Abstract
OBJECTIVE:
To examine the brain effects of transcutaneous auricular vagus nerve stimulation (taVNS) treatment of recurrent depression based on the functional brain network by using resting-state functional magnetic resonance imaging (fMRI).
METHODS:
Twenty-five patients with recurrent depression were enrolled in a single-arm trial of taVNS treatment for eight weeks. Clinical results were assessed by 17-item Hamilton Depression Rating Scale (HAMD-17), Hamilton Anxiety Scale (HAMA), Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS), and Ruminative Response Scale (RRS) scales. Resting-state fMRI was conducted to explore the brain effects before and after treatment. For the functional connectivity (FC) analysis, the bilateral nucleus accumbens, globus pallidus, caudate, and putamen were selected as seeds. Finally, the correlations between FC and the clinical scale scores were calculated.
RESULTS:
After treatment, the patients' scores of HAMD-17, HAMA, SDS, SAS, and RRS were significantly decreased (P < 0.05). FC was considerably decreased between the following areas: the left globus pallidus and the right postcentral gyrus, inferior parietal gyrus, the right globus pallidus and the left superior marginal gyrus, postcentral gyrus, superior parietal gyrus, inferior parietal gyrus, precuneus, right postcentral gyrus, superior marginal gyrus, and inferior parietal gyrus, between the right caudate and the right lingual gyrus, calcarine gyrus, and cerebellum. Changes in FC between the right globus pallidus and the left inferior parietal gyrus, between the left globus pallidus and the right postcentral gyrus were negatively correlated with HAMD-17 scores change before and after treatment (before, P = 0.003, r = –0.6; after, P = 0.009，r = –0.54). The change of FC between the right globus pallidus and the right postcentral gyrus was negatively correlated with the change in SDS (P = 0.026，r = –0.474). The difference in FC between the right globus pallidus and the right postcentral gyrus was negatively correlated with the change in SAS (P = 0.016，r = –0.513).
CONCLUSIONS:
Recurrent depression could be effectively treated with taVNS. The changes in brain FC involving the basal ganglia, default mode, and sensorimotor networks provide insight into the effects of taVNS treatment on recurrent depression.
Keywords: recurrence, depression, magnetic resonance imaging, basal ganglia, default mode network, transcutaneous auricular vagus nerve stimulation
1. INTRODUCTION
Major depressive disorder (MDD) is a physical and mental disorder characterized by significantly high relapse and suicide rates.1According to Traditional Chinese Medicine theory, MDD pathogenesis is primarily caused by malfunction of the heart, liver, and kidney, resulting in an imbalance of Qi movement.2Currently, the prevalence of depression is rising globally, leading to a serious burden on individuals, families, communities, and the global economy.3,4 Recurrent depression is defined as ≥ 2 depressive episodes, showing lower treatment efficacy and a higher suicide rate than first onset depression.5Previous studies suggested obvious differences in structural and functional brain imaging in patients with recurrent depression, compared to both healthy controls and first-episode depression patients, implying specific pathological mechanisms for recurrent depression.6,7
MDD patients commonly complain about the gastro-intestinal side effects associated with anti-depressant treatments and delayed drug curative effects.8,9 Vagus nerve stimulation (VNS) was introduced in 2005 to treat depression, but it is an invasive and expensive procedure.10Recent studies have demonstrated that transcutaneous auricular vagus nerve stimulation (taVNS) is effective for mild or moderate MDD patients who suffer from rare side effects.11-13
Furthermore, the first case report showed that taVNS had the potential therapeutic effects for treatment-resistant depression and improved the anxiety as well as rumination symptoms, both of which may trigger the recurrence of depression.14-16However, the clinical reaction and effects of taVNS in treating recurrent depression remain unclear.
