Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory

Previous studies have claimed that weak transcranial direct current stimulation (tDCS) induces persisting excitability changes in the human motor cortex that can be more pronounced than cortical modulation induced by transcranial magnetic stimulation, but there are no studies that have evaluated the effects of tDCS on working memory. Our aim was to determine whether anodal transcranial direct current stimulation, which enhances brain cortical excitability and activity, would modify performance in a sequential-letter working memory task when administered to the dorsolateral prefrontal cortex (DLPFC). Fifteen subjects underwent a three-back working memory task based on letters. This task was performed during sham and anodal stimulation applied over the left DLPFC. Moreover seven of these subjects performed the same task, but with inverse polarity (cathodal stimulation of the left DLPFC) and anodal stimulation of the primary motor cortex (M1). Our results indicate that only anodal stimulation of the left prefrontal cortex, but not cathodal stimulation of left DLPFC or anodal stimulation of M1, increases the accuracy of the task performance when compared to sham stimulation of the same area. This accuracy enhancement during active stimulation cannot be accounted for by slowed responses, as response times were not changed by stimulation. Our results indicate that left prefrontal anodal stimulation leads to an enhancement of working memory performance. Furthermore, this effect depends on the stimulation polarity and is specific to the site of stimulation. This result may be helpful to develop future interventions aiming at clinical benefits.Felipe Fregni and Paulo S. Boggio contributed equally to this work.     

跨颅磁刺激观察前额叶皮层在学习记忆中的作用

目的为了探讨前额叶皮层的功能。方法在被试进行联合搜索作业(conjunction search task)时,使用跨颅磁刺激干扰被试者右侧前额叶皮层的活动,观察被试者在训练前后反应时间的变化。结果发现磁刺激干扰前额叶的活动,明显地延长了被试者在训练前的反应时间,对训练之后的反应时间几乎没有变化。结论这说明右侧前额叶参与了记忆的编码,对记忆的提取没有作用。     

Laterality effects in selective attention to threat after repetitive transcranial magnetic stimulation at the prefrontal cortex in female subjects

Recently, several experiments have indicated that the left and right prefrontal cortex (PFC) are differently involved in emotional processing. The aim of this study was to investigate the role of the left and right PFC in selective attention to angry faces by using a pictorial emotional Stroop task. Slow repetitive transcranial magnetic stimulation (rTMS) was applied to the left and right PFC of 10 female subjects for 15 min on separate days. Results showed a significant effect of stimulation position: right PFC rTMS resulted in selective attention towards angry faces, whereas left PFC rTMS resulted in selective attention away from angry faces. This finding is in accordance with theoretical accounts of the neural implementation of approach and withdrawal systems.     

Effects of transcranial magnetic stimulation over the region of the supplementary motor area during sequences of memory-guided saccades

Transcranial magnetic stimulation (TMS) over the region of the supplementary motor area (SMA) was used to study the cortical control of sequences of memory-guided saccades. In ten healthy subjects, TMS was applied during (a) the target presentation (learning) phase, (b) the memorization phase, and (c) the execution phase of such saccade sequences. Stimulation during the presentation phase resulted in a significant increase in errors, compared to the results without stimulation. In contrast, stimulation during the memorization or execution phases had no significant influence on the performance of these sequences. The effect of TMS during the presentation phase seems to be specific for an interaction with the SMA function, since, in a control experiment with TMS of the occipital cortex during the same phase, the results were similar to those without stimulation. It is hypothesized that different cortical areas are involved in the learning, memorization and execution of sequences of memory-guided saccades. The SMA action could be crucial during the learning phase, but not during the memorization and execution phases of such sequences.     

Segregation of working memory functions within the dorsolateral prefrontal cortex

It is now widely accepted that the prefrontal cortex (PFC) plays a critical role in the neural network subserving working memory (WM). At least three related questions are still under debate: (1) is the PFC critical for all constituent processes of WM (i.e., short-term storage, manipulation, and utilization of mental representations) or only in one or a few of them? (2) Is there segregation of function among different cytoarchitectonic subdivisions of the PFC? (3) If this be the case, is this segregation based on the nature of the information being processed or on the type of cognitive operation performed? The present review article describes findings in the monkey supporting a modular "domain-specific" model of PFC functional organization with respect to WM operations. In this model, the dorsolateral prefrontal cortex (DLPFC) is composed of several subregions, based primarily on the nature of the information being processed in WM. Storage and processing functions are integrally related in each area. Future studies designed to map as yet uncharted areas of prefrontal cortex with refined anatomical and physiological approaches may provide a critical test of the model and evaluate the extent to which it applies generally or, instead, mainly to visual domains or only to dorsolateral convexity areas.     

