Serial Vagus Nerve Stimulation Functional MRI in Treatment-Resistant Depression

Department of Psychiatry, Brain Stimulation Laboratory, Mood Disorders Program, Institute of Psychiatry, Charleston, SC 29403, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 09/2007; 32(8):1649-60. DOI: 10.1038/sj.npp.1301288
Source: PubMed


Vagus nerve stimulation (VNS) therapy has shown antidepressant effects in open acute and long-term studies of treatment-resistant major depression. Mechanisms of action are not fully understood, although clinical data suggest slower onset therapeutic benefit than conventional psychotropic interventions. We set out to map brain systems activated by VNS and to identify serial brain functional correlates of antidepressant treatment and symptomatic response. Nine adults, satisfying DSM-IV criteria for unipolar or bipolar disorder, severe depressed type, were implanted with adjunctive VNS therapy (MRI-compatible technique) and enrolled in a 3-month, double-blind, placebo-controlled, serial-interleaved VNS/functional MRI (fMRI) study and open 20-month follow-up. A multiple regression mixed model with blood oxygenation level dependent (BOLD) signal as the dependent variable revealed that over time, VNS therapy was associated with ventro-medial prefrontal cortex deactivation. Controlling for other variables, acute VNS produced greater right insula activation among the participants with a greater degree of depression. These results suggest that similar to other antidepressant treatments, BOLD deactivation in the ventro-medial prefrontal cortex correlates with the antidepressant response to VNS therapy. The increased acute VNS insula effects among actively depressed participants may also account for the lower dosing observed in VNS clinical trials of depression compared with epilepsy. Future interleaved VNS/fMRI studies to confirm these findings and further clarify the regional neurobiological effects of VNS.

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    • "Consistent with these observations, clinical neuroimaging studies (fMRI, PET, SPECT) also show changes in medial temporal regions such as the hippocampus, parahippocampus and amygdala as well as the orbito- and pre-frontal cortices.51,52,53,54,55,56) However, a thorough review of these reports reveals that the changes were bilateral in some studies whereas they were limited to one side in others. "
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    ABSTRACT: Treatment resistant depression (TRD) is a global health concern affecting a large proportion of depressed patients who then require novel therapeutic options. One such treatment option that has received some attention in the past several years is vagal nerve stimulation (VNS). The present review briefly describes the relevance of this treatment in the light of other existing pharmacological and non-pharmacological options. It then summarizes clinical findings with respect to the efficacy of VNS. The anatomical rationale for its efficacy and other potential mechanisms of its antidepressant effects as compared to those employed by classical antidepressant drugs are discussed. VNS has been approved in some countries and has been used for patients with TRD for quite some time. A newer, fast-acting, non-invasive pharmacological option called ketamine is currently in the limelight with reference to TRD. This drug is currently in the investigational phase but shows promise. The clinical and preclinical findings related to ketamine have also been summarized and compared with those for VNS. The role of neurotrophin factors, specifically brain derived neurotrophic factor and its receptor, in the beneficial effects of both VNS and ketamine have been highlighted. It can be concluded that both these therapeutic modalities, while effective, need further research that can reveal specific targets for intervention by novel drugs and address concerns related to side-effects, especially those seen with ketamine.
    Clinical Psychopharmacology and Neuroscience 08/2014; 12(2):83-93. DOI:10.9758/cpn.2014.12.2.83
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    • "Briefly, the subgenual ROI was constructed by placing a 10 mm radius sphere at MNI coordinates (6, 16, − 10), masked to include only sampled gray matter voxels. These subgenual coordinates were chosen based on prior studies where a reduction in subgenual activity was associated with antidepressant response across a wide range of treatment modalities (Drevets et al., 2002; Kito et al., 2008, 2011; Mayberg et al., 2000, 2005; Nahas et al., 2007; Wu et al., 1999) (see Table 1 in Fox et al, 2012a). A large ROI designed to cover what is generally considered the left DLPFC was constructed by centering 25 mm radius spheres on MNI coordinates at the center of Brodmann area (BA) 9 (− 36, 39, 43), the center of BA46 (− 44, 40, 29), and the average DLPFC site stimulated using the standard 5 cm targeting technique (−41, 16, 54). "
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    ABSTRACT: Transcranial magnetic stimulation (TMS) to the left dorsolateral prefrontal cortex (DLPFC) is used clinically for the treatment of depression however outcomes vary greatly between patients. We have shown that average clinical efficacy of different left DLPFC TMS sites is related to intrinsic functional connectivity with remote regions including the subgenual cingulate and suggested that functional connectivity with these remote regions might be used to identify optimized left DLPFC targets for TMS. However it remains unclear if and how this connectivity-based targeting approach should be applied at the single-subject level to potentially individualize therapy to specific patients. In this article we show that individual differences in DLPFC connectivity are large, reproducible across sessions, and can be used to generate individualized DLPFC TMS targets that may prove clinically superior to those selected on the basis of group-average connectivity. Factors likely to improve individualized targeting including the use of seed maps and the focality of stimulation are investigated and discussed. The techniques presented here may be applicable to individualized targeting of focal brain stimulation across a range of diseases and stimulation modalities and can be experimentally tested in clinical trials.
    NeuroImage 11/2012; 66. DOI:10.1016/j.neuroimage.2012.10.082 · 6.36 Impact Factor
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    • "There has been recent interest in the effect of vagus nerve stimulation (VNS) in a wide variety of disorders. VNS is known as a safe and effective treatment for epilepsy (Beekwilder and Beems, 2010) and treatment resistant depression (Nahas et al., 2007), and is likely to serve as an effective treatment for protection against circulatory shock (Czura et al., 2010; Guarini et al., 2003), myocardial ischemia (De Ferrari and Schwartz, 2011; Kawada et al., 2008), ischemic stroke (Mravec, 2010) and ischemic brain injury (Sun et al., 2011). Mechanisms of these effects of VNS are not fully understood. "
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    ABSTRACT: The aim of this study was to investigate the effect of vagus nerve stimulation (VNS) on infarct volume and neurological recovery up to 3 weeks following transient focal cerebral ischemia. Transient ischemia was produced by filament occlusion of the proximal middle cerebral artery (MCA) in rats. The right vagus nerve was stimulated starting 30 min after MCA occlusion and consisted of 30-sec pulse trains (20 Hz) delivered to the animal's right vagus nerve every 5 min for a total period of 60 min (n = 10). All the procedures were duplicated, but no stimulus was delivered, in a control group (n = 10). Neurological evaluations were performed in all animals at 24 hr, 48 hr, 1 week, 2 weeks, and 3 weeks after MCA occlusion; animals were euthanized; and neuronal damage was evaluated in hematoxylin-eosin-stained sections. The ischemic lesion volume was smaller in the VNS-treated animals in comparison with the nonstimulated group (P < 0.02). Although the functional score in both treated and untreated groups improved over the 3-week observation period (P < 0.001), there was still a statistically significant improvement reszulting from VNS treatment compared with control animals (P < 0.05). Cerebral blood flow changes in the MCA territory during ischemia did not differ between the VNS-treated animals (31.9% ± 10.4% of baseline) and control animals (29.9% ± 9.1%; P = 0.6). Stimulation of the vagus nerve for only a brief period early in ischemia provides neuroprotection in transient ischemia, with neuroprotection persisting for at least 3 weeks.
    Journal of Neuroscience Research 04/2012; 90(4):887-94. DOI:10.1002/jnr.22812 · 2.59 Impact Factor
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