Resting-state functional magnetic resonance imaging (rs-fMRI) has been widely used in clinical and mechanistic studies of psychiatric disorders.6,9,14 In previous studies, dysfunction of the reward system has been associated with MDD, and it may be an essential brain network for reducing depression symptoms.17,18 These findings indicate that aberrant resting-state functional con-nectivity (rs-FC) increased caudate-insular and reduced ventral striatum-cerebellar in the reward system can predict the risk of depression recurrence in MDD patients with remission.17Thus, the core reward-processing brain regions, including bilateral nucleus accumbens, globus pallidus, caudate, and putamen, were included in this study as the regions of interest (ROIs).19,20In addition, in the current study, we collected the preliminary clinical data to observe the response to treatment and explore the underlying brain network effects of taVNS treatment using rs-fMRI.
2. MATERIALS AND METHODS
2.1. Subjects and study design
This pilot study was a single-arm, non-randomized, prospective study. The protocol was approved by the Clinical Research Ethics Board of the Guang'anmen Hospital (2017-021-SQ). The written informed consent was signed by all subjects before study. Demographic and clinical data were displayed in Table 1. The study was registered at China Clinical Trial Registry (ChiCTR1800014277). Originally 30 right-handed patients were recruited by advertisements or flyers from Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Xuanwu Hospital, Capital Medical University as well as Yuquan Hospital of Tsinghua University from April 2018 to July 2021. Inclusion criteria as follows: Conforms to DSM-IV criteria for recurrent depression: (a) HAMD-17 score>17, (b) number of depression episodes ≥ 2 times, (c) the intermittent period of each depressive episode ≥ 2 months, and the intermittent period does not meet the diagnostic criteria for major depressive episodes. Exclusion criteria: (a) history of drug or alcohol abuse, long term history of smoking or drinking (> 1 year), (b) bipolar disorder, (c) fertile woman or ongoing of breastfeeding, (d) contraindications to MRI scan.
Table 1.
Clinical scale scores of patients with recurrent depression before treatment (week 0) and after taVNS treatment (week 8) (n = 22)
| Clinical Scale | Scale scores of week 0 ( $\bar{x}$± s ) | Scale scores of week 8 ( $\bar{x}$± s ) | Reduction of 8th week ( $\bar{x}$± s ) | Comparison of scale scores before and after 8 weeks (P) |
|---|---|---|---|---|
| HAMD-17 | 23±4 | 5±3 | 18±4 | 0.00 |
| HAMA | 24±7 | 5±4 | 19±69 | 0.00 |
| SDS | 51±7 | 31±8 | 20±9 | 0.00 |
| SAS | 44±7 | 27±7a | 16±8 | 0.00 |
| RRS | 38±16 | 21±14 | 17±12 | 0.00 |
Notes: except for the 8th week of SAS, the scale score does not conform to the normal distribution (mark "a" in the upper right corner, and displayed by the median ± quartile). HAMD-17: Hamilton Depression Rating Scale; HAMA: Hamilton Anxiety Scale; SDS: Self-Rating Depression Scale; SAS: Self-Rating Anxiety Scale, Ruminative Response Scale.
All subjects were interviewed by two experienced psychiatrists and were screened by two experienced radiologists to ensure that all participants' baseline MRI were normal. Patients who had excessive head movement during the scan (head motion > 2 mm or maximum displacement in direction of x, y, and z more than 2°) were excluded according to MRI scan's quality control.
It's a self-controlled prospective clinical study with 8-week taVNS intervention. Stimulation points at ear concha bilaterally were similar to ear points “heart”, “kidney” and “liver”. Firstly, the stimulated areas were disinfected conventionally by 75% alcohol prior to each treatment. The therapeutic apparatus used for this study were developed by the cooperation of the Institute of Acupuncture and Moxibustion, China Academy of Chinese Medicine Sciences (Beijing, China) and Suzhou Medical Appliance Factory (Jiangsu, China).21,22 TaVNS were applied to all participants for 30 minutes before geting up in the morning and going to bed at night, respectively. The total intervention lasted for 8 weeks. Treatment parameters remained unchanged throughout 8 weeks (intensity in 4-6 mA, dilatational wave, frequency in 20 Hz, wave width less than 1 ms).
