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Depression in adults: Overview of neuromodulation procedures
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Depression in adults: Overview of neuromodulation procedures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Aug 25, 2015.

INTRODUCTION — Many patients with unipolar major depression do not respond to standard treatment with pharmacotherapy and psychotherapy [1,2], and are thus candidates for neuromodulation procedures [3-8]. Electroconvulsive therapy is the oldest neurostimulation procedure (it also predates all antidepressant drugs), and is the most effective intervention for unipolar major depression [3,4,7]. In addition to ECT, other noninvasive neurostimulation therapies include magnetic seizure therapy, focal electrically administered seizure therapy, transcranial magnetic stimulation, transcranial direct current stimulation, transcranial low voltage pulsed electromagnetic fields, and cranial electrical stimulation, including trigeminal nerve stimulation [9]. Invasive neuromodulation interventions (which require surgery and have generally been studied in more treatment-refractory patients) include vagus nerve stimulation, deep brain stimulation, direct cortical stimulation, and ablative neurosurgery.  

This topic provides an overview of noninvasive and invasive neuromodulation therapies for unipolar major depression. The initial treatment of depression and management of treatment resistant depression are discussed separately. (See "Unipolar major depression in adults: Choosing initial treatment" and "Unipolar depression in adults: Treatment of resistant depression".)

NONINVASIVE NEUROMODULATION THERAPIES — Noninvasive neuromodulation procedures use an electric current or magnetic field to stimulate the central nervous system [8].

Convulsive therapies — Noninvasive neurostimulation treatments for major depression include convulsive therapies:

Electroconvulsive therapy (ECT)

Magnetic seizure therapy (MST)

Focal electrically administered seizure therapy (FEAST)

Electroconvulsive therapy (ECT) — Electroconvulsive therapy (ECT) is a clinically available approach that uses an electric current that passes between two electrodes placed against the scalp to induce a generalized cerebral seizure while the patient is under general anesthesia. A course of ECT involves a series of treatments that are delivered over several days to weeks. ECT is superior to pharmacotherapy for unipolar major depression based upon meta-analyses of randomized trials [10,11], and is generally considered the most efficacious treatment for depression [12]. However, ECT is associated with safety risks, adverse effects, logistical constraints, and patient refusal, and relapse rates following remission are high, especially in patients with treatment resistant depression [13,14]. An overview of ECT (including adverse effects, number and frequency of treatments, use of ECT in patients with general medical conditions, information for patients, and informed consent), indications for and efficacy of ECT in unipolar major depression, medical consultation for ECT, and the technique for performing ECT are discussed separately. (See "Overview of electroconvulsive therapy (ECT) for adults" and "Unipolar major depression in adults: Indications for and efficacy of electroconvulsive therapy (ECT)" and "Medical consultation for electroconvulsive therapy" and "Technique for performing electroconvulsive therapy (ECT) in adults".)

Magnetic seizure therapy — Magnetic seizure therapy (MST) is an investigational approach that uses a transcranial magnetic stimulation device to induce a generalized seizure (a larger dose of magnetic stimulation is used in MST than transcranial magnetic stimulation) [15]. As with ECT, a series of seizures are induced over several days to weeks under general anesthesia. It is hypothesized that MST causes fewer adverse cognitive effects than ECT because MST stimulates a more focal (smaller) portion of the brain to induce a seizure [16]. In the United States, MST is available to patients with unipolar major depression only through a research protocol.

Efficacy — No sham controlled trials have been published for MST, and it is not clear if MST is as effective as ECT:

An open label randomized trial compared MST (12 treatments) with ECT in 20 patients with unipolar major depression; symptomatic improvement was comparable for the two groups [17].

A prospective observational study of 20 patients with unipolar major depression who were treated with either MST (10 to 12 treatments) or ECT found that improvement was greater with ECT than MST [15].

A prospective observational study of 26 patients with treatment resistant unipolar or bipolar major depression who received up to 22 treatments of MST found that remission occurred in 12 (46 percent) [18].

