2000a). The unidirectional feature is thought to minimize efferent side effects from stimulating vagal efferent (descending) fibers. However, some patients have had the leads accidentally reversed, without noticeable harm (Koo et al., 2001).

Indications and Clinical Use in Depression

The first self-contained devices were implanted in humans with medically unresponsive epilepsy in 1988. Results were positive in two large, acute, double-blind controlled studies of VNS for this indication (Handforth et al., 1998), and VNS was given an FDA indication for epilepsy in the United States in 1997. Long-term follow-up studies have shown that the time course for seizures to respond to VNS is gradual, with continued improvement up to one year and then stabilization of effect. There appears to be no tolerance to VNS.

Several lines of evidence suggested that VNS might be helpful in patients with depression, including anecdotal reports of mood improvement in VNS-implanted epilepsy patients and functional imaging studies demonstrating that VNS increased activity in several regions of the brain thought to be involved with depression (Henry et al., 1998). This led to promising pilot work on the study of VNS for patients with treatment-resistant depression (Sackeim et al., 2001b). Later, an open-label study with 59 patients with treatment-resistant depression demonstrated good results—30% response rate and 15% remission (p. 405) rate at 10 weeks, but even more encouraging were the extended results (Nahas et al., 2005). Patients continued to improve long after the acute phase of the trial and were clinically better at one year than they were at three months (Rush et al., 2006b; Rush et al., 2006a). A later European trial found similar but even slightly better results (Schlaepfer et al., 2008b).

A pivotal multi-centered, randomized, double-blinded trial of VNS was initially not as encouraging. In this trial, active VNS failed to statistically separate from sham treatment at 10 weeks post-implantation. The response rates for the acute treatment of treatment-resistant depression were 15% for active treatment and 10% for sham treatment (Rush et al., 2005). However, a parallel “treatment as usual” but non-randomized group compared at one year to the Rush et al. patients (Rush et al., 2005) showed significant improvements in response and remission rates in the VNS group (27% and 16%) over the “treatment as usual” group (13% and 7%) (George et al., 2005), suggesting that the duration of earlier randomized trial was probably too short to see a separation between groups. Additionally, as in other brain stimulation modalities, VNS dose does seems to matter. A large post-market study randomizing depressed patients to stimulation with three different intensities initially found no significant differences in dose effect. However, the proportion of responders who maintained response at one year was significantly greater in the groups getting medium and high doses (1.25–1.5 mA, pw 250 us; 88% and 81%, respectively) when compared to the low-dose group (.25 mA, pw 130 us; 44%) (Aaronson et al., 2013).

In 2005, the FDA approved VNS to treat patients with chronic or recurrent, unipolar or bipolar depression, with a history of failing to respond to at least four antidepressant trials. Unfortunately, though, because VNS is lacking a supportive, adequately powered, randomized control trial, insurance companies have resisted reimbursing the implant. Further hindering VNS utilization is that attempts to predict which patients are more likely to respond have not been successful. A solution may lie in refinements and enhancements of several forms of non-invasive vagus nerve stimulation currently on the market or in development, which stimulate the peripheral branches of the vagus nerve transcutaneously through the neck or through a cutaneous branch of the vagus in the ear (Kraus et al., 2013). These devices, if proven to be even close to as effective as implanted VNS, show promise in providing non-systemic, non-invasive relief to a wide variety of patients in whom implantations or heroic medication strategies are deemed impractical or impossible.

Deep Brain Stimulation (DBS)

The most invasive of all neurostimulation techniques is deep brain stimulation (DBS), a procedure wherein an electrode is implanted deep within the brain and then connected to a generator located in the chest wall that sends constant electrical current back into the brain. Theoretically, if antidepressant treatment is not effective, DBS electrodes can be removed or left non-functioning with minimal future risk, and thus DBS has less morbidity and mortality than does resective brain surgery, which cannot be reversed.

The neuropsychiatric use of DBS began with work on treatment-resistant obsessive-compulsive disorder (OCD) patients, with electrodes implanted in the anterior limb of the internal capsule, bilaterally (Greenberg et al., 2008; Nuttin et al., 1999). In 2009, the FDA granted a humanitarian device-exemption for DBS for this indication, meaning that there is enough supportive evidence in the medical literature to warrant the use of DBS in an approved facility overseen by an investigational review board, but that it is lacking the large-scale, randomized control trial (RCT) necessary to achieve full FDA approval.

