Electroconvulsive Therapy and Neurotherapeutics

Technique

TMS is a clinical application of Faraday's principle of electromagnetic induction. The basic equipment includes an electrical capacitor connected to a metallic coil encased in a protective plastic cover. The coil is placed on the surface of the skull and a powerful and rapidly changing electrical current is passed through it, generating a magnetic field that travels unimpeded through the soft tissue, bone, and cerebrospinal fluid (CSF) all the way to the cortex. The cortex, which is electrically conductive, acts as a pick-up coil and transforms the magnetic energy into a secondary electrical current, which in turn forces an action potential on neurons and a volley of activity through the axons to the synapse, leading to activation of the post-synaptic neuron and beyond.

TMS leads to circuit-wide modulation, and not just local stimulation. The direct effects of TMS are restricted to the superficial cortical neurons: the magnetic field weakens as it travels away from the TMS coil, and its capacity to induce neuronal action potentials disappears approximately 3 centimeters from the skull surface. However, the effects on these cortical neurons spread to the post-synaptic neuron, and then to the next post-synaptic neuron, initiating a cycle that is able to modulate an entire circuit of interest, including deep cortical or subcortical nodes. Thus, TMS allows for indirect trans-synaptic modulation of deep structures as long as the appropriate cortical target is selected.

The TMS parameter space includes anatomic variables (such as location and depth) and physiologic variables (such as stimulation frequency, pulse intensity, and duration). The anatomic target for stimulation is a window that provides modulatory access to a network of interest, and therefore has a critical impact on the effects of TMS, which are primarily determined by the functional anatomy and connectivity of the stimulated region. In the case of major depressive disorder (MDD), current guidelines set the DLPFC as the stimulation target, a node that has been shown to exert top-down control over limbic structures (e.g., anterior cingulate cortex, hippocampal regions, and amygdala) and is pathologically altered in MDD.

The depth of stimulation is proportional to the strength of the magnetic field, which decreases as it travels away from its source (the coil). Nevertheless, the primary factor affecting depth is the coil design. Different coil architectures are available, with two main types: the circular coil and the figure-of-8 coil, though the latter is most commonly used given its greater focality.

Therapeutically, TMS is applied as a series of consecutive pulses, called repetitive TMS (rTMS) and can be delivered at various frequencies. Low-frequency rTMS (1 Hz) has similar effects to long-term depression (LTD), causing inhibition of the stimulated area. Conversely, high-frequency rTMS (>5 Hz, though typically 10–20 Hz) resembles long-term potentiation (LTP) producing local facilitation. Other complex stimulation patterns—such as theta burst stimulation—have been developed recently and promise to add greater efficiency, with much shorter stimulation time and longer after-effects.

The stimulation intensity determines how much energy is applied with each individual TMS pulse. Intensity is generally individualized according to the patient's specific cortical excitability, assessed by the motor threshold, which can be determined by the clinician according to the protocols by Rossini and co-workers. This individualization of TMS stimulation is important for both its efficacy and safety.

Duration of stimulation applies to each session and also to an entire course of treatment. For example, a typical antidepressant therapeutic session uses 3000 pulses over the course of 37 minutes, and the treatment course involves 36 sessions over the course of 9 weeks.

The latest guidelines for TMS antidepressant treatment suggest stimulating the left DLPFC at a high frequency (10 Hz), using 3000 pulses per session at 120% of the motor threshold intensity. The acute course involves 30 daily sessions (given Monday through Friday) over 6 weeks, followed by a taper period with 2 weekly sessions for an additional 3 weeks.

Indications

TMS was approved in the United States in 2008, when the Food and Drug Administration (FDA) cleared high frequency repetitive TMS (rTMS) for “the treatment of [MDD] in adult patients who have failed to receive satisfactory improvement from prior antidepressant medication in the current episode”. In 2013, TMS H-coils—producing deeper stimulation—were approved for the same purpose. TMS is also used diagnostically for the assessment of pathologies affecting the motor system (such as brain or spinal cord injury or multiple sclerosis) and for the pre-surgical mapping of motor and language areas.

TMS is an effective primary or adjunctive treatment for depression. The pivotal trial that led to the FDA-clearance of therapeutic TMS demonstrated the antidepressant efficacy of TMS monotherapy with response rates of 23.9% to 24.5% (compared with 12.3% to 15.1% for placebo) and remission rates of 14.2% to 17.4% (compared with 5.5% to 8.9% for placebo) after 6 weeks of treatment. After the taper period, the therapeutic outcomes continued to improve (27.7% response and 20.6% remission rate). An NIMH-funded multi-center trial reported similar results.

Although large randomized controlled trials are crucial to identify the pure and true efficacy of a treatment, by design they generally recruit patients who do not reflect the standard clinic patient (who may have several psychiatric and medical comorbidities, varying degrees of severity, and treatment-resistance, and may be on several medications, including psychoactive agents). An open-label, naturalistic trial, sought to assess the antidepressant effectiveness of TMS in 339 typical clinical patients using the same FDA-approved protocols used in the pivotal trials. This study allowed patients to continue on their current psychiatric treatment (medication and therapy) while undergoing TMS. After the acute phase of treatment, the response rate was 41.5% to 58% and the remission rate was 26.5% to 37.1%. A separate study assessed the duration of benefit in this same population at 1-year follow-up, and found that two-thirds of the responders/remitters maintained their designation and less than 30% of the initial responders/remitters relapsed.

Safety

TMS has a remarkably benign profile. Absolute contraindications are limited to metallic implants in the area of stimulation (including brain stimulators, medication pumps, and cochlear implants) and cardiac pacemakers. Noteworthy, TMS has been tested in patients with DBS and considered relatively safe, granted the DBS pulse generator is turned off; extreme caution is advised since data are limited. As with any other therapy, the clinician should weigh the risk–benefit ratio carefully.

