Combined rTMS Research Articles

Simultaneous rTMS and psychotherapy in major depressive disorder: Clinical outcomes and predictors from a large naturalistic study

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is considered an efficacious non-invasive neuromodulation treatment for major depressive disorder (MDD). However, little is known about the clinical outcome of combined rTMS and psychotherapy (rTMS + PT). Through common neurobiological brain mechanisms, rTMS + PT may exert enhanced antidepressant effects compared to the respective monotherapies. ObjectiveThe current naturalistic study aimed to evaluate feasibility and clinical outcome of rTMS + PT in a large group of MDD patients. The second aim was to identify clinical predictors of response and remission. MethodsA total of 196 patients with MDD were treated with at least 10 sessions of simultaneous rTMS and PT. rTMS was applied over the DLPFC, either 10 Hz left or 1 Hz right. Psychotherapy was based on principles of cognitive behavioral therapy (CBT). Symptoms were measured using the BDI each fifth session until end of treatment and at 6-month follow-up. Comparisons were made between responders and non-responders, as well as between the 10 Hz and 1 Hz protocol. Additionally, baseline variables and early BDI change were evaluated as predictors of response/remission. Major findings and conclusions1) Combining rTMS and PT resulted in a 66% response and a 56% remission rate at the end of treatment with 60% sustained remission at follow-up. Compared to previous findings in RCTs, these rates are relatively high; 2) No differences were found between the 10 Hz and 1 Hz TMS regarding clinical outcome; 3) Clinical baseline variables were not predictive of treatment outcomes; 4) Early symptom improvement (at session 10) was highly predictive of response, and may therefore be used to guide rTMS + PT continuation; 5) Based on the current findings in a large naturalistic study, future studies employing a more standardized method are warranted to draw solid conclusions on the unique effect of rTMS + PT.

P093 Transcranial cortex stimulation, neuroplasticity and learning: An experimental and computational study

Question Noninvasive cortical stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) are capable of increasing and decreasing cortical excitability and thereby might be clinically relevant for rehabilitation of neurological and neuropsychiatric disorders. However, the induced after-effects are usually too short-lasting to be clinically relevant. In this study we investigated if combining rTMS with operant learning can induce long-lasting after-effects not achievable neither with rTMS alone nor with operant learning alone. Methods Experimental approach: Forty-six subjects were randomly assigned to three experimental groups. Experimental groups 1 & 2 received a psychophysical pretest of tactile discrimination abilities with the left ring finger, a training procedure to improve performance with this finger, and a posttest. In experimental group 1 the training procedure was combined with 15 Hz rTMS over the primary sensory cortex (SI) while in experimental group 2 the training was combined with sham rTMS. In the third experimental group, psychophysical pre- and posttests of tactile discrimination abilities were assessed. However, they received 15 Hz rTMS over SI without training. Computational approach: As a preliminary simulation trial we developed a neural model, which enabled us to discriminate between the encoding and decoding of particular input frequency represented in several scenarios. Results Combining rTMS with operant learning induced long-lasting after-effects not achievable neither with rTMS alone nor with operant learning alone. A conceptual framework for the efficiency of combining cortical stimulation with operant learning can be derived from the Bienenstock–Cooper–Munro theory of bidirectional synaptic plasticity. According to this theory the change of synaptic efficiency during learning processes is dependent on the preactivation level of the involved neural network, suggesting that high-frequency rTMS can transiently decrease the threshold for the induction of LTP-like effects and thereby gate practice-dependent plasticity. Conclusions Our findings provide important implications for the use of rTMS in combination with operant learning as a therapeutic tool for neurorehabilitation.

P058 A proof-of-concept study on the combination of repetitive transcranial magnetic stimulation and relaxation techniques in chronic tinnitus

