Antidepressant effects of different schedules of repetitive transcranial magnetic stimulation vs. clomipramine in patients with major depression: relationship to changes in cortical excitability

The antidepressant effects of repetitive transcranial magnetic stimulation (rTMS) that have been demonstrated in recent studies could be related to its ability to modulate cortical excitability. Yet, the relationship between stimulus location and frequency and treatment outcome has not been established. The aim of the present study was to compare efficacy of rTMS in various configurations and clomipramine treatment in patients with major depression (MD) and to evaluate the relationship between clinical outcome and changes in cortical excitability. Fifty-nine MD patients were randomized to receive (1) left (n = 12) or right (n = 12) 3 Hz rTMS with placebo medication; (2) left (n = 10) or right (n = 9) 10 Hz rTMS with placebo medication; (3) active medication (clomipramine) with sham rTMS (n = 16). Both 3 Hz and 10 Hz rTMS were administered to the prefrontal cortex by a circular coil at an intensity of 110% and 100% of the resting motor threshold (rMT) respectively. Measurements of cortical excitability were performed prior to and 24 h after completion of 2 wk of daily rTMS or pharmacological treatments. These included the rMT, silent period threshold (SPT), inter-threshold difference (ITD), MEP/M-wave amplitude ratio and silent period duration (SPD). Severity of depression was blindly assessed by the Hamilton Depression Rating Scale (HDRS). The best improvement scores were seen in patients who received left 3 Hz rTMS. The 10 Hz rTMS treatment was less tolerated resulting in a significantly higher dropout rate. A significant increase of the MEP/M wave amplitude ratio accompanied by a shortening of the SPD was evidenced in patients who showed marked clinical improvement (reduction in HDRS by 50% or more) following left rTMS regardless of stimulation frequency. Our results suggest that 3 Hz left rTMS has a higher therapeutic efficacy and tolerability in patients with MD. The enhancement of cortical excitability may be related to the antidepressant action of rTMS.     

Plasma concentrations of neuroactive steroids before and after repetitive transcranial magnetic stimulation (rTMS) in major depression.

There is evidence for altered levels of neuroactive steroids in major depression that normalize after successful antidepressant pharmacotherapy. Currently it is not known whether this is a general principle of clinically effective antidepressant therapy or a pharmacological effect of antidepressants. Here, we investigated whether repetitive transcranial magnetic stimulation (rTMS) may affect plasma concentrations of neuroactive steroids in a similar way as antidepressant pharmacotherapy. Progesterone, 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP), 3alpha,5beta- tetrahydroprogesterone (3alpha,5beta-THP), 3beta,5alpha-tetrahydroprogesterone (3beta, 5alpha-THP) and dehydroepiandrosterone (DHEA) were quantified in 37 medication-free patients suffering from a major depressive episode before and after 10 sessions of left prefrontal rTMS. Plasma samples were analyzed by means of a highly sensitive and specific combined gas chromatography/mass spectrometry analysis. There was a significant reduction of depressive symptoms after rTMS. However, plasma concentrations of neuroactive steroids were not affected by rTMS and not related to clinical response. Clinical improvement after extended daily treatment with rTMS is not accompanied by changes in neuroactive steroid levels. Changes in neuroactive steroid levels after antidepressant pharmacotherapy more likely reflect specific pharmacological effects of antidepressant drugs and are not necessary for the amelioration of depressive symptoms.     

Comparison of repetitive transcranial magnetic stimulation and electroconvulsive therapy in unipolar non-psychotic refractory depression: a randomized, single-blind study

Repetitive transcranial magnetic stimulation (rTMS) can induce significant antidepressant effects and, for some patients, might be an alternative to electroconvulsive therapy (ECT). The results of studies comparing the efficacy of rTMS and ECT are mixed and, therefore, comparison of these two therapies needs to be further explored. Forty-two patients aged between 18 and 65 yr, referred to ECT due to unipolar non-psychotic depression refractoriness entered the trial. They were randomly assigned to receive either rTMS or ECT. Depressive symptom changes were blindly measured by Hamilton Depression Rating Scale, Visual Analogue Scale and Clinical Global Impression at baseline, after 2 wk and after 4 wk of treatment. There was no difference in the antidepressant efficacy of ECT and rTMS. Response rates were relatively low in both groups (40% and 50% respectively), with no significant difference between them (p=0.55). Remission rates were also low for both groups (20% and 10% respectively), also with no significant difference (p=0.631). There was no significant difference in the neuropsychological test performance after either one of these therapies. Both treatments were associated with a degree of improvement in refractory depression and therefore add to the literature that rTMS can be an effective option to ECT as it is a less costly treatment and is not associated with anaesthetic and other ECT risks.     

