Concurrent TMS-fMRI Research Articles

EPI-based target tracking in concurrent TMS-fMRI

EPI-based target tracking in concurrent TMS-fMRI

Real-time neuronavigation feedback in concurrent TMS-fMRI

Introduction: Maintaining correct coil position is essential in transcranial magnetic stimulation (TMS). While neuronavigation and operator surveillance are available in typical therapy settings, concurrent TMS-fMRI experiments have to rely on positioning outside the MRI scanner without continuous verification throughout the session. Thus, subject motion during the TMS-fMRI experiment is usually unaccounted for and negatively affects results. Here, we present a new setup that (1) enables the use of neuronavigation inside the MRI scanner and (2) includes a real-time motion feedback system that allows subjects to correct their head positioning.

Spread of activity following TMS is related to intrinsic resting connectivity to the salience network: A concurrent TMS-fMRI study

Transcranial magnetic stimulation (TMS) modulates activity at local and regions distal to the site of simulation. TMS has also been found to modulate brain networks, and it has been hypothesized that functional connectivity may predict the neuronal changes at local and distal sites in response to a TMS pulse. However, a direct relationship between resting connectivity and change in TMS-induced brain activation has yet to be demonstrated. Concurrent TMS-fMRI is a technique to directly measure this spread activity following TMS in real time. In twenty-two participants, resting-state fMRI scans were acquired, followed by four ten minute sessions of concurrent TMS-fMRI over the left dorsolateral prefrontal cortex (DLPFC). Seed-based functional connectivity to the individualized TMS target was examined using the baseline resting fMRI scan data, and the change of activity resulting from TMS was determined using a general linear model (High vs Low intensity TMS). While at the group level the spatial pattern of resting connectivity related to the pattern of TMS-induced cortical changes, there was substantial variability across individuals. This variability was further probed by examining individual's connectivity from the TMS target to six resting state networks. Only connectivity between the salience network (SN) and the TMS target site correlated with the RSC-TMS score. This suggests that resting state connectivity is correlated with TMS-induced changes in activity following DLPFC stimulation, particularly when the DLPFC target interacts with the SN. These results highlight the importance of examining such relationships at the individual level and may help to guide individual treatment in clinical populations.

Differing Time of Onset of Concurrent TMS-fMRI during Associative Memory Encoding: A Measure of Dynamic Connectivity.

There has been a distinct shift in neuroimaging from localization of function into a more network based approach focused on connectivity. While fMRI has proven very fruitful for this, the hemodynamic signal is inherently slow which limits the temporal resolution of fMRI-only connectivity measures. The brain, however, works on a time scale of milliseconds. This study utilized concurrent transcranial magnetic stimulation (TMS)-fMRI in a novel way to obtain measures of dynamic connectivity by measuring changes in fMRI signal amplitude in regions distal to the site of stimulation following differing TMS onset times. Seventeen healthy subjects completed an associative memory encoding task known to involve the DLPFC, viewing pairs of objects which could be semantically related or unrelated. Three pulses of 10 Hz repetitive TMS were applied over the left DLPFC starting either at 200, 600, or 1000 ms after stimulus onset. Associations for related pairs were better remembered than unrelated pairs in a post-scan cued recall test. Differences in neural activity were assessed across different TMS onsets, separately for related and unrelated pairs. Time specific TMS effects were observed in several regions, including those associated with higher-level processing (lateral frontal, anterior cingulate), visual areas (occipital), and regions involved in semantic processing (e.g., left mid-temporal and medial frontal). Activity in the frontal cortex was decreased at 200 ms post-stimulus for unrelated pairs, and 1000 ms post-stimulus for related pairs. This suggests differences in the timing across conditions in which the DLFPC interacts with other PFC regions, consistent with the notion that the DLPFC is facilitating extended semantic processing for related items. This study demonstrates that time-varying TMS onset inside the MRI can be used to reliably measure fast dynamic connectivity with a temporal resolution in the hundreds of milliseconds.

947. Spread of Activity following TMS is Correlated with Intrinsic Resting Connectivity with the Target Region: A Concurrent TMS-fMRI Study

947. Spread of Activity following TMS is Correlated with Intrinsic Resting Connectivity with the Target Region: A Concurrent TMS-fMRI Study

Concurrent TMS-fMRI Reveals Interactions between Dorsal and Ventral Attentional Systems.

Adaptive behavior relies on combining bottom-up sensory inputs with top-down attentional control. Although the dorsal and ventral frontoparietal systems are key players in attentional control, their distinct contributions remain unclear. In this TMS-fMRI study, participants attended to the left visual field to detect weak visual targets presented on half of the trials. We applied brief TMS bursts (or Sham-TMS) to the dorsal intraparietal sulcus (IPS) 100 ms after visual stimulus onset. IPS-TMS abolished the visual induced response suppression in the ventral occipitotemporal cortex and the response enhancement to visual targets in the temporoparietal junction. Our results demonstrate that IPS causally influences neural activity in the ventral attentional system 100 ms poststimulus. They have important implications for our understanding of the neural mechanisms underlying attentional control.