After trained by an experienced doctor, all patients were supervised strictly by their family members during treatment process to ensure the treatment process was correct at home. Participants were asked to record the detail in diary every day during 8 weeks' treatment. Doctors regularly communicated with patients on WeChat and telephone, answered and solved various questions from patients in a timely manner to ensure the quality and frequency of taVNS treatment, furthermore, all patients are asked to write a treatment journal to record their treatment acography which contains treatment timetable and discomfort.
2.2. Clinical scale evaluation
17-item Hamilton Depression Rating Scale (HAMD-17), Hamilton Anxiety Scale (HAMA), Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS), Ruminative Response Scale (RRS) were used to test all participants by the same psychiatrist at week 0 as well as the end of treatment at 8th week, all above scales have good reliability and validity and were widely adopted in psychiatric clinical research.14,22,23 Because other conventional clinical antidepressants generally take 4-8 weeks for clinical trial,24and previous studies on the treatment of depression with acupuncture have found that significant improvement in symptoms about 4-8th week,12 thus the 8th week is selected as the time of observation node for this study.
2.3. MRI method
Rs-FC was selected as the observation index of brain effects by resting state fMRI. FC can explore the abnormal brain function between brain regions,14, 23 so it is commonly used to investigate the brain mechanism of depression.
Imaging was performed using a 3T Siemens MRI scanner (Magnetom Skyra, Siemens, Germany). The BOLD fMRI scans took 6 min and 46 s for all patients with the following parameters: repetition time (TR) 2000 ms, echo time (TE) 30 ms, slice number 32, field of view (FOV) 224 mm × 224 mm, resolution 64 × 64, slice thickness 3.5 mm, flip angle (FA) 90°. T1-weighted structural images were acquired with three-dimensional fast spoiled gradient-echo sequence with the following parameters: TR 2530 ms, TE 2.98 ms, slice number 32, FOV 256 mm × 256 mm, resolution 256×192, slice thickness 1mm, FA = 7°.
2.4. Data preprocessing
Image preprocessing was achieved with the Data Processing Assistant for Resting-State fMRI (DPARSF, http://rfmri.org/DPARSF) based on Statistical Para-metric Mapping 12 (http://www.fil.ion.ucl.ac.uk/spm).20The first 10 volumes were removed and the remaining 190 volumes were corrected for different acquisition times. The nuisance signals (containing liner trend, head-motion parameters based on Friston 24-parameter model signals of cerebrospinal fluid, white matter, and whole brain) were regressed out from the data,25acquired images were normalized to Montreal Neurological Institute (MNI) space and re-sampled with a 3 mm × 3 mm × 3 mm resolution using transformation data calculated by unified segmentation algorithm.26Images were then band-pass filtered afterwards (0.01-0.1 Hz). Considering the possibility confounding effect of micro-movements on resting-state FC, the framewise displacement (FD) values were computed for each subject using the Jenkinson formula to reflect the temporal derivative of the movement parameters. All participants meet the criterion of mean FD < 0.5 mm.27
2.5. Efficacy measures
The minimal important difference (MID) of HAMD-17 was a reduction in its total scores by 4. Any subject whose MID of HAMD-17 beyond 4 after 8 weeks of treatment was identified as taVNS's treatment efficacy.24
2.6. Statistical analysis
Clinical data
Data were processed with SPSS 26.0 (IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY, USA). If the measurement data conforms to the normal distribution, it is indicated by the mean ± standard deviation ( $\bar{x}$± s), otherwise it was displayed by the median (interquartile interval) [M(IQR)]. For the clinical data before and after treatment, except SAS was used in the paired Wilcoxon rank sum test, the others all were used with the paired t test, with P < 0.05 indicates statistical difference. Pearson correlation analysis was used for showing the correlation of the clinical scale scores and fMRI data.