Combining high and low frequencies in rTMS antidepressive treatment: preliminary results

The antidepressive potency of repetitive transcranial magnetic stimulation (rTMS) seems to depend on variables such as the stimulation placements, different frequencies, stimulus intensities, coil shape and interstimulus intervals. The aim of this pilot study was to investigate the augmentation properties of rTMS combining low and high frequencies. Thirty six depressed medicated in-patients were recruited and assigned to three different rTMS treatment modalities as an add-on strategy (each n = 12). In group 1 a stimulus intensity of 110% of the motor threshold (MT) was used with a frequency of 10 Hz over the left dorsolatero prefrontal cortex (DLPC). The right DLPC was stimulated in the same session with 110% MT at 1 Hz. In group 2 the patients were stimulated only over the left DLPC with alternating trains of 110% MT at 10 Hz and trains of 110% MT at 1 Hz in the same session. In group 3 the high frequency stimulation over the left DLPC was performed as an internal control group. None of the treatment modalities was superior but different side effects were observed. These preliminary findings suggest that rTMS, at varying frequencies and stimulation placements, evokes different psychoactive effects of clinical relevance.     

Motor-evoked potential amplitudes elicited by transcranial magnetic stimulation do not differentiate between patients and normal controls

Transcranial magnetic stimulation (TMS) applied over the motor cortex depolarizes neurons and leads to motor-evoked potentials (MEP). To assess cortico-spinal excitability we compared the motor threshold (MT) and the averaged MEP amplitude generated by TMS in patients with major depression (MD) and matched controls. Nineteen patients, who where participants in a protocol comparing the antidepressant effects of rTMS with those of ECT, and thirteen age- and gender-matched normal controls were studied. MT was similar between patients and normal controls. The MEP amplitude response was significantly increased by rTMS, however, the magnitude of the response was similar in patients and normal controls. Correlations between the averaged MEP amplitude and age revealed that older subjects demonstrated significantly lower responses at all time-points. We conclude that cortico-spinal excitability is increased following rTMS, however, differences between patients and normal controls were not apparent with the paradigm used.     

A randomized trial of low-frequency right-prefrontal-cortex transcranial magnetic stimulation as augmentation in treatment-resistant major depression

Low-frequency right prefrontal repetitive transcranial magnetic stimulation (rTMS) appears to have antidepressant properties although the effectiveness of this treatment in clinical practice has not been assessed nor have the optimal stimulation parameters been adequately defined. A total of 130 patients with treatment-resistant depression were randomized to either 1- or 2-Hz rTMS over the right prefrontal cortex (PFC) for 2 wk with a possible further 2 wk extension. Non-responders were randomized to either 5- or 10-Hz left PFC rTMS. Overall, 66 patients (51%) achieved response and 35 (27%) remission criteria. For right-sided treatment, depression significantly improved but there was no between-group difference. Twenty-eight (42%) patients in the 1-Hz group and 33 (53%) patients in the 2-Hz group achieved response criteria (chi2=1.40, p>0.05). Depression symptom scores also improved for patients who crossed over to left-sided treatment but there was no significant difference in response between 5- and 10-Hz rTMS. Despite a heterogeneous sample, a significant proportion of patients met clinical response criteria following treatment but response to 1 and 2 Hz did not differ. 2-Hz right PFC rTMS has antidepressant properties but offers no advantage over 1 Hz despite doubling pulse number.     

