Influence of BDNF Val66Met polymorphism on excitatory-inhibitory balance and plasticity in human motor cortex.

OBJECTIVE: While previous studies showed that the single nucleotide polymorphism (Val66Met) of brain-derived neurotrophic factor (BDNF) can impact neuroplasticity, the influence of BDNF genotype on cortical circuitry and relationship to neuroplasticity remain relatively unexplored in human. METHODS: Using individualised transcranial magnetic stimulation (TMS) parameters, we explored the influence of the BDNF Val66Met polymorphism on excitatory and inhibitory neural circuitry, its relation to I-wave TMS (ITMS) plasticity and effect on the excitatory/inhibitory (E/I) balance in 18 healthy individuals. RESULTS: Excitatory and inhibitory indexes of neurotransmission were reduced in Met allele carriers. An E/I balance was evident, which was influenced by BDNF with higher E/I ratios in Val/Val homozygotes. Both long-term potentiation (LTP-) and depression (LTD-) like ITMS plasticity were greater in Val/Val homozygotes. LTP- but not LTD-like effects were restored in Met allele carriers by increasing stimulus intensity to compensate for reduced excitatory transmission. CONCLUSIONS: The influence of BDNF genotype may extend beyond neuroplasticity to neurotransmission. The E/I balance was evident in human motor cortex, modulated by BDNF and measurable using TMS. Given the limited sample, these preliminary findings warrant further investigation. SIGNIFICANCE: These novel findings suggest a broader role of BDNF genotype on neurocircuitry in human motor cortex.

Differentiating responders and non-responders to rTMS treatment for depression after one week using resting EEG connectivity measures.

BACKGROUND: Non-response to repetitive transcranial magnetic stimulation (rTMS) treatment for depression is costly for both patients and clinics. Simple and cheap methods to predict response would reduce this burden. Resting EEG measures differentiate responders from non-responders, so may have utility for response prediction. METHODS: Fifty patients with treatment resistant depression and 21 controls had resting electroencephalography (EEG) recorded at baseline (BL). Patients underwent 5-8 weeks of rTMS treatment, with EEG recordings repeated at week 1 (W1). Forty-two participants had valid BL and W1 EEG data, and 12 were responders. Responders and non-responders were compared at BL and W1 in measures of theta (4-8 Hz) and alpha (8-13 Hz) power and connectivity, frontal theta cordance and alpha peak frequency. Control group comparisons were made for measures that differed between responders and non-responders. A machine learning algorithm assessed the potential to differentiate responders from non-responders using EEG measures in combination with change in depression scores from BL to W1. RESULTS: Responders showed elevated theta connectivity across BL and W1. No other EEG measures differed between groups. Responders could be distinguished from non-responders with a mean sensitivity of 0.84 (p = 0.001) and specificity of 0.89 (p = 0.002) using cross-validated machine learning classification on the combination of all EEG and mood measures. LIMITATIONS: The low response rate limited our sample size to only 12 responders. CONCLUSION: Resting theta connectivity at BL and W1 differ between responders and non-responders, and show potential for predicting response to rTMS treatment for depression.

Reward-driven decision-making impairments in schizophrenia.

The ability to use feedback to guide optimal decision-making is essential for goal-directed behaviour. While impairments in feedback-driven decision-making have been associated with schizophrenia and depression, this has been examined primarily in the context of binary probabilistic choice paradigms. In real-world decision-making, however, individuals must make choices when there are more than two competing options that vary in the frequency and magnitude of potential rewards and losses. Thus, the current study examined win-stay/lose-shift (WSLS) behaviour on the Iowa Gambling Task (IGT) in order to evaluate the influence of immediate rewards and losses in guiding real-world decision-making in patients with schizophrenia and major depressive disorder. Fifty-one patients with schizophrenia, 43 patients with major depressive disorder, and 51 healthy controls completed the IGT, as well as a series of clinical and cognitive measures. WSLS was assessed by quantifying trial-by-trial behaviour following rewards and losses on the IGT. Multivariate analyses of variance revealed that patients with schizophrenia demonstrated intact lose-shift behaviour, but significantly reduced win-stay rates compared to healthy controls. In contrast, no WSLS impairments emerged in the depressed group. Win-stay impairments in the schizophrenia group were significantly related to deficits in motivation and cognition. Patients with schizophrenia exhibit impaired reward-driven decision-making in the context of multiple choices with concurrent rewards and losses, and this appears to be driven by a reduced propensity for advantageous win-stay behaviour. With the importance of reward learning and decision-making in generating goal-directed behaviour, these findings suggest a potential mechanism contributing to the motivation deficits seen in schizophrenia.

