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1.  Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depressive Disorder 
Executive Summary
Objective
This review was conducted to assess the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD).
The Technology
rTMS is a noninvasive way to stimulate nerve cells in areas of the brain. During rTMS, an electrical current passes through a wire coil placed over the scalp. The current induces a magnetic field that produces an electrical field in the brain that then causes nerve cells to depolarize, resulting in the stimulation or disruption of brain activity.
Researchers have investigated rTMS as an option to treat MDD, as an add-on to drug therapy, and, in particular, as an alternative to electroconvulsive therapy (ECT) for patients with treatment-resistant depression.
The advantages of rTMS over ECT for patients with severe refractory depression are that general anesthesia is not needed, it is an outpatient procedure, it requires less energy, the simulation is specific and targeted, and convulsion is not required. The advantages of rTMS as an add-on treatment to drug therapy may include hastening of the clinical response when used with antidepressant drugs.
Review Strategy
The Medical Advisory Secretariat used its standard search strategy to locate international health technology assessments and English-language journal articles published from January 1996 to March 2004.
Summary of Findings
Some early meta-analyses suggested rTMS might be effective for the treatment of MDD (for treatment-resistant MDD and as an add-on treatment to drug therapy for patients not specifically defined as treatment resistant). There were, however, several crucial methodological limitations in the included studies that were not critically assessed. These are discussed below.
Recent meta-analyses (including 2 international health technology assessments) have done evidence-based critical analyses of studies that have assessed rTMS for MDD. The 2 most recent health technology assessments (from the Oxford Cochrane Collaboration and the Norwegian Centre for Health Technology Assessment) concluded that there is no evidence that rTMS is effective for the treatment of MDD, either as compared with a placebo for patients with treatment-resistant or nontreatment-resistant MDD, or as an alternative to ECT for patients with treatment-resistant MDD. This mainly due to the poor quality of the studies.
The major methodological limitations were identified in older meta-analyses, recent health technology assessments, and the most recently published trials (Level 2–4 evidence) on the effectiveness of rTMS for MDD are discussed below.
Small sample size was a limitation acknowledged by many of the authors. There was also a lack of a priori sample size calculation or justification.
Biased randomization may have been a problem. Generally, the published reports lacked detailed information on the method of allocation concealment used. This is important because it is impossible to determine if there was a possible influence (direct or indirect) in the allocation of the patients to different treatment groups.
The trials were single blind, evaluated by external blinded assessors, rather than double blind. Double blinding is more robust, because neither the participants nor the investigators know which participants are receiving the active treatment and which are getting a placebo. Those administering rTMS, however, cannot be blinded to whether they are administering the active treatment or a placebo.
There was patient variability among the studies. In some studies, the authors said that patients were “medication resistant,” but the definitions of resistant, if provided, were inconsistent or unclear. For example, some described “medication resistant” as failing at least one trial of drugs during the current depressive episode. Furthermore, it was unclear if the term “medication resistant” referred to antidepressants only or to combinations of antidepressants and other drug augmentation strategies (such as neuroleptics, benzodiazepine, carbamazepine, and lithium). Also variable was the type of depression (i.e., unipolar and/or bipolar), if patients were inpatients or outpatients, if they had psychotic symptoms or no psychotic symptoms, and the chronicity of depression.
Dropouts or withdrawals were a concern. Some studies reported that patients dropped out, but provided no further details. Intent-to-treat analysis was not done in any of the trials. This is important, because ignoring patients who drop out of a trial can bias the results, usually in favour of the treatment. This is because patients who withdraw from trials are less likely to have had the treatment, more likely to have missed their interim checkups, and more likely to have experienced adverse effects when taking the treatment, compared with patients who do not withdraw. (1)
Measurement of treatment outcomes using scales or inventories makes interpreting results and drawing conclusions difficult. The most common scale, the Hamilton Depression Rating Scale (HDRS) is based on a semistructured interview. Some authors (2) reported that rating scales based on semistructured interviews are more susceptible to observation bias than are self-administered questionnaires such as the Beck Depression Inventory (BDI). Martin et al. (3) argued that the lack of consistency in effect as determined by the 2 scales (a positive result after 2 weeks of treatment as measured by the HDRS and a negative result for the BDI) makes definitive conclusions about the nature of the change in mood of patients impossible. It was suggested that because of difficulties interpreting results from psychometric scales, (4) and the subjective or unstable character of MDD, other, more objective, outcome measures such as readmission to hospital, time to hospital discharge, time to adjunctive treatment, and time off work should be used to assess rTMS for the treatment of depression.
A placebo effect could have influenced the results. Many studies reported response rates for patients who received placebo treatment. For example, Klein et al. (5) reported a control group response rate as high as 25%. Patients receiving placebo rTMS may receive a small dose of magnetic energy that may alter their depression.
Short-term studies were the most common. Patients received rTMS treatment for 1 to 2 weeks. Most studies followed-up patients for 2 to 4 weeks post-treatment. Dannon et al. (6) followed-up patients who responded to a course of ECT or rTMS for up to 6 months; however, the assessment procedure was not blinded, the medication regimen during follow-up was not controlled, and initial baseline data for the patient groups were not reported. The long-term effectiveness of rTMS for the treatment of depression is unknown, as is the long-term use, if any, of maintenance therapy. The cost-effectiveness of rTMS for the treatment of depression is also unknown. A lack of long-term studies makes cost-effectiveness analysis difficult.
The complexity of possible combinations for administering rTMS makes comparing like with like difficult. Wasserman and Lisanby (7) have said that the method for precisely targeting the stimulation in this area is unreliable. It is unknown if the left dorsolateral prefrontal cortex is the optimal location for treatment. Further, differences in rTMS administration include number of trains per session, duration of each train, and motor threshold.
Clinical versus statistical significance. Several meta-analyses and studies have found that the degree of therapeutic change associated with rTMS across studies is relatively modest; that is, results may be statistically, but not necessarily clinically, significant. (8-11). Conventionally, a 50% reduction in the HDRS scores is commonly accepted as a clinically important reduction in depression. Although some studies have observed a statistically significant reduction in the depression rating, many have not shows the clinically significant reduction of 50% on the HDRS. (11-13) Therefore, few patients in these studies would meet the standard criteria for response. (9)
Clinical/methodological diversity and statistical heterogeneity. In the Norwegian health technology assessment, Aarre et al. (14) said that a formal meta-analysis was not feasible because the designs of the studies varied too much, particularly in how rTMS was administered and in the characteristics of the patients. They noted that the quality of the study designs was poor. The 12 studies that comprised the assessment had small samples, and highly variable inclusion criteria and study designs. The patients’ previous histories, diagnoses, treatment histories, and treatment settings were often insufficiently characterized. Furthermore, many studies reported that patients had treatment-resistant MDD, yet did not listclear criteria for the designation. Without this information, Aarre and colleagues suggested that the interpretation of the results is difficult and the generalizability of results is questionable. They concluded that rTMS cannot be recommended as a standard treatment for depression: “More, larger and more carefully designed studies are needed to demonstrate convincingly a clinically relevant effect of rTMS.”
