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Correlative evidence provides support for the idea that brain oscillations underpin neural computations. Recent work using rhythmic stimulation techniques in humans provide causal evidence but the interactions of these external signals with intrinsic rhythmicity remain unclear. Here, we show that sensorimotor cortex follows externally applied rhythmic TMS (rTMS) stimulation in the beta-band but that the elicited responses are strongest at the intrinsic individual beta peak frequency. While these entrainment effects are of short duration, even subthreshold rTMS pulses propagate through the network and elicit significant cortico-spinal coupling, particularly when stimulated at the individual beta-frequency. Our results show that externally enforced rhythmicity interacts with intrinsic brain rhythms such that the individual peak frequency determines the effect of rTMS. The observed downstream spinal effect at the resonance frequency provides evidence for the causal role of brain rhythms for signal propagation., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Although oscillatory activity in the alpha band was traditionally associated with lack of alertness, more recent work has linked it to specific cognitive functions, including visual attention. The emerging method of rhythmic transcranial magnetic stimulation (TMS) allows causal interventional tests for the online impact on performance of TMS administered in short bursts at a particular frequency. TMS bursts at 10 Hz have recently been shown to have an impact on spatial visual attention, but any role in featural attention remains unclear. Here we used rhythmic TMS at 10 Hz to assess the impact on attending to global or local components of a hierarchical Navon-like stimulus (D. Navon (1977) Forest before trees: The precedence of global features in visual perception. Cognit. Psychol., 9, 353), in a paradigm recently used with TMS at other frequencies (V. Romei, J. Driver, P.G. Schyns & G. Thut. (2011) Rhythmic TMS over parietal cortex links distinct brain frequencies to global versus local visual processing. Curr. Biol., 2, 334-337). In separate groups, left or right posterior parietal sites were stimulated at 10 Hz just before presentation of the hierarchical stimulus. Participants had to identify either the local or global component in separate blocks. Right parietal 10 Hz stimulation (vs. sham) significantly impaired global processing without affecting local processing, while left parietal 10 Hz stimulation vs. sham impaired local processing with a minor trend to enhance global processing. These 10 Hz outcomes differed significantly from stimulation at other frequencies (i.e. 5 or 20 Hz) over the same site in other recent work with the same paradigm. These dissociations confirm differential roles of the two hemispheres in local vs. global processing, and reveal a frequency-specific role for stimulation in the alpha band for regulating feature-based visual attention., (© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

While the frontal eye fields (FEF) are traditionally associated with eye movements, recent work indicates possible roles in controlling selective visual processing. We applied 10 Hz bursts of transcranial magnetic stimulation (TMS) over left or right human FEF while subjects performed a partial-report task that allowed quantitative estimates of top-down control and other parameters affecting visual performance. Participants selectively reported digits in a relevant color (targets) but not those in an irrelevant color (nontargets) from a brief masked display. A target could appear alone or together with an accompanying item (nontarget or target) in the same or opposite hemifield. Targets were normally identified better when presented with a nontarget than with another target, indicating prioritization of task-relevant targets and thus top-down control. We found this usual pattern of results without TMS, and also with TMS over left FEF. However, during right FEF TMS, the detrimental impact of accompanying distractors increased. Formal analysis in terms of Bundesen's (1990) theory of visual attention confirmed that right FEF TMS diminished the top-down control parameter for both hemifields, indicating an FEF role in top-down selection even for targets defined by the nonspatial property of color. Direct comparison with our previous findings for parietal TMS (Hung et al., 2005) confirmed the distinct role of FEF in top-down control, plus right-hemisphere predominance for this in humans.

Transcranial magnetic stimulation (TMS) is increasingly used to perturb targeted human brain sites non-invasively, to test for causal effects on performance of cognitive tasks. TMS might also be used in non-human primates to complement invasive work and compare with human studies. Here, we targeted the frontal eye fields (FEF) in two macaques with a continuous theta-burst (cTBS) protocol, testing the impact on visually guided saccades. After unilateral cTBS over the FEF in either hemisphere, a small (mean 7 ms) but highly consistent decrease in saccadic reaction times (RTs) was observed. Lower latencies arose for saccades both contra- and ipsilateral to the stimulated FEF after cTBS. These results provide the first demonstration that TMS can be used to affect saccadic behavior in non-human primates. The unexpectedly bilateral impact on RTs may reflect an impact on 'fixation' neurons in the FEF and/or transcallosal modulation of both FEFs induced by unilateral cTBS. In either case, this study demonstrates a clear behavioral effect induced by TMS in awake behaving monkeys performing a cognitive task. This opens new opportunities for investigating the causal roles of targeted brain areas in behavior, for measuring physiological consequences of TMS in the primate brain, and ultimately for human-monkey comparisons.

