Research paperTranscutaneous vagus nerve stimulation modulates amygdala functional connectivity in patients with depression
Introduction
Major depressive disorder (MDD) has a high lifetime prevalence rate and is the fourth leading cause of disability worldwide (Sackeim et al., 2001). It affects a large proportion of the population by significantly impairing their occupational, social, and academic functioning (Johnson et al., 1992; Lehtinen and Joukamaa, 1994). Nevertheless, the current treatments for this disorder are far from satisfactory (Rush et al., 2003). Vagus nerve stimulation (VNS) is a Food and Drug Administration (FDA) approved method for treatment-resistant MDD in the U.S. However, the application of the method is limited by the involvement of surgery and potential side effects.
Transcutaneous vagus nerve stimulation (tVNS), a variant of traditional VNS, has on the other hand drawn the attention of researchers in recent years. As a non-invasive and low cost neural modulation method (Daban et al., 2008, Fang et al., 2014, Nemeroff et al., 2006), it has been widely applied to treat disorders such as MDD (Fang et al., 2016, Hein et al., 2013; Rong et al., 2016), epilepsy (Rong et al., 2014, Stefan et al., 2012), and prediabetes (Huang et al., 2014). The rationale of tVNS is based on an anatomical study that found that there is vagus nerve innervation (Henry, 2002, Peuker and Filler, 2002) on the surface of the ear; thus, similar effects as VNS may be achieved by superficially stimulating this area.
Recent studies also found that both classic VNS and tVNS can affect similar brain networks (Conway et al., 2006, Dietrich et al., 2008, Frangos et al., 2015, Hein et al., 2013, Kosel et al., 2011, Kraus et al., 2007, Rush et al., 2005), including activation and deactivation across the orbitofrontal cortex, superior and medial frontal cortex, dorsolateral prefrontal cortex, anterior cingulate cortex, temporal cortex, parietal area, amygdala and nucleus accumbens. These regions have been shown to be involved in emotion regulation, self-representation, reward, and external stimulus (stress, distress) interactions (Davidson et al., 2002, Grimm et al., 2008, Hasler and Northoff, 2011; Jessica S. Damoiseaux and Greicius, 2009, Mwangi et al., 2012, Pizzagalli, 2011; Rong et al., 2012, Silbersweig, 2013).
Among them, the amygdala is one of the most well-studied regions in MDD (Cullen et al., 2014, Tahmasian et al., 2013). As part of the limbic system, it has been shown to play an important role in emotional processing, fear and motivation (Mears and Pollard, 2016). Imaging studies found that compared with healthy controls, MDD patients showed abnormal activation patterns during negative stimuli (Sheline et al., 2001, Siegle et al., 2007). For example, studies found that relative to healthy controls, MDD patients showed elevated activity in the amygdala and diminished activity in the prefrontal cortex when presented with negative stimuli (Phillips et al., 2015, Sheline et al., 2001, Siegle et al., 2002, Siegle et al., 2007). In a more recent meta-analysis, Ma (2015) found that antidepressant medication in treating patients with depression and other mood disorders affects the activity of the core emotional processing circuitry. Specifically, antidepressants increased activity in the dorsolateral prefrontal cortex (DLPFC) during both negative and positive emotional activity in patients.
In recent decades, resting-state functional connectivity (rsFC) analysis has been widely used in MDD research. rsFC measures the temporal dependency of neuronal activation patterns between anatomically separated brain regions during rest (Biswal et al., 1995), which allows us to probe the functional correlation of one brain region with other brain regions in terms of networks and explore how brain regions subserve common neural procedures (Jessica S. Damoiseaux and Greicius, 2009). Previous studies have revealed abnormal rsFC in patients with depression between the amygdala and parts of the frontal cortex, such as the ventral prefrontal cortex (Tang et al., 2013) and orbitofrontal cortex (Cullen et al., 2014). Additionally, studies also showed that antidepressant treatments can normalize rsFC between the amygdala and the anterior cingulate cortex (Anand et al., 2007) as well as task-based functional connectivity between the amygdala and prefrontal cortex (Chen et al., 2008).
In this study, we investigated the modulation effects of tVNS on rsFC in MDD patients. Previous studies (Cullen et al., 2014, Pannekoek et al., 2014, Tang et al., 2013) showed that the amygdala-frontal rsFC was aberrant in depression and was related to overall depression severity. We thus hypothesized that tVNS would significantly modulate the rsFC of the amygdala-frontal network in adults with MDD.
Section snippets
Materials and methods
Here we provide a brief description of the methods and focus on the procedures and analysis details relevant for this study. The full details of the study are reported elsewhere (Fang et al., 2016; Rong et al., 2016). In our previous study, we reported how tVNS modulates the resting state functional connectivity of the default network using independent component analysis (Fang et al., 2016). In this manuscript, we focus on how tVNS modulates the resting state functional connectivity of the
Clinical outcomes
There were no significant differences between the two groups with respect to age p=0.283), gender (χ2=0.017, p=0.897) and HAMD (p=0.997), HAMA (p=0.139), SAS (p=0.610) and SDS (p=0.903) scores at baseline (Table 1).
After 4 weeks of treatment, repeated measures analysis showed that there was significant interaction between the treatment mode (tVNS vs sham tVNS) and time points (pre- vs post-treatment) on all clinical outcomes (HAMD, F (1,30)=12.37, p=0.001; HAMA, F (1,30)=4.27, p=0.047; SDS, F
Discussion
In this study, we investigated the amygdala rsFC changes before and after four weeks of tVNS treatment as compared with sham tVNS. The results showed that HAMD, SAS and SDS scores were significantly decreased in the tVNS group as compared with the sham group. In addition, we found that tVNS can significantly increase the rsFC of the amygdala-DLPFC network, and this increase is also significantly associated with symptom severity changes as indicated by HAMD scores, implying that tVNS may achieve
Conclusion
In conclusion, we found that repeated tVNS treatment can significantly increase rsFC between the right amygdala and DLPFC as compared with sham tVNS treatment in MDD patients, and this change was significantly associated with a reduction in clinical severity. Our findings suggest that tVNS may achieve a treatment effect by enhancing the amygdala-PFC functional connectivity in patients with MDD.
Author disclosure document
All authors declare no conflict of interest.
Contributors
Experimental design: PR, BZ, JLF, JK.
Data collection: JLF, JL, YH, FYY, XLW.
Data analysis: JL, JK, ZJW.
Manuscript preparation: ZJW, JL, JK, JP, JLF, YJ, CHL.
Conflict of interest statement
All authors declare no conflict of interest.
Acknowledgments
The work is supported by the Special Program of Chinese Medicine of the National Basic Research Program of China (973 Program 2012CB518503), the “Twelfth Five-year Plan” National Science and Technology Support Program of China (2012BAF14B10), the National Natural Science Foundation of China (81273674, 81471389, 81473780), and the Beijing Natural Science Foundation of China (7111007). Jian Kong is supported by R01AT006364, R01 AT008563, R21AT008707, and P01 AT006663 from NIH/NCCIH.
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Cited by (0)
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Jun Liu and Jiliang Fang are co-first authors.