The Clinical Trial On Depression Treated By Electroacupuncture Of The Vagus Nerve In Auricular Conchea And Its Brain Response Monitored By FMRI

Objective:To observe the clinical therapeutic efficacy of electroacupuncture (EA) of the Vagus Nerve in Auricular Conchea (tVNS) on major Depression.Method:90patients with mild or moderate major depression were randomly enrolled into the group of tVNS at Auricular Conchea (60) and the control group of EA at the superior scapha (30). After4weeks’intervention, the following clinical rating scales were used for the efficacy evaluation, including24items of Hamilton Depression Rating Scale (24HAMD), Self-rating Depression Scale (SDS), Self-rating Anxiety Scale (SAS),14items of Hamilton Anxiety Rating Scale (14HAMA) and TCM signs’total scores.Results:The patients in tVNS group were significantly less depressed at the end of4weeks’treatment than the control group (p<0.05). The scores of24HAMD, SDS, SAS and14HAMA were decreased more significantly than those in the control (P<0.009), while no obvious difference of TCM signs’total scores was found between two groups (p>0.05).Conlusion:The therapeutic technique of tVNS is effective on the major depression. Objective:We investigated the BOLD fMRI response to transcutaneous electrical stimulation at right ACR on healthy and major depression patients respectively. It is hypothesized that tVNS modulate s of the network of nucleus of tract solitary-limbic system in healthy and depressive patient.Material and Method:Sixteen healthy subjects (18-27y) and22mild or moderate major depression patients (18-58y) participated in the fMRI study. The healthy subjects took part in the sham-controlled EA of the right ACR. The patients only joined the fMRI scan during tVNS at the right ACR. Before the test subjects gave their written informed consent, and the study was approved by the Guang An Men hospital’s ethics committee.tVNS was performed at the inner side of the right ear using a stand-alone electrical nerve stimulator, Huatou (TENS-200,manufactured by Suzhou Medical Appliance Manufactory, Jiangsu, China) connected with no-magnetic fibre wires to two electrodes. The electrodes were attached to the skin of the right ACR or the superior scapha with the adhesive tape. The tVNS stimulator was placed outside the scanner room. The stimulus was set in20Hz. Electrical current amplitude was varied individually between4and8mA. Before each of tVNS, the individual threshold of stimulus intensity was determined, defined by the subjects as a maximum strong sensation that is just not painful and therefore could be well tolerated. Brain imaging was conducted on a1.5Tesla GE Signa MRI system equipped with the standard two channels’Birdcage head coil. Experiment procedure of fMRI includes:1) resting state before tVNS,2) tVNS in block,3) resting state after tVNS.4) tVNS in6min. Each functional scan lasted for6minutes with a total of144time points.fMRI Data Analysis:(1) General Linear Model (GLM) Method. Imaging preprocessing and statistical analysis were performed using the SPM8software. Data preprocessing included motion correction in ART. For each tVNS session, the contrast between electric stimulation on and off was derived with a general linear model. Group analysis was performed using the fixed-effects model. The t-test was performed across all subjects to compare the hemodynamic response between tVNS and Control, or tNVS in the healthy and in patient. The threshold was set to P=0.005, corrected with3contiguous voxels for brainstem and20voxel for whole brain.(2) Functional Connectivity Analysis. MRI analysis procedures were optimized for seeding fcMRI analysis using SPM8. The nucleus tractus solitary (NTS) and the trigeminal nerve (TN) was set as the seeds in fcMRI analyses. For these analyses, the time course of seeding voxel from the participant’s brain defined within a whole-brain mask was correlated to the time course of every other voxel. Pearson correlation coefficients (r) were obtained between voxels, we chose a sphere of2mm radius around target voxel as Seed. The functional connectivity was calculated for the resting state, tVNS in6min EA. The maps were then compared between ACR and CON for the healthy group, tVNS in the healthy and patients.Results:1.1The average current for stimulation showed no differences between ACR and Control (6.5±2.1mA,6.85±1.8mA,P=0.72), and between the healthy and the patient (6.5±2.1mA,6.5±1.7mA,P=1).1.2The most striking characteristics of electroacupuncture sensations on auricular points were tingling, numbness and fullness. The frequencies of pressure, warm, heaviness and soreness were relative lower. The dull pain and coolness are rare. The features of electroacupuncture sensations were similar between the tVNS and control, or healthy subjects and patients.2. Hemodynamic Responses2.1The brain regions activated and deactivated by tVNS at the ACR in healthy subjectsIn healthy group, the activation is limited in left SII, bilateral parietal inferior gyrus (BA40),right temporal gyrus, left anterior insula, frontal lateral gyrus (BA44,47),frontal pole. However, the deactivation is predominant in the limbic-paralimbic regions, including hypothalamus, parahippocampus, amygdala, posterior cingulate gyrus, VMPF(ventral media prefrontal cortex); deactivation also distributed in cerebellum, temporal pole, precentral gyrus(BA4,6), superiror parietal gyrus (BA7). It is important the NTS was found in deactivation.2.2The Brain Regions activated and deactivated by stimulating at the Control region in healthy subjectsIn healthy group, the activation can be seen in bilateral parietal inferior gyrus (BA40), Lateral frontal lobe (BA6,8, BA44,46,47,BA10), right superior temporal gyrus, frontal pole. However, the deactivation showed in frontal lobe and temporal lobe, occipital, precuneus and MCC, cerebellum and midbrain in TN.2.3Comparison between tVNS at ACR and EA at superior scapha in healthy subjects.The tVNS induced more strong activation in the right optic area, left temporal pole, right superior frontal gyrus (BA6), right insula, cerebellum, right midbrain nucleus and substantia nigra (SN).2.4The Brain Regions activated and deactivated by stimulating at the ACR in depression patientsActivation:bilateral SII, occipital lobe, right cerebellum, right precentral gyrus in premotor areas, sup and mid frontal gyrus, thalamus, left angular gyrus, mid and inf frontal gyrus.Deactivation:the most of deactivated regions belonging to limbic-paralimbic sysytem. e.g. bilateral orbital frontal gyrus, left ACC, nuclear accumben, right HP and fusiform gyrus, hypothalamus, right sup and mid frontal gyrus, right precuneus.2.5The comparison between tVNS in healthy subjects and the depressived patientsActivation:right cerebellum, bilateral parahippocampus, middle and inferior temporal gyrus, hypothalamus, left TN, occipital lobe.2.6Functional Connectivity of the resting state network when seeding in NTS The functional connectivity between NTS and other brain regions included the following areas:the brainstem, TN, right frontal pole, bilateral dorsolateral prefrontal cortex (DLPF), right insular, left thalamus, inferior temporal gyrus, cerebellum.2.7Functional Connectivity of the resting state network when seeding in TN The functional connectivity between TN and other brain regions included the following areas:left locus coeruleus, right TN,SN, Right ACC, thalamus, left amygdala, Hp, MCC, PCC, Vermis, occipital gyrus.Conclusion:The current study investigated the brain effects of tVNS at ACR in healthy and depressive subjects, and demonstrated that tVNS elicited the similar effects in the limbic—paralimbic system as iVNS. It provided evidence for our hypothesis that tVNS modulates of the network of nucleus of tract solitary-limbic system in healthy and depressive patient. We propose that tVNS benefits the resistance epilepsy and depression via this important network.