In the Cochrane Collaboration systematic review, Martin et al. (3;15) said that the complexity of possible combinations for administering rTMS makes comparison of like versus like difficult. A statistical test for heterogeneity (chi-square test) examines if the observed treatment effects are more different from each other than one would expect due to random error (or chance) alone. (16) However, this statistical test must be interpreted with caution because it has low power in the (common) situation of a meta-analysis when the trials have small sample sizes or are few. This means that while a statistically significant result may indicate a problem with heterogeneity, a nonsignificant result must not be taken as evidence of no heterogeneity.
Despite not finding statistically significant heterogeneity, Martin et al. reported that the overall mean baseline depression values for the severity of depression were higher in the treatment group than in the placebo group. (3;15) Although these differences were not significant at the level of each study, they may have introduced potential bias into the meta-analysis of pooled data by accentuating the tendency for regression to the mean of the more extreme values. Individual patient data from all the studies were not available; therefore, an appropriate adjustment according to baseline severity was not possible. Martin et al. concluded that the findings from the systematic review and meta-analysis provided insufficient evidence to suggest that rTMS is effective in the treatment of depression. Moreover, there were several confounding factors (e.g., definition of treatment resistance) in the studies, thus the authors concluded, “The rTMS technique needs more high quality trials to show its effectiveness for therapeutic use.”
Conclusion
Due to several serious methodological limitations in the studies that have examined the effectiveness of rTMS in patients with MDD, it is not possible to conclude that rTMS either is or is not effective as a treatment for MDD (in treatment-resistant depression or in nontreatment-resistant depression).
PMCID: PMC3387754  PMID: 23074457
2.  Neuronavigation Increases the Physiologic and Behavioral Effects of Low-Frequency rTMS of Primary Motor Cortex in Healthy Subjects 
Brain topography  2010;24(1):54-64.
Low-frequency repetitive transcranial magnetic stimulation (rTMS) can exert local and inter-hemispheric neuromodulatory effects on cortical excitability. These physiologic effects can translate into changes in motor behavior, and may offer valuable therapeutic interventions in recovery from stroke. Neuronavigated TMS can maximize accurate and consistent targeting of a given cortical region, but is a lot more involved that conventional TMS. We aimed to assess whether neuronavigation enhances the physiologic and behavioral effects of low-frequency rTMS. Ten healthy subjects underwent two experimental sessions during which they received 1600 pulses of either navigated or non-navigated 1 Hz rTMS at 90% of the resting motor threshold (RMT) intensity over the motor cortical representation for left first dorsal interosseous (FDI) muscle. We compared the effects of navigated and non-navigated rTMS on motor-evoked potentials (MEPs) to single-pulse TMS, intracortical inhibition (ICI) and intracortical facilitation (ICF) by paired-pulse TMS, and performance in various behavioral tasks (index finger tapping, simple reaction time and grip strength tasks). Following navigated rTMS, the amplitude of MEPs elicited from the contralateral (unstimulated) motor cortex was significantly increased, and was associated with an increase in ICF and a trend to decrease in ICI. In contrast, non-navigated rTMS elicited nonsignificant changes, most prominently ipsilateral to rTMS. Behaviorally, navigated rTMS significantly improved reaction time RT and pinch force with the hand ipsilateral to stimulation. Non-navigated rTMS lead to similar behavioral trends, although the effects did not reach significance. In summary, navigated rTMS leads to more robust modulation of the contralateral (unstimulated) hemisphere resulting in physiologic and behavioral effects. Our findings highlight the spatial specificity of inter-hemispheric TMS effects, illustrate the superiority of navigated rTMS for certain applications, and have implications for therapeutic applications of rTMS.
doi:10.1007/s10548-010-0165-7
PMCID: PMC3589808  PMID: 21076861
Transcranial magnetic stimulation; Navigated brain stimulation; Motor cortex; Cortical excitability; Motor-evoked potentials; Silent period and paired-pulse stimulation
3.  Improvement of Tactile Discrimination Performance and Enlargement of Cortical Somatosensory Maps after 5 Hz rTMS 
PLoS Biology  2005;3(11):e362.
Repetitive transcranial magnetic stimulation (rTMS) is increasingly used to investigate mechanisms of brain functions and plasticity, but also as a promising new therapeutic tool. The effects of rTMS depend on the intensity and frequency of stimulation and consist of changes of cortical excitability, which often persists several minutes after termination of rTMS. While these findings imply that cortical processing can be altered by applying current pulses from outside the brain, little is known about how rTMS persistently affects learning and perception. Here we demonstrate in humans, through a combination of psychophysical assessment of two-point discrimination thresholds and functional magnetic resonance imaging (fMRI), that brief periods of 5 Hz rTMS evoke lasting perceptual and cortical changes. rTMS was applied over the cortical representation of the right index finger of primary somatosensory cortex, resulting in a lowering of discrimination thresholds of the right index finger. fMRI revealed an enlargement of the right index finger representation in primary somatosensory cortex that was linearly correlated with the individual rTMS-induced perceptual improvement indicative of a close link between cortical and perceptual changes. The results demonstrate that repetitive, unattended stimulation from outside the brain, combined with a lack of behavioral information, are effective in driving persistent improvement of the perception of touch. The underlying properties and processes that allow cortical networks, after being modified through TMS pulses, to reach new organized stable states that mediate better performance remain to be clarified.
Functional magnetic resonance imaging and sensory threshold testing demonstrate that brief periods of transcranial magnetic stimulation can induce changes in somatosensory processing.
doi:10.1371/journal.pbio.0030362
PMCID: PMC1255742  PMID: 16218766
4.  Evaluating frontal and parietal contributions to spatial working memory with repetitive transcranial magnetic stimulation 
Brain research  2008;1230:202-210.
