Transcranial Magnetic Stimulation Experiment Research Articles

Modeling the effects of transcranial magnetic stimulation on spatial attention

Objectives. Transcranial magnetic stimulation (TMS) has been widely used to modulate brain activity in healthy and diseased brains, but the underlying mechanisms are not fully understood. Previous research leveraged biophysical modeling of the induced electric field (E-field) to map causal structure–function relationships in the primary motor cortex. This study aims at transferring this localization approach to spatial attention, which helps to understand the TMS effects on cognitive functions, and may ultimately optimize stimulation schemes. Approach. Thirty right-handed healthy participants underwent a functional magnetic imaging (fMRI) experiment, and seventeen of them participated in a TMS experiment. The individual fMRI activation peak within the right inferior parietal lobule (rIPL) during a Posner-like attention task defined the center target for TMS. Thereafter, participants underwent 500 Posner task trials. During each trial, a 5-pulse burst of 10 Hz repetitive TMS (rTMS) was given over the rIPL to modulate attentional processing. The TMS-induced E-fields for every cortical target were correlated with the behavioral modulation to identify relevant cortical regions for attentional orientation and reorientation. Main results. We did not observe a robust correlation between E-field strength and behavioral outcomes, highlighting the challenges of transferring the localization method to cognitive functions with high neural response variability and complex network interactions. Nevertheless, TMS selectively inhibited attentional reorienting in five out of seventeen subjects, resulting in task-specific behavioral impairments. The BOLD-measured neuronal activity and TMS-evoked neuronal effects showed different patterns, which emphasizes the principal distinction between the neural activity being correlated with (or maybe even caused by) particular paradigms, and the activity of neural populations exerting a causal influence on the behavioral outcome. Significance. This study is the first to explore the mechanisms of TMS-induced attentional modulation through electrical field modeling. Our findings highlight the complexity of cognitive functions and provide a basis for optimizing attentional stimulation protocols.

Neurologically Healthy Humans’ Ability to Make Saccades Toward Unseen Targets

Some patients with a visual field loss due to a lesion in the primary visual cortex (V1) can shift their gaze to stimuli presented in their blind visual field. The extent to which a similar “blindsight” capacity is present in neurologically healthy individuals remains unknown. Using retinotopically navigated transcranial magnetic stimulation (TMS) of V1 (Experiment 1) and metacontrast masking (Experiment 2) to suppress conscious vision, we examined neurologically healthy humans’ ability to make saccadic eye movements toward visual targets that they reported not seeing. In the TMS experiment, the participants were more likely to initiate a saccade when a stimulus was presented, and they reported not seeing it, than in trials which no stimulus was presented. However, this happened only in a very small proportion (∼8%) of unseen trials, suggesting that saccadic reactions were largely based on conscious perception. In both experiments, saccade landing location was influenced by unconscious information: When the participants denied seeing the target but made a saccade, the saccade was made toward the correct location (TMS: 68%, metacontrast: 63%) more often than predicted by chance. Signal detection theoretic measures suggested that in the TMS experiment, saccades toward unseen targets may have been based on weak conscious experiences. In both experiments, reduced visibility of the target stimulus was associated with slower and less precise gaze shifts. These results suggest that saccades made by neurologically healthy humans may be influenced by unconscious information, although the initiation of saccades is largely based on conscious vision.

Motor Cortex Excitation/Inhibition Imbalance in Young Adults With Autism Spectrum Disorder: A MRS-TMS Approach.