Background Interference of ongoing neuronal activity and brain stimulation motivated this study to prove the concept of a combined treatment approach integrating repetitive transcranial magnetic stimulation (rTMS) and relaxation techniques in patients with chronic tinnitus. Methods Forty-two patients received rTMS consisting of ten sessions of high-frequency left dorsolateral prefrontal cortex followed by low-frequency left temporo-parietal cortex stimulation in this one-arm proof-of-concept study. During low-frequency stimulation patients listened to different kinds of relaxation audios selected according individual preferences (classical music; instructions to muscle or breath relaxation, imaginary journey or hypnosis). Variables of interest were tinnitus questionnaires, tinnitus numeric rating scales, depressivity, and quality of life. Results were compared to results of historical control groups having received the same rTMS protocol (active control) and sham treatment (placebo) without relaxation techniques. Results Drop-outs and adverse events were low. Responder rates (reduction in tinnitus questionnaire (TQ) score by at least 5 points ten weeks after treatment) were 44.7% in the study, 27.8% in the active control group, and 21.7% in the placebo group, differing between groups on a near-significant level. Combination of rTMS and relaxation showed higher amelioration in the tinnitus handicap inventory questionnaire (THI) in contrast to rTMS alone. Deepness of relaxation during rTMS and selection of active relaxation vs. passive listening to music predicted larger reductions in the TQ-score. All remaining secondary outcomes turned out non-significant. Discussion Combining rTMS and relaxation techniques has proven to be a safe, feasible and promising approach to enhance rTMS treatment effects in chronic tinnitus.

A Framework for Combining rTMS with Behavioral Therapy.

Upon its inception, repetitive transcranial magnetic stimulation (rTMS) was delivered at rest, without regard to the potential impact of activity occurring during or around the time of stimulation. rTMS was considered an experimental intervention imposed on the brain; therefore, the myriad features that might suppress or enhance its desired effects had not yet been explored. The field of rTMS has since grown substantially and therapeutic benefits have been reported, albeit with modest and inconsistent improvements. Work in this field accelerated following approval of a psychiatric application (depression), and it is now expanding to other applications and disciplines. In the last decade, experimental enquiry has sought new ways to improve the therapeutic benefits of rTMS, intended to enhance underlying brain reorganization and functional recovery by combining it with behavioral therapy. This concept is appealing, but poorly defined and requires clarity. We provide an overview of how combined rTMS and behavioral therapy has been delineated in the literature, highlighting the diversity of approaches. We outline a framework for study design and reporting such that the effects of this emerging method can be better understood.

Bursts of high-frequency repetitive transcranial magnetic stimulation (rTMS), together with lorazepam, suppress seizures in a rat kainate status epilepticus model.

Status epilepticus (SE) is a condition of prolonged or recurrent and often drug-resistant seizures where nonsedating SE therapy remains an important unmet need. Repetitive transcranial magnetic stimulation (rTMS) is emerging as a means to suppress seizures but has not been extensively studied in models. We aimed to test the antiepileptic potential of high-frequency rTMS in SE. As a step toward eventual coupling of rTMS with antiepileptic pharmacotherapy, we also tested whether high-frequency rTMS in combination with a low (ineffective but less likely to cause a side effect) lorazepam dose is as effective as a full lorazepam dose in suppressing seizures in a rat SE model. EEG was recorded to measure epileptic spike frequency in the rat kainate SE model. Epileptic spikes were counted before, during, and after either high-frequency rTMS treatment alone or high-frequency rTMS treatment in combination with lorazepam, a firstline SE treatment. We found that rTMS alone decreases epileptic spike frequency only acutely. However, combinatory treatment with half-dose lorazepam together with rTMS was as effective as a full lorazepam dose. We report that high-frequency rTMS has modest antiepileptic potential alone but acts in complement with lorazepam to suppress seizures.

Cortical time course of object naming investigated by repetitive navigated transcranial magnetic stimulation.

Human language organization models and language time course patterns are still predominantly derived from meta-analyses of numerous single publications, which only investigated scattered cortical regions. Moreover, there is not much literature available on the exact impact of repetitive navigated transcranial magnetic stimulation (rTMS) onset times on object naming. We, therefore, used a virtual lesion-based approach by mapping various cortical areas with rTMS to investigate the time course of object naming, and to specifically provide data on the pattern of rTMS language mapping results depending on different stimulation onset times. Ten healthy, right-handed subjects were enrolled, and rTMS in combination with an object-naming task was performed with different stimulation onset times (0ms, 100ms, 200ms, 300ms, 400ms, and 500ms). Subsequent to language mapping, all naming errors detected were systematically classified with respect to previous literature. The majority of errors was elicited within the opercular inferior frontal gyrus (opIFG) and ventral precentral gyrus (vPrG), and the spatial distribution of naming errors changed according to the time point of naming disruption by varying onset times. For instance, immediate rTMS onset led to a widespread cortical distribution of no responses, whereas performance and hesitation errors increased with higher stimulation onset times.