Functional neuroimaging studies have produced contradictory data about the extent to which specific regions of the frontal and the posterior parietal cortices contribute to the retention of information in spatial working memory. We used high frequency repetitive transcranial magnetic stimulation (rTMS) to assess the necessity for the short-term retention of spatial information of brain areas identified by previous functional imaging studies: dorsolateral prefrontal cortex (dlPFC), frontal eye fields (FEF), superior parietal lobule (SPL) and intraparietal sulcus (IPS). 10 Hz rTMS spanned the 3-sec delay period of a spatial delayed-recognition task. The postcentral gyrus (PCG) was included to control for any regionally nonspecific effects of rTMS. The only regionally specific effect was a significant decrease in reaction time when rTMS was applied to SPL. Additionally, rTMS lowered accuracy to a greater extent when applied to left than to right hemisphere, and was more disruptive when applied contralaterally vs. ipsilaterally to the visual field in which the memory probe was presented. Although seemingly paradoxical, the finding of rTMS-induced improvement in task performance has a precedent, and is consistent with the idea that regions associated with spatial sensory-motor processing make necessary contributions to the short-term retention of this information. Possible factors underlying rTMS-induced behavioral facilitation are considered.
doi:10.1016/j.brainres.2008.07.008
PMCID: PMC2612637  PMID: 18662678
Transcranial magnetic stimulation; Working memory; Prefrontal cortex; Parietal cortex; Spatial
5.  Modulatory effects of 5Hz rTMS over the primary somatosensory cortex in focal dystonia – an fMRI-TMS study 
Background
Dystonia is associated with impaired somatosensory ability. The electrophysiological method of repetitive transcranial magnetic stimulation (rTMS) can be used for non-invasive stimulation of the human cortex and can alter cortical excitability and associated behaviour. Among others, rTMS can alter/improve somatosensory discrimation abilities, as shown in healthy controls.
Methods
We applied 5Hz-rTMS over the left primary somatosensory cortex (S1) in 5 patients with right-sided writer's dystonia and 5 controls. We studied rTMS effects on tactile discrimination accuracy and concomitant rTMS-induced changes in hemodynamic activity measured by functional magnetic resonance imaging (fMRI).
Results
Prior to rTMS, patients performed worse on the discrimination task than controls even though fMRI showed greater task-related activation bilaterally in the basal ganglia (BG). In controls, rTMS led to improved discrimination; fMRI revealed this was associated with increased activity of the stimulated S1, bilateral premotor cortex and BG. In dystonia patients, rTMS had no effect on discrimination; fMRI showed similar cortical effects to controls except for no effects in BG.
Conclusion
Improved discrimination after rTMS in controls is linked to enhanced activation of S1 and BG. Failure of rTMS to increase BG activation in dystonia may be associated with the lack of effect on sensory discrimination in this group and may reflect impaired processing in BG-S1 connections. Alternatively, the increased BG activation seen in the baseline state without rTMS may reflect a compensatory strategy that saturates a BG contribution to this task.
doi:10.1002/mds.22825
PMCID: PMC2929458  PMID: 20058321
writer's cramp; primary dystonia; basal ganglia; sensory discrimination; sensorimotor cortex; premotor cortex; fMRI; TMS; repetitive TMS
6.  rTMS neuromodulation improves electrocortical functional measures of information processing and behavioral responses in autism 
Objectives: Reports in autism spectrum disorders (ASD) of a minicolumnopathy with consequent deficits of lateral inhibition help explain observed behavioral and executive dysfunctions. We propose that neuromodulation based on low frequency repetitive Transcranial Magnetic Stimulation (rTMS) will enhance lateral inhibition through activation of inhibitory double bouquet interneurons and will be accompanied by improvements in the prefrontal executive functions. In addition we proposed that rTMS will improve cortical excitation/inhibition ratio and result in changes manifested in event-related potential (ERP) recorded during cognitive tests.
Materials and Methods: Along with traditional clinical behavioral evaluations the current study used ERPs in a visual oddball task with illusory figures. We compared clinical, behavioral and electrocortical outcomes in two groups of children with autism (TMS, wait-list group). We predicted that 18 session long course in autistic patients will have better behavioral and ERP outcomes as compared to age- and IQ-matched WTL group. We used 18 sessions of 1 Hz rTMS applied over the dorso-lateral prefrontal cortex in 27 individuals with ASD diagnosis. The WTL group was comprised of 27 age-matched subjects with ASD tested twice. Both TMS and WTL groups were assessed at the baseline and after completion of 18 weekly sessions of rTMS (or wait period) using clinical behavioral questionnaires and during performance on visual oddball task with Kanizsa illusory figures.
Results: Post-TMS evaluations showed decreased irritability and hyperactivity on the Aberrant Behavior Checklist (ABC), and decreased stereotypic behaviors on the Repetitive Behavior Scale (RBS-R). Following rTMS course we found decreased amplitude and prolonged latency in the frontal and fronto-central N100, N200 and P300 (P3a) ERPs to non-targets in active TMS treatment group. TMS resulted in increase of P2d (P2a to targets minus P2a to non-targets) amplitude. These ERP changes along with increased centro-parietal P100 and P300 (P3b) to targets are indicative of more efficient processing of information post-TMS treatment. Another important finding was decrease of the latency and increase of negativity of error-related negativity (ERN) during commission errors that may reflect improvement in error monitoring and correction function. Enhanced information processing was also manifested in lower error rate. In addition we calculated normative post-error treaction time (RT) slowing response in both groups and found that rTMS treatment was accompanied by post-error RT slowing and higher accuracy of responses, whereas the WTL group kept on showing typical for ASD post-error RT speeding and higher commission and omission error rates.
Conclusion: Results from our study indicate that rTMS improves executive functioning in ASD as evidenced by normalization of ERP responses and behavioral reactions (RT, accuracy) during executive function test, and also by improvements in clinical evaluations.
doi:10.3389/fnsys.2014.00134
PMCID: PMC4123734  PMID: 25147508
TMS; autism; ERP; motor response time; behavioral performance
7.  Training Transfers the Limits on Perception from Parietal to Ventral Cortex 
Current Biology  2014;24(20):2445-2450.
Summary
Visually guided behavior depends on (1) extracting and (2) discriminating signals from complex retinal inputs, and these perceptual skills improve with practice [1]. For instance, training on aerial reconnaissance facilitated World War II Allied military operations [2]; analysts pored over stereoscopic photographs, becoming expert at (1) segmenting pictures into meaningful items to break camouflage from (noisy) backgrounds, and (2) discriminating fine details to distinguish V-weapons from innocuous pylons. Training is understood to optimize neural circuits that process scene features (e.g., orientation) for particular purposes (e.g., judging position) [3–6]. Yet learning is most beneficial when it generalizes to other settings [7, 8] and is critical in recovery after adversity [9], challenging understanding of the circuitry involved. Here we used repetitive transcranial magnetic stimulation (rTMS) to infer the functional organization supporting learning generalization in the human brain. First, we show dissociable contributions of the posterior parietal cortex (PPC) versus lateral occipital (LO) circuits: extracting targets from noise is disrupted by PPC stimulation, in contrast to judging feature differences, which is affected by LO rTMS. Then, we demonstrate that training causes striking changes in this circuit: after feature training, identifying a target in noise is not disrupted by PPC stimulation but instead by LO stimulation. This indicates that training shifts the limits on perception from parietal to ventral brain regions and identifies a critical neural circuit for visual learning. We suggest that generalization is implemented by supplanting dynamic processing conducted in the PPC with specific feature templates stored in the ventral cortex.