Excitatory/inhibitory imbalance has been suggested as a neurobiological substrate of the cognitive symptomatology in Autism Spectrum Disorder (ASD). Studies using magnetic resonance spectroscopy (MRS) attempted to characterize GABA and Glutamate brain levels in ASD. However mixed findings have been reported. Here, we characterize both neurochemical and physiological aspects of GABA system in ASD by implementing a more comprehensive approach combining MRS and transcranial magnetic stimulation (TMS). A group of 16 young ASD adults and a group of 17 controls participated in this study. We employed one MRS session to assess motor cortex GABA+ and Glutamate+Glutamine (Glx) levels using MEGAPRESS and PRESS sequences, respectively. Additionally, a TMS experiment was implemented including paired-pulse (SICI, ICF and LICI), input-output curve and cortical silent period to probe cortical excitability. Our results showed a significantly increased Glx, with unchanged GABA+ levels in the ASD group compared with controls. Single TMS measures did not differ between groups, although exploratory within-group analysis showed impaired inhibition in SICI5ms, in ASD. Importantly, we observed a correlation between GABA levels and measures of the input-output TMS recruitment curve (slope and MEP amplitude) in the control group but not in ASD, as further demonstrated by direct between group comparisons. In this exploratory study, we found evidence of increased Glx levels which may contribute to ASD excitatory/inhibitory imbalance while highlighting the relevance of conducting further larger-scale studies to investigate the GABA system from complementary perspectives, using both MRS and TMS techniques.

Lamotrigine and retigabine increase motor threshold in transcranial magnetic stimulation at the dose required to produce an antiepileptic effect against maximal electroshock-induced seizure in rats

Transcranial magnetic stimulation (TMS) is a neurophysiological technique that enables noninvasive evaluation of neuronal excitability in the brain. In the past, a large number of antiepileptic drugs were shown to increase the motor threshold (MT) in clinical TMS studies, suggesting the inhibition of excessive neuronal excitability. To facilitate drug development, the confirmation of similar changes in neurophysiological biomarkers in both preclinical and clinical studies is crucial; however, until now, there have been no data showing the drug efficacies on neuronal excitabilities as measured using TMS in rodents. In this study, we found that the antiepileptic drugs, lamotrigine (10 mg/kg) and retigabine (5 mg/kg), significantly increased the MT in rats using TMS, which is similar to clinical study findings. In addition, we demonstrated that these drugs could inhibit maximal electroshock (MES)-induced seizures in rats when given at the same dose required to be effective in the TMS experiment. These findings suggest that the effects of antiepileptic drugs in our rat TMS system have a similar sensitivity to that of the antiepileptic effects in rats with MES-induced seizures. The measurement of MT in a TMS study may be a noninvasive translational approach for predicting antiepileptic efficacy in drug development.

Reproducibility and Instruction Following in the Shop Floor Laboratory Work: The Case of a TMS Experiment

The article addresses the production of reproducibility as a topic that has become acutely relevant in the recent discussions on the replication crisis in science. It brings the ethnomethodological stance on reproducibility into the discussions, claiming that reproducibility is necessarily produced locally, on the shop floor, with methodological guidelines serving as references to already established practices rather than their origins. The article refers to this argument empirically, analyzing how a group of novice neuroscientists performs a series of measurements in a transcranial magnetic stimulation experiment. Based on ethnography and video analysis, the article traces a history of the local measurement procedure invented by the researchers in order to overcome the experimental uncertainty. The article aims to demonstrate (1) how reproducibility of the local procedure is achieved in the shop floor work of the practitioners and (2) how the procedure becomes normalized and questioned as incorrect in the course of experimental practice. It concludes that the difference between guidelines and practical actions is not problematic per se; what may be problematic is that researchers can be engaged in different working projects described by the same instruction.

The Extrastriate Body Area and identity processing: An fMRI guided TMS study.