We used concurrent transcranial magnetic stimulation and functional MRI (TMS-fMRI) during a visuospatial cueing paradigm in humans, to study the causal role of the right angular gyrus (AG) as a source of attentional control. Our findings show that TMS over the right AG (high vs. low intensity) modulates neural responses interhemispherically, in a manner that varies dynamically with the current attentional condition. The behavioural impact of such TMS depended not only on the target hemifield but also on exogenous cue validity, facilitating spatial reorienting to invalidly cued right visual targets. On a neural level, right AG TMS had corresponding interhemispheric effects in the left AG and left retinotopic cortex, including area V1. We conclude that the direction of covert visuospatial attention can involve dynamic interplay between the right AG and remote interconnected regions of the opposite left hemisphere, whereas our findings also suggest that the right AG can influence responses in the retinotopic visual cortex., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Neural networks underlying visual perception exhibit oscillations at different frequencies (e.g.,). But how these map onto distinct aspects of visual perception remains elusive. Recent electroencephalography data indicate that theta or beta frequencies at parietal sensors increase in amplitude when conscious perception is dominated by global or local features, respectively, of a reversible visual stimulus. But this provides only correlative, noninterventional evidence. Here we show via transcranial magnetic stimulation (TMS) interventions that short rhythmic bursts of right-parietal TMS at theta or beta frequency can causally benefit processing of global or local levels, respectively, for hierarchical visual stimuli, especially in the context of salient incongruent distractors. This double dissociation between theta and beta TMS reveals distinct causal roles for particular frequencies in processing global versus local visual features., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Combining transcranial magnetic stimulation (TMS) with concurrent functional magnetic resonance imaging (fMRI) allows study of how local brain stimulation may causally affect activity in remote brain regions. Here, we applied bursts of high- or low-intensity TMS over right posterior parietal cortex, during a task requiring sustained covert visuospatial attention to either the left or right hemifield, or in a neutral control condition, while recording blood oxygenation-level-dependent signal with a posterior MR surface coil. As expected, the active attention conditions activated components of the well-described "attention network," as compared with the neutral baseline. Also as expected, when comparing left minus right attention, or vice versa, contralateral occipital visual cortex was activated. The critical new finding was that the impact of high- minus low-intensity parietal TMS upon these visual regions depended on the currently attended side. High- minus low-intensity parietal TMS increased the difference between contralateral versus ipsilateral attention in right extrastriate visual cortex. A related albeit less pronounced pattern was found for left extrastriate visual cortex. Our results confirm that right human parietal cortex can exert attention-dependent influences on occipital visual cortex and provide a proof of concept for the use of concurrent TMS-fMRI in studying how remote influences can vary in a purely top-down manner with attentional demands.