2.7. Resting state fMRI data
It was used with the statistical module in the DPARSF toolbox to perform paired tests on the extracted FC values before and after treatment.28Age, educational level, and mean FD power were served as covariates.26 The results were corrected for multiple comparisons with a combination of cluster P < 0.05 and voxel P<0.01 based on Gaussian Random Field (GRF) theory. Cluster's voxels which less than 15 were discarded. We chose the atlas parcelled by Ye et al,29according to previous literature reports on depression fMRI studies,17,19,20 the bilateral nucleus accumbens, globus pallidus, caudate and putamen were used as seeds to calculate rs-FC. Finally, Difference of FC value of brain area in patients with recurrent depression were extracted before and after taVNS treatment, and made correlation analysis with the impairment of HAMD-17 in 0 week minus HAMD-17 in 8th week.
3. RESULTS
3.1. Clinical outcomes
Finally, five patients were excluded by inclusion criteria, 3 patients dropped out attributed to losing contact, and 22 cases finished 8 weeks' taVNS treatment and fMRI scan. The significant differences were showed in HAMD-17, HAMA, SDS, SAS between before and after treatment (P<0.05) (Table 1).
3.2. Safety
The side effect was reported with slight tolerable pain in ear by two patients.
3.3. Brain FC changes before and after taVNS treatments
Twenty two patients finished twice fMRI scans at week 0 and week 8. There were no significance FC change with the seeds of the bilateral nucleus accumbens and putamen (P > 0.05). The results demonstrated that FC decreased in following cortical and subcortical areas: FC between left globus and right postcentral gyrus, inferior parietal gyrus (P < 0.05), (Figure1A, Table 2), FC between right globus and left supramarginal gyrus, postcentral gyrus, superior parietal gyrus, inferior parietal gyrus, precuneus, and right postcentral gyrus, inferior parietal gyrus (P < 0.05), (Figure 1B, Table 2). Moreover, FC were decreased between right caudate and right lingual gyrus，calcarine gyrus，cerebellum (P < 0.05) (Figure 1C, Table 2). However, the bilateral nucleus accumbens showed no significant change in FC before and after 8 weeks of taVNS treatment (P = 0.07).
Figure 1. Brain functional connectivity changes before and after taVNS treatments.
A: seed point: left posterior globus. 1: right postcentral gyrus; 2: right inferior parietal lobule; B: seed point: right posterior globus. 1: right postcentral gyrus; 2: right inferior parietal lobule; 3: left inferior parietal gyrus; 4: right supermarginal gyrus; 5: left superior parietal gyrus; 6: left postcentral gyrus; 7: left precuneus; 8: left supramarginal gyrus; C: seed point: right posterior caudate tail. 9: right cerebellum; 10: right calcarine gyrus; 11: right lingual gyrus.
Table 2.
Changes of brain regions function connectivity in patients with recurrent depression after 8 weeks of taVNS treatment
| Seed | Brodmann's area | Region with altered FC | Peak MNI coordinate (X,Y,Z) |
Voxels | t valuea | |
|---|---|---|---|---|---|---|
| Left globus pallidus | 3 | Right postcentral gyrus | (52, –24,60) | 142 | –4.00 | |
| 1 | Right inferior parietal gyrus | (50,–33,57) | 26 | –4.86 | ||
| Right globus pallidus | 48 | Left superior marginal gyrus | (–60,-21,33) | 67 | –3.43 | |
| 48 | Left postcentral gyrus | (–58,-20,30) | 50 | –3.91 | ||
| 5 | Left superior parietal gyrus | (-19,–51,67) | 28 | –3.28 | ||
| 2 | Left inferior parietal gyrus | (–43,–28,39) | 39 | –2.99 | ||
| 5 | Left precuneus | (–12,–56,67) | 16 | –4.53 | ||
| 3 | Right postcentral gyrus | (45,–26,39) | 78 | –3.56 | ||
| 2 | Right superior marginal gyrus | (44,–31,39) | 38 | –3.51 | ||
| Right caudate | 18 | Right lingual gyrus | (11,–80,–5) | 104 | –2.93 | |
| 17 | Right calcarine gyrus | (6,–71,14) | 75 | –3.01 | ||
| 30 | Right cerebellum | (12,–43,–14) | 26 | –3.29 | ||
Notes: taVNS: transcutaneous auricular Vagus Nerve Stimulation; FC: functional connectivity; MNI: Montreal Neurological Institute. T-valuesa: T-values of brain areas that have significantly changed before and after taVNS treatment.