EXPLORING THE DICHOTOMY OF TRANSCRANIAL MAGNETIC STIMULATION’S FREQUENCIES ON BRAIN WAVE PATTERNS

Disturbance in brain oscillations is observed in many neuropsychiatric disorders. Any tool that has the potential to restore abnormal brain oscillations is therefore beneficial to patients with neuropsychiatric illnesses. Repetitive transcranial magnetic stimulation (rTMS) is one such tool. It is a non-invasive brain stimulation technique, which is able to alter brain oscillations depending on its parameters of stimulation and is used in clinical setting because of its potential therapeutic effects on the brain. However, the optimum stimulation parameters to induce the therapeutic effect of rTMS remains elusive. Therefore, it is important to investigate the differential effects between high versus low frequency of magnetic stimulation on the mechanism of brain oscillations in human subjects. Here we show, using combined rTMS and surface electroencephalography (EEG) that low and high frequencies of magnetic stimulation would induce dichotomy effects in EEG brain oscillatory activity. In particular, high-frequency rTMS 10Hz induces a synchronised oscillations for theta brain rhythm. In contrast, low-frequency rTMS 1Hz desynchronises neural oscillations on the same brain rhythm. Taken together, our results show that the desynchronisation effect of low-frequency rTMS 1Hz may potentially reverse the interference of altered neural oscillations. More extensive basic and clinical research using combined rTMS and EEG are needed to determine the optimum parameters of rTMS stimulation to restore adequate neural oscillations.

Brain stimulation and constraint for perinatal stroke hemiparesis: The PLASTIC CHAMPS Trial.

To determine whether the addition of repetitive transcranial magnetic stimulation (rTMS) and/or constraint-induced movement therapy (CIMT) to intensive therapy increases motor function in children with perinatal stroke and hemiparesis. A factorial-design, blinded, randomized controlled trial (clinicaltrials.gov/NCT01189058) assessed rTMS and CIMT effects in hemiparetic children (aged 6-19 years) with MRI-confirmed perinatal stroke. All completed a 2-week, goal-directed, peer-supported motor learning camp randomized to daily rTMS, CIMT, both, or neither. Primary outcomes were the Assisting Hand Assessment and the Canadian Occupational Performance Measure at baseline, and 1 week, 2 and 6 months postintervention. Outcome assessors were blinded to treatment. Interim safety analyses occurred after 12 and 24 participants. Intention-to-treat analysis examined treatment effects over time (linear mixed effects model). All 45 participants completed the trial. Addition of rTMS, CIMT, or both doubled the chances of clinically significant improvement. Assisting Hand Assessment gains at 6 months were additive and largest with rTMS + CIMT (β coefficient = 5.54 [2.57-8.51], p = 0.0004). The camp alone produced large improvements in Canadian Occupational Performance Measure scores, maximal at 6 months (Cohen d = 1.6, p = 0.002). Quality-of-life scores improved. Interventions were well tolerated and safe with no decrease in function of either hand. Hemiparetic children participating in intensive, psychosocial rehabilitation programs can achieve sustained functional gains. Addition of CIMT and rTMS increases the chances of improvement. This study provides Class II evidence that combined rTMS and CIMT enhance therapy-induced functional motor gains in children with stroke-induced hemiparetic cerebral palsy.

Combined rTMS treatment targeting the Anterior Cingulate and the Temporal Cortex for the Treatment of Chronic Tinnitus.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a tinnitus treatment option. Promising results have been obtained by consecutive stimulation of lateral frontal and auditory brain regions. We investigated a combined stimulation paradigm targeting the anterior cingulate cortex (ACC) with double cone coil rTMS, followed by stimulation of the temporo-parietal junction area with a figure-of-eight coil. The study was conducted as a randomized, double-blind pilot trial in 40 patients suffering from chronic tinnitus. We compared mediofrontal stimulation with double-cone-coil, (2000 stimuli, 10 Hz) followed by left temporo-parietal stimulation with figure-of-eight-coil (2000 stimuli, 1 Hz) to left dorsolateral-prefrontal-cortex stimulation with figure-of-eight-coil (2000 stimuli, 10 Hz) followed by temporo-parietal stimulation with figure-of-eight-coil (2000 stimuli, 1 Hz). The stimulation was feasible with comparable dropout rates in both study arms; no severe adverse events were registered. Responder rates did not differ in both study arms. There was a significant main effect of time for the change in the TQ score, but no significant time x group interaction. This pilot study demonstrated the feasibility of combined mediofrontal/temporoparietal-rTMS-stimulation with double cone coil in tinnitus patients but failed to show better outcome compared to an actively rTMS treated control group.