Responders to rTMS for depression show increased fronto-midline theta and theta connectivity compared to non-responders.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression, but only some individuals respond. Predicting response could reduce patient and clinical burden. Neural activity related to working memory (WM) has been related to mood improvements, so may represent a biomarker for response prediction. PRIMARY HYPOTHESES: We expected higher theta and alpha activity in responders compared to non-responders to rTMS. METHODS: Fifty patients with treatment resistant depression and twenty controls performed a WM task while electroencephalography (EEG) was recorded. Patients underwent 5-8 weeks of rTMS treatment, repeating the EEG at week 1 (W1). Of the 39 participants with valid WM-related EEG data from baseline and W1, 10 were responders. Comparisons between responders and non-responders were made at baseline and W1 for measures of theta (4-8 Hz), upper alpha (10-12.5 Hz), and gamma (30-45 Hz) power, connectivity, and theta-gamma coupling. The control group's measures were compared to the depression group's baseline measures separately. RESULTS: Responders showed higher levels of WM-related fronto-midline theta power and theta connectivity compared to non-responders at baseline and W1. Responder's fronto-midline theta power and connectivity was similar to controls. Responders also showed an increase in gamma connectivity from baseline to W1, with a concurrent improvement in mood and WM reaction times. An unbiased combination of all measures provided mean sensitivity of 0.90 at predicting responders and specificity of 0.92 in a predictive machine learning algorithm. CONCLUSION: Baseline and W1 fronto-midline theta power and theta connectivity show good potential for predicting response to rTMS treatment for depression.

Low medical morbidity and mortality after acute courses of electroconvulsive therapy in a population-based sample.

BACKGROUND: To determine event rates for specific medical events and mortality among individuals receiving electroconvulsive therapy (ECT). METHOD: Population-based cohort study using health administrative data of acute ECT treatments delivered in Ontario, Canada, from 2003 to 2011. We measured the following medical event rates, per 10 000 ECT treatments, up to 7 and 30 days post-treatment: stroke, seizure, acute myocardial infarction, arrhythmia, pneumonia, pulmonary embolus, deep vein thrombosis, gastrointestinal bleeding, falls, hip fracture, and mortality. RESULTS: A total of 135 831 ECT treatments were delivered to 8810 unique patients. Overall medical event rates were 9.1 and 16.8 per 10 000 ECT treatments respectively. The most common medical events were falls (2.7 and 5.5 per 10 000 ECT treatments) and pneumonia (1.8 and 3.8 per 10 000 ECT treatments). Fewer than six deaths occurred on the day of an ECT treatment. This corresponded to a mortality rate of less than 0.4 per 10 000 treatments. Deaths within 7 and 30 days of an ECT treatment, excluding deaths due to external causes (e.g., accidental and intentional causes of death), were 1.0 and 2.4 per 10 000 ECT treatments respectively. CONCLUSION: Morbidity and mortality events after ECT treatments were relatively low, supporting ECT as a low-risk medical procedure.

Investigating consummatory and anticipatory pleasure across motivation deficits in schizophrenia and healthy controls.