3.4. Correlation between the clinical data and the brain FCs
Correlations were investigated between the clinical scale scores and FC changes before and after 8 weeks of taVNS treatment. The recurrent depression patients' subtracted FC values were negatively correlated with HAMD-17 score subtracted value as following areas: FC subtracted values between right globus and left inferior parietal gyrus (P = 0.003，r = –0.6) (Figure 2A), and the left globus and right postcentral gyrus (P = 0.009，r = –0.54) (Figure 2B), respectively. The FC subtracted values between the right globus and right postcentral gyrus were negatively correlated with SDS subtracted values (P = 0.026，r = –0.474) (Figure 2C). The FC subtracted values between the right globus and right postcentral gyrus was negatively correlated with SAS subtracted values (P = 0.016, r = –0.513) (Figure 2D).
Figure 2. Correlation between the clinical data and the brain FCs.
A: the FC subtracted values between right globus and left inferior parietal gyrus were negatively correlated with HAMD -17 score subtracted values. B: the FC subtracted values between right globus and the left globus and right postcentral gyrus were negatively correlated with HAMD-17 score subtracted values; C: the FC subtracted values between the right globus and right postcentral gyrus were negatively correlated with SDS subtracted values; D: the FC subtracted values between the right globus and right postcentral gyrus was negatively correlated with SAS subtracted values. HAMD-17: 17-item Hamilton Depression Rating Scale; SDS: Self-Rating Depression Scale; SAS: Self-Rating Anxiety Scale.
4. DISCUSSION
According to traditional Chinese medicine theory, MDD affects the brain and involves the five viscera, most notably the heart, liver, and kidney. Acupoints in the auricle that correspond to organs such as the heart, liver, and kidney are concentrated in the concha, which coincides with the only somatic branch of the vagus nerve.30,31Consequently, taVNS, similar to VNS in ameliorating depression, is considered a novel technique of integrated traditional Chinese and Western medicine in MDD treatment. The taVNS treatment for up to eight weeks effectively reduced the symptoms of depression. In addition, the resting-state FC of multiple brain areas was significantly reduced in basal ganglia areas, default network areas, and sensorimotor regions. Furthermore, the changes in FC and clinical scale scores in recurrent depression were negatively correlated. These findings suggest that taVNS can alleviate the clinical symptoms of recurrent depression by modulating FC in abnormal basal ganglia, default network, and sensorimotor areas.
According to previous research findings from our group, eight weeks of taVNS is effective in treating mild to moderate depression.23This study aims to investigate further the evidence from the resting-state fMRI of taVNS in treating recurrent depression.
4.1. The brain function networks of the subcortical gray matter nuclei are involved in the pathogenesis of depression.
According to previous research, the functional reward network is associated with the pathogenesis of mental illness. 32The striatal system, which includes the caudate and putamen, is the core part of the reward system, which receives dopamine signals from the midbrain.33Kong et al34 stated that elderly depression patients who were treated with electric convulsive therapy (ECT), the results revealed that FC between bilateral orbitofrontal region and globus pallidus increased after treatment was completed suggesting that the changes in brain function of globus pallidus may be involved in the brain effect of ECT treatment in depression. Our present study found that taVNS treatment for up to eight weeks can induce FC changes between the basal ganglion areas and several other areas involving sensory-motor areas and the default mode network, which are closely correlated with pathology and treatment reaction of depression.