The extrastriate body area (EBA) is a body‐selective focal region located in the lateral occipito‐temporal cortex that responds strongly to images of human bodies and body parts in comparison with other classes of stimuli. Whether EBA contributes also to the body recognition of self versus others remains in debate. We investigated whether EBA contributes to self‐other distinction and whether there might be a hemispheric‐side specificity to that contribution using double‐pulse transcranial magnetic stimulation (TMS) in right‐handed participants. Prior to the TMS experiment, all participants underwent an fMRI localizer task to determine individual EBA location. TMS was then applied over either right EBA, left EBA or vertex, while participants performed an identification task in which images of self or others' right, or left hands were presented. TMS over both EBAs slowed responses, with no identity‐specific effect. However, TMS applied over right EBA induced significantly more errors on other's hands than noTMS, TMS over left EBA or over the Vertex, when applied at 100–110 ms after image onset. The last three conditions did not differ, nor was there any difference for self‐hands. These findings suggest that EBA participates in self/other discrimination.

Non-uniform Effects of Nociceptive Stimulation to Motoneurones during Experimental Muscle Pain

Nociceptive stimulation is predicted to uniformly inhibit motoneurone pools of painful muscles and those producing painful movements. Although reduced motoneurone discharge rate during pain provides some evidence, recent data show evidence of increased excitability of some motoneurones. These observations suggest non-uniform effects of nociception on motoneurone excitability. More direct measures are required, but this is difficult to assess as few measures enable in vivo evaluation of motoneurone excitability in humans. We investigated changes in motoneurone excitability during experimental pain using two methods in separate experiments: (i) estimation of the time-course of motoneurone afterhyperpolarization (AHP) from interval death rate analysis of interspike intervals of single motor unit discharge; and (ii) probability of early motoneurone discharge to a descending volley excited using transcranial magnetic stimulation (TMS). Tibialis anterior motor units were recorded with fine-wire electrodes before, during and after painful infusion of 5% hypertonic saline into the muscle. Activation of 17 units (16 participants) could be used for AHP analysis. Data show shortened (n = 11) and lengthened (n = 6) AHP time-course. Increased (n = 6) and decreased (n = 6) probability of early motoneurone discharge were observed in the TMS experiment. These convergent observations suggest non-uniform effects of nociceptive stimulation on motoneurone pools. This does not support the hypothesis that nociceptive input induces uniform inhibition of painful muscle. Instead, interpretation of results implies redistribution of activity between motor units, with possible benefit for unloading painful tissues. This finding supports an interpretation that differs from the generally accepted view in pain physiology regarding adaptation to motor function in pain.

Mapping Responses of Lumbar Paravertebral Muscles to Single-Pulse Cortical TMS Using High-Density Surface Electromyography.

Motor evoked potential (MEP), which was elicited by transcranial magnetic stimulation (TMS), has been widely used to detect corticospinal projection from TMS cortical site to trunk muscles. It can help to find the stimulation hotspot in the scalp. However, it fails to precisely describe coordinated activities of trunk muscle groups with only single-channel myoelectric signal. In this study, we aimed to use high-density surface electromyography (sEMG) to explore the effect of cortical TMS on lumbar paravertebral muscles in healthy subjects. The cortical site at 1 cm anterior and 4 cm lateral to vertex was chosen to simulate using a single-pulse TMS with different intensities and forward-bending angles. A high-density electrode array (45 channels) was placed on the surface of lumbar paravertebral muscles to record sEMG signals during a TMS experiment. MEP signals elicited by TMS were extracted from 45-channel recordings and one topographic map of the MEP amplitudes with six spatial features was constructed at each sampling point. The results showed TMS could successfully evoke an oval area with high intensity in the MEP topographic map, while this area mainly located in ipsilateral side of the TMS site. Intensity features related to the high intensity area rose significantly with TMS intensity and forward-bending angle increasing, but location features showed no change. The optimal stimulation parameters were 80% of maximum stimulator output (MSO) for TMS intensity and 30/60 degree for forward-bending angle. This study provided a potentially effective mapping tool to explore the hotspot for transcranial stimulation on trunk muscles.

