Transcutaneous Auricular Vagus Nerve Stimulation Modulating the Brain Topological Architecture of Functional Network in Major Depressive Disorder: An fMRI Study.

BACKGROUND: Transcutaneous auricular vagus nerve stimulation (taVNS) is effective in regulating mood and high-level cognition in patients with major depressive disorder (MDD). This study aimed to investigate the efficacy of taVNS treatment in patients with MDD and an altered brain topological organization of functional networks. METHODS: Nineteen patients with MDD were enrolled in this study. Patients with MDD underwent 4 weeks of taVNS treatments; resting-state functional magnetic resonance imaging (rs-fMRI) data of the patients were collected before and after taVNS treatment. The graph theory method and network-based statistics (NBS) analysis were used to detect abnormal topological organizations of functional networks in patients with MDD before and after taVNS treatment. A correlation analysis was performed to characterize the relationship between altered network properties and neuropsychological scores. RESULTS: After 4 weeks of taVNS treatment, patients with MDD had increased global efficiency and decreased characteristic path length (Lp). Additionally, patients with MDD exhibited increased nodal efficiency (NE) and degree centrality (DC) in the left angular gyrus. NBS results showed that patients with MDD exhibited reduced connectivity between default mode network (DMN)-frontoparietal network (FPN), DMN-cingulo-opercular network (CON), and FPN-CON. Furthermore, changes in Lp and DC were correlated with changes in Hamilton depression scores. CONCLUSIONS: These findings demonstrated that taVNS may be an effective method for reducing the severity of depressive symptoms in patients with MDD, mainly through modulating the brain's topological organization. Our study may offer insights into the underlying neural mechanism of taVNS treatment in patients with MDD.

Neural signatures of default mode network subsystems in first-episode, drug-naive patients with major depressive disorder after 6-week thought induction psychotherapy treatment.

Evidence indicates that the default mode network (DMN) plays a crucial role in the neuropathology of major depressive disorder (MDD). However, the neural signatures of DMN subsystems in MDD after low resistance Thought Induction Psychotherapy (TIP) remain incompletely understood. We collected functional magnetic resonance imaging data from 20 first-episode, drug-naive MDD and 20 healthy controls (HCs). The DMN was segmented into three subsystems and seed-based functional connectivity (FC) was computed. After 6-week treatment, the significantly reduced FCs with the medial temporal lobe memory subsystem in MDD at baseline were enhanced and were comparable to that in HCs. Changed Hamilton Depression Rating Scale scores were significantly related with changed FC between the posterior cingulate cortex (PCC) and the right precuneus (PCUN). Further, changed serotonin 5-hydroxytryptamine levels were significantly correlated with changed FCs between the PCC and the left PCUN, between the posterior inferior parietal lobule and the left inferior temporal gyrus, and between the retrosplenial cortex and the right inferior frontal gyrus, opercular part. Finally, the support vector machine obtained an accuracy of 67.5% to distinguish between MDD at baseline and HCs. These findings may deepen our understanding of the neural basis of the effects of TIP on DMN subsystems in MDD.

Altered functional brain activity in first-episode major depressive disorder treated with electro-acupuncture: A resting-state functional magnetic resonance imaging study.