Interplay between the cerebral hemispheres is vital for coordinating perception and behavior. One influential account holds that the hemispheres engage in rivalry, each inhibiting the other. In the somatosensory domain, a seminal paper claimed to demonstrate such interhemispheric rivalry, reporting improved tactile detection sensitivity on the right hand after transcranial magnetic stimulation (TMS) to the right parietal lobe (Seyal, Ro, & Rafal, 1995). Such improvement in tactile detection ipsilateral to TMS could follow from interhemispheric rivalry, if one assumes that TMS disrupted cortical processing under the coil and thereby released the other hemisphere from inhibition. Here we extended the study by Seyal et al. (1995) to determine the effects of right parietal TMS on tactile processing for either hand, rather than only the ipsilateral hand. We performed two experiments applying TMS in the context of median-nerve stimulation; one experiment required somatosensory detection, the second somatosensory intensity discrimination. We found different TMS effects on detection versus discrimination, but neither set of results followed the prediction from hemispheric rivalry that enhanced performance for one hand should invariably be associated with impaired performance for the other hand, and vice-versa. Our results argue against a strict rivalry interpretation, instead suggesting that parietal TMS can provide a pedestal-like increment in somatosensory response., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Contralesional dorsal premotor cortex (cPMd) may support residual motor function following stroke. We performed two complementary experiments to explore how cPMd might perform this role in a group of chronic human stroke patients. First, we used paired-coil transcranial magnetic stimulation (TMS) to establish the physiological influence of cPMd on ipsilesional primary motor cortex (iM1) at rest. We found that this influence became less inhibitory/more facilitatory in patients with greater clinical impairment. Second, we applied TMS over cPMd during functional magnetic resonance imaging (fMRI) in these patients to examine the causal influence of cPMd TMS on the whole network of surviving cortical motor areas in either hemisphere and whether these influences changed during affected hand movement. We confirmed that hand grip-related activation in cPMd was greater in more impaired patients. Furthermore, the peak ipsilesional sensorimotor cortex activity shifted posteriorly in more impaired patients. Critical new findings were that concurrent TMS-fMRI results correlated with the level of both clinical impairment and neurophysiological impairment (i.e., less inhibitory/more facilitatory cPMd-iM1 measure at rest as assessed with paired-coil TMS). Specifically, greater clinical and neurophysiological impairment was associated with a stronger facilitatory influence of cPMd TMS on blood oxygenation level-dependent signal in posterior parts of ipsilesional sensorimotor cortex during hand grip, corresponding to the posteriorly shifted sensorimotor activity seen in more impaired patients. cPMd TMS was not found to influence activity in other brain regions in either hemisphere. This state-dependent influence on ipsilesional sensorimotor regions may provide a mechanism by which cPMd supports recovered function after stroke.

Purpose: To characterize and eliminate a new type of image artifact in concurrent transcranial magnetic stimulation and functional MRI (TMS-fMRI) caused by small leakage currents originating from the high-voltage capacitors in the TMS stimulator system., Materials and Methods: The artifacts in echo-planar images (EPI) caused by leakage currents were characterized and quantified in numerical simulations and phantom studies with different phantom-coil geometries. A relay-diode combination was devised and inserted in the TMS circuit that shorts the leakage current. Its effectiveness for artifact reduction was assessed in a phantom scan resembling a realistic TMS-fMRI experiment., Results: The leakage-current-induced signal changes exhibited a multipolar spatial pattern and the maxima exceeded 1% at realistic coil-cortex distances. The relay-diode combination effectively reduced the artifact to a negligible level., Conclusion: The leakage-current artifacts potentially obscure effects of interest or lead to false-positives. Since the artifact depends on the experimental setup and design (eg, amplitude of the leakage current, coil orientation, paradigm, EPI parameters), we recommend its assessment for each experiment. The relay-diode combination can eliminate the artifacts if necessary.

Transcranial magnetic stimulation (TMS) has been used to document some apparent interhemispheric influences behaviorally, with TMS over the right parietal cortex reported to enhance processing of touch for the ipsilateral right hand (Seyal et al., 1995). However, the neural bases of such apparent interhemispheric influences from TMS remain unknown. Here, we studied this directly by combining TMS with concurrent functional magnetic resonance imaging (fMRI). We applied bursts of 10 Hz TMS over right parietal cortex, at a high or low intensity, during two sensory contexts: either without any other stimulation, or while participants received median nerve stimulation to the right wrist, which projects to left primary somatosensory cortex (SI). TMS to right parietal cortex affected the blood oxygenation level-dependent signal in left SI, with high- versus low-intensity TMS increasing the left SI signal during right-wrist somatosensory input, but decreasing this in the absence of somatosensory input. This state-dependent modulation of SI by parietal TMS over the other hemisphere was accompanied by a related pattern of TMS-induced influences in the thalamus, as revealed by region-of-interest analyses. A behavioral experiment confirmed that the same right parietal TMS protocol of 10 Hz bursts led to enhanced detection of perithreshold electrical stimulation of the right median nerve, which is initially processed in left SI. Our results confirm directly that TMS over right parietal cortex can affect processing in left SI of the other hemisphere, with rivalrous effects (possibly transcallosal) arising in the absence of somatosensory input, but facilitatory effects (possibly involving thalamic circuitry) in the presence of driving somatosensory input.