Safety and side effects — MST is usually well tolerated [17,19], and may cause fewer physical side effects (eg, headaches and myalgias) compared with ECT [20]. In addition, magnetic seizure stimulation appears to cause few if any cognitive side effects [18,21], and in this regard may be better tolerated than ECT [19,22]:

An open label, randomized trial compared MST with ECT in 20 patients with major depression; postprocedure time to full orientation was significantly shorter in patients who received MST (2 versus 8 minutes) [17]. However, performance on many neuropsychological tests was comparable for the two groups.

A prospective observational study of 20 patients with major depression treated with either MST or ECT found that postprocedure time to full orientation was significantly shorter in patients who received MST (4 versus 18 minutes) [15].

A prospective study examined the neuropsychological functioning of 10 patients with major depression who were treated with convulsive therapy [20]. MST was given in two of the first four sessions and ECT in the remaining sessions; the order of treatment was randomly assigned, cognition was evaluated for the first four sessions, and raters and patients were blind to treatment. Performance on tests measuring attention, retrograde amnesia, category fluency, and recovery of orientation was significantly better after MST than ECT.  

Mechanism of action — The mechanism by which MST may treat unipolar major depression is unknown, but is probably comparable to that of ECT. (See "Overview of electroconvulsive therapy (ECT) for adults", section on 'Mechanism of action'.)

Focal electrically administered seizure therapy — Focal electrically administered seizure therapy (FEAST) is an investigational approach that combines unidirectional current, control of polarity, and an asymmetric electrode arrangement (with one electrode much larger than the other) in an attempt to induce seizures more efficiently than ECT [23]. No human data have been published for focal electrically administered seizure therapy. In the United States, the intervention is available to patients with unipolar major depression only through a research protocol.  

Repetitive transcranial magnetic stimulation (TMS) — Repetitive transcranial magnetic stimulation (TMS) is a clinically available approach that uses an alternating current passed through a metal coil placed against the scalp to generate a magnetic field, which induces an electric current that depolarizes neurons in a focal area of the surface cortex [12]. The intervention involves a series of daily treatments that are administered over several days to weeks without anesthesia and with the patient fully awake. Meta-analyses of randomized trials indicate that the intervention is beneficial for treating unipolar major depression that has not responded to pharmacotherapy [24-33]. Transcranial magnetic stimulation is discussed separately. (See "Unipolar depression in adults: Treatment with transcranial magnetic stimulation (TMS)".)

Transcranial direct current stimulation — Transcranial direct current stimulation (tDCS) is an investigational approach that uses two scalp electrodes to deliver a constant, low intensity direct current to specific cortical regions [34,35]. Cathodal or anodal stimulation can be used, and each is associated with different neurophysiologic effects [36]. The target of stimulation is typically the left dorsolateral prefrontal cortex (as with most studies of TMS for depression), but other montages have been used [37,38]. A series of treatment sessions are generally administered over consecutive days for one or more weeks. In the United States, tCDS is available to patients with unipolar major depression only through a research protocol.

Efficacy — tDCS may be beneficial for acute treatment of major depression, based upon randomized trials [39]:

In a meta-analysis of six trials (176 patients with unipolar or bipolar major depression) that compared active tCDS with sham stimulation, reduction of depression rating scale scores was greater with active treatment, and beneficial effects persisted at the one month follow-up; however, response and remission rates were comparable for active and sham treatment [40]. In addition, heterogeneity across studies was substantial.

A subsequent meta-analysis of six trials (including five that were selected for the first meta-analysis) compared active tDCS with sham stimulation in 200 patients with unipolar or bipolar major depression [41]. Response (reduction of baseline symptoms ≥50 percent) occurred in more patients who received active stimulation (23 versus 12 percent). Although the difference between active and sham treatment was not statistically significant, a difference of this magnitude, if real, would be clinically meaningful. Remission rate was also numerically, but not statistically, greater for active compared with sham stimulation (12 and 5 percent).

A subsequent six week, randomized trial not included in either meta-analysis compared active tDCS with sham stimulation in 60 patients with unipolar major depression [42]. Remission occurred in more patients who received active stimulation than sham stimulation (40 versus 13 percent).

Another subsequent randomized trial compared active with sham anodal tDCS applied to the left dorsolateral prefrontal cortex in 24 patients with treatment-resistant depression [43]. Improvement in both groups was comparable.  