Background: Previous studies have found electroacupuncture could improve the clinical symptoms of first-episode major depressive disorder (MDD), but the exact neural mechanism of action needs to be further elucidated. Methods: Twenty-eight first-episode MDD patients were randomly divided into 14 electro-acupuncture stimulation (EAS) groups and 14 sham-acupuncture stimulation (SAS) groups, and clinical symptoms were assessed and functional magnetic resonance imaging (fMRI) scans were done in both groups. Amplitude of low-frequency fluctuations (ALFF) was used to observe the changes between the pre-treatment and post-treatment in the two groups, and the altered brain areas were selected as region of interest (ROI) to observe the FC changes. Meanwhile, the correlation between the altered clinical symptoms and the altered ALFF and FC of brain regions in the two groups was analyzed. Results: The EAS significantly decreased the HAMD-24 and HAMA-14 scores of MDD than SAS group. The imaging results revealed that both groups were able to increase the ALFF of the left middle temporal gyrus and the left cerebellar posterior lobe. When using the left middle temporal gyrus and the left posterior cerebellar lobe as ROIs, EAS group increased the FC between the left middle temporal gyrus with the left superior frontal gyrus, the left middle frontal gyrus, and the left hippocampus, and decreased the FC between the left posterior cerebellar lobe and the left calcarine gyrus, while SAS group only increased the FC between the left middle temporal gyrus with the left superior frontal gyrus. The alternations in clinical symptoms after EAS treatment were positively correlated with the altered ALFF values in the left middle temporal gyrus and the altered FC values in the left middle temporal gyrus and the left middle frontal gyrus. Conclusion: EA demonstrates modulation of functional activity in the default mode network (DMN), sensorimotor network (SMN), cognitive control network (CCN), limbic system, and visual network (VN) for the treatment of the first-episode MDD. Our findings contribute to the neuroimaging evidence for the efficacy of EAS.

Altered neural activity in the reward-related circuit associated with anhedonia in mild to moderate Major Depressive Disorder.

BACKGROUND: Anhedonia is a significant predictor of disease progression and treatment outcomes in Major Depressive Disorder (MDD), linked to reward network dysfunctions. However, understanding of its underlying neural mechanisms remains limited. This study aimed to investigate the brain functional mechanisms underlying MDD with anhedonia using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: The Snaith-Hamilton Pleasure Scale (SHAPS) was used to evaluation MDD with anhedonia (anMDD) and non-anhedonia MDD (non-anMDD). Forty-eight patients with anMDD, Forty-four patients with non-anMDD, and Fifty healthy controls (HCs) were enrolled for the fMRI scans. A seed-based functional connectivity (FC) method was employed to explore reward network abnormalities. RESULTS: anMDD patients exhibited lower FC values in Ventral Striatum (VS), right lateral Ventral Tegmental Area (VTA_R), left Thalamus (THA_L), and higher FC values in Ventromedial Prefrontal Cortex (vmPFC), left Anterior Insula (AI_L), and Presupplementary Motor Area (Pre-SMA) compared to HCs. Comparing anMDD to non-anMDD, significant differences were observed in FC values of VS, vmPFC, Pre-SMA, and THA_L regions. Correlation analysis revealed positive correlations between FC values of VS_R and NAc_R, as well as THA_L and Cerebellum_Crus1_L, with SHAPS scores. Negative correlations were observed between FC values of Pre-SMA and the right caudate, and between vmPFC and Frontal_Mid_Orb_L, and SHAPS scores. CONCLUSION: Both anMDD and non-anMDD groups demonstrated abnormal FCs in the reward network. These findings indicate distinct roles of reward-related circuits in the two subtypes, contributing to a refined understanding of depression phenotypes and potential directions for targeted interventions.

BMRMI Reduces Depressive Rumination Possibly through Improving Abnormal FC of Dorsal ACC.

Rumination is a common symptom of major depressive disorder (MDD) and has been characterized as a vulnerability factor for the onset or recurrence of MDD. However, the neurobiological mechanisms underlying rumination and appropriate treatment strategies remain unclear. In the current study, we used resting-state functional magnetic resonance imaging to investigate the effects of body-mind relaxation meditation induction (BMRMI) intervention in MDD with rumination. To this aim, we have recruited 25 MDD and 24 healthy controls (HCs). Changes in functional connectivity (FC) of the anterior cingulate cortex (ACC) subregion and the scores of clinical measurements were examined using correlation analysis. At baseline, MDD showed stronger FC between the right dorsal ACC (dACC) and right superior frontal gyrus than did the HC group. Compared to baseline, the HC group showed a significantly enhanced FC between the right dACC and right superior frontal gyrus, and the MDD group demonstrated a significantly weaker FC between the left dACC and right middle frontal gyrus (MFG) after the intervention. Furthermore, the FC between the right dACC and right superior frontal gyrus was positively associated with rumination scores across all participants at baseline. The above results indicate that BMRMI may regulate self-referential processing and cognitive function through modulating FC of the dACC in MDD with rumination.

