Online Repetitive Transcranial Magnetic Stimulation Research Articles

Role of the medial posterior parietal cortex in orchestrating attention and reaching.

The interplay between attention, alertness and motor planning is crucial for our manual interactions. To investigate the neural bases of this interaction, and challenging the views that attention cannot be disentangled from motor planning, we instructed human volunteers of both sexes to plan and execute reaching movements while attending to the target, while attending elsewhere, or without constraining attention. We recorded reaction times to reach initiation and pupil diameter and interfered with the functions of the medial posterior parietal cortex (mPPC) with online repetitive transcranial magnetic stimulation to test the causal role of this cortical region in the interplay between spatial attention and reaching. We found that mPPC plays a key role in the spatial association of reach planning and covert attention. Moreover, we have found that alertness, measured by pupil size, is a good predictor of the promptness of reach initiation only if we plan a reach to attended targets, and mPPC is causally involved in this coupling. Different from previous understanding, we suggest that mPPC is neither involved in reach planning per se, nor in sustained covert attention in absence of a reach plan, but it is specifically involved in attention functional to reaching.Significance Statement Attention is required to perform dexterous arm movements. In this work we show the neural bases of the interplay between attention and reaching preparation, with the aim to provide information useful to address effective rehabilitation strategies to treat functional deficits observed in attention-related diseases. We discuss how brain areas are involved in orchestrating attention and reaching by signaling the alignment of their spatial coordinates. Moreover, we found that pupil size changes during reach preparation are related to reach initiation, suggesting a coordination between vigilance and reach promptness when preparing a reach to attended targets.

Site- and frequency-specific enhancement of visual search performance with online individual alpha frequency (IAF) repetitive transcranial magnetic stimulation (rTMS) to the inferior frontal junction.

In this study, repetitive transcranial magnetic stimulation was applied to either the right inferior frontal junction or the right inferior parietal cortex during a difficult aerial reconnaissance search task to test its capacity to improve search performance. Two stimulation strategies previously found to enhance cognitive performance were tested: The first is called "addition by subtraction," and the second condition utilizes a direct excitatory approach by applying brief trains of high-frequency repetitive transcranial magnetic stimulation immediately before task trials. In a within-subjects design, participants were given active or sham repetitive transcranial magnetic stimulation at either 1Hz or at 1Hz above their individual peak alpha frequency (IAF + 1, mean 11.5Hz), delivered to either the right inferior frontal junction or the right inferior parietal cortex, both defined with individualized peak functional magnetic resonance imaging (fMRI) activation obtained during the visual search task. Results indicated that among the 13 participants who completed the protocol, only active IAF + 1 stimulation to inferior frontal junction resulted in significant speeding of reaction time compared to sham. This site- and frequency-specific enhancement of performance with IAF + 1 repetitive transcranial magnetic stimulation applied immediately prior to task trials provides evidence for the involvement of inferior frontal junction in guiding difficult visual search, and more generally for the use of online repetitive transcranial magnetic stimulation directed at specific functional networks to enhance visual search performance.

Online transcranial magnetic stimulation reveals differential effects of transitivity in left inferior parietal cortex but not premotor cortex during action naming

Accumulating evidence indicates two cortical regions, the left ventral premotor cortex (PMv) and left intraparietal sulcus (IPS), are involved in spoken verb production. Some evidence also indicates these regions may be differentially engaged by transitive (i.e., object-oriented) versus intransitive actions. We explored the role of these regions during action picture naming in two experiments, each employing high frequency (10 Hz) online repetitive Transcranial Magnetic Stimulation (rTMS) in 20 participants. In Experiment 1, participants named intransitive action pictures (e.g., LAUGH) accompanied by active and sham rTMS to the left PMv, left IPS, and right superior parietal lobule (SPL; control site). Application of rTMS to PMv resulted in slower naming latencies compared to sham and control site stimulation, whereas stimulation of the IPS did not result in any significant effects. Experiment 2 employed active and sham rTMS identical to Experiment 1 with transitive action pictures (e.g., PUSH). Stimulation of both regions induced changes in naming latencies compared to sham and control site stimulation, with rTMS applied to PMv slowing responses and IPS stimulation facilitating them. Surprisingly, stimulation of the right SPL control site also slowed naming compared to sham across both Experiments. Overall, these findings indicate different roles for PMv and IPS during action picture naming. Specifically, the divergent effects of PMv and IPS stimulation in the transitive action naming task indicate different processes likely operate in the two regions during verb production. Involvement of the right SPL across both transitive and intransitive action naming might reflect visuospatial or general attention mechanisms rather than language processes per se.