The main safety concern remains the potential for seizure induction when applying rTMS. Various reports have estimated the similar seizure risk: 20 seizures out of approximately 300,000 research and clinical sessions; seven events out of 250,000 clinical sessions applied to 8000 patients since the FDA clearance in 2008 until 2012; and six events in 5000 patients receiving stimulation with the deep H-coil. The estimated risk was one event in 30,000 treatment sessions; this was commensurate with the seizure risk of most antidepressant medications. Seizures triggered by TMS can happen during—but not after—a treatment session. Consequently, although rTMS can initiate a seizure it cannot cause epilepsy. Therefore, patients should be screened for personal and familial history of epilepsy, as well as other factors that increase seizure risk (e.g., concomitant medications that lower seizure threshold, history of head injury or malformations), in order to evaluate the risk and benefit more accurately. If a patient is considered to benefit greatly from rTMS, while being at a moderate risk of seizure, this appraisal allows for the implementation of special safety measures around their stimulation sessions. Other more frequent and more benign side effects are headaches, facial or muscle twitching, vasovagal syncope, discomfort limited to the area of stimulation, anxiety, and tinnitus. To minimize the impact on hearing, patients should wear earplugs.

Technique

The routine pre-ECT work-up should include taking a thorough medical history, performing a physical examination, and obtaining an electrocardiogram (ECG), and a comprehensive metabolic panel. Additional studies and consultations should be obtained as needed, based on co-morbid conditions.

The issue of whether to combine a psychotropic medication with ECT is a matter of much speculation. In general, a patient should be taken off medications that have not been beneficial, despite an adequate dosage and duration of therapy. Older case reports cautioned that patients undergoing ECT while taking lithium may be particularly prone to severe cognitive disturbance, a prolonged time to awakening or breathing, or prolonged or spontaneous seizures; however, more recent case series indicate that the combination may be used safely. Nonetheless, when lithium and ECT are used in combination, the patient should be monitored for signs of confusion and targeted for lower lithium serum levels. Benzodiazepines, which are antagonistic to the ictal process, should also be decreased or discontinued whenever possible. Second-generation antipsychotics and antihistaminic drugs can replace benzodiazepines as anxiolytic agents. Tricyclic antidepressants (TCAs) can create cardiovascular management problems and should be discontinued. Monoamine oxidase inhibitors (MAOIs) and ECT may be combined, while caution is advised to avoid toxic drug interactions. In patients with a pre-existing seizure disorder, anticonvulsants should be maintained for patient safety and the elevated seizure threshold over-ridden with a higher-intensity stimulus and the use of bilateral electrode placement. Anticonvulsants used for mood stabilization or augmentation are generally discontinued, or tapered if discontinuation is not possible.

ECT should be performed in collaboration with an anesthesiologist familiar with the techniques and cardiovascular effects of ECT. The American Society of Anesthesiologists has endorsed the use of cardiac monitoring and pulse oximetry on all patients undergoing general anesthesia. General anesthesia is induced with barbiturates (methohexital) or other short-acting induction agents (e.g., propofol or ketamine). Paralysis is most commonly achieved with use of succinylcholine.

The choice of electrode placement in ECT remains controversial. Both right unilateral (RUL) and bilateral (BL) placements have advantages and disadvantages. RUL ECT causes less cognitive impairment than BL ECT, but it is less efficacious. At the Massachusetts General Hospital, RUL ECT is used at the outset for most patients; the exceptions are patients with catatonia and treatment-resistant mania. Patients are switched to BL ECT when depressive symptoms prove refractory to 6 to 12 unilateral treatments. The factor most commonly associated with ineffective unilateral ECT is use of threshold stimulus intensity. RUL stimuli should be 300% to 600% above the seizure threshold with the electrodes placed in the d'Elia position.

Use of brief-pulse (0.5–1 ms) waveforms has become the standard practice in the United States. Although sine-wave stimuli were used previously, the brief-pulse waveform is more efficient and is associated with less post-treatment confusion and amnesia. Ultra-brief pulse-width (0.3 ms) RUL ECT, is slightly less efficacious than brief-pulse ECT but it can greatly minimize cognitive side effects.

The schedule of administration is usually three times a week, although new trends are favoring a twice-weekly schedule, as it appears to be as effective and to be associated with less memory impairment. The improvement, however, is slower with this approach, posing a challenge in inpatient settings. Once-a-week ECT administration has not provided additional advantages and it slows the antidepressant effect to a clinically unacceptable level.

Generalization of the seizure to the entire brain is essential for efficacy. Most ECT instruments have a built-in, dual-channel EEG monitor that can measure electrical activity in the brain. No relationship has been detected between the clinical antidepressant response to ECT and the duration of the induced seizure or total seizure time during the course of treatment. After ECT, a nurse should monitor patients carefully; vital signs should be taken regularly and pulse oximetry monitored.

The average number of ECT procedures necessary to treat major depression is consistently reported to be between 6 and 12. The use of more than one seizure per session (multiple-monitored ECT) has shown minimal advantage over conventional ECT and has dramatically increased the occurrence of cognitive side effects.

After successful treatment, the risk of relapse is greater than 50% at 6 months without the use of maintenance medication. In general, maintenance ECT (i.e., one treatment per month, on average) has been an efficacious, safe, well-tolerated, and cost-effective intervention compared with maintenance pharmacotherapy alone, with its greatest impact consisting of reducing relapse, recurrence, and re-hospitalization in treatment-resistant patients.