Effect and neural mechanisms of the transcutaneous vagus nerve stimulation for relapse prevention in patients with remitted major depressive disorder: protocol for a longitudinal study.

INTRODUCTION: After the first episode, patients with remitted major depressive disorder (MDD) have a 60% chance of experiencing a second episode. There are currently no accepted, effective methods to prevent the recurrence of MDD in remission. Transcutaneous vagus nerve stimulation (taVNS) is a non-invasive, safe and economical approach based on the efficacy of VNS in improving clinical depression symptoms. This clinical trial will study the efficacy of taVNS in preventing MDD relapse and investigate the underlying mechanisms of this. METHODS AND ANALYSIS: We will conduct a multicentre, randomised, patient-blinded and evaluators double-blinded trial. We will randomise 90 eligible participants with recurrent MDD in remission in a 1:1 ratio into a real or sham taVNS group. All participants will be given six biopsychosocial assessments: proinflammatory cytokines, serum monoamine neurotransmitters, cognition, affective neuropsychology, multimodal neuroimaging and endocrinology. After the baseline measurements, all participants will be given corresponding interference for 6 months and then complete a 1-year follow-up. The assessments will be performed three times: at baseline, post-treatment and at the end of 1-year follow-up (except for multimodal MRI scanning, which will be conducted at the first two assessments only). Change in 17-item Hamilton Depression Rating Scale scores for MDD is the primary outcome parameter. ETHICS AND DISSEMINATION: The study protocol was approved by the Medical Ethical Committee of Beijing Hospital of Traditional Chinese Medicine on 18 January 2019 (2018BL-076). The trial results will be published in peer-reviewed journals and at conferences. TRIAL REGISTRATION NUMBER: ChiCTR1900022618.

Body-mind relaxation meditation modulates the thalamocortical functional connectivity in major depressive disorder: a preliminary resting-state fMRI study.

Mindfulness-based interventions such as meditation have increasingly been utilized for the treatment of psychological disorders and have been shown to be effective in the treatment of depression and relapse prevention. However, it remains largely unclear the neural mechanism of the therapeutic effects of meditation among depressed individuals. In this study, we investigated how body-mind relaxation meditation (BMRM) can modulate the thalamocortical functional connectivity (FC) in major depressive disorder patients and healthy controls. In the present study, we recruited 21 medication-naive adolescents with major depressive disorder (MDDs) and 24 matched healthy controls (HCs). We designed an audio recording to induce body-mind relaxation meditation. Resting-state fMRI (rs-fMRI) scans were collected before and after the BMRM intervention in both groups. The thalamus subregions were defined according to the Human Brainnetome Atlas, and functional connectivity (FC) was measured and compared to find brain regions that were affected by the BMRM intervention. Before the BMRM intervention, MDDs showed reduced FC of the bilateral precuneus/post cingulate cortex with the left posterior parietal thalamus and left caudal temporal thalamus, as well as an increased FC of the left occipital thalamus with the left medial frontal cortex. Moreover, aberrant FCs in MDDs at baseline were normalized following the BMRM intervention. After the BMRM intervention, both MDDs and HCs showed decreased FC between the left rostral temporal thalamus and the left inferior occipital. Given the small sample used in this study, future studies are warranted to evaluate the generalizability of these findings. Our findings suggest that BMRM is associated with changes in thalamocortical functional connectivity in MDDs. BMRM may act by strengthening connections between the thalamus and the default mode network, which are involved in a variety of high-level functioning, such as attention and self-related processes.