Comparison of unlimited numbers of rapid transcranial magnetic stimulation (rTMS) and ECT treatment sessions in major depressive episode

Repetitive transcranial magnetic stimulation (rTMS) is a new technology which holds promise as a treatment of psychiatric disorders. Most work to date has been on depression. Superiority to placebo has been indicated in three small blind studies. We compared the antidepressant effects of rTMS and ECT in 32 patients suffering major depressive episode (MDE) who had failed to respond to at least one course of medication. There was no limit to the number of treatment sessions which could be given and treatment was continued until remission occurred or response plateaued. A significant main effect for treatment type was found [Pillai trace = 0.248, F(3,28) = 3.076, p = 0.044; power = 0.656], reflecting an advantage for ECT patients on measures of depression overall, however, rTMS produced comparable results on a number of measures. Blind raters using the 17-item Hamilton Depression Rating Scale (HDRS) found the rate of remission (HDRS = ? 8) was the same (68.8%), and the percentage improvement over the course of treatment of 55.6% (rTMS) and 66.4% (ECT), while favouring ECT, was not significantly different. Significant differences were shown (p & 0.03) in percentage improvement on Beck Depression Inventory ratings (rTMS, 45.5%; ECT, 69.1%), but not for improvement in Visual Analogue ratings of mood (rTMS 42.3%; ECT, 57%). rTMS has antidepressant effects of useful proportions and further studies are indicated.     

The influence of rapid-rate transcranial magnetic stimulation (rTMS) parameters on rTMS effects in Porsolt's forced swimming test

To assess the similarity of the behavioural effects of the rapid transcranial magnetic stimulation (rTMS) to those produced by other antidepressant treatments, in particular to repeated electroconvulsive shock (ECS), we carried out experiments on Wistar rats. The effects of a standard ECS procedure (9 daily treatments; the current parameters: 150 mA, 50 Hz, 0.5 s) were compared with 18 d treatment with rTMS of the same field intensity of 1.6 T but with different stimulation frequency (20 or 30 Hz) and a different number of sessions (9 or 18). Twenty-four hours after the last treatment the forced swimming test was carried out and the immobility time was recorded. The standard ECT reduced the immobility by 50%, the intensive rTMS (90 or 104 K impulses for the whole period of treatment) caused a significant effect, although smaller than that induced by ECT (reduction by 20-30%). The stimulation at 20 Hz required 18 treatment sessions to produce a significant effect, while only 9 sessions with stimulation at 30 Hz were sufficient to produce a comparable result. This suggests that the effectiveness of rTMS may be augmented by increasing the number or frequency of rTMS impulses.     

Prefrontal repetitive transcranial magnetic stimulation (rTMS) changes relative perfusion locally and remotely

Although transcranial magnetic stimulation has been used as a stand‐alone brain mapping tool, relatively few studies have attempted to couple TMS with functional brain imaging to understand the neurobiological effects of TMS. Technical problems of placing a TMS coil in a PET or MRI scanner have hampered previous efforts at imaging the immediate effects of TMS. Perfusion SPECT offers the advantage of tracer injection away from the camera, with later image development. We wondered if perfusion SPECT could be used to visualize brain changes during rTMS over the left prefrontal cortex—a region where rTMS has been shown to cause changes in mood or working memory. Eight healthy adult subjects were scanned with brain SPECT scintigraphy using 30 mCi (1110 MBq) Neurolite^® (DuPont Pharma) on a triple‐headed Picker camera. Each subject had three scans: (1) baseline, (2) bolus tracer injection during seconds 10–20 of a train of 2 min of left prefrontal rTMS (10 Hz; 60% motor threshold (MT); 10 s on/off, 600 stimuli) (2MIN), and (3) exactly as in the 2MIN, but immediately after subjects had received 18 min of high frequency stimulation (20 Hz; 80% MT; 2 s on/28 s off, 1440+600=2040 total stimuli) (20MIN). Scans were linearly transformed into Talairach space using SPM96b and compared across conditions (p<0·05 for display). Contrary to our prestudy hypothesis, there was no relative increase at the coil site during the 2 min or the 20 min scan compared to baseline. In fact, at the 20 min comparison perfusion was relatively decreased in the right prefrontal cortex, bilateral anterior cingulate, and anterior temporal cortex. Also, relative perfusion was significantly increased in the orbitofrontal cortex (L>R) and hypothalamus at 20 min and at 2 min, with thalamic increases occurring at the 20 min scan compared to baseline. There was an apparent TMS dose effect with twice as many decreases at 20 min than 2 min. Directly comparing the 20 min to the 2 min scans demonstrated opposite hemisphere decreases and relative increases in the ipsilateral (left) hemisphere as a function of more TMS stimuli. Full interpretation of these results is hampered by incomplete knowledge of the effect of the relative amount of stimulation to rest during tracer uptake, pharmacokinetics of tracer uptake, and depth and intensity of the magnetic field. Nevertheless, coupling rTMS with split‐dose perfusion SPECT appears to be a promising method for understanding the brain changes associated with rTMS, and for directly visualizing neural circuits. We have demonstrated that prefrontal rTMS at high frequencies has both local and remote effects. These imaging results may help explain the cognitive and behavioural effects demonstrated in other prefrontal rTMS studies involving mood and working memory. Copyright © 1999 John Wiley & Sons, Ltd.     