Short-term reduction of intracortical inhibition in the human motor cortex induced by repetitive transcranial magnetic stimulation

Ten healthy subjects and two patients who had an electrode implanted into the cervical epidural space underwent repetitive transcranial magnetic stimulation (rTMS; 50 stimuli at 5 Hz at active motor threshold intensity) of the hand motor area. We evaluated intracortical inhibition before and after rTMS. In healthy subjects, we also evaluated threshold and amplitude of motor evoked potentials (MEPs), duration of cortical silent period and short-latency intracortical facilitation. rTMS led to a short-lasting reduction in the amount of intracortical inhibition in control subjects with a high interindividual variability. There was no significant effect on other measures of motor cortex excitability. Direct recordings of descending corticospinal volleys from the patients were consistent with the idea that the effect of rTMS on intracortical inhibition occurred at the cortical level. Since the level of intracortical inhibition can be influenced by drugs that act on GABAergic systems, this may mean that low-intensity repetitive magnetic stimulation at 5 Hz can selectively modify the excitability of GABAergic networks in the human motor cortex. Electronic Publication     

Transcranial magnetic stimulation (TMS) applied to left dorsolateral prefrontal cortex disrupts verbal working memory performance in humans

Working memory refers to the temporary maintenance and processing of information and involves executive processes that manipulate the contents of the working memory. The role of the executive function in the human left dorsolateral prefrontal cortex (LDLPFC) was explored using transcranial magnetic stimulation (TMS) after confirming the LDLPFC activation using fMRI. We applied double-pulse TMS having a 100-ms inter-pulse interval to LDLPFC immediately after the subjects finished reading the sentences of the reading span test (RST) task, an efficient measure of verbal working memory, in which dual tasks that include both sentence comprehension and word maintenance are required. Using eight normal participants, we found a significant deterioration of performance, i.e., decreased number of correctly reported words, in RST due to TMS stimulation of LDLPFC. Evidence suggests that transient functional disruption of the LDLPFC impairs performance in the maintenance processing of the RST task.     

Low frequency transcranial magnetic stimulation on the posterior parietal cortex induces visuotopically specific neglect-like syndrome

The visuo-parietal (VP) region of the cerebral cortex is critically involved in the generation of orienting responses towards visual stimuli. In this study we use repetitive transcranial magnetic stimulation (rTMS) to unilaterally and non-invasively deactivate the VP cortex during a simple spatial visual detection task tested in real space. Adult cats were intensively trained over 4 months on a task requiring them to detect and orient to a peripheral punctuate static LED presented at a peripheral location between 0° and 90°, to the right or left of a 0° fixation target. In 16 different interleaved sessions, real or sham low frequency (1 Hz) rTMS was unilaterally applied during 20 min (1,200 pulses) to the VP cortex. The percentage of mistakes detecting and orienting to contralateral visual targets increased significantly during the 15–20 min immediately following real but not sham rTMS. Behavioral deficits were most marked in peripheral eccentricities, whereas more central locations were largely unaffected. Performance returned to baseline (pre-TMS) levels when animals were tested 45 min later and remained in pre-TMS levels 24 h after the end of the stimulation. Our results confirm that the VP cortex of the cat is critical for successful detection and orienting to visual stimuli presented in the corresponding contralateral visual field. In addition, we show that rTMS disrupts a robust behavioral task known to depend on VP cortex and does so for the far periphery of the visual field, but not for more central targets.Prof. Payne passed away May 2004. This article is submitted in his memory.     