Anhedonia has traditionally been considered a characteristic feature of schizophrenia, but the true nature of this deficit remains elusive. This study sought to investigate consummatory and anticipatory pleasure as it relates to motivation deficits. Eighty-four outpatients with schizophrenia and 81 healthy controls were administered the Temporal Experience of Pleasure Scale (TEPS), as well as a battery of clinical and cognitive assessments. Multivariate analyses of variance were used to examine the experience of pleasure as a function of diagnosis, and across levels of motivation deficits (i.e. low vs. moderate. vs. high) in schizophrenia. Hierarchical regression analyses were also conducted to evaluate the predictive value of amotivation in relation to the TEPS. There were no significant differences between schizophrenia and healthy control groups for either consummatory or anticipatory pleasure. Within the schizophrenia patients, only those with high levels of amotivation were significantly impaired in consummatory and anticipatory pleasure compared to low and moderate groups, and compared to healthy controls. Further, our results revealed that amotivation significantly predicts both consummatory and anticipatory pleasure, with no independent contribution of group. Utilizing study samples with a wide range of motivation deficits and incorporating objective paradigms may provide a more comprehensive understanding of hedonic deficits.

Evidence for increased motor cortical facilitation and decreased inhibition in atypical depression.

OBJECTIVE: Major depressive disorder (MDD) is a clinically heterogeneous condition. However, the role of cortical glutamate and gamma-aminobutyric acid (GABA) receptor-mediated activity, implicated in MDD pathophysiology, has not been explored in different MDD subtypes. Our aim was to assess the atypical and melancholic depression subtypes regarding potential differences in GABA and glutamate receptor-mediated activity through established transcranial magnetic stimulation (TMS) neurophysiological measures from the motor cortex. METHOD: We evaluated 81 subjects free of antidepressant medication, including 21 healthy controls and 20 patients with atypical, 20 with melancholic, and 20 with undifferentiated MDD. Single and paired-pulse TMS paradigms were used to evaluate intracortical facilitation (ICF), cortical silent period (CSP), and short intracortical inhibition (SICI), which index glutamate, GABAB receptor-, and GABAA receptor-mediated activity respectively. RESULTS: Patients with MDD demonstrated significantly decreased mean CSP values than healthy controls (Cohen's d = 0.22-0.3, P < 0.01 for all comparisons). Atypical depression presented a distinct cortical excitability pattern of decreased cortical inhibition and increased cortical facilitation, that is, an increased mean ICF and SICI ratios than other depression subtypes (d = 0.22-0.33, P < 0.01 for all comparisons). CONCLUSION: Different MDD subtypes may demonstrate different neurophysiology in relation to GABAA and glutamatergic activity. TMS as an investigational tool might be useful to distinguish between different MDD subtypes.

Neurobiological mechanisms of repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex in depression: a systematic review.

Depression is one of the most prevalent mental illnesses worldwide and a leading cause of disability, especially in the setting of treatment resistance. In recent years, repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising alternative strategy for treatment-resistant depression and its clinical efficacy has been investigated intensively across the world. However, the underlying neurobiological mechanisms of the antidepressant effect of rTMS are still not fully understood. This review aims to systematically synthesize the literature on the neurobiological mechanisms of treatment response to rTMS in patients with depression. Medline (1996-2014), Embase (1980-2014) and PsycINFO (1806-2014) were searched under set terms. Three authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. Of 1647 articles identified, 66 studies met both inclusion and exclusion criteria. rTMS affects various biological factors that can be measured by current biological techniques. Although a number of studies have explored the neurobiological mechanisms of rTMS, a large variety of rTMS protocols and parameters limits the ability to synthesize these findings into a coherent understanding. However, a convergence of findings suggest that rTMS exerts its therapeutic effects by altering levels of various neurochemicals, electrophysiology as well as blood flow and activity in the brain in a frequency-dependent manner. More research is needed to delineate the neurobiological mechanisms of the antidepressant effect of rTMS. The incorporation of biological assessments into future rTMS clinical trials will help in this regard.

Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee.