Transcranial magnetic stimulation (TMS) produces a direct causal effect on brain activity that can now be studied by new approaches that simultaneously combine TMS with neuroimaging methods, such as functional magnetic resonance imaging (fMRI). In this review we highlight recent concurrent TMS-fMRI studies that illustrate how this novel combined technique may provide unique insights into causal interactions among brain regions in humans. We show how fMRI can detect the spatial topography of local and remote TMS effects and how these may vary with psychological factors such as task-state. Concurrent TMS-fMRI may furthermore reveal how the brain adapts to so-called virtual lesions induced by TMS, and the distributed activity changes that may underlie the behavioural consequences often observed during cortical stimulation with TMS. We argue that combining TMS with neuroimaging techniques allows a further step in understanding the physiological underpinnings of TMS, as well as the neural correlated of TMS-evoked consequences on perception and behaviour. This can provide powerful new insights about causal interactions among brain regions in both health and disease that may ultimately lead to developing more efficient protocols for basic research and therapeutic TMS applications.

Posterior parietal cortex (PPC) has connections with motor and premotor cortex, thought to transfer information relevant for planning movements in space. We used twin-coil transcranial magnetic stimulation (tcTMS) methods to show that the functional interplay between human right PPC and ipsilateral motor cortex (M1) varies with current motor plans. tcTMS during the reaction time of a reach task revealed facilitatory influences of right PPC on right M1 only when planning a (contralateral) leftward rather than rightward reach, at two specific time intervals (50 and 125 ms) after an auditory cue. The earlier reach-direction-specific facilitatory influence from PPC on M1 occurred when subjects were blindfolded or when the targets were presented briefly, so that visual feedback corrections could not occur. PPC-M1 interplay was similar within the left hemisphere but was specific to (contralateral) rightward planned reaches, with peaks at 50 and 100 ms. Functional interplay between human parietal and motor cortex is enhanced during early stages of planning a reach in the contralateral direction.

It has often been proposed that regions of the human parietal and/or frontal lobe may modulate activity in visual cortex, for example, during selective attention or saccade preparation. However, direct evidence for such causal claims is largely missing in human studies, and it remains unclear to what degree the putative roles of parietal and frontal regions in modulating visual cortex may differ. Here we used transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) concurrently, to show that stimulating right human intraparietal sulcus (IPS, at a site previously implicated in attention) elicits a pattern of activity changes in visual cortex that strongly depends on current visual context. Increased intensity of IPS TMS affected the blood oxygen level-dependent (BOLD) signal in V5/MT+ only when moving stimuli were present to drive this visual region, whereas TMS-elicited BOLD signal changes were observed in areas V1-V4 only during the absence of visual input. These influences of IPS TMS upon remote visual cortex differed significantly from corresponding effects of frontal (eye field) TMS, in terms of how they related to current visual input and their spatial topography for retinotopic areas V1-V4. Our results show directly that parietal and frontal regions can indeed have distinct patterns of causal influence upon functional activity in human visual cortex.

Posterior parietal cortex (PPC) may contribute to visual selection by exerting top-down influences on visual processing. To seek direct evidence for this, we used 10 Hz repetitive transcranial magnetic stimulation (rTMS) over right or left PPC in nine healthy volunteers during a partial (selective) report task that allows quantitative assessment of top-down control and other parameters. Participants reported digits in a relevant color ("targets") but not those in an irrelevant color ("nontargets") from a brief masked display, in which a target could appear alone or together with an accompanying item (nontarget or target) in the same or opposite hemifield. Generally, a given target is identified better when presented with a nontarget than with another target, indicating top-down selection of task-relevant targets; this applied here with no rTMS or left PPC rTMS. However, rTMS over the right PPC changed the performance pattern. A left target no longer impeded report of a right target more strongly than did a left nontarget, whereas the greater impact of a right target than a right nontarget in disrupting report of a left target was increased. Formal analysis in terms of Bundesen's (1990) theory of visual attention indicated that right PPC rTMS diminished top-down control for the left hemifield while enhancing this for the right hemifield, particularly for bilateral two-item displays. These findings indicate a role for right PPC in top-down spatial selection, which applies even when the target is defined by a nonspatial property (here color).