4.2. The FC of the default mode network (DMN) played a key role in taVNS modulating recurrent depression.
DMN concept was first proposed by Raichle,35who proposed that the structure and function of the default network abnormality contribute significantly to the onset, disease progression, and prognostic treatment of depression.35-37 Rumination is a risk factor for aggravating depressive symptoms. The meta-analysis conducted by Yan et al 38 reveals that abnormal DMN is related to rumination symptoms, and FC of DMN is reduced in patients with depression compared to healthy subjects.
Fang et al enrolled mild-to-moderate depression patients and treated them for four weeks, the results revealed that FC between DMN, precuneus, and orbitofrontal areas was significantly increased among the participants in the taVNS group compared to the sham taVNS group.23 Precuneus is considered a vital node of the default network. 39 A case with Treatment-Resistant Depression showed the efficacy of taVNS after eight weeks of treatment. Thus, it was speculated that the effects of taVNS treatment were involved in DMN modulation.
The current study demonstrated that FC subtracted value of the right globus pallidus and the left inferior parietal gyrus in the default mode network was negatively correlated with HAMD-17 subtracted value after treatment with taVNS. It may imply that FC modulation between DMN and basal ganglions may be involved in the treatment effects of depression by taVNS.
4.3. The postcentral gyrus may be a brain target for depression treatment
According to recent research findings, abnormal brain function in the postcentral gyrus is common at the onset of depression. A study conducted by Si et al 40 on depression patients and healthy subjects revealed that the regional homogeneity (ReHo) of the right postcentral gyrus of depression patients was significantly lower than in healthy subjects. Furthermore, ReHo value was negatively correlated with HAMD score, indicating that the abnormal local brain function in the right postcentral gyrus may be associated with the pathological brain mechanism of depression.
This study found that depression and accompanying symptoms in patients with recurrent depression were decreased FC between the right postcentral gyrus and right globus was negatively correlated with SAS and SDS subtracted values in patients with recurrent depression，which would meant the changes in the brain function of the right postcentral gyrus may be closely related to depression and its accompanying symptoms.
Our study investigated the effects of taVNS on recurrent depression. The results showed the curative effect of taVNS on recurrent depression. The brain effects of taVNS treatment reaction may be involved in the brain function modulation in the reward network, default mode network and sensorimotor network. It is necessary to further study the multi-modal brain functional experiments for the mechanism of taVNS treating the recurrent depression in the future.
There are several limitations: (a) the short clinical observation duration. (b) Relative small sample size. (c) We employed a single-arm study which lack of controlled treatment. In the future, it is necessary to conduct a new study with big sample size and controlled modalities, such as physical therapies TMS, or antidepressant drugs.
Contributor Information
Yang Hong, Email: hongyang671129@126.com.
Jiliang FANG, Email: fangmgh@163.com.