These guidelines provide an up-date of previous IFCN report on "Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application" (Rossini et al., 1994). A new Committee, composed of international experts, some of whom were in the panel of the 1994 "Report", was selected to produce a current state-of-the-art review of non-invasive stimulation both for clinical application and research in neuroscience. Since 1994, the international scientific community has seen a rapid increase in non-invasive brain stimulation in studying cognition, brain-behavior relationship and pathophysiology of various neurologic and psychiatric disorders. New paradigms of stimulation and new techniques have been developed. Furthermore, a large number of studies and clinical trials have demonstrated potential therapeutic applications of non-invasive brain stimulation, especially for TMS. Recent guidelines can be found in the literature covering specific aspects of non-invasive brain stimulation, such as safety (Rossi et al., 2009), methodology (Groppa et al., 2012) and therapeutic applications (Lefaucheur et al., 2014). This up-dated review covers theoretical, physiological and practical aspects of non-invasive stimulation of brain, spinal cord, nerve roots and peripheral nerves in the light of more updated knowledge, and include some recent extensions and developments.

Dose-response curve of associative plasticity in human motor cortex and interactions with motor practice.

Associative plasticity is hypothesized to be an important neurophysiological correlate of memory formation and learning with potentials for applications in neurorehabilitation and for the development of new electrophysiological measures to study disorders of cortical plasticity. We hypothesized that the magnitude of the paired associative stimulation (PAS)-induced long-term potentiation (LTP)-like effect depends on the number of pairs in the PAS protocol. We also hypothesized that homeostatic interaction of PAS with subsequent motor learning is related to the magnitude of the PAS-induced LTP-like effect. We studied 10 healthy subjects. In experiment 1a, subjects received 90 (PAS90), 180 (PAS180), or 270 (PAS270) pairs of stimuli, followed by a dynamic motor practice (DMP) 1 h after the end of the PAS protocols. In experiment 1b, the DMP preceded the PAS protocol. In experiment 2, the time course of PAS270 was studied. We found that PAS270 resulted in greater increase in motor evoked potential (MEP) amplitude compared with protocols with fewer pairs of stimuli. Moreover, the interaction between PAS protocols with motor learning differed depending on the number of stimulus pairs used to induce PAS. While DMP alone increased MEP amplitudes, DMP during the LTP-like effects induced by PAS270 led to a long-term depression (LTD)-like effect (homeostatic interaction). This homeostatic interaction did not occur after PAS90 and PAS180. In conclusion, we found a dose-dependent effect of the number of stimulus pairs used in the PAS protocol on cortical plasticity. Homeostatic interaction between PAS and DMP was observed only after PAS270.

Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials.

BACKGROUND: Meta-analyses have shown that high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) has antidepressant properties when compared with sham rTMS. However, its overall response and remission rates in major depression (MD) remain unclear. Thus, we have systematically and quantitatively assessed the efficacy of HF-rTMS for MD based on randomized, double-blind and sham-controlled trials (RCTs). METHOD: We searched the literature from 1995 through to July 2012 using MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations & Theses. We used a random-effects model, odds ratios (ORs) and the number needed to treat (NNT). RESULTS: Data from 29 RCTs were included, totaling 1371 subjects with MD. Following approximately 13 sessions, 29.3% and 18.6% of subjects receiving HF-rTMS were classified as responders and remitters, respectively (compared with 10.4% and 5% of those receiving sham rTMS). The pooled OR was 3.3 (p < 0.0001) for both response and remission rates (with associated NNTs of 6 and 8, respectively). Furthermore, we found HF-rTMS to be equally effective as an augmentation strategy or as a monotherapy for MD, and when used in samples with primary unipolar MD or in mixed samples with unipolar and bipolar MD. Also, alternative stimulation parameters were not associated with differential efficacy estimates. Moreover, baseline depression severity and drop-out rates at study end were comparable between the HF-rTMS and sham rTMS groups. Finally, heterogeneity between the included RCTs was not statistically significant. CONCLUSIONS: HF-rTMS seems to be associated with clinically relevant antidepressant effects and with a benign tolerability profile.