Highlights
•Before training, dorsal, but not ventral, rTMS disrupts perception in noisy displays•Training on fine differences boosts feature templates, facilitating detection in noise•After training, ventral, but not dorsal, rTMS becomes disruptive for targets in noise•Functional reweighting of dorsal and ventral circuits supports learning transfer
Using TMS in human subjects, Chang et al. reveal differential roles of parietal and ventral cortex in extracting and discriminating visual targets, respectively. Training on fine discriminations causes a reweighting of the circuit: following learning, ventral, not parietal, activity determines target extraction task performance.
doi:10.1016/j.cub.2014.08.058
PMCID: PMC4204932  PMID: 25283780
8.  Theta, alpha and beta burst transcranial magnetic stimulation: brain modulation in tinnitus 
Introduction: Some forms of tinnitus are considered to be auditory phantom phenomena related to reorganization and hyperactivity of the auditory central nervous system. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool capable of modulating human brain activity, using single pulse or burst stimuli. Burst rTMS has only been performed in the theta range, and has not been used clinically. The authors analyze whether burst TMS at theta (5 Hz), alpha (10 Hz) and beta (20 Hz) frequencies can temporarily suppress narrow band noise/white noise tinnitus, which has been demonstrated to be intractable to tonic stimulation.
Methods: rTMS is performed both in tonic and burst mode in 46 patients contralateral to the tinnitus side, at 5, 10 and 20 Hz. Fourteen placebo negative rTMS responders are further analyzed.
Results: In 5 patients, maximal tinnitus suppression is obtained with theta, in 2 with alpha and in 7 with beta burst stimulation. Burst rTMS suppresses narrow band/white tinnitus much better than tonic rTMS t(13)=6.4, p<.000. Women experience greater suppression of their tinnitus with burst stimulation than men, t(12)=2.9, p<.05. Furthermore left sided tinnitus is perceived as more distressing on the TQ than right sided tinnitus, t(12)=3.2, p<.01. The lower the tinnitus pitch the more effectively rTMS suppresses tinnitus(r=-0.65, p<0.05).
Discussion: Burst rTMS can be used clinically, not only theta burst, but also alpha and beta burst. Burst rTMS is capable of suppressing narrow band/white noise tinnitus very much better than tonic rTMS. This could be due the simple fact that burst neuromodulation is more powerful than tonic neuromodulation or to a differential effect of burst and tonic stimulation on the lemniscal and extralemniscal auditory system. In some patients only alpha or beta burst rTMS is capable of suppressing tinnitus, and theta burst not. Therefore in future rTMS studies it could be worthwhile not to limit burst stimulation to theta burst rTMS.
PMCID: PMC2016868  PMID: 17952199
burst; neuromodulation; tinnitus; tonic; TMS
9.  rTMS with Motor Training Modulates Cortico-Basal Ganglia-Thalamocortical Circuits in Stroke Patients 
Background and Purpose
Repetitive transcranial magnetic stimulation (rTMS) may enhance plastic changes in the human cortex and modulation of behavior. However, the underlying neural mechanisms have not been sufficiently investigated. We examined the clinical effects and neural correlates of high-frequency rTMS coupled with motor training in patients with hemiparesis after stroke.
Methods
Twenty-one patients were randomly divided into two groups, and received either real or sham rTMS. Ten daily sessions of 1,000 pulses of real or sham rTMS were applied at 10 Hz over the primary motor cortex of the affected hemisphere, coupled with sequential finger motor training of the paretic hand. Functional MRIs were obtained before and after training using sequential finger motor tasks, and performances were assessed.
Results
Following rTMS intervention, movement accuracy of sequential finger motor tasks showed significantly greater improvement in the real group than in the sham group (p<0.05). Real rTMS modulated areas of brain activation during performance of motor tasks with a significant interaction effect in the sensorimotor cortex, thalamus, and caudate nucleus. Patients in the real rTMS group also showed significantly enhanced activation in the affected hemisphere compared to the sham rTMS group.
Conclusion
According to these results, a 10 day course of high-frequency rTMS coupled with motor training improved motor performance through modulation of activities in the cortico-basal ganglia-thalamocortical circuits.
doi:10.3233/RNN-2012-110162
PMCID: PMC3589123  PMID: 22555430
Stroke; Repetitive transcranial magnetic stimulation; Functional MRI; Motor function; Cortico-basal ganglia-thalamocortical circuits
10.  Low-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Affects Event-Related Potential Measures of Novelty Processing in Autism 
In our previous study on individuals with autism spectrum disorder (ASD) (Sokhadze et al., Appl Psychophysiol Biofeedback 34:37–51, 2009a) we reported abnormalities in the attention-orienting frontal event-related potentials (ERP) and the sustained-attention centro-parietal ERPs in a visual oddball experiment. These results suggest that individuals with autism over-process information needed for the successful differentiation of target and novel stimuli. In the present study we examine the effects of low-frequency, repetitive Transcranial Magnetic Stimulation (rTMS) on novelty processing as well as behavior and social functioning in 13 individuals with ASD. Our hypothesis was that low-frequency rTMS application to dorsolateral prefrontal cortex (DLFPC) would result in an alteration of the cortical excitatory/inhibitory balance through the activation of inhibitory GABAergic double bouquet interneurons. We expected to find post-TMS differences in amplitude and latency of early and late ERP components. The results of our current study validate the use of low-frequency rTMS as a modulatory tool that altered the disrupted ratio of cortical excitation to inhibition in autism. After rTMS the parieto-occipital P50 amplitude decreased to novel distracters but not to targets; also the amplitude and latency to targets increased for the frontal P50 while decreasing to non-target stimuli. Low-frequency rTMS minimized early cortical responses to irrelevant stimuli and increased responses to relevant stimuli. Improved selectivity in early cortical responses lead to better stimulus differentiation at later-stage responses as was made evident by our P3b and P3a component findings. These results indicate a significant change in early, middle-latency and late ERP components at the frontal, centro-parietal, and parieto-occipital regions of interest in response to target and distracter stimuli as a result of rTMS treatment. Overall, our preliminary results show that rTMS may prove to be an important research tool or treatment modality in addressing the stimulus hypersensitivity characteristic of autism spectrum disorders.
doi:10.1007/s10484-009-9121-2
PMCID: PMC2876218  PMID: 19941058
Event-related potentials; Autism; Novelty; Transcranial Magnetic Stimulation; Cortical excitation/inhibition balance; Minicolumns
11.  High-frequency repetitive transcranial magnetic stimulation to the cerebellum and implicit processing of happy facial expressions 
Background
Previous research has demonstrated that the cerebellum is involved in emotive and cognitive processes. Furthermore, recent findings suggest high-frequency repetitive transcranial magnetic stimulation (rTMS) to the cerebellum has mood-improving properties. We sought to further explore the effects of cerebellar high-frequency rTMS on implicit processing of emotional stimuli and mood.
