Multimodal transcranial magnetic stimulation: using concurrent neuroimaging to reveal the neural network dynamics of noninvasive brain stimulation

Since its introduction in the 1980s, Transcranial Magnetic Stimulation (TMS) has proven to be a versatile method to non-invasively study human brain function by reversibly altering ongoing neural processing. In addition, TMS has been explored as a therapeutic intervention in a number of neurological and neuropsychiatric conditions. However, our understanding of TMS-induced changes in neural activity patterns is still rather limited, particularly when it comes to changes in neural network dynamics beyond the cortical site directly targeted by TMS. In order to monitor both its local and remote neurophysiological effects, TMS has been combined with complementary neuroimaging methods that allow additional insights into how observed TMS effects at the behavioral level can be interpreted by taking into account the full scale of its impact throughout the brain. The current review provides a comprehensive overview of the existing multimodal TMS literature, covering studies in which TMS was combined with one of the three main neuroimaging modalities, namely Electroencephalography, Positron Emission Tomography, and functional Magnetic Resonance Imaging. Besides constituting a reflection of the status quo in this exciting multidisciplinary research field, this review additionally reveals both convergent and divergent observations across modalities that await corroboration or resolution, thereby further guiding ongoing basic research and providing useful constraints to optimize future clinical applications.     

Effects of DBS,premotor rTMS,and levodopa on motor function and silent period in advanced Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used and highly effective treatment for patients with advanced Parkinson's disease (PD). Repetitive TMS (rTMS) applied to motor cortical areas has also been shown to improve symptoms in PD and modulate motor cortical excitability. Here, we compared clinical and neurophysiological effects of STN stimulation with those of 1 Hz rTMS given to the dorsal premotor cortex (PMd) and those following intake of levodopa in a group of PD patients with advanced disease. Ten PD patients were studied on 2 consecutive days before and after surgery. Clinical effects were determined using the UPDRS motor score. Motor thresholds, motor‐evoked potential (MEP) amplitudes during slight voluntary contraction, and the cortical silent periods (SP) were measured using TMS. Before surgery effects of levodopa and 1 Hz PMd rTMS and after surgery those of STN stimulation with or without additional levodopa were determined. Levodopa significantly improved clinical symptoms and increased the SP duration. STN stimulation improved clinical symptoms without changing the SP duration. In contrast, 1 Hz PMd rTMS was not effective clinically but normalized the SP duration. Whereas levodopa had widespread effects at different levels of an abnormally active motor network in PD, STN stimulation and PMd rTMS led to either clinical improvement or SP normalization, i.e., only partially reversed abnormal motor network activity. © 2009 Movement Disorder Society     

Metabolic alterations in the dorsolateral prefrontal cortex after treatment with high-frequency repetitive transcranial magnetic stimulation in patients with unipolar major depression

Neuroimaging studies suggest a specific role of anterior cingulate cortex (ACC) and left dorsolateral prefrontal cortex (DLPFC) in major depression. Stimulation of the latter by means of repetitive transcranial magnetic stimulation (rTMS) as an antidepressant intervention has increasingly been investigated in the past. The objective of the present study was to examine in vivo neurochemical alterations in both brain regions in 17 patients with unipolar major depression before and after 10 days of high-frequency (20Hz) rTMS of the left DLPFC using 3-tesla proton magnetic resonance spectroscopy. Six out of seventeen patients were treatment responders, defined as a 50% reduction of the Hamilton depression rating scale. No neurochemical alterations in the ACC were detected after rTMS. As compared to the non-responders, responders had lower baseline concentrations of DLPFC glutamate which increased after successful rTMS. Correspondingly, besides a correlation between clinical improvement and an increase in glutamate concentration, an interaction between glutamate concentration changes and stimulation intensity was observed. Our results indicate that metabolic, state-dependent changes within the left DLPFC in major depressive disorder involve the glutamate system and can be reversed in a dose-dependent manner by rTMS.     