REFERENCES
- 1. Chisholm D, Sweeny K, Sheehan P, et al. Scaling-up treatment of depression and anxiety: a global return on investment analysis. Lancet Psychiatry 2016; 3: 415-24. [DOI] [PubMed] [Google Scholar]
- 2. Xie JQ. . Internal medicine of Traditional Chinese Medicine. Beijing: People's Medical Publishing House, 2001; 100- 2. [Google Scholar]
- 3. Shapero BG, Mischoulon D, Cusin C. . The massachusetts general hospital guide to depression. Berlin: Springer 2019: 5- 9. [Google Scholar]
- 4. Huang YQ, Lu J, Xu XF, et al. Prevalence of mental disorders in China: a cross-sectional epidemiological study. The Lancet Psychiatry 2019; 6: 211-24. [DOI] [PubMed] [Google Scholar]
- 5. Hidaka S, Ikejima C, Kodama C, et al. Prevalence of depression and depressive symptoms among older Japanese people: comorbidity of mild cognitive impairment and depression. Int J Geriatr Psychiatry 2012; 27: 271-79. [DOI] [PubMed] [Google Scholar]
- 6. Yan CG, Chen X, Li L, et al. Reduced default mode network FC in patients with recurrent major depressive disorder. Proc Natl Acad Sci U S A 2019; 116: 9078-83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Schmaal L, Veltman DJ, Van Erp TG, et al. Subcortical brain alterations in major depressive disorder: findings from the ENIGMA major depressive disorder working group. Mol Psychiatry 2016; 21: 806-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Oliva V, Lippi M, Paci R, et al. Gastrointestinal side effects associated with antidepressant treatments in patients with major depressive disorder: a systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2021; 109 : 110266. [DOI] [PubMed] [Google Scholar]
- 9. Li YF. . A hypothesis of monoamine (5-HT)-Glutamate/GABA long neural circuit: aiming for fast-onset antidepressant discovery. Pharmacol Ther 2020; 208: 1-10. [DOI] [PubMed] [Google Scholar]
- 10. Carreno FR, Frazer A. . Vagal nerve stimulation for treatment-resistant depression. Neurotherapeutics 2017; 14: 716-27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Rong P, Liu J, Wang L, et al. Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: a nonrandomized controlled pilot study. J Affect Disord 2016; 195: 172-79. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Li SY, Rong PJ, Wang Y, et al. Comparative effectiveness of transcutaneous auricular vagus nerve stimulation vs citalopram for major depressive disorder: a randomized trial. Neuromodulation 2021; 25: 450-60. [DOI] [PubMed] [Google Scholar]
- 13. Kong J, Fang JL, Joel Park, et al. Treating depression with transcutaneous auricular vagus nerve stimulation: state of the art and future perspectives. Front Psychiatry 2018; 9: 20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Li XJ, Wang L, Wang HX, et al. The effect of transcutaneous auricular vagus nerve stimulation on treatment-resistant depression monitored by resting-state fMRI and MRS: the first case report. Brain Stimulation 2019; 12: 377-79. [DOI] [PubMed] [Google Scholar]
- 15. Roberts JE, Gilboa E, Gotlib IH. . Ruminative response style and vulnerability to episodes of dysphoria: gender, neuroticism, and episode duration. Cogn Ther Res 1998; 22: 401-23. [Google Scholar]
- 16. Wu ZG, Chen J, Yuan CM, et al. Clinical characteristics of treatmentresistant depression with and without anxious features. Zhong Hua Jing Shen Ke Za Zhi 2010; 43: 196-200. [Google Scholar]
- 17. Wang L, Li F, Mitchell PB, et al. Striatal resting-state connectivity abnormalities associated with different clinical stages of major depressive disorder. J Clin Psychiatry 2020; 81:19m12790. [DOI] [PubMed] [Google Scholar]
- 18. Zhang WN, Chang SH, Guo LY, Zhang KL, Wang J. . The neural correlates of reward-related processing in major depressive disorder: a Meta-analysis of functional magnetic resonance imaging studies. J Affect Disord 2013, 151: 531-39. [DOI] [PubMed] [Google Scholar]