Dissociation between cortical and spinal excitability of the antagonist muscle during combined motor imagery and action observation

Inhibitory neural control of antagonist muscle is one of the fundamental neural mechanism of coordinated human limb movement. Previous studies have revealed that motor execution (ME) and motor imagery (MI) share many common neural substrates; however, whether inhibitory neural activity occurs during MI remains unknown. In addition, recent studies have demonstrated that a combined MI and action observation (MI + AO) produces strong neurophysiological changes compared with MI or AO alone. Therefore, we investigated inhibitory changes in cortical and spinal excitability of the antagonist muscle during MI + AO and ME. Single-pulse transcranial magnetic stimulation (TMS) experiments revealed that corticospinal excitability of the antagonist muscle was decreased during MI + AO. Conversely, F-wave experiments showed that F-wave persistence of the antagonist muscle increased. Paired-pulse TMS experiment also demonstrated that short-interval intracortical inhibition (SICI) did not contribute to this inhibition. Therefore, cortical mediated inhibition, except for SICI, may be related to this inhibition. Conversely, such clear inhibition of the antagonist muscle was not observed during ME, presumably owing to the effects of muscle contraction to decelerate the movements and/or sensory input accompanying the joint movements. These findings provide important insights into the neurophysiological differences between MI + AO and ME.

Cortical Excitability Dynamics During Fear Processing.

Background:Little is known about the modulation of cortical excitability in the prefrontal cortex during fear processing in humans. Here, we aimed to transiently modulate and test the cortical excitability during fear processing using transcranial magnetic stimulation (TMS) and brain oscillations in theta and alpha frequency bands with electroencephalography (EEG).Methods:We conducted two separate experiments (no-TMS and TMS). In the no-TMS experiment, EEG recordings were performed during the instructed fear paradigm in which a visual cue (CS+) was paired with an aversive unconditioned stimulus (electric shock), while the other visual cue was unpaired (CS-). In the TMS experiment, in addition the TMS was applied on the right dorsomedial prefrontal cortex (dmPFC). The participants also underwent structural MRI (magnetic resonance imaging) scanning and were assigned pseudo-randomly to both experiments, such that age and gender were matched. The cortical excitability was evaluated by time-frequency analysis and functional connectivity with weighted phase lag index (WPLI). We further linked the excitability patterns with markers of stress coping capability.Results:After visual cue onset, we found increased theta power in the frontal lobe and decreased alpha power in the occipital lobe during CS+ relative to CS- trials. TMS of dmPFC increased theta power in the frontal lobe and reduced alpha power in the occipital lobe during CS+. The TMS pulse increased the information flow from the sensorimotor region to the prefrontal and occipital regions in the theta and alpha bands, respectively during CS+ compared to CS-. Pre-stimulation frontal theta power (0.75–1 s) predicted the magnitude of frontal theta power changes after stimulation (1–1.25 s). Finally, the increased frontal theta power during CS+ compared to CS- was positively correlated with stress coping behavior.Conclusion:Our results show that TMS over dmPFC transiently modulated the regional cortical excitability and the fronto-occipital information flows during fear processing, while the pre-stimulation frontal theta power determined the strength of achieved effects. The frontal theta power may serve as a biomarker for fear processing and stress-coping responses in individuals and could be clinically tested in mental disorders.

Non-orthogonal one-step calibration method for robotized transcranial magnetic stimulation