The frequency-dependent stimulation effects of rTMS on the performance of problem-solving tasks and ongoing oscillations

IntroductionRecent studies suggest that online repetitive transcranial magnetic stimulation (rTMS) can induce local entrainment of ongoing endogenous oscillatory activity that impacts cognitive performance, and the effect may depend on the function of the oscillation. However, little is known about the effects of task-specific frequencies, especially when using an online rTMS paradigm. Our previous electroencephalogram (EEG) study showed that the frontal theta rhythm is associated with the cognitive giving-up processes during problem-solving tasks.ObjectivesIn this study, we combined online rTMS and EEG to examine the frequency-dependent stimulation effects of rTMS on the performance of problem-solving tasks and ongoing oscillations. We hypothesized that rTMS at the theta frequency would induce ongoing theta activity and accelerate the giving-up behaviour.MethodsrTMS was applied during problem-solving tasks with the following conditions: individual theta (4-6Hz)- and alpha (9-13Hz)-TMS, no-TMS, and sham-TMS; the order of conditions was counterbalanced across participants.ResultsOur results showed that theta-frequency rTMS application induced an increase in theta amplitudes and shortened the giving-up response, while a control alpha-frequency rTMS application induced an increase in alpha amplitudes, but did not change giving-up responses.ConclusionsThis study demonstrated the effectiveness of using specific task-relevant stimulation frequency and target location for the modulation of cognitive and behavioral performance. Furthermore, considering the close resemblance between giving-up behaviour and rumination in depression, neuromodulation of cognitive giving-up processes may lead to a new intervention to treat depression by rTMS.DisclosureNo significant relationships.

Recovered grasping performance after stroke depends on interhemispheric frontoparietal connectivity.

Activity changes in the ipsi- and contralesional parietal cortex and abnormal interhemispheric connectivity between these regions are commonly observed after stroke, however, their significance for motor recovery remains poorly understood. We here assessed the contribution of ipsilesional and contralesional anterior intraparietal cortex (aIPS) for hand motor function in 18 recovered chronic stroke patients and 18 healthy control subjects using a multimodal assessment consisting of resting-state functional MRI, motor task functional MRI, online-repetitive transcranial magnetic stimulation (rTMS) interference, and 3D movement kinematics. Effects were compared against two control stimulation sites, i.e. contralesional M1 and a sham stimulation condition. We found that patients with good motor outcome compared to patients with more substantial residual deficits featured increased resting-state connectivity between ipsilesional aIPS and contralesional aIPS as well as between ipsilesional aIPS and dorsal premotor cortex. Moreover, interhemispheric connectivity between ipsilesional M1 and contralesional M1 as well as ipsilesional aIPS and contralesional M1 correlated with better motor performance across tasks. TMS interference at individual aIPS and M1 coordinates led to differential effects depending on the motor task that was tested, i.e. index finger-tapping, rapid pointing movements, or a reach-grasp-lift task. Interfering with contralesional aIPS deteriorated the accuracy of grasping, especially in patients featuring higher connectivity between ipsi- and contralesional aIPS. In contrast, interference with the contralesional M1 led to impaired grasping speed in patients featuring higher connectivity between bilateral M1. These findings suggest differential roles of contralesional M1 and aIPS for distinct aspects of recovered hand motor function, depending on the reorganization of interhemispheric connectivity.