Continuation treatment with tDCS was evaluated in a six month, prospective observational study of 26 patients who responded to an acute course of treatment [44]. The intervention was initially administered weekly and then every two weeks, and most patients also received antidepressants. The estimated probability of avoiding relapse was approximately 50 percent.

Safety and side effects — tDCS is generally safe and well tolerated [22,45-47]. Randomized trials indicate that side effects are usually transient, and have found that active and sham treatment are associated with comparable rates of adverse effects, including uncomfortable scalp sensations (described as tingling or itchiness), fatigue, dizziness, nausea, concentration difficulties, and visual phenomena [42,48-50]. In addition, neuropsychological functioning in two randomized trials was not adversely affected by tDCS [48,49], and in a third trial, memory improved significantly more with active treatment compared with sham [51]. However, skin burns and lesions can occur with tDCS [52,53], and multiple studies suggest that patients can switch from depression to hypomania [48,49,54,55].

Mechanism of action — tDCS does not directly cause neuronal depolarization, but rather, is associated with changes in spontaneous neuronal firing [56]. Thus, it is hypothesized that the primary mechanism of action involves modulation of cortical excitatory tone. Cathodal stimulation is generally associated with a decrease of spontaneous cell firing, while anodal stimulation is typically associated with an increase in spontaneous firing [36,57]. Comparable with other brain stimulation interventions, tDCS is thought to exert its antidepressant effects via functional changes within a neural network of brain regions involved in mood regulation. The left dorsolateral prefrontal cortical (DLFPC) is often targeted for stimulation [46-49].

Transcranial low voltage pulsed electromagnetic fields — Transcranial low voltage pulsed electromagnetic fields stimulation (T-PEMF) is an investigational approach that uses a generator to provide electrical pulses to a set of coils (placed around the head), which produce low intensity electromagnetic fields. These give rise to low-voltage alternating currents within the underlying brain tissue [58]. The intensity of stimulation is less than that generated by transcranial magnetic stimulation equipment and is insufficient to depolarize cortical neurons. A series of treatment sessions are generally administered over consecutive days for several weeks. In the United States, transcranial low voltage pulsed electromagnetic fields stimulation is available to patients with unipolar major depression only through a research protocol.

Efficacy — Evidence for the efficacy of T-PEMF includes a five week randomized trial that compared active with sham treatment in 50 patients with major depression [58]. Remission occurred in more patients who received active stimulation compared with sham (34 versus 4 percent).  

Safety and side effects — Based upon limited data, there is no noticeable sensation with transcranial low voltage pulsed electromagnetic fields stimulation, and it appears to be well-tolerated. A randomized trial that compared active with sham treatment found that the incidence of specific adverse effects did not differ significantly between groups [58].

Mechanism of action — The mechanism by which transcranial low voltage pulsed electromagnetic fields stimulation treats unipolar major depression is unknown. Neurostimulation techniques comparable to transcranial low voltage pulsed electromagnetic fields stimulation have been shown to increase cortical excitability in healthy controls [59]. In addition, transcranial low voltage pulsed electromagnetic fields stimulation may increase angiogenesis [60] and alter intracellular signaling [61].

Trigeminal nerve stimulation — Trigeminal nerve stimulation is an investigational procedure for treatment resistant depression as well as drug resistant epilepsy [62,63]. An external pulse generator delivers an electrical current via bilateral cutaneous electrodes that are placed on the forehead to stimulate the supraorbital and supratrochlear nerves of the V1 branch of the trigeminal nerve (cranial nerve V).

Efficacy — A two-week randomized trial compared active trigeminal nerve stimulation (administered each weekday for 30 minutes) with sham stimulation in 40 patients with treatment resistant unipolar major depression [64]. Improvement was greater with active treatment, and the benefit persisted for two weeks after the end of treatment.

Safety and side effects — In one randomized trial [64] and two observational studies [63,65], in which a total of 36 patients were treated with trigeminal nerve stimulation, no serious adverse events occurred and the intervention was well tolerated. Transient and mild paresthesias occurred during the first few seconds of stimulation [64].

