| Objective:1. Repetitive transcranial magnetic stimulation (rTMS) would be applied to treat the patients with unipolar resistant depression. The clinical effect, therapeutic parameters and safety of rTMS were investigated. This would explore new sights in the etiology of depression, as well new ways to treat the disease.2.1H-MRS would be used to investigate quantitative levels of NAA, Glx, Cho, Cr and MI in prefrontal lobe and anterior cingulate cortex. We would test these metabolites in both TRD patients group and normal control group to explore their distribution, which may help to explore the neurophysiologic basis of the depression.3. We would exam longitudinally the levels of metabolites by 1H-MRS, before and after treatment of rTMS. It may help to explore the biological marker and therapeutic mechanism of rTMS, and to find new way and evidence in the etiology and clinical diagnosis of depression.Methods:1. Thirty-six patients with TRD patients were randomized to receive treatment of active rTMS or sham rTMS. The active rTMS was applied to the DLPFC, with high frequency (15Hz), high intensity (110% MT), and additional amount of stimuli (3000 pulses/day). Sham rTMS was applied with TMS coil perpendicular to the head surface. There were totally 20 times of rTMS treatment, with 5 times each week, and it lasted for 4 weeks. The HAMD, BDI, GAF and PSQI were used to estimate the clinical symptoms and treatment effectiveness at three time points:before treatment, after 2 weeks treatment, and after 4 weeks treatment.2. There were 34 patients with TRD and 28 normal controls, with no difference in age and gender. The MRS images were collected with Siemens 3.0T MRI scanner, and multi-voxel CSI-SE sequence was adapted. The ROI was set at left/right DLPFC, left/right ACC. After the MRS curve was drawn, peak area was calculated for each metabolite separately. The ratios of NAA/Cr, Glx/Cr, Cho/Cr, MI/Cr were figured out and were compared between patients with TRD and normal controls.3. After active rTMS treatment, the same procedure of MRS collection and image analysis were applied to 34 patients with TRD, and the ratios of NAA/Cr, Glx/Cr, Cho/Cr, MI/Cr were figured out. This was to detect the potential alteration after treatment of rTMS.4. SPSS 16.0 was used to analyze the data statistically. The relative concentrations were represented in mean±SD. Analysis of variance (ANOVA), pair T-test, and partial correlations analysis were used to exam the differences between groups. P< 0.05 was set a statistical significance.Results:1. After 4 weeks of rTMS, there were 12 effective cases, including 2 cases of remission. The effective power was 63.2%. There were 2 effective cases in the sham treatment group, with 11.8% effective power. The score of PSQI declined significantly after 2 weeks of rTMS treatment (P< 0.05). There were significant differences in measurement of HAMD, GAF, BDI and PSQI after 4 weeks treatment of active rTMS; whereas no similar difference was found in group with sham rTMS treatment (P> 0.05). The reduction of HAMD was correlated with age of onset (N=19, r=0.71, p=0.001), after controlling the effect of age, course of disease. No correlation was found between reduction of HAMD and age, gender, course of disease, and the number of depression onset (P> 0.05). No adverse effect like epilepsy or cognitive impairment occurred during or after the rTMS treatment.2. The results of 1H-MRS of TRD patients were separated according to the type of treatment, age of onset, course of disease, and these sub-groups were compared with normal group respectively. We found that all subgroups of TRD patients, including active rTMS subgroup, sham rTMS subgroup, early-onset subgroup, late-onset subgroup, long and short course of disease subgroups, all had significant lower MI/Cr ratio in left DLPFC when comparing to normal group. Active rTMS subgroup, sham rTMS subgroup, early-onset subgroup, long course of disease subgroups all had significant lower Cho/Cr ratio in left ACC when comparing to normal group.3. We set 50% reduction in HAMD as effective.12 TRD patients in active rTMS group and 1 TRD patient in sham rTMS group had effective treatment. In this effective treatment subgroup, the MI/Cr ratio in left DLPFC increased significantly after active rTMS treatment, and the ratio was similar to that of normal group (p> 0.05). A positive correlation was found between the increment of MI/Cr in left DLPFC and reduction of HAMD. There was a significant reduction of NAA/Cr in right ACC in active rTMS effective treatment subgroup. There was a significant increase of Cho/Cr in left DLPFC in sham rTMS treatment non-effective subgroup.Conclusion:1. High frequency rTMS is effective to the TRD patients, without changing the original drug treatment. It can ameliorate the sleep and depressive symptoms of the patients, with no obvious adverse effect. The potential mechanism may be that rTMS treatment has a positive effect on the brain metabolism.2.1H-MRS is sensitive to detect the spectrum of metabolites like NAA, Glx, Cho, Cr, MI, which applies a valuable method to explore the neurophysiological mechanism of disease. We find biochemical and histological structure alterations in the prefrontal cortex and limbic system in patients with depression. By detecting the concentration of some specific metabolites, such as NAA, Glx, Cho, Cr, MI,1H-MRS applies a new way to reveal the etiology of depression in aspect of neurobiochemistry.
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