BackgroundRobotized transcranial magnetic stimulation (TMS) combines the benefits of neuro-navigation with automation and provides a precision brain stimulation method. Since the coil will normally remain unmounted between different clinical uses, hand/eye calibration and coil calibration are required before each experiment. Today, these two steps are still separate: hand/eye calibration is performed using methods proposed by Tsai/Lenz or Floris Ernst, and then the coil calibration is carried out based on the traditional TMS experimental step. The process is complex and time-consuming, and traditional coil calibration using a handheld probe is susceptible to greater calibration error.MethodsA novel one-step calibration method has been developed to confirm hand/eye and coil calibration results by formulating a matrix equation system and estimating its solution. Hand/eye calibration and coil calibration are performed to confirm the pose relationships of the marker/end effector ‘X’, probe/end effector ‘Y’, and robot/world ‘Z’. First, the coil is fixed on the end effector of the robot. During the one-step calibration process, a marker is mounted on the top of the coil and a calibration probe is fixed at the actual effective position of the coil. Next, the robot end effector is moved to a series of random positions ‘A’, the tracking data of marker ‘B’ and probe ‘C’ is obtained correspondingly. Then, a matrix equation system AX = ZB and AY = ZC can be acquired, and it is computed using a least-squares approach. Finally, the calibration probe is removed after calibration, while the marker remains fixed to the coil during the TMS experiment. The methods were evaluated based on simulation data and on experimental data from an optical tracking device. We compared our methods with two classical methods: the QR24 method proposed by Floris Ernst and the handheld coil calibration method.ResultsThe new methods outperform the QR24 method in the aspect of translational accuracy and performs similarly in the aspect of rotational accuracy, the total translational error decreased more than fifty percent. The new approach also outperforms traditional handheld coil calibration of navigated TMS systems, the total translational error decreased three- to fourfold, and the rotational error decreased six- to eightfold. Furthermore, the convergence speed is improved 16- to 27-fold for the new algorithms.ConclusionThese results suggest that the new method can be used for hand/eye and coil calibration of a robotized TMS system. Two complex steps can be simplified using a least-squares approach.

Observation of an action with a congruent contextual background facilitates corticospinal excitability: A combined TMS and eye-tracking experiment

Action observation produces activity in similar regions of the brain to those involved in action execution and can offer an effective intervention for motor (re)learning, although optimal viewing conditions for such interventions remain to be established. In this experiment, single-pulse transcranial magnetic stimulation (TMS) and eye-tracking were used simultaneously to investigate the effect of manipulating background context on both corticospinal excitability and visual attention during action observation. Twenty-four participants observed four different videos: (i) a static hand holding a sponge (control condition); and an index finger-thumb pinch of a sponge against (ii) a plain black background; (iii) a background containing objects that were incongruent with the observed action; and (iv) a background containing objects that were congruent with the observed action. TMS was delivered to the hand representation of the left primary motor cortex, and motor evoked potentials were recorded from the first dorsal interosseous and abductor digiti minimi muscles of the right hand. Eye movements were recorded throughout the experiment. Results indicated that corticospinal excitability was facilitated during the congruent context condition compared to both the static hand and plain black background conditions. In addition, the number of fixations and percentage of time participants spent fixating on the background scene were significantly greater during the incongruent and congruent conditions compared to the static hand and plain black background conditions. These results indicate that the provision of additional visual information that is congruent with the observed movement contributes to a facilitation of corticospinal excitability by providing the observer with information regarding the goal and intention of the observed action. Providing congruent contextual information may enhance the efficacy of action observation interventions for motor (re)learning.

Anticipating actions and corticospinal excitability: A preregistered motor TMS experiment

Past research on action observation and imitation suggests that observing a movement activates a corresponding motor representation in the observer. However, recent research suggests that individuals may not only reflexively simulate the observed behavior but also simulate and engage in anticipated action without another person actually engaging in it. For example, it has been demonstrated that observing a triggering event (i.e., nose wrinkling) that potentially leads to the anticipation of an action (i.e., nose scratching) increases the likelihood that the observer will perform that action. In the present research, we applied motor Transcranial Magnetic Stimulation (TMS) to investigate such anticipated social action effects at the neurophysiological level within a trial-by-trial measure. While a pilot study suggests that observing nose wrinkling elicits stronger motor evoked potentials (MEPs) in participants' biceps muscles than observing control events, this effect could not be fully replicated in a preregistered study. Although a post hoc meta-analysis across both studies supports the general hypothesis, these results need to be taken cautiously. Implications of the results reported in the manuscript are discussed.

Deficient inhibition in alcohol-dependence: a transcranial magnetic stimulation study.