Behavioural effects of task-relevant neuromodulation by rTMS on giving-up

Recent studies suggest that online repetitive transcranial magnetic stimulation (rTMS) can induce local entrainment of ongoing endogenous oscillatory activity during a task. This effect may impact cognitive performance, depending on the function of the oscillation. In this study, we aimed to investigate the effects of stimulation frequency and target location that are relevant to the cognitive processes of giving-up. We first investigated the correlations between the EEG oscillations and cognitive giving-up processes during problem-solving tasks (Experiment 1). We then conducted online rTMS to examine the frequency-dependent stimulation effects of rTMS on the performance of problem-solving tasks and ongoing oscillations (Experiment 2). The results of Experiment 1 suggested that the frontal theta rhythm is associated with the giving-up processes and that the frontal alpha rhythm is associated with problem-solving behaviour. Accordingly, we hypothesised that rTMS at the theta frequency would induce ongoing theta activity and accelerate the giving-up behaviour, while rTMS at the alpha frequency would induce ongoing alpha activity and slow down the giving-up behaviour in Experiment 2. The results showed that theta-frequency rTMS application induced an increase in theta amplitudes and shortened the giving-up response. Alpha-frequency rTMS application induced an increase in alpha amplitudes, but did not change giving-up responses. Considering the close resemblance between giving-up behaviour and rumination in depression, neuromodulation of cognitive giving-up processes may lead to a new intervention to treat depression by rTMS. Furthermore, this study strengthens the hypothesis that modulating task-relevant oscillations by rTMS could induce behavioural changes related to cognitive performance.

Network-based rTMS to modulate working memory: The difficult choice of effective parameters for online interventions.

BackgroundOnline repetitive transcranialmagnetic stimulation (rTMS) has been shown to modulate working memory (WM) performance in a site‐specific manner, with behavioral improvements due to stimulation of the dorsolateral prefrontal cortex (DLPFC), and impairment from stimulation to the lateral parietal cortex (LPC). Neurobehavioral studies have demonstrated that subprocesses of WM allowing for the maintenance and manipulation of information in the mind involve unique cortical networks. Despite promising evidence of modulatory effects of rTMS on WM, no studies have yet demonstrated distinct modulatory control of these two subprocesses. The current study therefore sought to explore this possibility through site‐specific stimulation during an online task invoking both skills.MethodsTwenty‐nine subjects completed a 4‐day protocol, in which active or sham 5Hz rTMS was applied over the DLPFC and LPC in separate blocks of trials while participants performed tasks that required either maintenance alone, or both maintenance and manipulation (alphabetization) of information. Stimulation targets were defined individually based on fMRI activation and structural network properties. Stimulation amplitude was adjusted using electric field modeling to equate induced current in the target region across participants.ResultsDespite the use of advanced techniques, no significant differences or interactions between active and sham stimulation were found. Exploratory analyses testing stimulation amplitude, fMRI activation, and modal controllability showed nonsignificant but interesting trends with rTMS effects.ConclusionWhile this study did not reveal any significant behavioral changes in WM, the results may point to parameters that contribute to positive effects, such as stimulation amplitude and functional activation.

Perturbation of the right prefrontal cortex disrupts interference control

Resolving cognitive interference is central for successful everyday cognition and behavior. The Stroop task is a classical measure of cognitive interference. In this task, participants have to resolve interference on a trial-by-trial basis and performance is also influenced by the trial history, as reflected in sequence effects. Previous neuroimaging studies have associated the left and right prefrontal cortex with successful performance in the Stroop task. Yet, the causal relevance of both regions for interference processing remains largely unclear. We probed the functional relevance of the left and right prefrontal cortex for interference control. In three sessions, 25 healthy participants received online repetitive transcranial magnetic stimulation (rTMS) over the left and right dorsolateral prefrontal cortex, and sham stimulation over the vertex. During each session, participants completed a verbal-response Stroop task. Relative to sham rTMS and rTMS over the left prefrontal cortex, rTMS over the right prefrontal cortex selectively disrupted the Stroop sequence effect (i.e., the congruency sequence effect; CSE). This effect was specific to sequential modulations of interference since rTMS did not affect the Stroop performance in the ongoing trial. Our results demonstrate the functional relevance of the right dorsolateral prefrontal cortex for the processing of interference control. This finding points towards process-specific lateralization within the prefrontal cortex. The observed process- and site-specific TMS effect provides new insights into the neurophysiological underpinnings of Stroop task performance and more general, the role of the prefrontal cortex in the processing of interference control.

