Closing the Loop on Deep Brain Stimulation for Treatment-Resistant Depression

Abstract

Major depressive episodes are the largest cause of psychiatric disability, and can often resist treatment with medication and psychotherapy. Advances in the understanding of the neural circuit basis of depression, combined with the success of deep brain stimulation (DBS) in movement disorders, spurred several groups to test DBS for treatment-resistant depression. Multiple brain sites have now been stimulated in open-label and blinded studies. Initial open-label results were dramatic, but follow-on controlled/blinded clinical trials produced inconsistent results, with both successes and failures to meet endpoints. Data from follow-on studies suggest that this is because DBS in these trials was not targeted to achieve physiologic responses. We review these results within a technology-lifecycle framework, in which these early trial “failures” are a natural consequence of over-enthusiasm for an immature technology. That framework predicts that from this “valley of disillusionment,” DBS may be nearing a “slope of enlightenment.” Specifically, by combining recent mechanistic insights and the maturing technology of brain-computer interfaces (BCI), the next generation of trials will be better able to target pathophysiology. Key to that will be the development of closed-loop systems that semi-autonomously alter stimulation strategies based on a patient's individual phenotype. Such next-generation DBS approaches hold great promise for improving psychiatric care.

Bipolar depression: a major unsolved challenge

“…Vagal nerve stimulation (VNS) is FDA-approved for treatment-resistant depression, with evidence of efficacy in depression of BD and MDD (Cimpianu et al 2017;Conway et al 2018), though with some risk of inducing mania (Salloum et al 2017). Repeated transcranial magnetic stimulation (rTMS) and various forms of electrical stimulation of brain from the surface or through stereotaxically placed deep-brain electrodes remain experimental for bipolar depression (Nierenberg et al 2008;Vázquez et al 2017a;Widge et al 2018;Filkowski and Sheth 2019).…”

Consistent linear and non-linear responses to invasive electrical brain stimulation across individuals and primate species with implanted electrodes

“…Pulsatile electrical stimulation of the brain parenchyma via implanted intracranial electrodes is employed clinically to treat movement, psychiatric, and seizure disorders [1e6], but the mechanisms by which stimulation modulates neural activity are highly debated [6e10]. Different frequencies affect different diseases [6,8]: high frequency stimulation (>100 Hz) treats Parkinson's disease [10e12], while a lower frequency range (~10 Hz) may interrupt seizures [11,13]. Little is known about the effects of different frequencies on neural circuitry or why specific frequencies are less effective in certain diseases [3,6,8,10].…”

“…Different frequencies affect different diseases [6,8]: high frequency stimulation (>100 Hz) treats Parkinson's disease [10e12], while a lower frequency range (~10 Hz) may interrupt seizures [11,13]. Little is known about the effects of different frequencies on neural circuitry or why specific frequencies are less effective in certain diseases [3,6,8,10]. Theoretical approaches have focused on modeling the spread of current from implanted electrodes [14,15], and empirical work on the general physiology of invasive neurostimulation has focused heavily on avoiding tissue damage or over-excitation [16,17].…”

Deep brain stimulation for treatment-resistant depression: current status and future perspectives

“…Perhaps, the largest concern levied against the industrysponsored RCTs was that the primary outcome endpoints were assessed too early to distinguish the DBS effect from that of placebo [8]. In both RCTs, substantial placebo effects were observed in the sham-stimulation groups, with 14% and 20% meeting response criteria.…”