Antidepressant-like effect of magnetic resonance imaging-based stimulation in mice

INTRODUCTION: It has been reported that a novel type of magnetic resonance imaging (MRI) scan called echo planar magnetic resonance spectroscopic imaging (EP-MRSI) may show antidepressant effects. We examined whether the two routine diagnostic protocols of MRI [T1 and echo planar diffusion weighted imaging (EPI-DWI)], have antidepressant-like effects in an animal model of depression. METHODS: The effects of standard EPI-DWI and T1 MRI on immobility, swimming and climbing times in the modified forced swimming test (FST) in mice were examined. After exposure to the first session of modified forced swimming test, we randomly divided the mice into four groups. The first group (T1 MRI group, n=21) received a 15-minute stimulation of T1 sequence. The second group (EPI-DWI MRI group, n=21) received a 15-minute stimulation of EPI-DWI protocol. The third group (sham group, n=21) spent 15 min in a tunnel similar to the MRI gantry in terms of size, temperature and light intensity and received recorded sounds from a normal session of EPI-DWI with similar duration and intensity. The fourth group acted as controls (n=21).The second session of the modified FST was conducted twelve hours later. The mean of immobility, swimming and climbing times in this session were compared to the control group. RESULTS: T1 weighted and EPI-DWI MRI groups showed a reduction in immobility time compared to the control group (P value<0.002, P value<0.017 respectively). This effect is comparable to that seen in the FST after the administration of antidepressant agents. The climbing time in the group subjected to EPI-DWI MRI was longer than the control group (P value<0.035). Previous studies showed similar effects after the administration of antidepressant drugs affecting the catecholamine systems. The swimming time in the T1 MRI group was significantly longer than the control group (P value<0.037). Previous studies showed qualitatively similar effect to that of anti-depressant drugs affecting the serotoninergic systems. The swimming, climbing and immobility times in the sham and control groups showed no significant difference. CONCLUSIONS: Our findings raise the possibility that MRI-based stimulation may have antidepressant-like effects in mice. This is likely to be through different mechanisms in T1 weighted and EPI-DWI protocols. However the possible biological basis of this effect is not yet understood and we would advocate further studies of MRI-based stimulation effects on transmitters in the different organs in the body specially the brain.     

Patients with a major depressive episode responding to treatment with repetitive transcranial magnetic stimulation (rTMS) are resistant to the effects of rapid tryptophan depletion

Repetitive transcranial magnetic stimulation (rTMS) appears to be efficacious in the treatment of major depression based on the results of controlled studies, but little is known about its antidepressant mechanism of action. Mood sensitivity following rapid tryptophan depletion (RTD) has been demonstrated in depressed patients responding to SSRI antidepressants and phototherapy, but not in responders to electroconvulsive therapy (ECT). We sought to study the effects of RTD in patients with major depression responding to a course of treatment with rTMS. Twelve subjects treated successfully with rTMS monotherapy underwent both RTD and sham depletion in a double-blind crossover design. Depressive symptoms were assessed using both a modified Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). The differential change in depression scores across the procedures was compared. No significant difference in mood symptoms was noted between RTD and the sham-depletion procedure on either continuous measures of depression, or in the proportions of subjects that met predefined criteria for a significant degree of mood worsening. Responders to rTMS are resistant to the mood perturbing effects of RTD. This suggests that rTMS does not depend on the central availability of serotonin to exert antidepressant effects in major depression.     

Treatment of depression with transcranial direct current stimulation (tDCS): A Review

Major Depression Disorder (MDD) is usually accompanied by alterations of cortical activity and excitability, especially in prefrontal areas. These are reflections of a dysfunction in a distributed cortico-subcortical, bihemispheric network. Therefore it is reasonable to hypothesize that altering this pathological state with techniques of brain stimulation may offer a therapeutic target. Besides repetitive transcranial magnetic stimulation, tonic stimulation with weak direct currents (tDCS) modulates cortical excitability for hours after the end of stimulation, thus, it is a promising non-invasive therapeutic option. Early studies from the 1960s suggested some efficacy of DC stimulation to reduce symptoms in depression, but mixed results and development of psychotropic drugs resulted in an early abandonment of this technique. In the last years tDCS protocols have been optimized. Application of the newly developed stimulation protocols in patients with major depression has shown promise in few pilot studies. Further studies are needed to identify the optimal parameters of stimulation and the clinical and patient characteristics that may condition response to tDCS.     