Intracortical inhibition of lower limb motor-evoked potentials after paired transcranial magnetic stimulation

The aim of the present study was to determine the characteristics of intracortical inhibition in the motor cortex areas representing lower limb muscles using paired transcranial magnetic (TMS) and transcranial electrical stimulation (TES) in healthy subjects. In the first paradigm (n=8), paired magnetic stimuli were delivered through a double cone coil and motor evoked potentials (MEPs) were recorded from quadriceps (Q) and tibialis anterior (TA) muscles during relaxation. The conditioning stimulus strength was 5% of the maximum stimulator output below the threshold MEP evoked during weak voluntary contraction of TA (33±5%). The test stimulus (67±2%) was 10% of the stimulator output above the MEP threshold in the relaxed TA. Interstimulus intervals (ISIs) from 1–15 ms were examined. Conditioned TA MEPs were significantly suppressed (P<0.01) at ISIs of less than 5 ms (relative amplitude from 20–50% of the control). TA MEPs tended to be only slightly facilitated at 9-ms and 10-ms ISIs. The degree of MEP suppression was not different between right and left TA muscles despite the significant difference in size of the control responses (P<0.001). Also, conditioned MEPs were not significantly different between Q and TA. The time course of TA MEP suppression, using electrical test stimuli, was similar to that found using TMS. In the second paradigm (n=2), the suppression of TA MEPs at 2, 3, and 4 ms ISIs was examined at three conditioning intensities with the test stimulation kept constant. For the pooled 2- to 4-ms ISI data, relative amplitudes were 34±6%, 61±5%, and 98±9% for conditioning intensities of 0.95, 0.90, and 0.85× active threshold, respectively (P<0.01). In conclusion, the suppression of lower limb MEPs following paired TMS showed similar characteristics to the intracortical inhibition previously described for the hand motor area. Received: 21 June 1996 / Accepted: 23 May 1997     

Visual object memory and memory-guided saccades rely on shared mental representations

We investigated the organisation of working memory processes by examining how a secondary memory task interferes with the accuracy of memory-guided saccades. A target was flashed at a random location, followed by a Kanji character. Subjects had to remember the location of the target and the Kanji character, and then they had to make a saccade towards the remembered target location. A second Kanji character was displayed and the subject had to decide if it was same or different. The performance of seven non-Kanji reader's were compared with six fluent Kanji readers in the task. Memorisation of Kanji characters was found to interfere with the accuracy of memory-guided saccades made by non-Kanji, but not by Kanji readers. These findings directly contradict accounts of working memory function which propose that spatial and visual object memory are functionally discrete.     

Influence of transcranial magnetic stimulation on the execution of memorised sequences of saccades in man

Memorised sequences of saccades are cortically controlled by the supplementary motor area (SMA), as shown in animal experiments and in humans with isolated SMA lesions. We applied transcranial magnetic stimulation (TMS) in eight healthy subjects executing memorised sequences of saccades. Sequences of three targets were presented. Then, upon a go-signal, the subjects had to execute the appropriate sequences. Ten to fifteen sequences were performed in each experiment, and the number of errors were counted. The number of errors increased significantly if TMS was given 80 ms before or 60 ms after the go-signal, with the stimulation coil overlying the SMA. There was no significant increase in errors if different stimulation intervals were chosen (160ms and 120ms before the go-signal; 100 ms, 140 ms or 240 ms after the go-signal), if the coil was positioned inappropriately (e.g. over the occipital cortex), or if the stimulator output was too low. We conclude that TMS can interfere specifically with the function of the SMA during a critical time interval close to the go-signal.     

Treating anxious depression using repetitive transcranial magnetic stimulation

Background

A subset of patients given a clinical diagnosis of major depressive disorder (MDD) are described as having “anxious depression,” a presentation that, in some studies, has been an indicator of poor response to pharmacotherapy. The aim of this study was to determine if anxious depression is associated with attenuated response to repetitive transcranial magnetic stimulation (rTMS), an FDA-approved treatment for MDD.

Methods

Participants were 32 adult outpatients with treatment resistant MDD who were referred for rTMS. The Hamilton Rating Scale for Depression (HAMD) was administered to assess treatment response, and anxious depression was defined as a score of seven or above on the anxiety/somatization factor of the HAMD. A quarter of the sample met the anxious depression criterion at pretreatment.