Erratum to: The impact of repetitive navigated transcranial magnetic stimulation coil positioning and stimulation parameters on human language function

Repetitive navigated transcranial magnetic stimulation (rTMS) in combination with object naming is able to elicit naming errors by stimulating language-related brain regions. However, stimulation results mainly depend on coil positioning and stimulation parameters, which have not been investigated since the implementation of neuronavigation to transcranial magnetic stimulation. Therefore, the following three parameters were systematically examined in the present study: coil angulation, stimulation frequency, and stimulation intensity. Five healthy, right-handed subjects underwent rTMS language mapping of Broca’s as well as Wernicke’s areas of the left hemisphere. During mapping sessions, coil angulation was changed clockwise in 45° steps, and the stimulation frequency and intensity were varied within a considerably wide range. For angulation, the anterior-posterior (ap) coil orientation was used as reference position. An angulation of 90° to ap coil orientation led to the highest rate of naming errors within Broca’s area, whereas an inhomogeneous distribution of angulations was observed during stimulation of Wernicke’s area. Therefore, ap coil orientation, which is regarded as standard in rTMS language mapping, could not be approved as the optimal position. With regard to stimulation parameters, 20 Hz and 120% of the resting motor threshold (RMT) were defined as optimal. Coil angulation, stimulation frequency, and stimulation intensity have significant impacts on language impairment during rTMS mapping. The variation of only one of these parameters already leads to a clearer disruption of language performance. Therefore, individually adapted stimulation protocols have to be determined prior to language mapping in order to improve mapping results.

Brain stimulation and constraint for hemiparesis after perinatal stroke: The PLASTIC CHAMPS trial

Background: Perinatal stroke causes hemiparetic cerebral palsy. Constraint therapy (CIMT) improves function in congenital hemiparesis and adult stroke. Repetitive transcranial magnetic stimulation (rTMS) may improve function in adult stroke. The two have not been tested in perinatal stroke. Methods: PLASTIC CHAMPS (www.clinicaltrials.gov/NCT01189058) was a controlled factorial trial of rTMS and CIMT in perinatal-stroke hemiparesis. Children 6-18 years participated in a 2 week peer-supported motor learning camp, randomized to daily inhibitory rTMS (1200 stimulations, contralesional M1), CIMT, both or neither. Primary outcomes were Assisting Hand Assessment (AHA) and Canadian Occupational Performance Measure (COPM) at 1, 8, and 24 weeks. Quality-of-life, safety and tolerability were evaluated. Change was assessed across treatment groups over time (linear mixed effects model). Results: All forty-five subjects completed the trial (median 11.4yrs). COPM scores increased >100% with maximal gains at 6 months (p<0.002). Addition of rTMS and/or CIMT doubled the chances of clinically significant gains. Combined rTMS+CIMT resulted in larger AHA gains at all time points (6 months p=0.006). CIMT or rTMS alone had more modest effects. Neither treatment decreased function in either hand. Procedures were well tolerated. Conclusions: Children with hemiparesis participating in intensive, psychosocial rehabilitation programs perceive marked increases in function. Non-invasive brain stimulation may enhance motor learning therapy in perinatal stroke hemiparesis.

OP29 – 2815: Brain stimulation and constraint for perinatal stroke hemiparesis: The PLASTIC CHAMPS trial