Mechanism of action — It is hypothesized that the procedure acts upon afferent fibers in the trigeminal nerve, which project to central nervous system structures that may be involved in depression, such as the locus coeruleus and the nucleus tractus solitarius [63,65].

Low field magnetic stimulation — Low field magnetic stimulation is an investigational procedure for treatment resistant depression. The device includes a magnetic coil, power source, and amplifier that generates a magnetic field, which induces a rapidly oscillating, low voltage electric field (<1 V/m, 1 kHz) in the brain [66]. The patient lies supine and the head is inserted into one end of the cylindrical coil. Low field magnetic stimulation has also been administered using a system referred to as synchronized transcranial magnetic stimulation (sTMS), which provides stimulation synchronized to the patient’s baseline EEG-determined alpha rhythm [67].

Efficacy — Although one randomized trial found that low field magnetic stimulation was efficacious [66], a more recent and more rigorous randomized trial found otherwise. The second trial, lasting six weeks, compared active sTMS (daily treatment five days per week) with sham sTMS in patients (n = 202) with unipolar major depression who were medication free. Improvement in the two groups was comparable [67].  

Safety and side effects — The US Food and Drug Administration has declared that the device poses a nonsignificant risk [66]. Randomized trials have found that low field magnetic stimulation caused no significant adverse effects [66,67].

Mechanism of action — It is hypothesized that the low strength electromagnetic field (which is too low to depolarize neurons) affects the electrical activity of cortical neurons, which project to subcortical regions that are involved in mood regulation [66]. Positron emission tomography indicates that low field magnetic stimulation reduces glucose metabolism in the cerebral cortex (and thus affects brain activity).

Cranial electrical stimulation — Cranial electrical stimulation is a clinically available, noninvasive approach that uses a battery operated device to deliver low-voltage alternating current to the brain via electrodes attached to the scalp or infra- or supra-auricular structures (eg, earlobes, mastoid processes, zygomatic arches, or maxilla-occipital junctions) [36]. There are numerous methods for delivering the electrical current, though the basic intervention remains the same.

A few small studies have tested the safety and efficacy of cranial electrical stimulation for treating unipolar major depression [9]:

Two separate randomized trials, each lasting two weeks, compared active auricular transcutaneous electrical nerve stimulation (also referred to as transcutaneous vagus nerve stimulation) with sham stimulation [68]. Analysis of the pooled data (total n = 37 patients) found that improvement of scores on the self-administered depression rating scale were greater with active than sham stimulation, whereas improvement on the clinician-administered scale was comparable for the two groups.

An observational study administered active auricular transcutaneous electrical nerve stimulation to a cohort of patients for four weeks and subsequently administered sham stimulation to a separate cohort [69]. Among the patients who completed the study (n = 34), active treatment was associated with greater improvement of depression.

INVASIVE/SURGICAL NEUROMODULATION THERAPIES — Invasive neuromodulation therapies for treating unipolar major depression include:

Vagus nerve stimulation

Deep brain stimulation

Direct cortical stimulation

Ablative neurosurgery

Invasive neuromodulation interventions require surgery and have generally been studied in patients with chronic, treatment-refractory, debilitating depression, because most clinicians view invasive interventions as riskier than the noninvasive techniques described above.

Among the surgical approaches, vagus nerve stimulation, deep brain stimulation, and direct cortical stimulation are generally:

Reversible – Hardware can be removed

Revisable – Stimulating electrodes can be moved to optimize response

Adjustable – Stimulation parameters can be modified to optimize response

However, ablative surgery does not involve:

Indwelling metal hardware and contraindications to magnetic resonance imaging and metal detectors

Surgical follow-up to replace batteries or pulse generators every few years or to revise dysfunctional systems

Additional information about surgical neuromodulation therapies is discussed separately. (See "Unipolar depression in adults: Treatment with surgical approaches".)