Functional connectivity along the arcuate fasciculus investigated with concurrent TMS-fMRI

s / Brain Stimulation 8 (2015) 378e394 381 the subthalamic nucleus (STN) of 11 patients with Parkinson’s disease and in the nucleus ventralis intermedius (Vim) of two other subjects with essential tremor. At the trajectory chosen for implantation of the definitive electrode, we assessed the current threshold window between positive and side effects, defined as the therapeutic window. A computed finite element model (COMSOL) was used to compare the volume of tissue activated when one directional electrode was stimulated, or in case of omnidirectional stimulation. Results: All but one patient showed a benefit of directional stimulation compared to omnidirectional. A best direction of stimulation was observed in all the patients. The therapeutic window in the best direction was wider than the second best direction (P 1⁄4 0.003) and wider than the third best direction (P 1⁄4 0.002). Compared to omnidirectional direction, the therapeutic window in the best direction was 41.3% wider (P 1⁄4 0.037). The current threshold producing meaningful therapeutic effect in the best direction was 0.67mA (0.3e1.0 mA) and was 43% lower than in omnidirectional stimulation (P 1⁄4 0.002). No complication as a result of insertion of the directional electrode or during testing was encountered. The computed model revealed a volume of tissue activated of 10.5 mm3 in omnidirectional mode, compared with 4.2 mm3 when only one electrode was used. Conclusion: Directional deep brain stimulation with a reduced electrode size applied intraoperatively in the STN as well as in Vim significantly widened the therapeutic window and lowered the current needed for beneficial effects, compared to omnidirectional stimulation. The observed side effects related to direction of stimulation were consistent with the anatomical location of surrounding structures. This new approach opens the door to an improved deep brain stimulation therapy. Chronic implantation is further needed to confirm these findings.

Efficient and robust identification of cortical targets in concurrent TMS–fMRI experiments

Transcranial magnetic stimulation (TMS) can be delivered during fMRI scans to evoke BOLD responses in distributed brain networks. While concurrent TMS-fMRI offers a potentially powerful tool for non-invasively investigating functional human neuroanatomy, the technique is currently limited by the lack of methods to rapidly and precisely localize targeted brain regions - a reliable procedure is necessary for validly relating stimulation targets to BOLD activation patterns, especially for cortical targets outside of motor and visual regions. Here we describe a convenient and practical method for visualizing coil position (in the scanner) and identifying the cortical location of TMS targets without requiring any calibration or any particular coil-mounting device. We quantified the precision and reliability of the target position estimates by testing the marker processing procedure on data from 9 scan sessions: Rigorous testing of the localization procedure revealed minimal variability in coil and target position estimates. We validated the marker processing procedure in concurrent TMS-fMRI experiments characterizing motor network connectivity. Together, these results indicate that our efficient method accurately and reliably identifies TMS targets in the MR scanner, which can be useful during scan sessions for optimizing coil placement and also for post-scan outlier identification. Notably, this method can be used generally to identify the position and orientation of MR-compatible hardware placed near the head in the MR scanner.

On the feasibility of concurrent human TMS-EEG-fMRI measurements

Simultaneously combining the complementary assets of EEG, functional MRI (fMRI), and transcranial magnetic stimulation (TMS) within one experimental session provides synergetic results, offering insights into brain function that go beyond the scope of each method when used in isolation. The steady increase of concurrent EEG-fMRI, TMS-EEG, and TMS-fMRI studies further underlines the added value of such multimodal imaging approaches. Whereas concurrent EEG-fMRI enables monitoring of brain-wide network dynamics with high temporal and spatial resolution, the combination with TMS provides insights in causal interactions within these networks. Thus the simultaneous use of all three methods would allow studying fast, spatially accurate, and distributed causal interactions in the perturbed system and its functional relevance for intact behavior. Concurrent EEG-fMRI, TMS-EEG, and TMS-fMRI experiments are already technically challenging, and the three-way combination of TMS-EEG-fMRI might yield additional difficulties in terms of hardware strain or signal quality. The present study explored the feasibility of concurrent TMS-EEG-fMRI studies by performing safety and quality assurance tests based on phantom and human data combining existing commercially available hardware. Results revealed that combined TMS-EEG-fMRI measurements were technically feasible, safe in terms of induced temperature changes, allowed functional MRI acquisition with comparable image quality as during concurrent EEG-fMRI or TMS-fMRI, and provided artifact-free EEG before and from 300 ms after TMS pulse application. Based on these empirical findings, we discuss the conceptual benefits of this novel complementary approach to investigate the working human brain and list a number of precautions and caveats to be heeded when setting up such multimodal imaging facilities with current hardware.

