Cortical Stimulation for Depression

Introduction

The economic and societal burden of treatment-resistant depression, which is suffered by 12%–20% of all depressed patients, remains a significant challenge to the psychiatric and neurosurgical communities ( ). In the United States alone its overall societal cost is estimated to be $106–$118 billion per year in lost productivity and healthcare costs ( ). Unfortunately, adequate medical treatment options for refractory depression remain scarce and clinicians have increasingly turned toward surgical therapies ( ). Cortical stimulation, in its various forms, has been used for decades as an effective treatment option for treatment-resistant depression ( ). Stimulation of the cerebral cortex achieves a desired effect through two main pathways: harnessing the brain’s inherent neuronal plasticity, and disrupting patterns of aberrant connectivity ( ). Through these pathways, cortical stimulation functions to ameliorate abnormal brain signaling, or the “cortical node” of depression. This chapter focuses on several of these techniques, including electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS).

Electroconvulsive Therapy

ECT has long been a mainstay therapy for treatment-resistant depression ( ). First developed in 1938 by Ugo Cerletti and Lucio Bini in Italy, ECT has withstood the test of time despite significant controversy surrounding its routine use in medical practice ( ). ECT is currently indicated for the rapid treatment of major depression (unipolar and bipolar), acute mania, and treatment-resistant schizophrenia ( ). Approximately 100,000 patients undergo ECT every year in the United States ( ). Patients receive a rapid burst of electrical stimulation from scalp electrodes under general anesthesia and paralytics, which induces a generalized seizure. Although ECT’s mechanism of action is still unknown, it is thought to function through γ-aminobutyric acid (GABA) and glutamate neurotransmission ( ). Electrodes can be placed unilaterally or bilaterally depending on the severity of symptoms and treatment response ( ). However, bilateral electrode placement has been associated with a higher incidence of retrograde amnesia ( ).

In a metaanalysis published by Dierckx et al. in the overall remission rates for unipolar and bipolar depression after ECT were quoted as 50.9% and 53.2%, respectively. Although patients reported a high incidence of transient somatic and cognitive side-effects (approximately 50% and 30%, respectively), mortality has been quoted to be <0.01% ( ). Thus ECT is generally considered a safe procedure with minimal risk of long-term side-effects, dependence, and procedural mortality.

The number and duration of ECT sessions are patient and disorder specific. For patients with major depression, the typical number of sessions is somewhere between 6 and 12 over several weeks. A typical ECT session involves the patient being placed under general anesthesia under the supervision of an anesthesiologist or nurse anesthetist. Once the patient is adequately sedated, electrodes are placed on the patient’s scalp and the stimulation is delivered, which induces a brief generalized seizure. Numerous studies have determined that the waveform characteristics of the electrical stimulus (sinusoidal versus pulsed) and electrode placement (unilateral versus bilateral) can significantly influence treatment response and the side-effects profile ( ).

The earliest ECT treatments delivered a sinusoidal electrical waveform to the cortex ( ). Although effective in alleviating symptoms of depression, this waveform was eventually found to be inferior to “brief-pulse” ECT due to its high incidence of cognitive side-effects. “Brief-pulse” ECT was developed in the 1970s and has, for most purposes, become the “gold standard” of electrical stimulus waveform administered during a session ( ). Brief-pulse ECT has demonstrated equal efficacy and a more tolerable side-effect profile than sinusoidal ECT in numerous randomized blinded studies ( ). In addition, electrode placement has also been shown to be a major contributing factor to ECT effectiveness. Bilateral electrode placement was utilized until the late 1940s, when unilateral electrode placement was shown to provide equivalent results with less side-effects ( ). Since then numerous authors have published different ECT treatment paradigms with varying electrode locations, stimulation waveforms, and unilateral versus bilateral placement. In general, most ECT practitioners utilize unilateral brief-pulse ECT and avoid placing the electrodes over regions of the scalp that may overlie eloquent cortex.

As mentioned previously, the most common cognitive side-effect is memory disturbance ( ). identify four different types of memory disturbances after ECT: stereotypical and transient postictal disorientation, anterograde amnesia, short-term retrograde amnesia, and extensive retrograde memory loss. The most common form, transient postictal disorientation, is due to the effects of the generalized seizure and resolves in a limited time. Anterograde and retrograde amnesia are also quite common, and most patients recover fully after a few hours to days. Patient-specific traits such as advanced age, presence of comorbid conditions such as dementia, level of education, and socioeconomic background have all been shown to be risk factors for prolonged memory loss and cognitive dysfunction after ECT. The most disabling and severe form of memory disturbance, retrograde memory loss, is very rare and has only been described in a minority of patients. Recovery time can depend on electrode placement, ECT waveform pattern, and number of treatments ( ).

Somatic side-effects such as headache, nausea, and muscle soreness are experienced by approximately 50% of patients ( ). Postictal headache is the most common symptom and is usually frontal and throbbing in nature ( ). In the majority of patients, acetaminophen or an over-the-counter nonsteroidal antiinflammatory medication will resolve the symptoms. Headache is more commonly observed in younger patients with a history of migraines ( ). The majority of these somatic side-effects are a result of seizure induction, and generally resolve over a limited amount of time. Complications from general anesthesia, although reported, are also relatively uncommon.

Unfortunately, despite the evidence-based benefits of ECT, there is still significant social stigma surrounding its use ( ). As a result, it remains an underutilized therapeutic option for treatment-resistant depression. Improvements in its administration, the regular use of general anesthesia, and continued efforts in patient education have slowly increased its acceptance over the past two decades ( ). New noninvasive therapies such as TMS, discussed later in this chapter, have gained growing favor with clinicians and patients.

