Search

The simultaneous combination of TMS with fMRI has emerged as a promising means to investigate the direct interaction between stimulation-induced changes at the behavioral and neural activity level. This enables the investigation of whole brain neurobehavioral interactions underlying cognitive disruption or facilitation. Yet to date, the literature on interleaved TMS-fMRI in cognitive neuroscience is sparse and neuromodulatory patterns of different TMS protocols are still poorly understood. Here, we synthesize interleaved TMS-fMRI studies on the relationship between direct stimulation-induced changes on task related neural activity and behavior. The following main findings are discussed. First, approximately half of the studies report a relationship between neural activity and behavioral changes as a marker for network excitation or inhibition. Secondly, task difficulty and stimulation timing are crucial factors that impact the interaction between neural activity changes and behavior. Third, stimulation-induced changes in remote, connected areas seem to be stronger associated with facilitation effects at the behavioral level. A better understanding of the relationship between stimulation-induced changes at the neural and behavioral level will increase the current understanding of the neuromodulatory potential of TMS at different levels and may help to develop more efficient stimulation protocols for basic and applied research.

Hierarchical syntactic structure processing is proposed to be at the core of the human language faculty. Syntactic processing is supported by the left fronto-temporal language network, including a core area in the inferior frontal gyrus as well as its interaction with the posterior temporal lobe (i.e., “IFG + pTL”). Moreover, during complex syntactic processes, left IFG also interacts with executive control regions, such as the superior parietal lobule (SPL). However, the functional relevance of these network interactions is largely unclear. In particular, it remains to be demonstrated whether the language network plays a specific causal role in comparatively challenging syntactic processes, separable from the interaction between IFG and other general cognitive regions (i.e., “IFG + SPL” in the present study). The present study was designed to address this question. Thirty healthy adult Chinese native speakers underwent four continuous theta-burst stimulation (cTBS) sessions: stimulation over IFG, stimulation over IFG + pTL, stimulation over IFG + SPL, and sham stimulation over IFG + irrelevant region in a pseudo-randomized order. In each session, participants were required to label the syntactic categories of jabberwocky sequences retaining real Chinese function words (e.g., “ム了ウ” is labeled as a verb phrase (VP): “[VP [V了]N]”, similar to “ziff-ed a wug”, where “ziff” and “wug” are nonsense pseudowords, and the whole phrase is a VP). Contrasted with sham cTBS, change percentage of accuracy rates (ΔACCR%), reaction times (ΔRT%), and coefficient of variation (ΔCV%) were calculated and compared across conditions. First-order behavioral results showed a significantly higher ΔCV% after stimulating IFG + pTL compared to stimulating the IFG + SPL, indicating that syntactic processing became more unstable. Second-order representational similarity analysis (RSA) results revealed that cTBS effects on IFG + pTL selectively depended on the hierarchical embedding depth, a key measure of syntactic hierarchical complexity, whereas the effects on IFG + SPL were sensitive to the dependency length, a crucial index reflecting the working memory load. Collectively, these findings reveal the specific causal relevance of the language areas for hierarchical syntactic processing, separable from other general cognitive (such as working memory) capacities. These results shed light on the uniqueness and the specific causal role of the language network for the human language faculty, further supporting the causally separable view of the functional dissociation between the language network and the domain-general/multiple-demand network.

The human brain comprises large-scale networks that flexibly interact to support diverse cognitive functions and adapt to variability in daily life. The inferior parietal lobe (IPL) is a hub of multiple brain networks that sustain various cognitive domains. It remains unclear how networks respond to acute regional perturbations to maintain normal function. To provoke network-level adaptive responses to local inhibition, we combined offline transcranial magnetic stimulation (TMS) over left or right IPL with neuroimaging during attention, semantic and social cognition tasks, and rest. Across tasks, TMS specifically affected task-active network activity with inhibition and facilitation. Network interaction responses differed between rest and tasks. After TMS over both IPL regions, large-scale network interactions were exclusively facilitated at rest, but mainly inhibited during tasks. Overall, responses to TMS primarily occurred in and between domain-general default mode and frontoparietal subnetworks. These findings elucidate short-term adaptive plasticity in response to network node inhibition.

Transcranial direct current stimulation (tDCS) has been studied extensively for its potential to enhance human cognitive functions in healthy individuals and to treat cognitive impairment in various clinical populations. However, little is known about how tDCS modulates the neural networks supporting cognition and the complex interplay with mediating factors that may explain the frequently observed variability of stimulation effects within and between studies. Moreover, research in this field has been characterized by substantial methodological variability, frequent lack of rigorous experimental control and small sample sizes, thereby limiting the generalizability of findings and translational potential of tDCS. The present manuscript aims to delineate how these important issues can be addressed within a neuroimaging context, to reveal the neural underpinnings, predictors and mediators of tDCS-induced behavioral modulation. We will focus on functional magnetic resonance imaging (fMRI), because it allows the investigation of tDCS effects with excellent spatial precision and sufficient temporal resolution across the entire brain. Moreover, high resolution structural imaging data can be acquired for precise localization of stimulation effects, verification of electrode positions on the scalp and realistic current modeling based on individual head and brain anatomy. However, the general principles outlined in this review will also be applicable to other imaging modalities. Following an introduction to the overall state-of-the-art in this field, we will discuss in more detail the underlying causes of variability in previous tDCS studies. Moreover, we will elaborate on design considerations for tDCS-fMRI studies, optimization of tDCS and imaging protocols and how to assure high-level experimental control. Two additional sections address the pressing need for more systematic investigation of tDCS effects across the healthy human lifespan and implications for tDCS studies in age-associated disease, and potential benefits of establishing large-scale, multidisciplinary consortia for more coordinated tDCS research in the future. We hope that this review will contribute to more coordinated, methodologically sound, transparent and reproducible research in this field. Ultimately, our aim is to facilitate a better understanding of the underlying mechanisms by which tDCS modulates human cognitive functions and more effective and individually tailored translational and clinical applications of this technique in the future.