A System for Concurrent TMS-fMRI and Evaluation of Imaging Effects

A System for Concurrent TMS-fMRI and Evaluation of Imaging Effects

The Role of Contralesional Dorsal Premotor Cortex after Stroke as Studied with Concurrent TMS-fMRI

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.

New approaches to the study of human brain networks underlying spatial attention and related processes

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.

Studying the Role of Human Parietal Cortex in Visuospatial Attention with Concurrent TMS-fMRI

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.

State-dependent interregional influences in the human motor system probed with concurrent TMS-fMRI

State-dependent interregional influences in the human motor system probed with concurrent TMS-fMRI

Hemispheric differences in frontal and parietal influences on human occipital cortex: direct confirmation with concurrent TMS-fMRI.

We used concurrent TMS-fMRI to test directly for hemispheric differences in causal influences of the right or left fronto-parietal cortex on activity (BOLD signal) in the human occipital cortex. Clinical data and some behavioral TMS studies have been taken to suggest right-hemisphere specialization for top-down modulation of vision in humans, based on deficits such as spatial neglect or extinction in lesioned patients, or findings that TMS to right (vs. left) fronto-parietal structures can elicit stronger effects on visual performance. But prior to the recent advent of concurrent TMS and neuroimaging, it was not possible to directly examine the causal impact of one (stimulated) brain region upon others in humans. Here we stimulated the frontal or intraparietal cortex in the left or right hemisphere with TMS, inside an MR scanner, while measuring with fMRI any resulting BOLD signal changes in visual areas V1-V4 and V5/MT+. For both frontal and parietal stimulation, we found clear differences between effects of right- versus left-hemisphere TMS on activity in the visual cortex, with all differences significant in direct statistical comparisons. Frontal TMS over either hemisphere elicited similar BOLD decreases for central visual field representations in V1-V4, but only right frontal TMS led to BOLD increases for peripheral field representations in these regions. Hemispheric differences for effects of parietal TMS were even more marked: Right parietal TMS led to strong BOLD changes in V1-V4 and V5/MT+, but left parietal TMS did not. These data directly confirm that the human frontal and parietal cortex show right-hemisphere specialization for causal influences on the visual cortex.

Stimulus-Response Profile during Single-Pulse Transcranial Magnetic Stimulation to the Primary Motor Cortex

We examined the stimulus-response profile during single-pulse transcranial magnetic stimulation (TMS) by measuring motor-evoked potentials (MEPs) with electromyographic monitoring and hemodynamic responses with functional magnetic resonance imaging (fMRI) at 3 Tesla. In 16 healthy subjects, single TMS pulses were irregularly delivered to the left primary motor cortex at a mean frequency of 0.15 Hz with a wide range of stimulus intensities. The measurement of MEP proved a typical relationship between stimulus intensity and MEP amplitude in the concurrent TMS-fMRI environment. In the population-level analysis of the suprathreshold stimulation conditions, significant increases in hemodynamic responses were detected in the motor/somatosensory network, reflecting both direct and remote effects of TMS, and also the auditory/cognitive areas, perhaps related to detection of clicks. The stimulus-response profile showed both linear and nonlinear components in the direct and remote motor/somatosensory network. A detailed analysis suggested that the nonlinear components of the motor/somatosensory network activity might be induced by nonlinear recruitment of neurons in addition to sensory afferents resulting from movement. These findings expand our basic knowledge of the quantitative relationship between TMS-induced neural activations and hemodynamic signals measured by neuroimaging techniques.

Mapping causal interregional influences with concurrent TMS–fMRI

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.

Distinct Causal Influences of Parietal Versus Frontal Areas on Human Visual Cortex: Evidence from Concurrent TMS-fMRI

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.

Concurrent TMS-fMRI and Psychophysics Reveal Frontal Influences on Human Retinotopic Visual Cortex

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. 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. 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.

Cortical correlates of TMS-induced phantom hand movements revealed with concurrent TMS-fMRI

We studied an amputee patient who experiences a conscious sense of movement (SoM) in her phantom hand, without significant activity in remaining muscles, when transcranial magnetic stimulation (TMS) is applied at appropriate intensity over the corresponding sector of contralateral motor cortex. We used the novel methodological combination of TMS during fMRI to reveal the neural correlates of her phantom SoM. A critical contrast concerned trials at intermediate TMS intensities: low enough not to produce overt activity in remaining muscles; but high enough to produce a phantom SoM on approximately half such trials. Comparing trials with versus without a phantom SoM reported phenomenally, for the same intermediate TMS intensities, factored out any non-specific TMS effects on brain activity to reveal neural correlates of the phantom SoM itself. Areas activated included primary motor cortex, dorsal premotor cortex, anterior intraparietal sulcus, and caudal supplementary motor area, regions that are also involved in some hand movement illusions and motor imagery in normals. This adds support to proposals that a conscious sense of movement for the hand can be conveyed by activity within corresponding motor-related cortical structures.