Dorsolateral prefrontal cortex (DLPFC) is recruited during visual working memory (WM) when relevant information must be maintained in the presence of distracting information. The mechanism by which DLPFC might ensure successful maintenance of the contents of WM is, however, unclear; it might enhance neural maintenance of memory targets or suppress processing of distracters. To adjudicate between these possibilities, we applied time-locked transcranial magnetic stimulation (TMS) during functional MRI, an approach that permits causal assessment of a stimulated brain region's influence on connected brain regions, and evaluated how this influence may change under different task conditions. Participants performed a visual WM task requiring retention of visual stimuli (faces or houses) across a delay during which visual distracters could be present or absent. When distracters were present, they were always from the opposite stimulus category, so that targets and distracters were represented in distinct posterior conical areas. We then measured whether DLPFC-TMS, administered in the delay at the time point when distracters could appear, would modulate posterior regions representing memory targets or distracters. We found that DLPFCTMS influenced posterior areas only when distracters were present and, critically, that this influence consisted of increased activity in regions representing the current memory targets. DLPFC-TMS did not affect regions representing current distracters. These results provide a new line of causal evidence for a top-down DLPFC-based control mechanism that promotes successful maintenance of relevant information in WM in the presence of distraction. [ABSTRACT FROM AUTHOR]

Cognitive processes, such as spatial attention, are thought to rely on extended networks in the human brain. Both clinical data from lesioned patients and fMRI data acquired when healthy subjects perform particular cognitive tasks typically implicate a wide expanse of potentially contributing areas, rather than just a single brain area. Conversely, evidence from more targeted interventions, such as transcranial magnetic stimulation (TMS) or invasive microstimulation of the brain, or selective study of patients with highly focal brain damage, can sometimes indicate that a single brain area may make a key contribution to a particular cognitive process. But this in turn raises questions about how such a brain area may interface with other interconnected areas within a more extended network to support cognitive processes. Here, we provide a brief overview of new approaches that seek to characterise the causal role of particular brain areas within networks of several interacting areas, by measuring the effects of manipulations for a targeted area on function in remote interconnected areas. In human participants, these approaches include concurrent TMS-fMRI and TMS-EEG, as well as combination of the focal lesion method in selected patients with fMRI and/or EEG measures of the functional impact from the lesion on interconnected intact brain areas. Such approaches shed new light on how frontal cortex and parietal cortex modulate sensory areas in the service of attention and cognition, for the normal and damaged human brain. [ABSTRACT FROM AUTHOR]

Summary: Conscious perception depends not only on sensory input, but also on attention . Recent studies in monkeys and humans suggest that influences of spatial attention on visual awareness may reflect top-down influences on excitability of visual cortex. Here we tested this specifically, by providing direct input into human visual cortex via cortical transcranial magnetic stimulation (TMS) to produce illusory visual percepts, called phosphenes. We found that a lower TMS intensity was needed to elicit a conscious phosphene when its apparent spatial location was attended, rather than unattended. Our results indicate that spatial attention can enhance visual-cortex excitability, and visual awareness, even when sensory signals from the eye via the thalamic pathway are bypassed. [Copyright &y& Elsevier]

Summary: Background: Regions in human frontal cortex may have modulatory top-down influences on retinotopic visual cortex, but to date neuroimaging methods have only been able to provide indirect evidence for such functional interactions between remote but interconnected brain regions. Here we combined transcranial magnetic stimulation (TMS) with concurrent functional magnetic resonance imaging (fMRI), plus psychophysics, to show that stimulation of the right human frontal eye-field (FEF) produced a characteristic topographic pattern of activity changes in retinotopic visual areas V1-V4, with functional consequences for visual perception. Results: FEF TMS led to activity increases for retinotopic representations of the peripheral visual field, but to activity decreases for the central field, in areas V1-V4. These frontal influences on visual cortex occurred in a top-down manner, independently of visual input. TMS of a control site (vertex) did not elicit such visual modulations, and saccades, blinks, or pupil dilation could not account for our results. Finally, the effects of FEF TMS on activity in retinotopic visual cortex led to a behavioral prediction that we confirmed psychophysically by showing that TMS of the frontal site (again compared with vertex) enhanced perceived contrast for peripheral relative to central visual stimuli. Conclusions: Our results provide causal evidence that circuits originating in the human FEF can modulate activity in retinotopic visual cortex, in a manner that differentiates the central and peripheral visual field, with functional consequences for perception. More generally, our study illustrates how the new approach of concurrent TMS-fMRI can now reveal causal interactions between remote but interconnected areas of the human brain. [Copyright &y& Elsevier]