- 19. Ottenheimer DJ, Bari BA, Sutlief E, et al. A quantitative reward prediction error signal in the ventral pallidum. Nat Neurosci 2020; 23: 1267-76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Ottenheimer D, Richard JM, Janak PH. . Ventral pallidum encodes relative reward value earlier and more robustly than nucleus accumbens. Nat Commun 2018; 9: 1-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Feng H, Dong J, Jian K, et al. Effect of transcutaneous auricular vagus nerve stimulation on impaired glucose tolerance: a pilot randomized study. BMC Complement Altern Med 2014; 14: 1-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Rong PJ, Fang JL, Wang LP, et al. Transcutaneous vagus nerve stimulation for the treatment of depression: a study protocol for a double blinded randomized clinical trial. BMC Complement Altern Med 2012; 12: 255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Fang JL, Rong PL, Hong Y, et al. Transcutaneous vagus nerve stimulation modulates default mode network in major depressive disorder. Biol Psychiatry 2016; 79: 266-73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Berton O, Nestler E J. . New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 2006; 7: 137. [DOI] [PubMed] [Google Scholar]
- 25. Friston KJ. . Unified segmentation. NeuroImage 2005; 26: 839-51. [DOI] [PubMed] [Google Scholar]
- 26. Friston KJ, Williams S, Howard R, Frackowiak RS, Turner R. . Movement-related effects in fMRI time-series. Magn Reson Med 1996; 35: 346-55. [DOI] [PubMed] [Google Scholar]
- 27. Yan CG, Cheung B, Kelly C, et al. A comprehensive assessment of regional variation in the impact of head micromovements on functional connectomics. Neuroimage 2013; 76: 183-201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Yan CG, Wang XD, Zuo XN, et al. DPABI: data processing & analysis for (Resting-State) brain imaging. Neuroinformatics 2016; 14: 339-51. [DOI] [PubMed] [Google Scholar]
- 29. Ye T, Margulies DS, Breakspear M, et al. Topographic organization of the human subcortex unveiled with FC gradients. Nature Neuroscience 2020; 23: 1421-32. [DOI] [PubMed] [Google Scholar]
- 30. Yuan H, Silberstein SD. . Vagus nerve and vagus nerve stimulation, a comprehensive review: Part I. Headache 2016; 56: 71-8. [DOI] [PubMed] [Google Scholar]
- 31. Huang LC. . Ear acupoint diagnosis and therapy. Beijing: Science and Technology Literature Press, 2017: 65- 97. [Google Scholar]
- 32. Shepherd G. . Corticostriatal connectivity and its role in disease. Nat Rev Neurosci 2013; 14: 278-91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Aristieta A, Barresi M, Lindi S A, et al. A disynaptic circuit in the globus pallidus controls locomotion inhibition. Curr Biol 2021; 31: 707-21. [DOI] [PubMed] [Google Scholar]
- 34. Kong XM, Sun Y, Zhu DM. . The effect of electroconvulsive therapy on low-frequency amplitude and changes in related brain networks in elderly patients with depression. Zhong Guo Quan Ke Yi Xue Za Zhi 2020; 23: 672-77. [Google Scholar]
- 35. Raichle M E, Snyder A Z. . A default mode of brain function: a brief history of an evolving idea. NeuroImage 2007; 37: 1083-90. [DOI] [PubMed] [Google Scholar]
- 36. Hamilton JP, Farmer M, Fogelman P, Gotlib IH. . Depressive rumination, the default-mode network, and the dark matter of clinical neuroscience. Biol Psychiatry 2015; 78: 224-30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Wise T, Marwood L, Perkins A M, et al. Instability of default mode network connectivity in major depression: a two-sample confirmation study. Transl Psychiatry 2017; 7: e1105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Zhou HX, Chen X, Shen YQ, Li L, Yan CG. . Rumination and the default mode network: meta-analysis of brain imaging studies and implications for depression. NeuroImage 2019; 206: 116287. [DOI] [PubMed] [Google Scholar]
- 39. Bullmore E, Sporns O. . Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev Neurosci 2009; 10: 186-98. [DOI] [PubMed] [Google Scholar]
- 40. Xia MR, Si TM, Sun XY, et al. Reproducibility of functional brain alterations in major depressive disorder: evidence from a multisite resting-state functional MRI study with 1434 individuals. NeuroImage 2019; 189: 700-14. [DOI] [PubMed] [Google Scholar]