Results

Both depression (total score) and anxiety symptoms improved from pre- to post-treatment with moderate to large treatment effects. Patients with and without anxious depression demonstrated similar rates of improvement in depression. Patients with versus without anxious depression demonstrated larger improvements in anxiety.

Limitations

The sample size was small, and assessments did not include structured diagnostic interview or independent measures of anxiety symptoms.

Conclusions

For the sample as a whole, there were significant improvements in both depression and anxiety. Anxious depression was not associated with attenuated treatment response to rTMS.     

Effect of contraction strength on responses in biceps brachii and adductor pollicis to transcranial magnetic stimulation

The sizes of the motor-evoked potentials (MEPs) and the durations of the silent periods after transcranial magnetic stimulation were examined in biceps brachii, brachioradialis and adductor pollicis in human subjects. Stimuli of a wide range of intensities were given during voluntary contractions producing 0–75% of maximal force (maximal voluntary contraction, MVC). In adductor pollicis, MEPs increased in size with stimulus intensity and with weak voluntary contractions (5% MVC), but did not grow larger with stronger contractions. In the elbow flexors, MEPs grew little with stimulus intensity, but increased in size with contractions of up to 50% of maximal. In contrast, the duration of the silent period showed similar changes in the three muscles. In each muscle it increased with stimulus intensity but was unaffected by changes in contraction strength. Comparison of the responses evoked in biceps brachii by focal stimulation over the contralateral motor cortex with those evoked by stimulation with a round magnetic coil over the vertex suggests an excitatory contribution from the ipsilateral cortex during strong voluntary contractions. Received: 12 August 1996 / Accepted: 14 May 1997     

Mechanism of the silent period following transcranial magnetic stimulation Evidence from epidural recordings

We investigated the nature of the silent period (SP) following transcranial magnetic stimulation by recording corticospinal volleys in a patient with implanted cervical epidural electrodes. Single suprathreshold test stimuli and paired stimuli at interstimulus intervals (ISIs) of 50–200 ms were delivered while the subject maintained a constant background contraction. The silent period duration from a single test stimulus was 357±62 ms. The test motor-evoked potentials were markedly reduced at all the ISIs tested. The I (indirect) waves induced by the test stimulus were largely unchanged at an ISI of 50 ms, suggesting that there was little change in motor cortex excitability. However, the corticospinal volleys, especially the late I waves, were substantially reduced at ISIs of 100 ms, 150 ms, and 200 ms. Our findings suggest that the early part of the SP is mainly due to spinal mechanisms, while the late part of the SP is related to reduced motor cortex excitability. Received: 21 January 1999 / Accepted: 14 April 1999     

Effects of anterior cingulate cortex lesions on ocular saccades in humans

Cerebral blood flow studies in humans suggest that the anterior cingulate cortex (ACC) could be involved in eye movement control. In two patients with a small infarction affecting the posterior part of this area (on the right side) and in ten control subjects, we studied several paradigms of saccadic eye movements: gap task, overlap task, antisaccades (using either a 5° or 25° lateral target), memory-guided saccades with a short (1 s) or long (7 s) delay, and sequences of memory-guided saccades. Compared with controls, patients had normal latency in the gap task but increased latency in the other tasks. The gain of memory-guided saccades was markedly decreased, bilaterally, whatever the duration of the delay. Patients made more errors than controls in the antisaccade task when the 5° lateral target was used, and a higher percentage of chronological errors in the sequences of saccades. These results show that the posterior part of the right ACC plays an important role in eye movement control and suggest that this area could correspond to a “cingulate eye field” (CEF). The role of this hypothetical CEF could be an early activation exerted on the frontal ocular motor areas involved in intentional saccades and also a direct action on brainstem ocular premotor structures. Received: 8 November 1996 / Accepted: 14 October 1997     