Vagus nerve stimulation — Vagus nerve stimulation (VNS) is a clinically available treatment in which a battery powered pulse generator is implanted in the chest wall and connected to an electrode that is attached around one vagus nerve (typically the left). Although stimulating the vagus nerve with electrical impulses is an established option for medication refractory epilepsy [70], acute efficacy for treatment resistant major depression has not been demonstrated in rigorous studies [71]. Additional information about VNS is discussed separately. (See "Unipolar depression in adults: Treatment with surgical approaches", section on 'Vagus nerve stimulation (VNS)' and "Vagus nerve stimulation therapy for the treatment of epilepsy".)

Deep brain stimulation — Deep brain stimulation (DBS) is an investigational procedure for treatment resistant depression, in which one or more electrodes is implanted into specific brain regions using a stereotactic frame and magnetic resonance imaging [72]. The electrodes are connected to a subcutaneously implanted pulse generator that controls stimulation parameters, comparable to vagus nerve stimulation. Stimulating deep brain centers with electrical impulses is an established treatment for treatment-resistant Parkinson disease, essential tremor, and dystonia, and an experimental treatment for incapacitating and treatment refractory obsessive-compulsive disorder (OCD) [73,74].

Additional information about deep brain stimulation for major depression and other disorders is discussed separately.  (See "Unipolar depression in adults: Treatment with surgical approaches", section on 'Deep brain stimulation' and "Deep brain stimulation for treatment of obsessive-compulsive disorder" and "Surgical treatment of Parkinson disease", section on 'Deep brain stimulation' and "Surgical treatment of essential tremor", section on 'Deep brain stimulation' and "Treatment of dystonia", section on 'Deep brain stimulation'.)

Direct cortical stimulation — Direct cortical stimulation (DCS) is an investigational approach for treating refractory unipolar major depression, in which electrodes are implanted outside, upon, or beneath the dura mater to directly stimulate the cortex. Stimulation parameters are controlled by a subcutaneously implanted pulse generator, comparable to vagus nerve stimulation and deep brain stimulation. Additional information about direct cortical stimulation is discussed separately. (See "Unipolar depression in adults: Treatment with surgical approaches", section on 'Direct cortical stimulation'.)

Ablative neurosurgery — Ablative neurosurgery for intractable major depression is a clinically available but rarely used approach in which a lesion is made in limbic or paralimbic structures. Early ablative procedures for psychiatric illness, such as the prefrontal leucotomy [75], have been supplanted by stereotactic neurosurgical techniques that allow for more focal lesions with fewer side effects, including [76-78]:

Anterior capsulotomy – Lesion in the anterior limb of the internal capsule

Anterior cingulotomy – Lesion in the dorsal anterior cingulate

Subcaudate tractotomy – Lesion in thalamocortical white matter tracts inferior to the anterior striatum

Limbic leucotomy – Combines cingulotomy with subcaudate tractotomy

Additional information about ablative surgery is discussed separately. (See "Unipolar depression in adults: Treatment with surgical approaches", section on 'Ablative neurosurgery'.)

OUTSIDE SOURCES OF PATIENT EDUCATION — Educational material explaining electroconvulsive therapy, transcranial magnetic stimulation, magnetic seizure therapy, vagus nerve stimulation, and deep brain stimulation is available in a document entitled “Brain Stimulation Therapies” that is published by the National Institute of Mental Health. This publication can be obtained through a toll-free number, 866-615-6464, or online at the website http://www.nimh.nih.gov/health/topics/brain-stimulation-therapies/brain-stimulation-therapies.shtml. The website also provides information about depression in language intended for the lay public.

SUMMARY

Many patients with unipolar major depression do not respond to standard treatment with pharmacotherapy and psychotherapy, and are thus candidates for noninvasive and invasive neuromodulation procedures. (See 'Introduction' above.)

Electroconvulsive therapy (ECT) is a noninvasive, clinically available procedure that induces a generalized cerebral seizure with an electric current that passes between two electrodes placed against the scalp. Although ECT is the most efficacious treatment for major depression, it is associated with safety risks, adverse effects, logistical constraints, patient refusal, and high relapse rates. (See 'Electroconvulsive therapy (ECT)' above and "Overview of electroconvulsive therapy (ECT) for adults" and "Unipolar major depression in adults: Indications for and efficacy of electroconvulsive therapy (ECT)" and "Technique for performing electroconvulsive therapy (ECT) in adults" and "Medical consultation for electroconvulsive therapy".)