Event Abstract Back to Event Deficient inhibition in alcohol-dependence: a transcranial magnetic stimulation study. Caroline Quoilin1*, Philippe De Timary1 and Julie Duque1 1 Institute of Neuroscience, Catholic University of Leuven, Belgium Background: The development, maintenance, and relapse phenomena in alcohol-dependence has been related to an impaired inhibitory control, but the neural correlates of this deficit are still unclear1. As impaired inhibition has been classically understood as a pure cognitive deficit, most studies have focused on prefrontal areas, while little attention has been given to the role of more “primary” structures, such as the motor system. Importantly, recent transcranial magnetic stimulation (TMS) studies have observed profound inhibitory changes in the motor output pathway during the preparation of actions2-6; this neural motor inhibition is thought to assist goal-directed behaviors by suppressing neural activity that could cause premature or inappropriate responses7-9. Thus, as inhibition of the motor system supports the ability to subjugate inappropriate behaviors and because this aptitude is altered in alcohol-dependence, we tested the hypothesis that alcohol-dependent (AD) patients may suffer from a shortage of neural motor inhibition. Methods: Single TMS pulses were applied over the right and the left primary motor cortex to elicit motor-evoked potentials (MEPs) in the left and the right hand, respectively, of 20 detoxified ADs and 20 matched healthy subjects performing a choice reaction time task. In addition, behavioral inhibitory aptitudes and trait impulsivity were assessed in all participants. Finally, the patients were called back one year after the experiment to evaluate their relapse status and the potential relationship with motor inhibition. Results: As expected, AD patients exhibited poorer behavioral inhibition and higher trait impulsivity than control subjects. More importantly, the TMS experiment revealed a considerable shortage of neural motor inhibition in AD patients. Interestingly, the patients who resumed consuming alcohol within the year following the experiment were those displaying the strongest deficits, both at the behavioral and the neural levels, while the relapse status did not depend on the trait impulsivity measure. Conclusions: Our data suggest a strong motor component in the neural correlate of altered inhibitory control in AD patients. They also highlight an intriguing relationship with relapse and the perspective of a new biomarker to follow strategies aiming at reducing relapse in AD patients. Short lay summary: Impaired inhibitory control is a core element of alcohol-dependence. So far, most studies investigating the neural correlates of this deficit have focused on prefrontal areas, overlooking the contribution of more “primary” structures, such as the motor cortex. Yet, appropriate neural motor inhibition may be a central aspect of healthy behavior. Here, by using transcranial magnetic stimulation, we revealed a deficit in neural motor inhibition in alcohol-dependent patients relative to control subjects. Moreover, this alteration was stronger in patients who ended-up relapsing during the year following the experiment, suggesting that it may represent a new biomarker of the risk for relapse.

Why Do Irrelevant Alternatives Matter? An fMRI-TMS Study of Context-Dependent Preferences.

Both humans and animals are known to exhibit a violation of rationality known as "decoy effect": introducing an irrelevant option (a decoy) can influence choices among other (relevant) options. Exactly how and why decoys trigger this effect is not known. It may be an example of fast heuristic decision-making, which is adaptive in natural environments, but may lead to biased choices in certain markets or experiments. We used fMRI and transcranial magnetic stimulation to investigate the neural underpinning of the decoy effect of both sexes. The left ventral striatum was more active when the chosen option dominated the decoy. This is consistent with the hypothesis that the presence of a decoy option influences the valuation of other options, making valuation context-dependent even when choices appear fully rational. Consistent with the idea that control is recruited to prevent heuristics from producing biased choices, the right inferior frontal gyrus, often implicated in inhibiting prepotent responses, connected more strongly with the striatum when subjects successfully overrode the decoy effect and made unbiased choices. This is further supported by our transcranial magnetic stimulation experiment: subjects whose right inferior frontal gyrus was temporarily disrupted made biased choices more often than a control group. Our results suggest that the neural basis of the decoy effect could be the context-dependent activation of the valuation area. But the differential connectivity from the frontal area may indicate how deliberate control monitors and corrects errors and biases in decision-making.SIGNIFICANCE STATEMENT Standard theories of rational decision-making assume context-independent valuations of available options. Motivated by the importance of this basic assumption, we used fMRI to study how the human brain assigns values to available options. We found activity in the valuation area to be consistent with the hypothesis that values depend on irrelevant aspects of the environment, even for subjects whose choices appear fully rational. Such context-dependent valuations may lead to biased decision-making. We further found differential connectivity from the frontal area to the valuation area depending on whether biases were successfully overcome. This suggests a mechanism for making rational choices despite the potential bias. Further support was obtained by a transcranial magnetic stimulation experiment, where subjects whose frontal control was temporarily disrupted made biased choices more often than a control group.