Structural Controllability Predicts Functional Patterns and Brain Stimulation Benefits Associated with Working Memory.

The brain is an inherently dynamic system, and much work has focused on the ability to modify neural activity through both local perturbations and changes in the function of global network ensembles. Network controllability is a recent concept in network neuroscience that purports to predict the influence of individual cortical sites on global network states and state changes, thereby creating a unifying account of local influences on global brain dynamics. While this notion is accepted in engineering science, it is subject to ongoing debates in neuroscience as empirical evidence linking network controllability to brain activity and human behavior remains scarce. Here, we present an integrated set of multimodal brain-behavior relationships derived from fMRI, diffusion tensor imaging, and online repetitive transcranial magnetic stimulation (rTMS) applied during an individually calibrated working memory task performed by individuals of both sexes. The modes describing the structural network system dynamics showed direct relationships to brain activity associated with task difficulty, with difficult-to-reach modes contributing to functional brain states in the hard task condition. Modal controllability (a measure quantifying the contribution of difficult-to-reach modes) at the stimulated site predicted both fMRI activations associated with increasing task difficulty and rTMS benefits on task performance. Furthermore, fMRI explained 64% of the variance between modal controllability and the working memory benefit associated with 5 Hz online rTMS. These results therefore provide evidence toward the functional validity of network control theory, and outline a clear technique for integrating structural network topology and functional activity to predict the influence of stimulation on subsequent behavior.SIGNIFICANCE STATEMENT The network controllability concept proposes that specific cortical nodes are able to steer the brain into certain physiological states. By applying external perturbation to these control nodes, it is theorized that brain stimulation is able to selectively target difficult-to-reach states, potentially aiding processing and improving performance on cognitive tasks. The current study used rTMS and fMRI during a working memory task to test this hypothesis. We demonstrate that network controllability correlates with fMRI modulation because of working memory load and with the behavioral improvements that result from a multivisit intervention using 5 Hz rTMS. This study demonstrates the validity of network controllability and offers a new targeting approach to improve efficacy.

Site-Specific Effects of Online rTMS during a Working Memory Task in Healthy Older Adults.

The process of manipulating information within working memory is central to many cognitive functions, but also declines rapidly in old age. Improving this process could markedly enhance the health-span in older adults. The current pre-registered, randomized and placebo-controlled study tested the potential of online repetitive transcranial magnetic stimulation (rTMS) applied at 5 Hz over the left lateral parietal cortex to enhance working memory manipulation in healthy elderly adults. rTMS was applied, while participants performed a delayed-response alphabetization task with two individually titrated levels of difficulty. Coil placement and stimulation amplitude were calculated from fMRI activation maps combined with electric field modeling on an individual-subject basis in order to standardize dosing at the targeted cortical location. Contrary to the a priori hypothesis, active rTMS significantly decreased accuracy relative to sham, and only in the hardest difficulty level. When compared to the results from our previous study, in which rTMS was applied over the left prefrontal cortex, we found equivalent effect sizes but opposite directionality suggesting a site-specific effect of rTMS. These results demonstrate engagement of cortical working memory processing using a novel TMS targeting approach, while also providing prescriptions for future studies seeking to enhance memory through rTMS.

Reevaluating hMT+ and hV4 functional specialization for motion and static contrast using fMRI-guided repetitive transcranial magnetic stimulation.