Effects of TIP treatment on brain network topology of frontolimbic circuit in first-episode, treatment-naïve major depressive disorder.

BACKGROUND: The Low Resistance Thought Induction Psychotherapy (TIP) is a comprehensive psychological treatment which could improve the clinical symptoms of major depressive disorder (MDD). However, the neural mechanisms for TIP treating MDD still remain unclear. This study aimed to investigate the topology of intrinsic connectivity network and the therapeutic effects of TIP in MDD on these topological properties. METHODS: Longitudinal study was conducted in 20 first-episode, treatment-naive MDD patients at baseline and after 6 weeks (12 sessions) of TIP treatment based on resting-state functional magnetic resonance image (rsfMRI) in conjunction with graph theoretical analysis. We constructed functional connectivity matrices and extracted the attribute features of the small-world networks in both MDD and age-, education level-, and gender-matched healthy controls (HCs). The global and local small-world network properties were explored and compared between MDD at baseline and HCs. The therapeutic effect of TIP was examined by comparing alterations in global and local network properties between MDD at baseline and after treatment. RESULTS: At baseline, MDD showed altered small-worldness and aberrant nodal properties in the frontolimbic circuit particularly in the orbital frontal gyrus, insula, precuneus and middle cingulate gyrus as compared with HCs. Following 6 weeks treatment, the abnormalities in the small-worldness and the nodal metrics were modulated, which were accompanied by a significant improvement in the clinical symptoms. CONCLUSIONS: Our findings contributed to the understanding of the abnormal topological patterns in the frontolimbic systems in MDD and implicated that these disruptions may be modified by TIP treatment.

Enhanced functional connectivity between insular subregions correlates with the efficacy of music and instruction-guided relaxation in depression.

Music and instruction-guided relaxation (MIGR) is a complementary therapeutic tool used in the treatment of the major depressive disorder (MDD). However, the neural mechanism that underlies the effect of MIGR on MDD patients is not known. Twenty-three right-handed MDD patients and 23 age-, sex-, handedness-, and educational level-matched healthy controls were enrolled. Resting-state functional MRI data were acquired from patients before and after MIGR and from healthy controls. The relationships between insular subregion-based functional connectivity and Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale (HAM-A), Automatic Thoughts Questionnaire, and Ruminative Responses Scale scores were examined. One-way analysis of variance exhibited significant differences among the three groups in functional connectivity between the left dorsal anterior insula (dAI) and left superior medial frontal gyrus (SMFG), left dAI and left precuneus, left posterior insula and left gyrus rectus, right ventral anterior insula (vAI) and left posterior cingulate cortex (PCC), right vAI and right inferior frontal gyrus (R-IFG). Further comparisons in regions of interest showed that MDD patients before MIGR showed decreased functional connectivity between the left dAI and left SMFG, left dAI and left precuneus, left posterior insula, and left gyrus rectus, right vAI and left PCC, right vAI and R-IFG relative to those in healthy controls. The strength of functional connectivity between the right dAI and left putamen also exhibited a negative correlation with the HAM-A score in MDD cases before MIGR. MIGR may result in enhanced functional connectivity in insular subregions, thereby potentially increasing the regulatory influence of cognitive reappraisal.

The effect of body-mind relaxation meditation induction on major depressive disorder: A resting-state fMRI study.