Repetitive transcranial magnetic stimulation : does it have potential in the treatment of depression?

Transcranial magnetic stimulation (TMS) has become a major research tool in experimental clinical neurophysiology as a result of its potential to noninvasively and focally stimulate cortical brain regions. Currently, studies are being conducted to investigate whether repetitive TMS (rTMS)-mediated modulation of cortical function may also provide a therapeutic approach in neurological and psychiatric disorders. Preclinical findings have shown that prefrontal rTMS can modulate the function of fronto-limbic circuits, which is reversibly altered in major depression. rTMS has also been found to exert effects on neurotransmitter systems involved in the pathophysiology of major depression (e.g. stimulates subcortical dopamine release and acts on the hypothalamic pituitary adrenal axis, which is dysregulated in depression). To date, numerous open and controlled clinical trials with widely differing stimulation parameters have explored the antidepressant potential of rTMS. Though conducted with small sample sizes, the majority of the controlled trials demonstrated significant antidepressant effects of active rTMS compared with a sham condition. Effect sizes, however, varied from modest to substantial, and the patient selection focused on therapy-resistant cases. Moreover, the average treatment duration was approximately 2 weeks, which is short compared with other antidepressant interventions. Larger multicentre trials, which would be mandatory to demonstrate the antidepressant effectiveness of rTMS, have not been conducted to date.A putative future application of rTMS may be the treatment of patients who did not tolerate or did not respond to antidepressant pharmacotherapy before trying more invasive strategies such as electroconvulsive therapy and vagus nerve stimulation. Theoretically, rTMS may be also applied early in the course of disease in order to speed up and increase the effects of antidepressant pharmacotherapy. However, this application has not been a focus of clinical trials to date. Research efforts should be intensified to further investigate the effectiveness of rTMS as an antidepressant intervention and to test specific applications of the technique in the treatment of depressive episodes.     

Prefrontal TMS produces smaller EEG responses than motor-cortex TMS: implications for rTMS treatment in depression

Rationale The stimulus intensity of prefrontal repetitive transcranial magnetic stimulation (rTMS) during depression treatment is usually determined by adjusting it with respect to the motor threshold (MT). There is some evidence that reactivity of the prefrontal cortex to transcranial magnetic stimulation (TMS) is lower than that of the motor cortex at MT stimulation. However, it is unknown whether this is true when other stimulus intensities are used. We investigated whether the magnitude and shape of the overall TMS-evoked electroencephalographic (EEG) responses differ between prefrontal and motor cortices. Methods Magnetic pulses to the left motor and prefrontal cortices (the middle frontal gyrus identified from magnetic resonance images) were delivered at four intensities (60, 80, 100, and 120% of MT of the right abductor digiti minimi muscle) for six subjects. Simultaneously, EEG was recorded with 60 scalp electrodes. Results Global mean-field amplitudes (GMFAs) reflecting overall cortical activity were significantly smaller after prefrontal- than after motor-cortex TMS. A significant positive correlation (r _s=0.84, p<0.01) was found between GMFAs of motor- and prefrontal-cortex TMS across the experiments. However, when correlation between the responses of motor and prefrontal cortices was examined, significant positive correlations were found at 80 and 100% intensities only. Conclusions This study provides further evidence that the prefrontal and motor cortices have different reactivity to TMS, but the MT may be used for determining the stimulus intensity of prefrontal rTMS treatment in depression, at least at motor threshold intensities or near to it.     