Active and resting motor threshold are efficiently obtained with adaptive threshold hunting.

Transcranial magnetic studies typically rely on measures of active and resting motor threshold (i.e. AMT, RMT). Previous work has demonstrated that adaptive threshold hunting approaches are efficient for estimating RMT. To date, no study has compared motor threshold estimation approaches for measures of AMT, yet this measure is fundamental in transcranial magnetic stimulation (TMS) studies that probe intracortical circuits. The present study compared two methods for acquiring AMT and RMT: the Rossini-Rothwell (R-R) relative-frequency estimation method and an adaptive threshold-hunting method based on maximum-likelihood parameter estimation by sequential testing (ML-PEST). AMT and RMT were quantified via the R-R and ML-PEST methods in 15 healthy right-handed participants in an experimenter-blinded within-subject study design. AMT and RMT estimations obtained with both the R-R and ML-PEST approaches were not different, with strong intraclass correlation and good limits of agreement. However, ML-PEST required 17 and 15 fewer stimuli than the R-R method for the AMT and RMT estimation, respectively. ML-PEST is effective in reducing the number of TMS pulses required to estimate AMT and RMT without compromising the accuracy of these estimates. Using ML-PEST to estimate AMT and RMT increases the efficiency of the TMS experiment as it reduces the number of pulses to acquire these measures without compromising accuracy. The benefits of using the ML-PEST approach are amplified when multiple target muscles are tested within a session.

Hierarchically Organized Medial Frontal Cortex-Basal Ganglia Loops Selectively Control Task- and Response-Selection.

Adaptive behavior requires context-sensitive configuration of task-sets that specify time-varying stimulus-response mappings. Intriguingly, response time costs associated with changing task-sets and motor responses are known to be strongly interactive: switch costs at the task level are small in the presence of a response-switch but large when accompanied by a response-repetition, and vice versa for response-switch costs. The reasons behind this well known interdependence between task- and response-level control processes are currently not well understood. Here, we formalized and tested a model assuming a hierarchical organization of superordinate task-set and subordinate response-set selection processes to account for this effect. The model was found to successfully explain the full range of behavioral task- and response-switch costs across first and second order trial transitions. Using functional magnetic resonance imaging (fMRI) in healthy humans, we then characterized the neural circuitry mediating these effects. We found that presupplementary motor area (preSMA) activity tracked task-set control costs, SMA activity tracked response-set control costs, and basal ganglia (BG) activity mirrored the interaction between task- and response-set regulation processes that characterized participants' response times. A subsequent fMRI-guided transcranial magnetic stimulation experiment confirmed dissociable roles of the preSMA and SMA in determining response costs. Together, these data provide evidence for a hierarchical organization of posterior medial frontal cortex and its interaction with the BG, where a superordinate preSMA-BG loop establishes task-set selection, which imposes a (unidirectional) constraint on a subordinate SMA-BG loop that determines response-selection, resulting in the characteristic interdependence in task- and response-switch costs in behavior.SIGNIFICANCE STATEMENT The ability to use context-sensitive task-sets to guide our responses is central to human adaptive behavior. Task and response selection are strongly interactive: it is more difficult to repeat a response in the context of a changing task-set, and vice versa. However, the neurocognitive architecture giving rise to this interdependence is currently not understood. Here we use modeling, neuroimaging, and noninvasive neurostimulation to show that this phenomenon derives from a hierarchical organization of posterior medial frontal cortex and its interaction with the basal ganglia, where a more anterior corticostriatal loop establishes task-set selection, which constrains a more posterior loop responsible for response-selection. These data provide a neural explanation for a key behavioral signature of human cognitive control.