Methods
In a double-blind, crossover study, 15 healthy volunteers received 15 minutes of 20 Hz (5 s on, 5 s off) rTMS over the medial cerebellum, occipital cortex or sham in a randomized counterbalanced order on 3 consecutive days. A masked emotional faces response task measured implicit emotional processing of happy, fearful and neutral facial expressions. We used positive and negative affect scales to evaluate rTMS-related changes in mood.
Results
High-frequency rTMS over the cerebellum was associated with significant increases in masked emotional responses to happy facial expressions only. We observed no changes in consciously experienced mood.
Limitations
Although the sham rTMS served as our baseline measurement, additional pre-rTMS data showing that reaction time increases immediately after cerebellar rTMS would have made our results more compelling.
Conclusion
The results replicate and extend previous findings by establishing a direct relation between the cerebellum and emotive information-processing. The parallel between the present effects of high-frequency cerebellar rTMS and short-term antidepressant therapy regarding the change in implicit processing of positive stimuli in the absence of mood changes is notable and warrants further research.
PMCID: PMC2612080  PMID: 19125214
12.  Repetitive Transcranial Magnetic Stimulation Affects behavior by Biasing Endogenous Cortical Oscillations 
A governing assumption about repetitive transcranial magnetic stimulation (rTMS) has been that it interferes with task-related neuronal activity – in effect, by “injecting noise” into the brain – and thereby disrupts behavior. Recent reports of rTMS-produced behavioral enhancement, however, call this assumption into question. We investigated the neurophysiological effects of rTMS delivered during the delay period of a visual working memory task by simultaneously recording brain activity with electroencephalography (EEG). Subjects performed visual working memory for locations or for shapes, and in half the trials a 10-Hz train of rTMS was delivered to the superior parietal lobule (SPL) or a control brain area. The wide range of individual differences in the effects of rTMS on task accuracy, from improvement to impairment, was predicted by individual differences in the effect of rTMS on power in the alpha-band of the EEG (∼10 Hz): a decrease in alpha-band power corresponded to improved performance, whereas an increase in alpha-band power corresponded to the opposite. The EEG effect was localized to cortical sources encompassing the frontal eye fields and the intraparietal sulcus, and was specific to task (location, but not object memory) and to rTMS target (SPL, not control area). Furthermore, for the same task condition, rTMS-induced changes in cross-frequency phase synchrony between alpha- and gamma-band (>40 Hz) oscillations predicted changes in behavior. These results suggest that alpha-band oscillations play an active role cognitive processes and do not simply reflect absence of processing. Furthermore, this study shows that the complex effects of rTMS on behavior can result from biasing endogenous patterns of network-level oscillations.
doi:10.3389/neuro.07.014.2009
PMCID: PMC2707056  PMID: 19587850
oscillations; alpha band; transcranial magnetic stimulation; rTMS; electroencephalography; working memory; spatial
13.  Repetitive Transcranial Magnetic Stimulation (rTMS) Modulates Event-Related Potential (ERP) Indices of Attention in Autism 
Translational neuroscience  2012;3(2):170-180.
Individuals with autism spectrum disorder (ASD) have previously been shown to have significantly augmented and prolonged event-related potentials (ERP) to irrelevant visual stimuli compared to controls at both early and later stages (e.g., N200, P300) of visual processing and evidence of an overall lack of stimulus discrimination. Abnormally large and indiscriminative cortical responses to sensory stimuli may reflect cortical inhibitory deficits and a disruption in the excitation/inhibition ratio. Low-frequency (≤1HZ) repetitive transcranial magnetic stimulation (rTMS) has been shown to increase inhibition of stimulated cortex by the activation of inhibitory circuits. It was our prediction that after 12 sessions of low-frequency rTMS applied bilaterally to the dorsolateral prefrontal cortices in individuals with ASD there would be a significant improvement in ERP indices of selective attention evoked at later (i.e., 200–600 ms) stages of attentional processing as well as an improvement in motor response error rate. We assessed 25 participants with ASD in a task of selective attention using illusory figures before and after 12 sessions of rTMS in a controlled design where a waiting-list group of 20 children with ASD performed the same task twice. We found a significant improvement in both N200 and P300 components as a result of rTMS as well as a significant reduction in response errors. We also found significant reductions in both repetitive behavior and irritability according to clinical behavioral questionnaires as a result of rTMS. We propose that rTMS has the potential to become an important therapeutic tool in ASD research and treatment.
doi:10.2478/s13380-012-0022-0
PMCID: PMC3966618  PMID: 24683490
Autism; TMS; Event-related potentials; Attention; Perception
14.  Low-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Modulates Evoked-Gamma Frequency Oscillations in Autism Spectrum Disorder (ASD) 
Journal of neurotherapy  2010;14(3):179-194.
Introduction
It has been reported that individuals with Autism Spectrum Disorder (ASD) have abnormal reactions to the sensory environment and visuo-perceptual abnormalities. Electrophysiological research has provided evidence that gamma band activity (30-80 Hz) is a physiological indicator of the co-activation of cortical cells engaged in processing visual stimuli and integrating different features of a stimulus. A number of studies have found augmented and indiscriminative gamma band power at early stages of visual processing in ASD; this may be related to decreased inhibitory processing and an increase in the ratio of cortical excitation to inhibition. Low frequency or ‘slow’ (≤1HZ) repetitive transcranial magnetic stimulation (rTMS) has been shown to increase inhibition of stimulated cortex by the activation of inhibitory circuits.
Methods
We wanted to test the hypothesis of gamma band abnormalities at early stages of visual processing in ASD by investigating relative evoked (i.e. ~ 100 ms) gamma power in 25 subjects with ASD and 20 age-matched controls using Kanizsa illusory figures. Additionally, we wanted to assess the effects of 12 sessions of bilateral ‘slow’ rTMS to the dorsolateral prefrontal cortex (DLPFC) on evoked gamma activity using a randomized controlled design.
Results
In individuals with ASD evoked gamma activity was not discriminative of stimulus type, whereas in controls early gamma power differences between target and non-target stimuli were highly significant. Following rTMS individuals with ASD showed significant improvement in discriminatory gamma activity between relevant and irrelevant visual stimuli. We also found significant improvement in the responses on behavioral questionnaires (i.e., irritability, repetitive behavior) as a result of rTMS.