Priming stimulation enhances the effectiveness of low-frequency right prefrontal cortex transcranial magnetic stimulation in major depression

OBJECTIVES: Low-frequency, right-sided repetitive transcranial magnetic stimulation (rTMS) to the prefrontal cortex has been shown to have antidepressant effects. Recent research has suggested that preceding low-frequency rTMS with a period of low-intensity, 6-Hz stimulation ("priming") enhances the physiological effects of low-frequency stimulation. The aim of this study was to investigate whether priming stimulation would enhance therapeutic response to low-frequency rTMS in patients with depression. METHOD: The study consisted of a 2-arm, double-blind, randomized, controlled trial in 60 patients with treatment-resistant depression. Right 1-Hz rTMS was provided in one continuous, 15-minute train to all subjects. The priming stimulation (twenty 5-second, 6-Hz trains) or an equivalent, sham preceded 1-Hz stimulation. The primary outcome variable was the score on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: There was a significant overall reduction in MADRS scores across the 4 weeks of the study and a significantly greater reduction in MADRS scores in the active-priming group compared with the sham-priming group. CONCLUSIONS: Low-intensity, high-frequency priming stimulation appears to enhance the response to low-frequency, right-sided rTMS treatment in patients with treatment-resistant depression.     

Partial clinical response to 2 weeks of 2 Hz repetitive transcranial magnetic stimulation to the right parietal cortex in depression

The aim of this treatment study was to evaluate the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) over the right parietal cortex in depression. In a double-blind, sham-controlled design ten consecutive sessions of 2 Hz rTMS (inter-pulse interval 0.5 s) at 90% motor threshold to the right parietal cortex (2400 pulses per session) were applied to 34 patients with the primary diagnosis of DSM-IV depression and a score of > or =15 on the 17-item Hamilton Rating Scale for Depression (HAMD). The primary outcome measures were the percentage change from baseline on the 17-item HAMD scores after ten sessions, and the percentage of clinical (defined as > or =50% reduction in HAMD score) and partial clinical (defined as > or =30% reduction in HAMD score) responders. Reduction of HAMD scores in the real rTMS treatment (mean real+/-S.D., -19.9+/-32.5%) was not statistically different from the sham rTMS treatment (mean sham+/-S.D., -5.6+/-28.4%), and the number of clinical responders did not differ between treatments. However, a significant greater number of partial clinical responders were observed in the real (43.8%) compared to the sham rTMS treatment (6.3%). This study provides the first evidence showing that 2 Hz rTMS over the right parietal cortex may have antidepressant properties, and warrants further research.     

One session of high frequency repetitive transcranial magnetic stimulation (rTMS) to the right prefrontal cortex transiently reduces cocaine craving

BACKGROUND: Cocaine dependence is a public health problem affecting 2 million individuals in USA. Craving is a predictor of subsequent cocaine use and is related to changes in brain activity in networks involving the prefrontal cortex. METHODS: We investigated the efficacy of one session of high frequency repetitive transcranial magnetic stimulation (rTMS) to reduce craving in cocaine addicted subjects. Six patients underwent two sessions of 10Hz rTMS over left or right dorsolateral prefrontal cortex (DLPFC). Before, immediately after and 4h after rTMS we measured craving using visual analogue scales. RESULTS: Right, but not left, DLPFC stimulation significantly reduced craving over time (F(2,10)=11.07, p=0.0029). The reduction was 19% (13.4-24.6%) from baseline and disappeared after 4h. The interaction of time by site of stimulation for craving was also significant (F(2,25)=6.13, p=0.0068). CONCLUSION: One session of 10Hz rTMS over right, but not left, DLPFC transiently reduces craving in cocaine dependent individuals. These results highlight the potential of non-invasive neuromodulation as a therapeutic tool for cocaine addiction.     

