Evidence-Based Reviews

The re-emerging role of therapeutic neuromodulation

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Recent developments have revived interest in brain stimulation for difficult-to-treat patients


 

References

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The brain is an electrochemical organ, and its activity can be modulated for therapeutic purposes by electrical, pharmacologic, or combined approaches. In general, neuromodulation induces electrical current in peripheral or central nervous tissue, which is accomplished by various techniques, including:

  • electroconvulsive therapy (ECT)
  • vagus nerve stimulation (VNS)
  • transcranial magnetic stimulation (TMS)
  • deep brain stimulation (DBS).

It is thought that therapeutic benefit occurs by regulating functional disturbances in relevant distributed neural circuits.1 Depending on the stimulation method, the frequencies chosen may excite or inhibit different or the same areas of the brain in varying patterns. Unlike medication, neuromodulation impacts the brain episodically, which may mitigate adaptation to the therapy’s beneficial effects and avoid systemic adverse effects.

Neuromodulation techniques are categorized based on their risk level as invasive or noninvasive and seizurogenic or nonseizurogenic (Table 1). Although these and other approaches are being considered for various neuropsychiatric disorders (Table 2), the most common application is for severe, treatment-resistant depression. Therefore, this article focuses on FDA-approved neuromodulation treatments for depression, with limited discussion of other indications.

Table 1

Therapeutic neuromodulation: Categorization based on risk

Noninvasive, nonseizurogenic
  TMS, tDCS, CES
Noninvasive, seizurogenic
  ECT, MST, FEAST
Invasive, nonseizurogenic
  VNS, DBS, EpCS
CES: cranial electrotherapy stimulation; DBS: deep brain stimulation; ECT: electroconvulsive therapy; EpCS: epidural prefrontal cortical stimulation; FEAST: focal electrically administered seizure therapy; MST: magnetic seizure therapy; tDCS: transcranial direct current stimulation; TMS: transcranial magnetic stimulation; VNS: vagus nerve stimulation

Table 2

Approved and investigational indications of neuromodulation

ApproachDescriptionClinical application
CESUses small pulses of electrical current delivered across the head focused on the hypothalamic region with electrodes usually placed on the ear at the mastoid near the faceDepression
Anxiety
Sleep disorders
DBS‘Functional neurosurgical’ procedure that uses electrical current to directly modulate specific areas of the CNSDepression
OCD*
Parkinson’s disease* Dystonia*
ECTShort-term electrical stimulation sufficient to induce a seizureDepression*
Schizophrenia
Mania
EpCSUses implantable stimulating paddles that do not come in contact with the brain and target the anterior frontal poles and the lateral prefrontal cortexDepression Pain
FEASTAn alternate form of ECT that involves passage of electrical current unidirectionally from a small anode to a larger cathode electrodeDepression
MSTIntense, high-frequency magnetic pulses sufficient to induce a seizureDepression
tDCSSustained, low-intensity constant current flow usually passing from anode to cathode electrodes placed on the scalpDepression
TMSUse of intense high- or low-frequency magnetic pulses to produce neuronal excitation or inhibitionDepression*
PTSD
OCD
Schizophrenia Substance use disorders Tinnitus
VNSUse of intermittent mild electrical pulses to the left vagus nerve, whose afferent fibers impact structures such as the locus ceruleus and the raphe nucleusEpilepsy*
Depression*
*FDA-approved indications
CES: cranial electrotherapy stimulation; DBS: deep brain stimulation; ECT: electroconvulsive therapy; EpCS: epidural prefrontal cortical stimulation; FEAST: focal electrically administered seizure therapy; MST: magnetic seizure therapy; OCD: obsessive-compulsive disorder; PTSD: posttraumatic stress disorder; tDCS: transcranial direct current stimulation; TMS: transcranial magnetic stimulation; VNS: vagus nerve stimulation

ECT: Oldest and most effective

ECT has remained the most effective therapeutic neuromodulation technique for more than 7 decades. It is indicated primarily for severe depressive episodes (eg, psychotic, melancholic), particularly in older patients.

ECT delivers electrical current to the CNS that is sufficient to produce a seizure. Under modified conditions, a typical course of 6 to 12 sessions can resolve severe depressive episodes and may also benefit other disorders, such as bipolar mania and acute psychosis. Although ECT is potentially life-saving, its use was markedly curtailed with the advent of effective antidepressants in the 1950s. Multiple factors impede its use, including:

  • access and expertise are limited in many areas
  • cognition is at least temporarily adversely affected
  • relapse rates after acute benefit are high
  • cost
  • public perception often is negative.

Studies are addressing several of these concerns. For example, the National Institute of Mental Health-sponsored Consortium on Research with ECT (CORE) group is considering how to more effectively maintain acute benefits of ECT. They compared the potential merits of maintenance ECT with maintenance pharmacotherapy (nortriptyline plus lithium) over 6 months. Although the 2 strategies had comparable results, retention rates were <50% and about one-third relapsed in both groups.2,3 Potential alternative strategies include a more frequent ECT maintenance schedule and/or combining maintenance ECT with medication(s).

Magnetic seizure therapy (MST) and focal electrically administered seizure therapy (FEAST) are attempts to produce similar efficacy and less cognitive disruption compared with ECT.4,5 Work also continues on electrode placement (eg, bifrontal) and alteration of waveform characteristics (eg, ultra-brief) to maintain or enhance efficacy while minimizing adverse effects.6,7

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