Magnetic seizure therapy (MST) is a noninvasive, investigational approach that uses a transcranial magnetic stimulation device to induce a generalized seizure. It is not clear if MST is as effective as ECT. However, MST may cause fewer physical (eg, headaches and myalgias) and cognitive side effects than ECT. (See 'Magnetic seizure therapy' above.)

Focal electrically administered seizure therapy is a noninvasive, investigational approach that combines unidirectional current, control of polarity, and an asymmetric electrode arrangement in an attempt to induce seizures more efficiently than ECT. No human data have been published for focal electrically administered seizure therapy. (See 'Focal electrically administered seizure therapy' above.)

Transcranial magnetic stimulation (TMS) is a noninvasive, clinically available treatment with demonstrated efficacy; the procedure uses an alternating current passed through a metal coil placed against the scalp to generate a magnetic field, which induces an electric current that depolarizes neurons in a focal area of the surface cortex. (See 'Repetitive transcranial magnetic stimulation (TMS)' above and "Unipolar depression in adults: Treatment with transcranial magnetic stimulation (TMS)".)

Transcranial direct current stimulation is a noninvasive, investigational approach that uses two scalp electrodes to deliver a current to specific cortical regions. Most randomized trials have found that the treatment is efficacious for unipolar major depression and is generally safe and well-tolerated. However, skin burns and lesions can occur, and multiple studies suggest that patients may switch from depression to hypomania. (See 'Transcranial direct current stimulation' above.)

Transcranial low voltage pulsed electromagnetic fields stimulation is a noninvasive, investigational approach that uses a generator to provide electrical pulses to a set of coils, which produce low intensity electromagnetic fields. These give rise to low-voltage currents within the underlying brain tissue. (See 'Transcranial low voltage pulsed electromagnetic fields' above.)

Trigeminal nerve stimulation is an investigational procedure that uses an external pulse generator to deliver an electrical current via bilateral cutaneous electrodes that are placed on the forehead to stimulate the supraorbital and supratrochlear nerves of the trigeminal nerve. (See 'Trigeminal nerve stimulation' above.)

Cranial electrical stimulation is a clinically available approach that uses a battery operated device to deliver low-voltage alternating current to the brain via electrodes attached to the scalp or infra- or supra-auricular structures. (See 'Cranial electrical stimulation' above.)

Invasive neuromodulation therapies for major depression include vagus nerve stimulation, deep brain stimulation, direct cortical stimulation, and ablative neurosurgery. These treatments require surgery and have generally been studied in patients with chronic, treatment-refractory, debilitating depression. (See 'Invasive/surgical neuromodulation therapies' above.)

Vagus nerve stimulation (VNS) is a clinically available treatment for major depression in which a battery powered pulse generator is implanted in the chest wall and connected to an electrode that is attached around one vagus nerve. (See "Unipolar depression in adults: Treatment with surgical approaches", section on 'Vagus nerve stimulation (VNS)'.)

Deep brain stimulation is an investigational procedure for major depression in which one or more electrodes is implanted into specific brain regions using a stereotactic frame and magnetic resonance imaging. The electrodes are connected to a subcutaneously implanted pulse generator that controls stimulation parameters. (See "Unipolar depression in adults: Treatment with surgical approaches", section on 'Deep brain stimulation'.)

Direct cortical stimulation is an investigational approach for treating refractory unipolar major depression, in which electrodes are implanted outside, upon, or beneath the dura mater to directly stimulate the cortex. Stimulation parameters are controlled by a subcutaneously implanted pulse generator. (See "Unipolar depression in adults: Treatment with surgical approaches", section on 'Direct cortical stimulation'.)

Ablative neurosurgery for intractable major depression is a clinically available but rarely used approach in which a lesion is made in limbic or paralimbic structures. Early ablative procedures for psychiatric illness, such as the prefrontal leucotomy, have been supplanted by stereotactic neurosurgical techniques that allow for more focal lesions with fewer side effects. (See "Unipolar depression in adults: Treatment with surgical approaches", section on 'Ablative neurosurgery'.)

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