Objective Perinatal stroke causes hemiparetic cerebral palsy and lifelong disability. Constraint-induced movement therapy (CIMT) can improve motor function in congenital hemiparesis and adult stroke. Repetitive transcranial magnetic stimulation (rTMS) may improve motor function in adult stroke. The two have not been formally tested in perinatal stroke hemiparesis. Methods PLASTIC CHAMPS ( www.clinicaltrials.gov/NCT01189058 ) was a blinded, controlled, factorial trial of rTMS and CIMT in perinatal stroke hemiparesis. Children 6–18 years participated in a 2 week, goal-directed, peer-supported, motor learning camp. Subjects were randomized to daily inhibitory rTMS (1Hz, 1200 stimulations) over contralesional primary motor cortex, CIMT, both or neither. Primary outcomes were the Assisting Hand Assessment (AHA) and Canadian Occupational Performance Measure (COPM) at 1 week, 2 months, and 6 months. Additional outcomes included the Melbourne Assessment, quality-of-life, safety and tolerability. Corticospinal tract arrangement was defined using single-pulse TMS. Intent-to-treat analysis assessed change across treatment groups over time (ANOVA, linear mixed effects model). Results All forty-five children completed the trial (median 11.4 years). Across all subjects, COPM performance and satisfaction scores increased >100% with sustained, maximal gains at 6 months (p 5 logit units). Combined rTMS+CIMT resulted in larger AHA gains at all time points (6 months p=0.006). CIMT alone increased AHA at 2 months (p=0.007), rTMS alone increased AHA at 1 week (p=0.002). Neither treatment decreased unaffected hand function. Affected hand function did not decrease with rTMS in children with ipsilateral corticospinal tract arrangements. Procedures were well tolerated. Conclusion Children with hemiparesis participating in intensive, psychosocial rehabilitation programs perceive marked and sustained increases in goal-specific function. Non-invasive brain stimulation trials are feasible in children with CP. Contralesional inhibitory rTMS may enhance motor learning therapy in children with perinatal stroke.

The impact of repetitive navigated transcranial magnetic stimulation coil positioning and stimulation parameters on human language function.

BackgroundRepetitive navigated transcranial magnetic stimulation (rTMS) in combination with object naming is able to elicit naming errors by stimulating language-related brain regions. However, stimulation results mainly depend on coil positioning and stimulation parameters, which have not been investigated since the implementation of neuronavigation to transcranial magnetic stimulation. Therefore, the following three parameters were systematically examined in the present study: coil angulation, stimulation frequency, and stimulation intensity.MethodsFive healthy, right-handed subjects underwent rTMS language mapping of Broca’s as well as Wernicke’s areas of the left hemisphere. During mapping sessions, coil angulation was changed clockwise in 45° steps, and the stimulation frequency and intensity were varied within a considerably wide range. For angulation, the anterior-posterior (ap) coil orientation was used as reference position.ResultsAn angulation of 90° to ap coil orientation led to the highest rate of naming errors within Broca’s area, whereas an inhomogeneous distribution of angulations was observed during stimulation of Wernicke’s area. Therefore, ap coil orientation, which is regarded as standard in rTMS language mapping, could not be approved as the optimal position. With regard to stimulation parameters, 20 Hz and 120% of the resting motor threshold (RMT) were defined as optimal.ConclusionsCoil angulation, stimulation frequency, and stimulation intensity have significant impacts on language impairment during rTMS mapping. The variation of only one of these parameters already leads to a clearer disruption of language performance. Therefore, individually adapted stimulation protocols have to be determined prior to language mapping in order to improve mapping results.

Non-invasive Repeated Therapeutic Stimulation for Aphasia Recovery: A Multilingual, Multicenter Aphasia Trial

Noninvasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) has been used in case series and small randomized controlled trials to improve recovery from poststroke aphasia in combination with speech and language therapy. Results of these studies suggest possible clinical efficacy and an excellent safety profile. Therefore, a larger international multicenter proof-of-concept trial was launched, to directly compare the safety and efficacy of rTMS, tDCS, and sham stimulation as adjuvant therapy to speech and language therapy in subacute poststroke aphasia. In the 4 participating centers, subacute stroke patients with aphasia are randomized between 5 and 30days after ischemic stroke to either receive rTMS, tDCS, or sham stimulation in combination with a daily 45minutes speech and language therapy session for 10days. Efficacy is evaluated at 1 and 30days after the last of the 10 treatment sessions using 3 outcome measures, validated in all participating languages: Boston naming test, Token test, and verbal fluency test. Additionally, adverse events are recorded to prove safety. In this study, a total of 90 patients will be recruited, and data analysis will be completed in 2016. This is the first multilingual and multinational randomized and controlled trial in poststroke aphasia and if positive, will add aneffective new strategy for early stage poststroke aphasia rehabilitation.