重复经颅磁刺激联合帕利哌酮对精神分裂症患者认知功能的影响

目的探讨重复经颅磁刺激(rTMS)联合帕利哌酮缓释片对精神分裂症患者认知功能的疗效及安全性。方法选择符合入组条件的首发精神分裂症患者61名,随机分成治疗组30例(帕利哌酮缓释片联合rTMS),对照组31例(单纯药物)。分别于治疗前及治疗4周后应用阳性与阴性症状量表(PANSS)评定临床症状;应用数字划消测验(CT)、修订版韦氏记忆量表(WMS-RC)、威斯康星卡片分类测验(WCST)分别评定患者的注意功能、记忆功能及执行功能。结果治疗后,两组PANSS总分均低于治疗前,治疗组总分明显低于对照组(P<0.01);两组CT、WMS-RC各指标的得分均优于治疗前(P<0.01),治疗组明显高于于对照组(P<0.05);治疗组WCST各项评分优于治疗前,对照组总应答数、持续错误数、非持续性错误数较治疗前明显降低(P<0.05);治疗组的总应答数、持续错误数及非持续性错误数明显低于对照组(P<0.05)。两组均未出现明显副反应。结论重复经颅磁刺激联合帕利哌酮缓释片对改善精神分裂症患者的认知功能有增效作用,安全性好。     

Inhibitory stimulation of the ventral premotor cortex temporarily interferes with musical beat rate preference

Behavioral studies suggest that preference for a beat rate (tempo) in auditory sequences is tightly linked to the motor system. However, from a neuroscientific perspective the contribution of motor‐related brain regions to tempo preference in the auditory domain remains unclear. A recent fMRI study (Kornysheva et al. [ 2010 ]: Hum Brain Mapp 31:48‐64) revealed that the activity increase in the left ventral premotor cortex (PMv) is associated with the preference for a tempo of a musical rhythm. The activity increase correlated with how strongly the subjects preferred a tempo. Despite this evidence, it remains uncertain whether an interference with activity in the left PMv affects tempo preference strength. Consequently, we conducted an offline repetitive transcranial magnetic stimulation (rTMS) study, in which the cortical excitability in the left PMv was temporarily reduced. As hypothesized, 0.9 Hz rTMS over the left PMv temporarily affected individual tempo preference strength depending on the individual strength of tempo preference in the control session. Moreover, PMv stimulation temporarily interfered with the stability of individual tempo preference strength within and across sessions. These effects were specific to the preference for tempo in contrast to the preference for timbre, bound to the first half of the experiment following PMv stimulation and could not be explained by an impairment of tempo recognition. Our results corroborate preceding fMRI findings and suggest that activity in the left PMv is part of a network that affects the strength of beat rate preference. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.     

Involvement of the parietal cortex in perceptual learning (Eureka effect): An interference approach using rTMS

The neural mechanisms underlying perceptual learning are still under investigation. Eureka effect is a form of rapid, long-lasting perceptual learning by which a degraded image, which appears meaningless when first seen, becomes recognizable after a single exposure to its undegraded version. We used online interference by focal 10-Hz repetitive transcranial magnetic stimulation (rTMS) to evaluate whether the parietal cortex (PC) is involved in Eureka effect, as suggested by neuroimaging data. RTMS of the PC did not affect recognition of degraded pictures when displayed 2 s after the presentation of their undegraded version (learning phase). However, rTMS delivered over either right or left intraparietal sulcus simultaneously to the undegraded image presentation, disrupted identification of the degraded version of the same pictures when displayed 30 min after the learning phase. In contrast, recognition of degraded images was unaffected by rTMS over the vertex or by sham rTMS, or when rTMS of either PC was delivered 2 s after the presentation of the undegraded image. Findings strongly support the hypothesis that both PC at the level of the intraparietal sulcus play a pivotal role in the Eureka effect particularly in consolidation processes, and contribute to elucidate the neural network underlying rapid perceptual learning.