Future directions of ECT include the combined use of functional magnetic resonance imaging (fMRI) and advanced electroencephalogram (EEG) to characterize its mechanism of action further ( ). A study by McCormick et al. in demonstrated an increase in theta frequency in the subgenual cingulate gyrus after ECT. As mentioned previously, the subgenual cingulate gyrus (Brodmann area 25) was a potential target of interest for deep brain stimulation in the context of depression. demonstrated an increase in task-related activation of the orbital frontal cortex on fMRI in ECT responders. As ECT’s mechanism of action is better understood, the ability to target more specific brain regions with varying amounts of stimulation may improve its side-effect profile.

Transcranial Magnetic Stimulation

TMS is a noninvasive therapy that stimulates focal areas of the cerebral cortex through the use of magnetic fields ( Fig. 92.1 ) ( ). First developed by Anthony Barker in , TMS activates neurons indirectly through modulating excitatory and inhibitory synaptic inputs. High-frequency stimulation (>10 Hz) has been shown to increase local cortical metabolism and activate excitatory synaptic input ( ). Low-frequency stimulation (1 Hz) has been shown to decrease local cortical metabolism, thus potentiating intracortical inhibition via GABA neurotransmission ( ). GABA is the main neurotransmitter involved in inhibitory neurotransmission. TMS is currently approved by the United States Food and Drug Administration (FDA) for the acute treatment of treatment-resistant major depression and migraine disorder ( ).

The idea of using TMS for the treatment of depression stems from the concept that the cardinal symptoms of depression are less a problem of abnormal neurotransmitter release but more a problem of brain circuit pathology ( ). Numerous metabolic functional imaging and functional connectivity studies have suggested that depression is generated from dorsal and ventral functional brain “compartments” ( ). The dorsal functional compartment comprises the dorsolateral prefrontal cortex (DLPFC), lateral orbital frontal cortex, and the dorsal and perigenual cingulate gyrus ( ). The ventral compartment comprises the medial orbital frontal cortex and subgenual cingulate gyrus ( ). Metabolic and functional connectivity studies in patients with depression have demonstrated an increase in metabolism in the ventral compartment and a decrease in metabolism in the dorsal compartment. With successful treatment, aberrations in local regional metabolism can normalize. Numerous theories exist to explain the mechanisms behind TMS’s ability to affect this transition from abnormal to normal process; however, none has been firmly proven.

Once a patient with treatment-resistant depression is enrolled in a TMS program, he or she undergoes approximately five treatment sessions as an outpatient administered weekly for 4–6 weeks ( Fig. 92.1 ) ( ). Each session lasts approximately 40 min and does not require sedation or general anesthesia. The stimulation parameters for depression are tailored to each patient’s observed motor threshold, determined by observing twitching of the contralateral hand with gradually increasing levels of stimulation. administered fixed-dose stimulation at 120% of each patient’s motor threshold and repetition rate of 10 pulses per second. A total of 3000 pulses were administered in each treatment session.

Although rare, transient headache is the most common side-effect reported ( ). Long-term efficacy and safety have yet to be established, although more recent studies have addressed these issues ( ).

In 2007 a pivotal trial demonstrated the efficacy of TMS for the treatment of major depressive disorder after one single failed medication ( ). The study investigators stimulated the left DLPFC and examined outcomes at 1 month; a 21% response rate versus 12% sham was observed ( ). The authors noted that there was potential for increased treatment efficacy when TMS was used in combination with medications and cognitive behavioral therapy. The left DLPFC was selected as the treatment target because this area has demonstrated decreased metabolic function in depression ( ). This data has since been corroborated by several nonindustry sponsored Class I trials ( ).

Since its introduction in clinical practice, there have been numerous upgrades and modifications to Barker’s original head coil ( ). In fact, there are currently over 50 coils commercially available for use in both animals and humans ( ) ( Fig. 92.2 ). Standard TMS coils can generate a 1–1.5 cm field of stimulation; newer head coils (the H-coil) can now generate 5–6 cm stimulation fields ( ). In 2013 the FDA approved the H-coil (deep TMS) for use in major depression ( ). Compared to sham, patients who underwent deep TMS experienced 36.7% and 30.4% response and remission rates, respectively ( ). More recently, the TMS clinical society issued the first set of TMS depression guidelines in 2016 ( ). These were the first guidelines to provide Class I/II evidence supporting the use of TMS as a first-line treatment for acute major depression after a single drug failure for at least 6 weeks of treatment, for patients with relapse after initial response, and as a maintenance treatment for those who benefit from an acute course ( ).

Current barriers to the widespread acceptance of TMS therapy include close reliance on patient adherence, which can be cumbersome given the need for daily 40 min sessions for 4–6 weeks; the need for more studies characterizing its mechanism of action on synaptic connectivity and stimulation of the cerebral cortex; inconsistent technique and outcome reporting; increased cost relative to other treatment modalities; and the need for operator expertise and training ( ). With passing time and increased utilization, these factors will likely decrease in prevalence. For example, a recent study by demonstrated increased patient preference for TMS versus ECT, although ECT was found to be more cost effective.

Future applications of TMS for depression will likely require the use of real-time image feedback, functional connectivity analysis, and high density electroencephalography to guide treatment. This will allow clinicians to obtain further physiologic data, which can open doors to newer coils and different stimulation targets. Cognitive behavioral therapy in tandem with TMS will also play a larger role in extending the neuroplastic benefits of TMS to other mental disorders such as schizophrenia and bipolar disorder. Finally, TMS will likely be utilized with advanced surgical techniques as an adjuvant or treatment-potentiating therapy to provide a full continuum of patient care.