不同频率的功能性磁刺激对于脊髓损伤所致高反应性膀胱临床疗效研究

目的应用2组不同频率功能性磁刺激(5Hz、10Hz)治疗脊髓损伤高反应性膀胱,与低频电刺激组进行对照,评估治疗疗效,选取更优治疗频率。方法选取2017年10月1日至2020年3月31日我院脊髓损伤高反应性膀胱功能障碍患者38例,根据入院时间随机分为3组,在常规康复治疗的基础上,对照组为低频电刺激组,功能磁刺激组为5Hz治疗组及10Hz治疗组。入组时进行膀胱功能评定,在完成10次治疗后,再次进行膀胱功能评定,对比治疗前后及各组间的疗效差异。结果3组膀胱功能参数治疗前后,差异具有统计学意义。3组治疗前膀胱的最大容量、最大压力、残余尿量差异无统计学意义。3组治疗后,2组不同频率功能性磁刺激治疗组间差异无统计学意义;5 Hz功能性磁刺激治疗组与低频电刺激组相比,膀胱最大容量、膀胱最大压力差异有统计学意义。结论5 Hz、10 Hz功能性磁刺激及低频电刺激对于脊髓损伤高反应性膀胱功能障碍均有临床治疗疗效,其中5 Hz功能性磁刺激治疗的疗效优于低频电刺激组。     

Predictors of antidepressant response in clinical trials of transcranial magnetic stimulation

Although previous clinical trials have suggested that repetitive transcranial magnetic stimulation (rTMS) has a significant antidepressant effect, the results of these trials are heterogeneous. We hypothesized that individual patients' characteristics might contribute to such heterogeneity. Our aim was to identify predictors of antidepressant response to rTMS. We pooled data from six separate clinical trials conducted independently, which evaluated the effects of rapid rTMS of the left dorsolateral prefrontal cortex in patients with major depression. We investigated 195 patients with regard to demographic, depression and treatment characteristics, psychiatric and drug history. Results showed that age and treatment refractoriness were significant negative predictors of depression improvement when adjusting these variables to other significant predictors and confounders. These findings were not confounded by methodological differences from the six studies, as the results were adjusted for the study site. In conclusion TMS antidepressant therapy in younger and less treatment-resistant patients is associated with better outcome.     

草酸艾司西酞普兰联合rTMS治疗脑梗死后抑郁的疗效及对神经功能的影响

目的：探寻草酸艾西酞普兰联合重复经颅磁刺激（rTMS）治疗脑梗死后抑郁的临床疗效，并观察其对神经功能的影响。方法：选取某院2015年5月-2017年5月收治的100例脑梗死后抑郁患者为研究对象，将其按随机数字表法分为观察组和对照组，对照组行草酸艾西酞普兰治疗，观察组行草酸艾西酞普兰联合rTMS治疗，观察2组患者的抑郁缓解情况、神经功能恢复情况、HAMD评分、BI评分、不同时间段的NIHSS评分变化情况。结果：观察组抑郁缓解总有效率76%显著高于对照组总有效率60%（χ²=3.945，P<0.05），观察组神经功能恢复总有效率78%显著高于对照组总有效率68%（χ²=5.195，P<0.05）。治疗后，观察组患者的HAMD评分[（14.85±1.95）分]显著低于对照组[（18.27±2.57）分]，BI评分[（86.22±6.51）分]显著高于对照组[（65.37±7.21）分]，差异具有显著性（P均<0.05）。治疗前2组NIHSS评分无差异（P>0.05），治疗后7 d观察组NIHSS评分[（11.38±3.17）分]显著低于对照组[（13.34±3.31）分]，治疗后28 d观察组NIHSS评分[（5.29±2.56）分]显著低于对照组[（8.06±3.25）分]，差异具有显著性（P均<0.05）。结论：草酸艾西酞普兰联合rTMS治疗脑梗死后抑郁患者具有较好临床疗效，可进一步缓解患者的抑郁症状，促进其神经功能恢复。     

rTMS treatment for depression in Parkinson's disease increases BOLD responses in the left prefrontal cortex