Equivalent beneficial effects of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in a large randomized trial in treatment-resistant major depression.

Repetitive transcranial magnetic stimulation treatment (rTMS) is an effective treatment for depression but the optimal methods of administration have yet to be determined. Recent studies have produced conflicting results as to whether unilateral rTMS is more or less effective than sequentially applied bilateral rTMS. To address this we conducted a trial comparing sequential bilateral rTMS to right-sided unilateral rTMS using a priming protocol. Patients with treatment-resistant depression (n = 179) were enrolled in a two-arm randomized controlled trial across a 4-wk time period. The primary outcome assessment was the Hamilton Depression Rating Scale. Overall, there was a substantial response rate of >50% (and a 40% remission rate); however, there were no significant differences in clinical response between the two treatment groups. rTMS was well tolerated with a very low discontinuation rate. There was no relationship between response in the current trial and previous response, or non-response, to electroconvulsive therapy. We found no significant differences in clinical response between sequential bilateral rTMS and right-sided unilateral rTMS applied with a priming protocol. The results of this study do not support superior efficacy of bilateral rTMS and instead suggest that other approaches should be explored to increase treatment efficacy.

The genome-wide supported microRNA-137 variant predicts phenotypic heterogeneity within schizophrenia.

We examined the influence of the genome-wide significant schizophrenia risk variant rs1625579 near the microRNA (miRNA)-137 (MIR137) gene on well-established sources of phenotypic variability in schizophrenia: age-at-onset of psychosis and brain structure. We found that the MIR137 risk genotype strongly predicts an earlier age-at-onset of psychosis across four independently collected samples of patients with schizophrenia (n=510; F1,506=17.7, P=3.1 × 10(-5)). In an imaging-genetics subsample that included additional matched controls (n=213), patients with schizophrenia who had the MIR137 risk genotype had reduced white matter integrity (F3,209=13.6, P=3.88 × 10(-8)) throughout the brain as well as smaller hippocampi and larger lateral ventricles; the brain structure of patients who were carriers of the protective allele was no different from healthy control subjects on these neuroimaging measures. Our findings suggest that MIR137 substantially influences variation in phenotypes that are thought to have an important role in clinical outcome and treatment response. Finally, the possible consequences of genetic risk factors may be distinct in patients with schizophrenia compared with healthy controls.

High-frequency repetitive transcranial magnetic stimulation accelerates and enhances the clinical response to antidepressants in major depression: a meta-analysis of randomized, double-blind, and sham-controlled trials.

OBJECTIVE: High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is a safe and effective treatment for major depression. However, its utility as a strategy to accelerate and improve clinical response to antidepressants is still unclear. DATA SOURCES: We searched the literature from 1995 through May 2012 using EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, Scopus, and ProQuest Dissertations and Theses, and, from October 2008 until May 2012, by using MEDLINE. We included only studies written in the English language. STUDY SELECTION: We selected all randomized, double-blind, and sham-controlled trials on HF-rTMS used as an accelerating (add-on) strategy to antidepressants for major depression. DATA EXTRACTION: We performed a random effects meta-analysis using odds ratios (ORs) for response and remission rates following HF-rTMS and sham rTMS. Two time points were considered: the end of the add-on HF-rTMS stimulation period (T1) and the end of the study (T2). RESULTS: Data were obtained from 6 randomized controlled trials (RCTs), totaling 392 subjects with major depression. For T1 (at mean ± SD 2.67 ± 0.82 weeks following start of combined rTMS + antidepressant treatment), 6 studies reported on response and 4 on remission rates. We found significantly higher response rates for active HF-rTMS (43.3%; 84/194) compared to sham rTMS (26.8%; 53/198) (OR = 2.5; 95% CI, 1.12-5.56; P = .025); however, remission rates did not differ between groups (P = .33). Heterogeneity between the included RCTs reporting data on response and remission rates at T1 was significant (response: Q5 = 11.4, P = .044, I2 = 56.12; remission: Q3 = 12.24, P = .007, I2 = 75.45). For study end (T2; at mean ± SD 6.80 ± 3.11 weeks following start of combined rTMS + antidepressant treatment), 5 studies reported on response and 4 on remission rates; overall, response rates at T2 were significantly higher for subjects receiving HF-rTMS in comparison to those receiving sham rTMS (62% [104/168] and 46% [79/172], respectively; OR = 1.9; 95% CI, 1.003-3.56; P = .049). Also, 53.8% (57/106) and 38.64% (36/107) of subjects receiving active HF-rTMS and sham rTMS, respectively, were in remission at T2 (OR = 2.42; 95% CI, 1.27-4.61; P = .007). Heterogeneity between the included RCTs reporting data on remission rates at T2 was not significant, although RCTs reporting on response rates at T2 were heterogeneous. The baseline depression scores for active and sham rTMS groups were similar. Finally, HF-rTMS was comparable to sham rTMS in terms of dropout rates. CONCLUSIONS: HF-rTMS is a promising strategy for accelerating clinical response to antidepressants in major depression, providing clinically meaningful benefits that are comparable to those of other agents such as triiodothyronine and pindolol. Furthermore, HF-rTMS seems to be an acceptable treatment for depressed subjects.