BACKGROUND: Meditation has been increasingly evaluated as an important complementary therapeutic tool for the treatment of depression. The present study employed resting-state functional magnetic resonance imaging (rs-fMRI) to examine the effect of body-mind relaxation meditation induction (BMRMI) on the brain activity of depressed patients and to investigate possible mechanisms of action for this complex intervention. METHOD: 21 major depressive disorder patients (MDDs) and 24 age and gender-matched healthy controls (HCs) received rs-fMRI scans at baseline and after listening to a selection of audio designed to induce body-mind relaxation meditation. The rs-fMRI data were analyzed using Matlab toolbox to obtain the amplitude of low-frequency fluctuations (ALFF) of the BOLD signal for the whole brain. A mixed-design repeated measures analysis of variance (ANOVA) was performed on the whole brain to find which brain regions were affected by the BMRMI. An additional functional connectivity analysis was used to identify any atypical connection patterns after the BMRMI. RESULTS: After the BMRMI experience, both the MDDs and HCs showed decreased ALFF values in the bilateral frontal pole (BA10). Additionally, increased functional connectivity from the right dorsal medial prefrontal cortex (dmPFC) to the left dorsal lateral prefrontal cortex (dlPFC) and the left lateral orbitofrontal cortex (OFC) was identified only in the MDDs after the BMRMI. LIMITATION: In order to exclude the impact of other events on the participants׳ brain activity, the Hamilton Rating Scales for Depression (HDRS) was not measured after the body-mind relaxation induction. CONCLUSION: Our findings support the hypothesis that body-mind relaxation meditation induction may regulate the activities of the prefrontal cortex and thus may have the potential to help patients construct reappraisal strategies that can modulate the brain activity in multiple emotion-processing systems.

Abnormal spontaneous neural activity in the anterior insular and anterior cingulate cortices in anxious depression.

OBJECTIVE: Anxious depression is a distinct clinical subtype of major depressive disorder (MDD) characterized by palpitations, somatic complaints, altered interoceptive awareness, high risk of suicide, and poor response to pharmacotherapy. However, the neural mechanisms of anxious depression are still not well understood. In this study we investigated changes in neural oscillation during the resting-state of patients with anxious depression by measuring differences in the amplitude of low-frequency fluctuation (ALFF). METHODS: Resting-state functional magnetic resonance imaging was acquired in 31 patients with anxious depression, 18 patients with remitted depression, as well as 68 gender- and age-matched healthy participants. We compared the differences both in the ALFF and fractional ALFF (fALFF) among the three groups. We also examined the correlation between the ALFF/fALFF and the severity of anxiety as well as depression. RESULTS: Anxious depression patients showed increased ALFF/fALFF in the right dorsal anterior insular cortex and decreased ALFF/fALFF in the bilateral lingual gyrus relative to remitted depression patients and healthy controls. The increased ALFF in the dorsal anterior insula was also positively correlated with stronger anxiety in the anxious depression group. Anxious depression patients also displayed increased fALFF in the right ventral anterior cingulate cortex (ACC) compared to remitted depression patients and healthy controls. CONCLUSIONS: Our results suggest that alterations of the cortico-limbic networks, including the right dorsal anterior insula and right ventral ACC, may play a critical role in the physiopathology of anxious depression.

White matter abnormalities in major depression: a tract-based spatial statistics and rumination study.

Increasing evidence indicates that major depressive disorder (MDD) is usually accompanied by altered white matter in the prefrontal cortex, the parietal lobe and the limbic system. As a behavioral abnormity of MDD, rumination has been believed to be a substantial indicator of the mental state of the depressive state. So far, however, no report that we are aware of has evaluated the relationship between white matter alterations and the ruminative state. In this study, we first explored the altered white matter using a tract-based spatial statistics (TBSS) method based on diffusion tensor imaging of 19 healthy and 16 depressive subjects. We then investigated correlations between the altered white matter microstructure in the identified altered regions and the severity of ruminations measured by the ruminative response scale. Our results demonstrated altered white matter microstructure in circuits connecting the prefrontal lobe, the parietal lobe and the limbic system (p<0.005, uncorrected), findings which support previous research. More importantly, the result also indicated that a greater alteration in the white matter is associated with a more ruminative state (p<0.05, Bonferroni corrected). The detected abnormalities in the white matter should be interpreted cautiously because of the small sample size in this study. This finding supports the psychometric significance of white matter deficits in MDD.