The mechanisms underlying the effects of antidepressant treatment in patients with Parkinson's disease (PD) are unclear. The neural changes after successful therapy investigated by neuroimaging methods can give insights into the mechanisms of action related to a specific treatment choice. To study the mechanisms of neural modulation of repetitive transcranial magnetic stimulation (rTMS) and fluoxetine, 21 PD depressed patients were randomized into only two active treatment groups for 4 wk: active rTMS over left dorsolateral prefrontal cortex (DLPFC) (5 Hz rTMS; 120% motor threshold) with placebo pill and sham rTMS with fluoxetine 20 mg/d. Event-related functional magnetic resonance imaging (fMRI) with emotional stimuli was performed before and after treatment - in two sessions (test and re-test) at each time-point. The two groups of treatment had a significant, similar mood improvement. After rTMS treatment, there were brain activity decreases in left fusiform gyrus, cerebellum and right DLPFC and brain activity increases in left DLPFC and anterior cingulate gyrus compared to baseline. In contrast, after fluoxetine treatment, there were brain activity increases in right premotor and right medial prefrontal cortex. There was a significant interaction effect between groups vs. time in the left medial prefrontal cortex, suggesting that the activity in this area changed differently in the two treatment groups. Our findings show that antidepressant effects of rTMS and fluoxetine in PD are associated with changes in different areas of the depression-related neural network.     

Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome.

This open pilot study of vagus nerve stimulation (VNS) in 60 patients with treatment-resistant major depressive episodes (MDEs) aimed to: 1) define the response rate; 2) determine the profile of side effects; and, most importantly; 3) establish predictors of clinical outcome. Participants were outpatients with nonatypical, nonpsychotic, major depressive or bipolar disorder who had not responded to at least two medication trials from different antidepressant classes in the current MDE. While on stable medication regimens, the patients completed a baseline period followed by device implantation. A 2-week, single blind, recovery period (no stimulation) was followed by 10 weeks of VNS. Of 59 completers (one patient improved during the recovery period), the response rate was 30.5% for the primary HRSD(28) measure, 34.0% for the Montgomery-Asberg Depression Rating Scale (MADRAS), and 37.3% for the Clinical Global Impression-Improvement Score (CGI-I of 1 or 2). The most common side effect was voice alteration or hoarseness, 55.0% (33/60), which was generally mild and related to output current intensity. History of treatment resistance was predictive of VNS outcome. Patients who had never received ECT (lifetime) were 3.9 times more likely to respond. Of the 13 patients who had not responded to more than seven adequate antidepressant trials in the current MDE, none responded, compared to 39.1% of the remaining 46 patients (p =.0057). Thus, VNS appears to be most effective in patients with low to moderate, but not extreme, antidepressant resistance. Evidence concerning VNS' long-term therapeutic benefits and tolerability will be critical in determining its role in treatment-resistant depression.     

Modulation of frequency and duration of repetitive magnetic stimulation affects catecholamine levels and tyrosine hydroxylase activity in human neuroblastoma cells: implication for the antidepressant effect of rTMS

Transcranial magnetic stimulation (TMS), which is produced by strong non-static magnetic fields, is a non-invasive means to stimulate the cerebral cortex. Studies from recent years show that TMS affects mood in healthy subjects and improves depressive symptoms in patients with major depression. However, the relationship between the clinical efficacy of TMS and stimulation parameters is still obscure. In the present study we have investigated the effects of different stimulation frequencies and number of treatments on catecholamine turnover in SH-SY5Y cell cultures. A single session of magnetic stimulation (1.7 T) caused a significant decrease in intracellular dopamine and L-DOPA and in noradrenaline (NE) release at a rate of 3 Hz for 10 s but increased NE release at a rate of 9 Hz. These alterations were associated with a reduction (47.8%) or an increase (48%) in tyrosine hydroxylase (TH) activity after 3 and 9 Hz magnetic stimulation, respectively. The latter may be related to the known sensitivity of TH to neuronal firing rates and NE concentrations. Higher stimulation frequencies (15, 20, 45 Hz) had no effect on catecholamine metabolism. Unlike 3 Hz acute treatment, chronic treatment (3 Hz, 11 sessions, for 4 d) had no effect on monoamines and TH activity was increased by 54.5% with no change in its protein level. The results of the present study demonstrate that in tissue culture system frequency and treatment duration of the magnetic stimulation are important factors in affecting catecholamine turnover. Considering the major role of catecholamine in the pathophysiology of depression, these findings may be of relevance to the application of rTMS in humans with major depression.