Safety of Primed Repetitive Transcranial Magnetic Stimulation and Modified Constraint-Induced Movement Therapy in a Randomized Controlled Trial in Pediatric Hemiparesis

ObjectiveTo investigate the safety of combining a 6-Hz primed low-frequency repetitive transcranial magnetic stimulation (rTMS) intervention in the contralesional hemisphere with a modified constraint-induced movement therapy (mCIMT) program in children with congenital hemiparesis. DesignPhase 1 randomized, double-blinded, placebo-controlled pretest/posttest trial. SettingUniversity academic facility and pediatric specialty hospital. ParticipantsSubjects (N=19; age range, 8–17y) with congenital hemiparesis caused by ischemic stroke or periventricular leukomalacia. No subject withdrew because of adverse events. All subjects included completed the study. InterventionsSubjects were randomized to 1 of 2 groups: either real rTMS plus mCIMT (n=10) or sham rTMS plus mCIMT (n=9). Main Outcome MeasuresAdverse events, physician assessment, ipsilateral hand function, stereognosis, cognitive function, subject report of symptoms assessment, and subject questionnaire. ResultsNo major adverse events occurred. Minor adverse events were found in both groups. The most common events were headaches (real: 50%, sham: 89%; P=.14) and cast irritation (real: 30%, sham: 44%; P=.65). No differences between groups in secondary cognitive and unaffected hand motor measures were found. ConclusionsPrimed rTMS can be used safely with mCIMT in congenital hemiparesis. We provide new information on the use of rTMS in combination with mCIMT in children. These findings could be useful in research and future clinical applications in advancing function in congenital hemiparesis.

Combined Central and Peripheral Stimulation for Treatment of Chronic Tinnitus

Background. Tinnitus is a common untreatable condition that originates from central maladaptive plasticity initiated by peripheral injury. Repetitive transcranial magnetic stimulation (rTMS), direct cochlear low-level laser therapy (LLLT), and acupuncture were tried for tinnitus treatment, but the results of these methods were clinically unsatisfactory. Objective. This study aimed to test the combined effect of the 3 methods targeting both peripheral and central auditory areas as a new therapeutic strategy for tinnitus. Methods. For this, 30 patients were randomized to 3 equal groups receiving 3 different interventions: inhibitory rTMS to the left auditory cortex, LLLT (which includes a combination of direct cochlear LLLT and laser acupuncture) to the affected ear(s), and finally, a combination of rTMS and LLLT. The Tinnitus Handicap Inventory (THI) and Visual Analogue Scale (VAS) were assessed before, immediately after, and at 2 weeks and 4 weeks after 10 consecutive every-other-day sessions for each intervention type. Results. We found that combined stimulation was effective in tinnitus treatment. This effect remained for 4 weeks after the end of the treatment. However, each of rTMS and LLLT alone had no significant effect. Repeated-measures ANOVA showed a significant effect of Time and Time × Intervention interaction for THI and VAS scores. The post hoc t test for different time points per intervention revealed a significant difference between baseline and all postintervention measurements of both THI and VAS for the combination intervention. Conclusion. Combined central rTMS and peripheral LLLT is more beneficial as a new method for management of tinnitus rather than these two used separately.

Efficacy of repetitive transcranial magnetic stimulation in the prevention of relapse of depression: study protocol for a randomized controlled trial

BackgroundDepression is a chronic illness that generally requires lifelong therapy. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique with few side effects that has been reported to be useful in the treatment of depression. However, no studies to date have evaluated in a randomized controlled trial (RCT) the efficacy of rTMS for maintenance treatment of depression.Methods/designIn this article, we report the design and protocol of a randomized, single-blind, placebo-controlled, parallel-group, multicenter study in China to evaluate the efficacy of rTMS in the prevention of relapse of depressive symptoms. In total, 540 patients, aged 18 to 60 years, diagnosed with depression and experiencing an acute exacerbation of depressive symptoms, will be enrolled. The study will consist of four phases: a screening/tolerability phase of up to 7 days; an open-label, flexible-dose lead-in phase of 8 weeks; an open-label, fixed-dose stabilization phase of 6 weeks; and a single-blind relapse prevention phase of 12 months. During the open-label phase, all patients will be treated with venlafaxine. Remitters with Hamilton Rating Scale for Depression (HAM-D17) score ≤7 will be eligible to enter the single-blind phase and will be randomly assigned to one of three groups: group 1 on active rTMS and venlafaxine; group 2 on sham rTMS and venlafaxine; and group 3 on venlafaxine alone. Efficacy will be evaluated during the study using relapse assessment (time between subject randomization to treatment and the first occurrence of relapse). Secondary outcome measures will include: symptom changes, measured by the HAM-D17; illness severity changes, measured by the Clinical Global Impression of Severity for Depression (CGI-S-DEP); and changes in subject functioning, assessed with the Personal and Social Performance (PSP)scale. Safety will be assessed throughout the study by monitoring of adverse events, clinical laboratory tests, electrocardiography (ECG), and measurements of vital signs (temperature, pulse, and blood pressure) and weight. Suicidality will be assessed by the Columbia Suicide Severity Rating Scale (C-SSRS).DiscussionThe result of this trial will assess the efficacy of rTMS in the prevention of relapse of symptoms of depression by determining whether rTMS in combination with an antidepressant is more efficacious than the antidepressant alone for maintenance of the clinical response.Trial registrationClinicalTrials.gov, NCT01516931