New targets for rTMS in depression: a review of convergent evidence.

Although rTMS is moving steadily into the mainstream as a treatment for medically refractory depression, its efficacy continues to lag behind that of more invasive neuromodulation treatments such as ECT or DBS. Here we review evidence to suggest that a fruitful, but neglected, strategy for improving rTMS efficacy may be to explore alternatives to the conventional stimulation target in the dorsolateral prefrontal cortex (DLPFC). The convergent evidence of lesion, stimulation, connectivity, and correlative neuroimaging studies suggests that the DLPFC may have a relatively peripheral role in mood regulation, at least compared to several alternative areas within the prefrontal cortex. In particular, we consider the evidence base in support of four new potential targets for rTMS in depression: dorsomedial prefrontal cortex (DMPFC), frontopolar cortex (FPC), ventromedial prefrontal cortex (VMPFC), and ventrolateral prefrontal cortex (VLPFC). Each of these regions enjoys broader support, from a more diverse evidence base, than the DLPFC in terms of its role in emotion regulation in major depression. We discuss the relative merits of each of these novel targets, including potential obstacles to stimulation using currently available technologies, and potential strategies for overcoming these obstacles. It is hoped that this detailed review will spur a more vigorous exploration of new targets for rTMS in depression. The use of new targets may help to propel rTMS across the threshold of efficacy required of a first-line treatment, to assume a more widespread role in the treatment of depressed mood.

Clinical utility of transcranial direct current stimulation (tDCS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials.

OBJECTIVE: tDCS is a promising novel therapeutic intervention for major depression (MD). However, clinical trials to date have reported conflicting results concerning its efficacy, which likely resulted from low statistical power. Thus, we carried out a systematic review and meta-analysis on randomized, double-blind and controlled trials of tDCS in MD with a focus on clinically relevant outcomes, namely response and remission rates. METHOD: We searched the literature for English language randomized, double-blind and sham-controlled trials (RCTs) on tDCS for treating MD from 1998 through July 2012 using MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials and SCOPUS. We also consulted the Web of Science's Citations Index Expanded for the selected RCTs up to July 2012. The main outcome measures were response and remission rates. We used a random-effects model and Odds Ratios (OR). RESULTS: Data were obtained from 6 RCTs that included a total of 200 subjects with MD. After an average of 10.8 ± 3.76 tDCS sessions, no significant difference was found between active and sham tDCS in terms of both response (23.3% [24/103] vs. 12.4% [12/97], respectively; OR = 1.97; 95% CI = 0.85-4.57; p = 0.11) and remission (12.2% [12/98] vs. 5.4% [5/92], respectively; OR = 2.13; 95% CI = 0.64-7.06; p = 0.22). Also, no differences between mean baseline depression scores and dropout rates in the active and sham tDCS groups were found. Furthermore, sensitivity analyses excluding RCTs that involved less than 10 treatment sessions or stimulus intensity of less than 2 mA did not alter the findings. However, tDCS used as monotherapy was associated with higher response rates when compared to sham tDCS (p = 0.043). Finally, the risk of publication bias in this meta-analysis was found to be low. CONCLUSIONS: The clinical utility of tDCS as a treatment for MD remains unclear when clinically relevant outcomes such as response and remission rates are considered. Future studies should include larger and more representative samples, investigate how tDCS compares to other therapeutic neuromodulation techniques, as well as identify optimal stimulation parameters.