Abstract Dyslexia, a frequent learning disorder, is characterized by severe impairments in reading and writing and hypoactivation in reading regions in the left hemisphere. Despite decades of research, it remains unclear to date if observed behavioural deficits are caused by aberrant network interactions during reading and whether differences in functional activation and connectivity are directly related to reading performance. Here we provide a comprehensive characterization of reading-related brain connectivity in adults with and without dyslexia. We find disrupted functional coupling between hypoactive reading regions, especially between the left temporo-parietal and occipito-temporal cortices, and an extensive functional disruption of the right cerebellum in adults with dyslexia. Network analyses suggest that individuals with dyslexia process written stimuli via a dorsal decoding route and show stronger reading-related interaction with the right cerebellum. Moreover, increased connectivity within networks is linked to worse reading performance in dyslexia. Collectively, our results provide strong evidence for aberrant task-related connectivity as a neural marker for dyslexia that directly impacts behavioural performance. The observed differences in activation and connectivity suggest that one effective way to alleviate reading problems in dyslexia is through modulating interactions within the reading network with neurostimulation methods.

Background: The continuous decline of executive abilities with age is mirrored by increased neural activity of domain-general networks during task processing. So far, it remains unclear how much domain-general networks contribute to domain-specific processes such as language when cognitive demands increase. The current neuroimaging study explored the potential of intermittent theta-burst stimulation (iTBS) over a domain-general hub to enhance executive and semantic processing in healthy middle-aged to older adults. Methods: We implemented a cross-over within-subject study design with three task-based neuroimaging sessions per participant. Using an individualized stimulation approach, each participant received once effective and once sham iTBS over the pre-supplementary motor area (pre-SMA), a region of domain-general control. Subsequently, task-specific stimulation effects were assessed in functional MRI using a semantic and a non-verbal executive task with varying cognitive demand. Results: Effective stimulation increased activity only during semantic processing in visual and dorsal attention networks. Further, iTBS induced increased seed-based connectivity in task-specific networks for semantic and executive conditions with high cognitive load but overall reduced whole-brain coupling between domain-general networks. Notably, stimulation-induced changes in activity and connectivity related differently to behavior: While stronger activity of the parietal dorsal attention network was linked to poorer semantic performance, its enhanced coupling with the pre-SMA was associated with more efficient semantic processing. Conclusions: iTBS modulates networks in a task-dependent manner and generates effects at regions remote to the stimulation site. These neural changes are linked to more efficient semantic processing, which underlines the general potential of network stimulation approaches in cognitive aging.

Abstract Stopping an already initiated action is crucial for human everyday behavior and empirical evidence points toward the prefrontal cortex playing a key role in response inhibition. Two regions that have been consistently implicated in response inhibition are the right inferior frontal gyrus (IFG) and the more superior region of the dorsolateral prefrontal cortex (DLPFC). The present study investigated the effect of offline 1 Hz transcranial magnetic stimulation (TMS) over the right IFG and DLPFC on performance in a gamified stop-signal task (SSG). We hypothesized that perturbing each area would decrease performance in the SSG, albeit with a quantitative difference in the performance decrease after stimulation. After offline TMS, functional short-term reorganization is possible, and the domain-general area (i.e., the right DLPFC) might be able to compensate for the perturbation of the domain-specific area (i.e., the right IFG). Results showed that 1 Hz offline TMS over the right DLPFC and the right IFG at 110% intensity of the resting motor threshold had no effect on performance in the SSG. In fact, evidence in favor of the null hypothesis was found. One intriguing interpretation of this result is that within-network compensation was triggered, canceling out the potential TMS effects as has been suggested in recent theorizing on TMS effects, although the presented results do not unambiguously identify such compensatory mechanisms. Future studies may result in further support for this hypothesis, which is especially important when studying reactive response in complex environments.

Bayesian modeling of anatomical lesion patterns and clinical language outcomes in a cohort of 1401 stroke patients identifies sex-biased lesion-outcome effects after stroke.