Combined rTMS to the auditory cortex and prefrontal cortex for tinnitus control in patients with depression: a pilot study

Conclusion: The study showed that combined repetitive transcranial magnetic stimulation (rTMS) on the auditory cortex and prefrontal cortex has more benefit than rTMS on the auditory cortex alone for tinnitus control in patients with depression. Further studies for the most optimal combination of stimulation on both areas are needed. Objective: Recent studies suggest that the neuronal network changes of chronic tinnitus are beyond the auditory pathway. There is increasing evidences for the application of rTMS on multiple brain cortices in addition to the auditory cortex for the treatment of tinnitus. Sequential rTMS was performed on the auditory cortex alone as well as the auditory cortex combined with prefrontal cortex in patients with both chronic tinnitus and depression. Methods: Patients who presented with chronic tinnitus of more than 1 year were enrolled in the present study (seven males, four females; mean age 54 years). To select the site for the rTMS, PET CT was performed. Patients received the first rTMS on the primary auditory cortex for 5 days and on the primary auditory cortex and prefrontal cortex in the second application after tinnitus relapse. The Tinnitus Handicap Inventory (THI), visual analog scale (VAS), and Beck Depression Inventory (BDI) were evaluated before and after rTMS. Results: The mean THI score of the eight patients with depression changed from 77.5 ± 15 to 61.8 ± 20.1 after the second rTMS. There was statistical significance only for the second rTMS. The VAS score changed from 8.6 ± 1.6 to 6.3 ± 1.8 after the first rTMS and from 7.6 ± 2.4 to 4.6 ± 2.7 after the second rTMS, showing statistically significant changes both times. The THI changes after the second rTMS were greater than after the first rTMS, and the changes in VAS score showed a similar pattern. The changes in BDI score, which indicates the severity of depression, showed a variable pattern after rTMS. Patients with mild depression (10≤ BDI score <16, n = 4) showed significant improvement of THI with the second combined rTMS (ΔTHI = 24.5) as compared with the first rTMS on the auditory area (ΔTHI = 6). In contrast, combined rTMS did not show any better improvement on THI (ΔTHI = 6.5) than the first rTMS on the auditory cortex (ΔTHI = 7) in patients without depression (BDI <10, n = 3) and patients with moderate to severe depression (BDI ≥16, n = 4).

High-Frequency Repetitive Transcranial Magnetic Stimulation Accelerates and Enhances the Clinical Response to Antidepressants in Major Depression

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. 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. 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. 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). 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. 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.

Transcranial magnetic stimulation in complex therapy of epilepsy

Analysis of clinical, electroencephalographic and neuroimaging data of 19 patients with epilepsy after a course of repetitive transcranial magnetic stimulation (rTMS) in combination with subtherapeutic doses of anticonvulsants was performed. It was found that 1 Hz low-frequency temporal rTMS combined with anticonvulsants helps to reduce the number of weekly seizures by 91.9% during the course of this procedure, and by 75% during the month after completion of the combined course. rTMS courses lead to reduction of interictal epileptiform activity and decrease in the number of patients with pathological epileptic EEG phenomena, which may be seen not only in the stimulation period, but also during the following 4–12 weeks. rTMS has the long lasting effects on EEG parameters: increase in the alpharhythm power with frequency-spatial structure improvement, and decrease in the theta-rhythm and pathological beta-rhythm with minimization of the number and size of their focuses. The use of low-frequency and low-intensity rTMS together with subtherapeutic doses of anticonvulsants allows avoiding the development of side effects and ensuring high anti-seizure activity