Recent findings. Several brain structures play a role in the development and maintenance of depression. TRMD studies are targeting the anterior cingulate cortex (Cg25), the anterior limb of the capsula interna (ALIC), the nucleus accumbens (NAcc), and the medial forebrain bundle (MFB).
Long-term data on Cg25, ALIC, and NAcc are available from studies with small sample sizes (N < 30). These targets are in close anatomical or functional relationship (neural networks), and an overlap of effect is seen.24 The superolateral branch of the MFB has also been proposed as a target.24 Higher stimulation intensities have been used in DBS for depression than in DBS for neurological indications; the generated large electric fields thus stimulate structures beyond the intended target sites. Electric field stimulation and probabilistic fiber tracking have shown that the superolateral branch of the MFB is anatomically and functionally connected with other DBS targets (Cg25, ALIC, and NAcc).25
This has led to the hypothesis that these targets are all clinically effective because of their common relationship to the MFB, leading to rapid (within days) and substantial antidepressant effects.26 A study using optogenetic neuromodulation together with DBS has recently shown that activation and modulation of afferent fiber tracts are a plausible mechanism of action in DBS.27
Understanding how DBS works. Four general hypotheses exist concerning the mechanism of action of DBS: depolarization blockade, synaptic inhibition, synaptic depression, and stimulation-induced modulation of pathological network activity.28 However, the therapeutic mechanism is likely a combination of several of these phenomena. DBS at specific stimulation parameters induces a functional lesion that is a reversible and controlled modification/inhibition of the function of a given neuronal circuit. DBS can thus be seen as an improved alternative to ablative neurosurgical procedures, which are used for well-defined groups of patients with extremely severe treatment-refractory mental disorders.
The future. After a decade of DBS research in TRMD, there is consensus about its efficacy: this neurostimulation modality holds considerable promise in lessening the suffering of patients who hitherto have had little or no hope of having MDD symptom remission. Nonetheless, substantial surgical risks and high costs are associated with DBS.
DBS has the additional potential to be used as a research tool, informing us about the underlying neurobiology of MDD. Thus far, existing studies have contributed to a novel view of depression that moves away from a synaptocentric view toward a conceptualization of disordered brain networks, ie, networks processing responses to affective stimuli.29 Future DBS studies may reveal that several psychiatric disorders are correlated with similar network dysfunctions.
Transcutaneous trigeminal stimulation for TRMD
Treatment overview and future studies. Transcutaneous, high-frequency stimulation of the V1 branch of the trigeminal nerve has been successfully used in medication-resistant epilepsy.30,31 Currently, very limited and only open-label data exist regarding its use for TRMD.
Two open-label studies describe the application of this treatment modality in 11 patients with TRMD.32,33 Study participants received nightly (approximately 8 hours per night) bilateral transcutaneous electrical stimulation of the V1 trigeminal branch for 8 weeks. Stimulation was delivered at a 120-Hz repetition frequency, with 250-microsecond pulse width, and with a duty cycle of 30 seconds on and 30 seconds off. A statistically significant reduction in depressive symptoms (both rater- and patient-rated) was seen after 8 weeks of stimulation: 6 patients had treatment response (50% or greater reduction in depressive symptoms) and 4 patients had symptom remission. These positive findings suggest that larger, prospective, double-blind studies are warranted.
Dr Conway is Associate Professor of Psychiatry at Washington University in St Louis. Dr Cristancho is Assistant Professor of Psychiatry at Washington University. Dr Schlaepfer is Vice Chair and Professor of Psychiatry and Psychotherapy at University Hospital Bonn, Dean of Medical Education at the University of Bonn in Germany, and Associate Professor of Psychiatry and Mental Health at The Johns Hopkins University School of Medicine in Baltimore. The authors report no conflicts of interest concerning the subject matter of this article.
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