Although visual areas hMT+ and hV4 are considered to have segregated functions for the processing of motion and form within dorsal and ventral streams, respectively, more recent evidence favors some functional overlap. Here we use fMRI-guided online repetitive transcranial magnetic stimulation (rTMS) to test two associated hypotheses: that area hV4 is causally involved in the perception of motion and hMT+ in the perception of static form. We use variations of a common global stimulus to test two dynamic motion-based tasks and two static form-based tasks in ipsilateral and contralateral visual fields. We find that rTMS to both hMT+ and hV4 significantly impairs direction discrimination and causes a perceptual slowing of motion, implicating hV4 in motion perception. Stimulation of hMT+ impairs motion in both visual fields, implying that disruption to one hMT+ disrupts the other with both needed for optimal performance. For the second hypothesis, we find the novel result that hV4 stimulation markedly reduces perceived contrast of a static stimulus. hMT+ stimulation also produces an effect, implicating it in static contrast perception. Our findings are the first to show that rTMS of hV4 can produce a large perceptual effect and, taken together, suggest a less rigid functional segregation between hMT+ and hV4 than previously thought.

Online repetitive transcranial magnetic stimulation during working memory in younger and older adults: A randomized within-subject comparison.

Working memory is the ability to perform mental operations on information that is stored in a flexible, limited capacity buffer. The ability to manipulate information in working memory is central to many aspects of human cognition, but also declines with healthy aging. Given the profound importance of such working memory manipulation abilities, there is a concerted effort towards developing approaches to improve them. The current study tested the capacity to enhance working memory manipulation with online repetitive transcranial magnetic stimulation in healthy young and older adults. Online high frequency (5Hz) repetitive transcranial magnetic stimulation was applied over the left dorsolateral prefrontal cortex to test the hypothesis that active repetitive transcranial magnetic stimulation would lead to significant improvements in memory recall accuracy compared to sham stimulation, and that these effects would be most pronounced in working memory manipulation conditions with the highest cognitive demand in both young and older adults. Repetitive transcranial magnetic stimulation was applied while participants were performing a delayed response alphabetization task with three individually-titrated levels of difficulty. The left dorsolateral prefrontal cortex was identified by combining electric field modeling to individualized functional magnetic resonance imaging activation maps and was targeted during the experiment using stereotactic neuronavigation with real-time robotic guidance, allowing optimal coil placement during the stimulation. As no accuracy differences were found between young and older adults, the results from both groups were collapsed. Subsequent analyses revealed that active stimulation significantly increased accuracy relative to sham stimulation, but only for the hardest condition. These results point towards further investigation of repetitive transcranial magnetic stimulation for memory enhancement focusing on high difficulty conditions as those most likely to exhibit benefits.

Effects of online repetitive transcranial magnetic stimulation (rTMS) on cognition: a meta-analysis and recommendations for future studies

Online repetitive transcranial magnetic stimulation (rTMS), applied during a task, is widely used to investigate the neural bases of cognition. However, while some studies claim that online rTMS induces “noise” that disrupts performance; other studies suggest online rTMS enhances performance by entraining neural oscillations. Given the rapid proliferation of this approach, it is crucial to better understand how online rTMS influences cognition, and to determine the optimal parameters to achieve desired effects.

Site-specifics effects of online repetitive transcranial magnetic stimulation (rTMS) on working memory (WM)

Two similar 6-day studies were conducted to enhance WM abilities in healthy subjects by applying online rTMS over the left dorsolateral prefrontal cortex (l-DLPFC, study 1) or the left parietal cortex (l-PC, study 2). On the first visit, participants were trained on a Delayed-Response Alphabetization Task (DRAT) in which they alphabetized an array of letters during a delay period. At the end of the delay, a letter with a number above it appeared, and participants indicated whether the number matched the letter position in its reorganized alphabetical order. During the second visit, the DRAT was performed in the MRI scanner to identify individualized rTMS targets, defined as the peak fMRI activation within the l-DLPFC, or the l-PC. Electric field (E-field) modeling was used to define the optimal coil position and orientation. On days 3 through 6, five seconds of 5 Hz-rTMS was applied: before the encoding (study 1) and/or during the delay period of the DRAT (study 1, study 2) with either active or sensory-matched electrical sham rTMS.