Conclusion
We proposed that ‘slow’ rTMS may have increased cortical inhibitory tone which improved discriminatory gamma activity at early stages of visual processing. rTMS has the potential to become an important therapeutic tool in ASD treatment and has shown significant benefits in treating core symptoms of ASD with few, if any side effects.
doi:10.1080/10874208.2010.501500
PMCID: PMC2992386  PMID: 21116441
Autism; EEG; gamma oscillations; visual processing; evoked potentials
15.  Suppression of Motor Cortical Excitability in Anesthetized Rats by Low Frequency Repetitive Transcranial Magnetic Stimulation 
PLoS ONE  2014;9(3):e91065.
Repetitive transcranial magnetic stimulation (rTMS) is a widely-used method for modulating cortical excitability in humans, by mechanisms thought to involve use-dependent synaptic plasticity. For example, when low frequency rTMS (LF rTMS) is applied over the motor cortex, in humans, it predictably leads to a suppression of the motor evoked potential (MEP), presumably reflecting long-term depression (LTD) – like mechanisms. Yet how closely such rTMS effects actually match LTD is unknown. We therefore sought to (1) reproduce cortico-spinal depression by LF rTMS in rats, (2) establish a reliable animal model for rTMS effects that may enable mechanistic studies, and (3) test whether LTD-like properties are evident in the rat LF rTMS setup. Lateralized MEPs were obtained from anesthetized Long-Evans rats. To test frequency-dependence of LF rTMS, rats underwent rTMS at one of three frequencies, 0.25, 0.5, or 1 Hz. We next tested the dependence of rTMS effects on N-methyl-D-aspartate glutamate receptor (NMDAR), by application of two NMDAR antagonists. We find that 1 Hz rTMS preferentially depresses unilateral MEP in rats, and that this LTD-like effect is blocked by NMDAR antagonists. These are the first electrophysiological data showing depression of cortical excitability following LF rTMS in rats, and the first to demonstrate dependence of this form of cortical plasticity on the NMDAR. We also note that our report is the first to show that the capacity for LTD-type cortical suppression by rTMS is present under barbiturate anesthesia, suggesting that future neuromodulatory rTMS applications under anesthesia may be considered.
doi:10.1371/journal.pone.0091065
PMCID: PMC3960125  PMID: 24646791
16.  Does high-frequency repetitive transcranial magnetic stimulation produce residual and/or cumulative effects within an experimental session? 
Brain topography  2010;23(4):355-367.
A common procedure for studying the effects on cognition of repetitive transcranial magnetic stimulation (rTMS) is to deliver rTMS concurrent with task performance, and to compare task performance on these trials versus on trials without rTMS. Recent evidence that TMS can have effects on neural activity that persist longer than the experimental session itself, however, raises questions about the assumption of the transient nature of rTMS that underlies many concurrent (or “online”) rTMS designs. To our knowledge, there have been no studies in the cognitive domain examining whether the application of brief trains of rTMS during specific epochs of a complex task may have effects that spill over into subsequent task epochs, and perhaps into subsequent trials. We looked for possible immediate spill-over and longer-term cumulative effects of rTMS in data from two studies of visual short-term delayed recognition. In 54 subjects, 10-Hz rTMS trains were applied to five different brain regions during the 3-second delay period of a spatial task, and in a second group of 15 subjects, electroencephalography (EEG) was recorded while 10-Hz rTMS was applied to two brain areas during the 3-sec delay period of both spatial and object tasks. No evidence for immediate effects was found in the comparison of the memory probe-evoked response on trials that were vs. were not preceded by delay-period rTMS. No evidence for cumulative effects was found in analyses of behavioral performance, and of EEG signal, as a function of task block. The implications of these findings, and their relation to the broader literature on acute vs. long-lasting effects of rTMS, are considered.
doi:10.1007/s10548-010-0153-y
PMCID: PMC2978750  PMID: 20623171
repetitive transcranial magnetic stimulation; long-term effects; electroencephalography; working memory
17.  5 Hz repetitive transcranial magnetic stimulation over the ipsilesional sensory cortex enhances motor learning after stroke 
Sensory feedback is critical for motor learning, and thus to neurorehabilitation after stroke. Whether enhancing sensory feedback by applying excitatory repetitive transcranial magnetic stimulation (rTMS) over the ipsilesional primary sensory cortex (IL-S1) might enhance motor learning in chronic stroke has yet to be investigated. The present study investigated the effects of 5 Hz rTMS over IL-S1 paired with skilled motor practice on motor learning, hemiparetic cutaneous somatosensation, and motor function. Individuals with unilateral chronic stroke were pseudo-randomly divided into either Active or Sham 5 Hz rTMS groups (n = 11/group). Following stimulation, both groups practiced a Serial Tracking Task (STT) with the hemiparetic arm; this was repeated for 5 days. Performance on the STT was quantified by response time, peak velocity, and cumulative distance tracked at baseline, during the 5 days of practice, and at a no-rTMS retention test. Cutaneous somatosensation was measured using two-point discrimination. Standardized sensorimotor tests were performed to assess whether the effects might generalize to impact hemiparetic arm function. The active 5 Hz rTMS + training group demonstrated significantly greater improvements in STT performance {response time [F(1, 286.04) = 13.016, p < 0.0005], peak velocity [F(1, 285.95) = 4.111, p = 0.044], and cumulative distance [F(1, 285.92) = 4.076, p = 0.044]} and cutaneous somatosensation [F(1, 21.15) = 8.793, p = 0.007] across all sessions compared to the sham rTMS + training group. Measures of upper extremity motor function were not significantly different for either group. Our preliminary results suggest that, when paired with motor practice, 5 Hz rTMS over IL-S1 enhances motor learning related change in individuals with chronic stroke, potentially as a consequence of improved cutaneous somatosensation, however no improvement in general upper extremity function was observed.
doi:10.3389/fnhum.2014.00143
PMCID: PMC3968757  PMID: 24711790
repetitive transcranial magnetic stimulation; stroke; hemiparesis; primary sensory cortex; upper extremity; motor learning
18.  Remediation of Sleep-Deprivation–Induced Working Memory Impairment with fMRI-Guided Transcranial Magnetic Stimulation 
Cerebral Cortex (New York, NY)  2008;18(9):2077-2085.