Does listening to action-related sentences modulate the activity of the motor system? Replication of a combined TMS and behavioral study.

The neurophysiological and behavioral correlates of action-related language processing have been debated for long time. A precursor in this field was the study by Buccino et al. (2005) combining transcranial magnetic stimulation (TMS) and behavioral measures (reaction times, RTs) to study the effect of listening to hand- and foot-related sentences. In the TMS experiment, the authors showed a decrease of motor evoked potentials (MEPs) recorded from hand muscles when processing hand-related verbs as compared to foot-related verbs. Similarly, MEPs recorded from leg muscles decreased when participants processed foot-related as compared to hand-related verbs. In the behavioral experiment, using the same stimuli and a semantic decision task the authors found slower RTs when the participants used the body effector (hand or foot) involved in the actual execution of the action expressed by the presented verb to give their motor responses. These findings were interpreted as an interference effect due to a simultaneous involvement of the motor system in both a language and a motor task. Our replication aimed to enlarge the sample size and replicate the findings with higher statistical power. The TMS experiment showed a significant modulation of hand MEPs, but in the sense of a motor facilitation when processing hand-related verbs. On the contrary, the behavioral experiment did not show significant results. The results are discussed within the general debate on the time-course of the modulation of motor cortex during implicit and explicit language processing and in relation to the studies on action observation/understanding.

Mirror neuron dysfunction and ego-boundary disturbances in schizophrenia: a transcranial magnetic stimulation study.

Background:Ego-boundary disturbance (EBD) is a unique symptom cluster characterized by passivity experiences (involving thoughts, actions, emotions and sensations) attributed by patients to some external agency. The neurobiology of these “first rank” symptoms is poorly understood. Aberrant mirror neuron activation may explain impaired self-monitoring and agency attribution underlying these symptoms. We aim to study mirror neuron activity (MNA) in schizophrenia patients with and without EBD using transcranial magnetic stimulation (TMS).Materials and Methods:50 right-handed schizophrenia patients (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) were evaluated using the Mini-International Neuropsychiatric Interview and the Positive and Negative Syndrome Scale. They completed a TMS experiment to assess putative premotor MNA. Motor evoked potential (MEP) was recorded in the right first dorsal interosseous muscle (FDI) with (a) 120% of resting motor threshold (RMT), (b) stimulus intensity set to evoke MEP of motor threshold 1 mV amplitude (MT1), (c) two paired pulse paradigms (short- and long interval intra-cortical inhibition). These were done in three states: Actual observation of an action using the FDI, virtual-observation (video) of this action and resting state. The percent change of MEP from resting to action-observation states formed the measure of putative MNA.Results:MNA measured using MT1 and 120% RMT paradigms was significantly lower in the 18 patients with EBD (thought-broadcast/withdrawal/insertion, made-act/impulse/affect and somatic passivity) than the 32 patients without EBD (t = 2.431, P = 0.020; t = 2.051, P = 0.04 respectively for the two paradigms). The two groups did not differ on age, gender, education and total symptom scores.Conclusion:Schizophrenia patients with EBD have lower premotor MNA. This highlights the role of MNA dysfunction in the pathophysiology of this unique and intriguing symptom cluster in schizophrenia.

Body form and body motion processing are dissociable in the visual pathways.

Body form and body motion processing are dissociable in the visual pathways.