In addition to the positive effects found in OCD symptoms, mood improvements are also seen with DBS (Greenberg et al., 2003). Open-label DBS in the anterior limb of the internal capsule (ALIC) in 15 patients with treatment-resistant depression resulted in significant reduction in Hamilton scores over six months (entry mean 33, six months 17.5) with one case of emergent hypomania (Malone et al., 2009). However, a large, industry-sponsored (Medtronic) multi-site RCT with ALIC implantation stopped enrollment partway through their trial, and results have not been published.

Following a different line of reasoning, implanting electrodes in white matter fiber tracts next to the rostral anterior cingulate (CG25) had shown positive and durable results in initial open-label trials (Lozano et al., 2012). However, a recent multi-site pivotal study organized by St. Jude’s was also terminated before completion for reasons that have not yet been revealed.

Additionally, several small studies may point towards other sites of intervention. In one, bilateral (p. 406) high frequency stimulation to the nucleus accumbens (NAcc) has resulted in response in about half of patients (n = 10; Schlaepfer et al., 2008a; Kayser et al., 2009), with one remitted patient committing suicide during a relapse. The same group later presented unpublished work on bilateral stimulation in the medial forebrain bundle of 10 treatment-resistant depressed (TRD) patients, with preliminary results suggesting a more robust antidepressant response than observed with NAcc or anterior cingulate cortex (ACC) stimulation at lower currents.

Thus, DBS for TRD is exciting, as it offers hope for patients who have failed all other treatments. Unfortunately, to date, there are no positive double-blind data, and it remains experimental.

Epidural and Subdural Stimulation

In epidural and subdural stimulation, electrodes are placed on the surface of the cortex. These placements confer added benefits over deep brain stimulation in their ability to target dysfunction limited to the cortex, and in minimizing the surgical complications, such as infections, seen with DBS. A small (n = 12) initial industry (Northstar) study of subdural stimulation targeted Brodmann area 9/46 in the left hemisphere, but showed no statistical difference between sham and active stimulation during a sham-controlled phase. In the open-label phase however, six patients had ≥40% improvement, five patients had ≥50% improvement, and four subjects achieved remission at some point during the study (Kopell et al., 2011), again suggesting that benefits of cortical stimulation continue many months beyond time of initial implantation.

At Medical University of South Carolina, Nahas and colleagues used bilateral epidural prefrontal cortical stimulation (EpCS) in five TRD patients (Nahas et al., 2009). Four cortical stimulation leads were stereotactically placed: two bilaterally (left, right) over the anterior frontal poles, and two over the mid-lateral prefrontal cortex. At seven-month follow up, the average improvement from pre-implant baseline on the HRSD24 and the Inventory of Depressive Symptoms Self Report (IDS-SR) were 54.9% (±37.7) and 60.1% (±34.1), respectively. Three of the five implanted subjects reached remission. One of the two patients who did not remit required left hemisphere lead replacement at 12 weeks post-surgery because of a scalp infection. At a recent five-year follow-up (Williams, et al. 2016), the remitters continued to be in remission. There were five serious adverse events over this timeframe: one paddle infection and four device malfunctions, all resulting in suicidal ideation and/or hospitalization. Further research into this modality is needed.


Brain stimulation devices are an important class of intervention in the management of acute and chronic phases of mood disorders. ECT, TMS, and VNS are all FDA approved, but there are several more brain stimulation modalities in research and development stages that also show promise in the treatment of mood disorders. Further research is likely to lead to increased safety and effectiveness with many of these devices. Additionally, understanding how these treatments work to reverse depression offers, not only the potential for better treating debilitating mood disorders, but also the potential for better understanding disease pathophysiology.

Future directions for research include exploring the mechanisms behind currently effective brain stimulation modalities, investigating how we can best pair brain stimulation with other behavioral or pharmacological treatments to improve efficacy and durability, and searching for a better way to identify treatment responders or use less-invasive brain stimulation modalities (TMS, cranial electrostimulation [CES]) to inform the use of more invasive modalities (ECT, VNS, DBS).


Dr. Mark S. George has no equity stake in any device manufacturer and does not accept speaker or consultant fees from TMS device manufacturers because of his role in a large VA TMS clinical trial. He has had research studies within the past three years with Neuronetics, Brainsway, Cervel, Neosync, St. Jude’s, Medtronic, and MECTA. The Medical University of South Carolina (MUSC) Brain Stimulation Division has machines (purchased from research grants) manufactured by Magstim, Neuronetics, MagVenture, and Brainsway. The MUSC Brain Stimulation Service has purchased one clinical TMS machine manufactured by Neuronetics, and another one donated through private philanthropy. The service also has one Brainsway device donated through private philanthropy.

Drs. Short and Kerns report no potential conflicts.


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