Deficit in Complex Sequence Processing after a Virtual Lesion of Left BA45

Although the contribution of Broca's area to motor cognition is generally accepted, its exact role remains controversial. A previous functional imaging study has suggested that Broca's area implements hierarchically organised motor behaviours and, in particular, that its anterior (Brodmann area 45, BA45) and posterior (BA44) parts process, respectively, higher and lower-level hierarchical elements. This function of Broca's area could generalize to other cognitive functions, including language. However, because of the correlative nature of functional imaging data, the causal relationship between Broca's region activation and its behavioural significance cannot be ascertained. To circumvent this limitation, we used on-line repetitive transcranial magnetic stimulation to disrupt neuronal processing in left BA45, left BA44 or left dorsal premotor cortex, three areas that have been shown to exhibit a phasic activation when participants performed hierarchically organised motor behaviours. The experiment was conducted in healthy volunteers performing the same two key-press sequences as those used in a previous imaging study, and which differed in terms of hierarchical organisation. The performance of the lower-order hierarchical task (Experiment #1) was unaffected by magnetic stimulation. In contrast, in the higher-order hierarchical task (Experiment #2, “superordinate” task), we found that a virtual lesion of the anterior part of Broca's area (left BA45) delayed the processing of the cue initiating the sequence in an effector-independent way. Interestingly, in this task, the initiation cue only informed the subjects about the rules to be applied to produce the appropriate response but did not allow them to anticipate the entire motor sequence. A second important finding was a RT decrease following left PMd virtual lesions in the superordinate task, a result compatible with the view that PMd plays a critical role in impulse control. The present study therefore demonstrates the role of left BA45 in planning the higher-order hierarchical levels of motor sequences.

Impairing somatosensory working memory using rTMS

Numerous studies in animals and humans have related central aspects of somatosensory working memory function to neural activity in the inferior frontal gyrus (IFG). However, as previous studies have almost exclusively used correlational analyses, the question whether sustained neural activity in the IFG is causally involved in successful maintenance of somatosensory information remains unanswered. We used an online repetitive transcranial magnetic stimulation (rTMS) protocol to disrupt neuronal activity in the IFG while participants were maintaining tactile information throughout the delay for later comparison against a probe stimulus. rTMS impaired participants' performance in the working memory task, but not in a physically matched perceptual control task. Targeting the IFG in either hemisphere led to comparable working memory impairment. Our results show that the neural activity in the IFG plays a causal role in successful maintenance of somatosensory information.

Specificity of Human Parietal Saccade and Reach Regions during Transcranial Magnetic Stimulation

Single-unit recordings in macaque monkeys have identified effector-specific regions in posterior parietal cortex (PPC), but functional neuroimaging in the human has yielded controversial results. Here we used on-line repetitive transcranial magnetic stimulation (rTMS) to determine saccade and reach specificity in human PPC. A short train of three TMS pulses (separated by an interval of 100 ms) was delivered to superior parieto-occipital cortex (SPOC), a region over the midposterior intraparietal sulcus (mIPS), and a site close to caudal IPS situated over the angular gyrus (AG) during a brief memory interval while subjects planned either a saccade or reach with the left or right hand. Behavioral measures then were compared to controls without rTMS. Stimulation of mIPS and AG produced similar patterns: increased end-point variability for reaches and decreased saccade accuracy for contralateral targets. In contrast, stimulation of SPOC deviated reach end points toward visual fixation and had no effect on saccades. Contralateral-limb specificity was highest for AG and lowest for SPOC. Visual feedback of the hand negated rTMS-induced disruptions of the reach plan for mIPS and AG, but not SPOC. These results suggest that human SPOC is specialized for encoding retinally peripheral reach goals, whereas more anterior-lateral regions (mIPS and AG) along the IPS possess overlapping maps for saccade and reach planning and are more closely involved in motor details (i.e., planning the reach vector for a specific hand). This work provides the first causal evidence for functional specificity of these parietal regions in healthy humans.