Clinically meaningful efficacy and acceptability of low-frequency repetitive transcranial magnetic stimulation (rTMS) for treating primary major depression: a meta-analysis of randomized, double-blind and sham-controlled trials.

Clinical trials on low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) over the right dorsolateral prefrontal cortex have yielded conflicting evidence concerning its overall efficacy for treating major depression (MD). As this may have been the result of limited statistical power of individual trials, we have carried the present systematic review and meta-analysis to examine this issue. We searched the literature for English language randomized, double-blind and sham-controlled trials (RCTs) on LF-rTMS for treating MD from 1995 through July 2012 using EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations & Theses, and from October 2008 until July 2012 using MEDLINE. The main outcome measures were response and remission rates as well as overall dropout rates at study end. We used a random-effects model, odds ratios (ORs) and number needed to treat (NNT). Data were obtained from eight RCTs, totaling 263 subjects with MD. After an average of 12.6±3.9 rTMS sessions, 38.2% (50/131) and 15.1% (20/132) of subjects receiving active LF-rTMS and sham rTMS were classified as responders (OR=3.35; 95% CI=1.4-8.02; p=0.007). Also, 34.6% (35/101) and 9.7% (10/103) of subjects receiving active LF-rTMS and sham rTMS were classified as remitters (OR=4.76; 95% CI=2.13-10.64; p<0.0001). The associated NNT for both response and remission rates was 5. Sensitivity analyses have shown that protocols delivering >1200 magnetic pulses in total as well as those offering rTMS as a monotherapy for MD were associated with higher rates of response to treatment. No differences on mean baseline depression scores and dropout rates for active and sham rTMS groups were found. Finally, the risk of publication bias was low. In conclusion, LF-rTMS is a promising treatment for MD, as it provides clinically meaningful benefits that are comparable to those of standard antidepressants and high-frequency rTMS. Furthermore, LF-rTMS seems to be an acceptable intervention for depressed subjects.

A systematic review and meta-analysis on the efficacy and acceptability of bilateral repetitive transcranial magnetic stimulation (rTMS) for treating major depression.

BACKGROUND: Bilateral repetitive magnetic stimulation (rTMS) is a promising novel therapeutic intervention for major depression (MD). However, clinical trials to date have reported conflicting evidence concerning its overall efficacy, which might have resulted from low statistical power. Thus, meta-analytical approaches could be useful in examining this issue by allowing the integration of findings from multiple studies and thus producing more accurate estimates of the treatment effect. METHOD: We searched the literature for randomized, double-blind and sham-controlled trials (RCTs) on bilateral rTMS for treating MD from 1995 to July 2012 using EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations and Theses, and from October 2008 until May 2012 using Medline. The main outcome measures were response and remission rates. We used a random-effects model, odds ratios (ORs) and the number needed to treat. RESULTS: Data were obtained from seven RCTs, totaling 279 subjects with MD. After an average of 12.9 (s.d. = 2.7) sessions, 24.7% (40/162) and 6.8% (8/117) of subjects receiving active bilateral rTMS and sham rTMS were classified as responders [OR 4.3, 95% confidence interval (CI) 1.95-9.52, p < 0.0001]. Also, 19% (23/121) and 2.6% (2/77) of subjects were remitters following active bilateral rTMS and sham rTMS, respectively (OR 6.0, 95% CI 1.65-21.8, p = 0.006). No difference between baseline mean depression scores for the bilateral and sham rTMS groups was found, and the former was comparable with the latter in terms of drop-out rates at study end. Furthermore, we did not find significant differences efficacy- and acceptability-wise between active bilateral and unilateral rTMS at study end. Finally, heterogeneity between the included RCTs was not significant, and the risk of publication bias was found to be low. CONCLUSIONS: Bilateral rTMS is a promising treatment for MD as it provides clinically meaningful benefits that are comparable with those of standard antidepressants and unilateral rTMS. Furthermore, bilateral rTMS seems to be an acceptable treatment for depressed subjects.