Motor cortex excitability following short trains of repetitive magnetic stimuli

Trains of repetitive transcranial magnetic stimuli (rTMS) appear to have effects on corticospinal excitability that outlast the duration of the train. In order to investigate the mechanism of this effect in more detail we applied short periods of rTMS consisting of up to 20 stimuli at 5 Hz, 10 Hz or 20 Hz (rTMS) to the motor cortex at an intensity equal to resting threshold in 11 healthy, relaxed subjects. Spinal excitability, as judged by effects on the H-reflex or on transcranial anodal facilitation of the H-reflex, was not affected by the rTMS. However, cortical excitability, as judged by the effect on the size of EMG responses evoked by a suprathreshold TMS pulse, was decreased for up to 1 s after the end of rTMS. Post-train suppression was more powerful following longer trains or higher frequencies of rTMS. The predominant suppression contrasts with previous reports of facilitation, particularly after high-frequency rTMS. A second set of experiments, however, showed that this could be converted into facilitation if the intensity of rTMS was increased. We conclude that the after-effects of rTMS depend on its frequency, intensity and duration. The results are consistent with a model in which inhibition and facilitation build up gradually during the course of a conditioning train. Inhibition reaches its maximum effect after only a small number of stimuli, whereas facilitation takes longer. The threshold for evoking inhibition is lower than that for facilitation. Thus if moderate intensities of conditioning train are applied, inhibition is predominant after short trains, whereas facilitation dominates after long trains.     

经颅脉冲磁刺激对鼠大脑皮层癎样放电的作用

目的：观察经颅脉冲磁刺激（TIMS）大鼠对青霉素所致大脑皮层痫样放电的作用。方法：制作青霉素癫痫鼠模型，以大脑皮层痫样放电的频率和波幅为指标，观察TIMS一侧大脑皮层、小脑蚓部对青霉素所致大脑皮层痫样放电的影响。结果：TIMS一侧大脑、小脑蚓部均可使大脑痫样放电的频率及波幅降低，刺激小脑蚓部时作用更明显，侧脑室注射纳洛酮可部分翻转TIMS的抑制作用。结论：TIMS大脑皮层和小脑蚓部对大脑皮层痫样放电有抑制作用。     

Theta burst stimulation of dorsolateral prefrontal cortex modulates pathological language switching: A case report

Although different lesion and neuroimaging studies had highlighted the importance of the dorsolateral prefrontal cortex (DLPFC) in language switching, the nature of this higher cortical disorder of communication and its neural correlates have not been clearly established. To further investigate the functional involvement of the DLPFC, we used transcranial magnetic stimulation (TMS) given as theta burst stimulation (TBS) in a bilingual patient showing pathologic language switching after an ischemic stroke involving the left frontal lobe. Inhibitory and excitatory TBS were applied to the left DLPFC, to the right DLPFC, or to an occipital cortical control site. A short-lasting interruption of the pathological language switching occurred after excitatory left DLPFC stimulation, while inhibitory left DLPFC TBS transiently increased the number of utterances produced in the unwanted second language. Effects were non-significant after right DLPFC and occipital TBS. Our findings suggest that left DLPFC is actively involved in language switching. TMS techniques may help in understanding the neural bases of bilingualism.     

The effects of 10 Hz repetitive transcranial magnetic stimulation on resting EEG power spectrum in healthy subjects

10 Hz rTMS over the left prefrontal cortex may be useful in the treatment of depressive disorders. However, the effects of 10 Hz rTMS applied in potentially effective doses on electroencephalographic activity are not well studied. Using EEG, we aimed to investigate the neurobiological effects of the 10 Hz rTMS set of parameters currently used for depression treatment in a sample of healthy subjects. In 18 healthy subjects, either 10 Hz real rTMS or sham stimulation were given in a crossover design. Real rTMS stimulation was carried out with an intensity of 110% of motor threshold (MT) over the left dorsolateral prefrontal cortex. For the sham condition, the coil was angled over a parietotemporal position and the intensity was reduced to 90% of MT. EEG recordings were taken before and after a single rTMS session. EEG power spectrum was extracted using the complex demodulation method and changes in power were evaluated statistically. Real 10 Hz rTMS induced an overall increase in delta power. This increase prevailed throughout the sample, whereas effects on the power of the alpha, beta and theta EEG bands were highly variable. Sham stimulation had no substantial effects on the EEG power spectrum. Furthermore, no changes in EEG asymmetry were detected. Real 10 Hz rTMS applied at 2000 stimuli and 110% intensity may induce significant changes in resting EEG in healthy subjects.