Repetitive transcranial magnetic stimulation (rTMS) was applied to test the role of selected cortical regions in remediating sleep-deprivation–induced deficits in visual working memory (WM) performance. Three rTMS targets were chosen using a functional magnetic resonance imaging (fMRI)–identified network associated with sleep-deprivation–induced WM performance impairment: 2 regions from the network (upper left middle occipital gyrus and midline parietal cortex) and 1 nonnetwork region (lower left middle occipital gyrus). Fifteen participants underwent total sleep deprivation for 48 h. rTMS was applied at 5 Hz during a WM task in a within-subject sham-controlled design. The rTMS to the upper-middle occipital site resulted in a reduction of the sleep-induced reaction time deficit without a corresponding decrease in accuracy, whereas stimulation at the other sites did not. Each subject had undergone fMRI scanning while performing the task both pre- and postsleep deprivation, and the degree to which each individual activated the fMRI network was measured. The degree of performance enhancement with upper-middle occipital rTMS correlated with the degree to which each individual failed to sustain network activation. No effects were found in a subset of participants who performed the same rTMS procedure after recovering from sleep deprivation, suggesting that the performance enhancements seen following sleep deprivation were state dependent.
doi:10.1093/cercor/bhm231
PMCID: PMC2981026  PMID: 18203694
facilitation; fMRI; sleep deprivation; TMS; working memory
19.  Effects of Low Frequency Prefrontal Repetitive Transcranial Magnetic Stimulation on the N2 Amplitude in a GoNogo Task 
PLoS ONE  2013;8(6):e67136.
During the last decade, repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex has become established as a treatment for various mental diseases. The rational of prefrontal stimulation has been adapted from the mode of action known from rTMS using motor-evoked potentials though little is known about the precise effect of rTMS at prefrontal sites. The objective of the current study is to investigate the inhibitory effect of prefrontal 1 Hz rTMS by stimulating the generators of event-related potentials (ERP) which are located in the prefrontal cortex. Thus, 1 Hz rTMS was applied offline over the left dorsolateral prefrontal cortex (DLPFC) and the medial prefrontal cortex (MPFC) in 18 healthy subjects who subsequently underwent a GoNogo task. Both active conditions were compared to sham rTMS within a randomized and counterbalanced cross-over design in one day. ERPs were recorded during task performance and the N2 and the P3 were analysed. After 1 Hz rTMS of the left DLPFC (but not of the MPFC), an inhibitory effect on the N2 amplitude was observed, which was related to inhibitory control. In contrast, after 1 Hz rTMS of the MPFC (but not at the left DLPFC) a trend towards an increased P3 amplitude was found. There was no significant modulation of latencies and behavioural data. The results argue in favour of an inhibitory effect of 1 Hz rTMS on N2 amplitudes in a GoNogo task. Our findings suggest that rTMS may mildly modulate prefrontally generated ERP immediately after stimulation, even where behavioural effects are not measurable. Thus, combined rTMS-ERP approaches need to be further established in order to serve as paradigms in experimental neuroscience and clinical research.
doi:10.1371/journal.pone.0067136
PMCID: PMC3694966  PMID: 23826214
20.  Cognitive correlates of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression- a pilot study 
BMC Psychiatry  2012;12:163.
Background
The aim of the current study was to investigate the cognitive correlates of repetitive transcranial magnetic stimulation (rTMS) in 10 treatment-resistant depression patients.
Methods
Patients received forty 20-min sessions of fast-frequency (10 Hz) rTMS of the left dorsolateral prefrontal cortex (DLPFC) over 20 days. Concept-shift ability (accuracy and duration of performance) was assessed daily with a Modified Concept-Shifting Task (mCST) in patients and in eight healthy volunteers. General cognitive functioning test (Repeatable Battery for the Assessment of Neuropsychological Status; RBANS), Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HAM-D) were applied before the first and after the last rTMS.
Results
Compared to before rTMS on the first 10 days, the patients performed the mCST significantly more accurately after rTMS on the last 10 days (p < .001, partial eta squared=.78) while the same comparison in healthy volunteers was not statistically significant (p = .256, partial eta squared=.18). A significant improvement in immediate memory on RBANS and reduction in BDI and HAM-D scores were also observed after the last compared to before the first rTMS.
Conclusion
The rTMS is associated with an improvement in selective cognitive functions that is not explained by practice effects on tasks administered repeatedly.
Trial registration
Name: "Repetitive Transcranial Magnetic Stimulation (rTMS) in the treatment of depression, assessed with HAM-D over a four week period."
URL: www.actr.org.au
Registration number: ACTRN012605000145606
doi:10.1186/1471-244X-12-163
PMCID: PMC3515465  PMID: 23031294
Repetitive transcranial magnetic stimulation (rTMS); Treatment-resistant depression; Modified concept-shifting task (mCST); Left dorsolateral prefrontal cortex (DLPFC)
21.  Noninvasive Brain Stimulation With High-Frequency and Low-Intensity Repetitive Transcranial Magnetic Stimulation Treatment for Posttraumatic Stress Disorder 
Objective
We aimed to investigate the efficacy of 20 Hz repetitive transcranial magnetic stimulation (rTMS) of either right or left dorsolateral prefrontal cortex (DLPFC) as compared to sham rTMS for the relief of posttraumatic stress disorder (PTSD)–associated symptoms.
Method
In this double-blind, placebo-controlled phase II trial conducted between October 2005 and July 2008, 30 patients with DSM-IV–diagnosed PTSD were randomly assigned to receive 1 of the following treatments: active 20 Hz rTMS of the right DLPFC, active 20 Hz rTMS of the left DLPFC, or sham rTMS. Treatments were administered in 10 daily sessions over 2 weeks. A blinded rater assessed severity of core PTSD symptoms, depression, and anxiety before, during, and after completion of the treatment protocol. In addition, a battery of neuropsychological tests was measured before and after treatment.
Results
Results show that both active conditions—20 Hz rTMS of left and right DLPFC—induced a significant decrease in PTSD symptoms as indexed by the PTSD Checklist and Treatment Outcome PTSD Scale; however, right rTMS induced a larger effect as compared to left rTMS. In addition, there was a significant improvement of mood after left rTMS and a significant reduction of anxiety following right rTMS. Improvements in PTSD symptoms were long lasting; effects were still significant at the 3-month follow-up. Finally, neuropsychological evaluation showed that active 20 Hz rTMS is not associated with cognitive worsening and is safe for use in patients with PTSD.
Conclusions
These results support the notion that modulation of prefrontal cortex can alleviate the core symptoms of PTSD and suggest that high-frequency rTMS of right DLPFC might be the optimal treatment strategy.
doi:10.4088/JCP.08m04638blu
PMCID: PMC3260527  PMID: 20051219
22.  Excitatory repetitive transcranial magnetic stimulation induces improvements in chronic post-stroke aphasia 
Summary
Background
Aphasia affects 1/3 of stroke patients with improvements noted only in some of them. The goal of this exploratory study was to provide preliminary evidence regarding safety and efficacy of fMRI-guided excitatory repetitive transcranial magnetic stimulation (rTMS) applied to the residual left-hemispheric Broca’s area for chronic aphasia treatment.