Meta-analysis of repetitive transcranial magnetic stimulation in the treatment of auditory verbal hallucinations: update and effects after one month.

OBJECTIVE: Several meta-analyses considering repetitive transcranial magnetic stimulation (rTMS) for auditory verbal hallucinations (AVH) have been performed with moderate to high mean weighted effect sizes. Since then several negative findings were reported in relatively large samples. The aim of this study was to provide an update of the literature on the efficacy of rTMS for AVH and to investigate the effect of rTMS one month after the end of treatment. DATA SOURCES: A literature search was performed from 1966 through August 2012 using Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Embase Psychiatry, Ovid Medline, PsycINFO and PubMed. Randomized, double blind, sham-controlled studies with severity of AVH or severity of psychosis as an outcome measure were included. STUDY SELECTION: Data were obtained from 17 randomized studies of rTMS for AVH. Five studies fulfilled the criteria for the meta-analysis on the effect of rTMS one month after the end of treatment. DATA EXTRACTION: Standardized mean weighted effect sizes of rTMS versus sham were computed on pre- and posttreatment comparisons. DATA SYNTHESIS: The mean weighted effect size of rTMS directed at the left temporoparietal area was 0.44 (95% CI 0.19-0.68). A separate meta-analysis including studies directing rTMS at other brain regions revealed a mean weighted effect size of 0.33 (95% CI 0.17-0.50) in favor of real TMS. The effect of rTMS was no longer significant at one month of follow-up (mean weighted effect size=0.40, 95% CI -0.23-0.102). Side effects were mild and the number of dropouts in the real TMS group was not significantly higher than in the sham group. CONCLUSIONS: With the inclusion of studies with larger patient samples, the mean weighted effect size of rTMS directed at the left temporoparietal area for AVH has decreased, although the effect is still significant. The duration of the effect of rTMS may be less than one month. More research is needed in order to optimize parameters and further evaluate the clinical relevance of this intervention.

A double blind randomized trial of unilateral left and bilateral prefrontal cortex transcranial magnetic stimulation in treatment resistant major depression.

OBJECTIVE: A substantive body of research has demonstrated the efficacy of repetitive transcranial magnetic stimulation treatment (rTMS) in patients with depression. However, the parameters needed to optimize therapeutic efficacy remain unclear. The aim of this study was to investigate whether there is an advantage in efficacy of sequential bilateral rTMS compared to standard high-frequency left sided rTMS. METHOD: Sixty seven patients with treatment resistant depression were included in a randomised double-blind sham controlled trial of sequential bilateral rTMS compared to standard high-frequency left sided rTMS and sham rTMS over a three-week period. The study also included a further three week comparison of the two active treatment conditions. The primary outcome variable was scores on the 17-item Hamilton Depression Rating Scale (HAMD). RESULTS: In the three-week double-blind phase of the trial there was a greater antidepressant response to unilateral left sided rTMS compared with sham or bilateral rTMS. Across the full six weeks of active rTMS, there was also a consistent pattern of improved response in unilateral left compared to bilateral treatment. Response rates were low in both active groups. CONCLUSIONS: This study does not support the hypothesis that sequential bilateral rTMS is more effective than unilateral high-frequency left-sided rTMS.