Material/Methods
We enrolled 8 patients with moderate or severe aphasia >1 year after LMCA stroke. Linguistic battery was administered pre-/post-rTMS; a semantic decision/tone decision (SDTD) fMRI task was used to localize left-hemispheric Broca’s area. RTMS protocol consisted of 10 daily treatments of 200 seconds each using an excitatory stimulation protocol called intermittent theta burst stimulation (iTBS). Coil placement was targeted individually to the left Broca’s.
Results
6/8 patients showed significant pre-/post-rTMS improvements in semantic fluency (p=0.028); they were able to generate more appropriate words when prompted with a semantic category. Pre-/post-rTMS fMRI maps showed increases in left fronto-temporo-parietal language networks with a significant left-hemispheric shift in the left frontal (p=0.025), left temporo-parietal (p=0.038) regions and global language LI (p=0.018). Patients tended to report subjective improvement on Communicative Activities Log (mini-CAL; p=0.075). None of the subjects reported ill effects of rTMS.
Conclusions
FMRI-guided, excitatory rTMS applied to the affected Broca’s area improved language skills in patients with chronic post-stroke aphasia; these improvements correlated with increased language lateralization to the left hemisphere. This rTMS protocol appears to be safe and should be further tested in blinded studies assessing its short- and long-term safety/efficacy for post-stroke aphasia rehabilitation.
PMCID: PMC3057942  PMID: 21358599
aphasia; language; fMRI; rTMS; rehabilitation; stroke
23.  Excitatory repetitive transcranial magnetic stimulation induces improvements in chronic post-stroke aphasia 
Summary
Background
Aphasia affects 1/3 of stroke patients with improvements noted only in some of them. The goal of this exploratory study was to provide preliminary evidence regarding safety and efficacy of fMRI-guided excitatory repetitive transcranial magnetic stimulation (rTMS) applied to the residual left-hemispheric Broca’s area for chronic aphasia treatment.
Material/Methods
We enrolled 8 patients with moderate or severe aphasia >1 year after LMCA stroke. Linguistic battery was administered pre-/post-rTMS; a semantic decision/tone decision (SDTD) fMRI task was used to localize left-hemispheric Broca’s area. RTMS protocol consisted of 10 daily treatments of 200 seconds each using an excitatory stimulation protocol called intermittent theta burst stimulation (iTBS). Coil placement was targeted individually to the left Broca’s.
Results
6/8 patients showed significant pre-/post-rTMS improvements in semantic fluency (p=0.028); they were able to generate more appropriate words when prompted with a semantic category. Pre-/post-rTMS fMRI maps showed increases in left fronto-temporo-parietal language networks with a significant left-hemispheric shift in the left frontal (p=0.025), left temporo-parietal (p=0.038) regions and global language LI (p=0.018). Patients tended to report subjective improvement on Communicative Activities Log (mini-CAL; p=0.075). None of the subjects reported ill effects of rTMS.
Conclusions
FMRI-guided, excitatory rTMS applied to the affected Broca’s area improved language skills in patients with chronic post-stroke aphasia; these improvements correlated with increased language lateralization to the left hemisphere. This rTMS protocol appears to be safe and should be further tested in blinded studies assessing its short- and long-term safety/efficacy for post-stroke aphasia rehabilitation.
doi:10.12659/MSM.881446
PMCID: PMC3057942  PMID: 21358599
aphasia; language; fMRI; rTMS; rehabilitation; stroke
24.  Superior antidepressant effect occurring 1 month after rTMS: add-on rTMS for subjects with medication-resistant depression 
Depression is a major psychiatric disorder. The standard treatment for depression is antidepressant medication, but the responses to antidepressant treatment are only partial, even poor, among 30%–45% of patients. Refractory depression is defined as depression that does not respond to antidepressant therapy after 4 weeks of use. There is evidence that repetitive transcranial magnetic stimulation (rTMS) may exert effects in treating psychiatric disorder through moderating focal neuronal functions. High-frequency rTMS on the left prefrontal area and low-frequency rTMS on the right prefrontal area were shown to be effective in alleviating depressive symptoms. Given the statistically significant antidepressant effectiveness noted, the clinical application of rTMS as a depression treatment warrants further studies. Application of rTMS as an add-on therapy would be a practical research model. High-frequency (5–20 Hz) rTMS over the left dorsolateral prefrontal cortex was found to have a significant effect on medication-resistant depression. In the present study, we not only measured the acute antidepressant effect of rTMS during treatment and immediately after its completion but also evaluated participants 1 month after completion of the treatment protocol. Study participants were divided into two groups: an active rTMS group (n = 10) and a sham group (n = 10). The active rTMS group was defined as participants who received the rTMS protocol, and the sham group was defined as participants who received a sham rTMS procedure. A significant Hamilton Depression Rating Scale score reduction was observed in both groups after the fifth and tenth treatments. However, those in the active rTMS group maintained their improvement as measured one month after completion of the rTMS protocol. Participants who received active rTMS were more likely to have persistent improvement in depression scores than participants who received sham rTMS.
doi:10.2147/NDT.S40466
PMCID: PMC3617929  PMID: 23576870
major depressive disorder; repetitive transcranial magnetic stimulation; treatment-resistant depression; efficacy; adverse effect
25.  Is 1 Hz rTMS Always Inhibitory in Healthy Individuals? 
1 Hz repetitive Transcranial Magnetic Stimulation (rTMS) is considered to have an inhibitory effect in healthy people because it suppresses the excitability of the motor or visual cortex that is expressed as an increase in the motor or the phosphene threshold (PT), respectively. However, the underlying mechanisms and the brain structures involved in the action of rTMS are still unknown. In this study we used two sessions of simultaneous TMS-functional magnetic resonance imaging (fMRI), one before and one after, 15 minutes of 1Hz rTMS to map changes in brain function associated with the reduction in cortical excitability of the primary visual cortex induced by 1 Hz rTMS, when TMS was applied on the occipital area of healthy volunteers. Two groups were evaluated, one group composed of people that can see phosphenes, and another of those lacking this perception. The inhibitory effect, induced by the 1 Hz rTMS, was observed through the increase of the PT, in the first group, but did not lead to a global reduction in brain activation, instead, showed change in the activation pattern before and after rTMS. Conversely, for the second group, changes in brain activation were observed just in few brain areas, suggesting that the effect of 1 Hz rTMS might not be inhibitory for everyone and that the concept of inhibitory/excitatory effect of rTMS may need to be revised.
doi:10.2174/1874440001206010069
PMCID: PMC3428632  PMID: 22930669
TMS-functional magnetic resonance imaging; phosphene threshold.

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