Objective: The goal of awake craniotomy in glioma patients is sparing of cognitive function. Previous investigations suggest that patients in the postoperative state may reach their preoperative level regarding domain-based criteria. Data on significant postoperative improvement beyond the preoperative level is sparse. This article examines the prospective neuropsychological assessment of a glioma patient who underwent awake craniotomy and has shown functional improvement exceeding preoperative levels. Methods: A 34-year-old patient with high premorbid cognitive function level who underwent awake craniotomy for left frontal oligodendroglioma was neuropsychologically assessed and took part in a fMRI-examination at 3 different time points. Results: Preoperative examination revealed severe isolated impairment of working memory, long-term narrative memory in free recall and recognition, and alertness with intact language production and comprehension. After transient global aphasia in the postoperative state, the follow-up examination showed significant improvement in memory and attention exceeding the preoperative level. Conclusions: Tumor location is an important factor in terms of surgical procedures. Cognitive impairment is, however, not always associated with a specific location. Mechanical pressure of the tumor might have led to the isolated consolidation deficit which fully recovered after tumor removal. Psychological disorders should be taken into account regarding prodromal symptoms of neurooncological diseases.

Language is organized in large-scale networks in the human brain that show a strong potential for flexible interactions and adaptation. Neuroplasticity is the central mechanism that allows such dynamic modulation to changing conditions across the life span and is particularly important for network reorganization after brain lesions. Most studies on language reorganization focused on language recovery after stroke. Yet, a strong degree of adaptive neuroplasticity can also be observed in patients with brain tumors in language-eloquent brain areas.This review discusses key mechanisms for neural reorganization in patients with brain tumors. Our main aim is to elucidate the underlying mechanisms for intra- and interhemispheric plasticity in the language network in these patients. The following reorganization patterns are discussed: 1) Persisting function within the tumor; 2) Reorganization in perilesional regions; 3) Reorganization in a distributed network of the affected hemisphere; 4) Reorganization to the contralesional hemisphere.In this context, we shed light on language-related reorganization patterns in frontal and temporo-parietal areas and discuss their functional relevance. We also address tumor-related changes in structural and functional connectivity between eloquent brain regions. Thereby, we aim to expand the general understanding of the plastic potential of the neural language network and facilitate clinical decision-making processes for effective, function-preserving tumor treatment.

The neuroanatomical correlates of basic semantic composition have been investigated in previous neuroimaging and lesion studies, but research on the electrophysiology of the involved processes is scarce. A large literature on sentence-level event-related potentials (ERPs) during semantic processing has identified at least two relevant components – the N400 and the P600. Other studies demonstrated that these components are reduced and/or delayed in people with aphasia (PWA). However, it remains to be shown if these findings generalize beyond the sentence level. Specifically, it is an open question if an alteration in ERP responses in PWA can also be observed during basic semantic composition, providing a potential future diagnostic tool.The present study aimed to elucidate the electrophysiological dynamics of basic semantic composition in a group of post-stroke PWA. We included 20 PWA and 20 age-matched controls (mean age 58 years) and measured ERP responses while they performed a plausibility judgment task on two-word phrases that were either meaningful (“anxious horse”), anomalous (“anxious wood”) or had the noun replaced by a pseudoword (“anxious gufel”).The N400 effect for anomalous versus meaningful phrases was similar in both groups. In contrast, unlike the control group, PWA did not show an N400 effect between pseudoword and meaningful phrases. Moreover, both groups exhibited a parietal P600 effect towards pseudoword phrases, while PWA showed an additional P600 over frontal electrodes. Finally, PWA showed an inverse correlation between the magnitude of the N400 and P600 effects: PWA exhibiting no or even reversed N400 effects towards anomalous and pseudoword phrases showed a stronger P600 effect. These results may reflect a compensatory mechanism which allows PWA to arrive at the correct interpretation of the phrase. When compositional processing capacities are impaired in the early N400 time-window, PWA may make use of a more elaborate re-analysis process reflected in the P600.

BackgroundThe causal relationships between neural substrates and human language have been investigated by transcranial magnetic stimulation (TMS). However, the robustness of TMS neuromodulatory effects is still largely unspecified. This study aims to systematically examine the efficacy of TMS on healthy participants’ language performance.MethodsFor this meta-analysis, we searched PubMed, Web of Science, PsycINFO, Scopus, and Google Scholar from database inception until October 15, 2022 for eligible TMS studies on language comprehension and production in healthy adults published in English. The quality of the included studies was assessed with the Cochrane risk of bias tool. Potential publication biases were assessed by funnel plots and the Egger Test. We conducted overall as well as moderator meta-analyses. Effect sizes were estimated using Hedges’g (g) and entered into a three-level random effects model.ResultsThirty-seven studies (797 participants) with 77 effect sizes were included. The three-level random effects model revealed significant overall TMS effects on language performance in healthy participants (RT: g = 0.16, 95% CI: 0.04–0.29; ACC: g = 0.14, 95% CI: 0.04–0.24). Further moderator analyses indicated that (a) for language tasks, TMS induced significant neuromodulatory effects on semantic and phonological tasks, but didn’t show significance for syntactic tasks; (b) for cortical targets, TMS effects were not significant in left frontal, temporal or parietal regions, but were marginally significant in the inferior frontal gyrus in a finer-scale analysis; (c) for stimulation parameters, stimulation sites extracted from previous studies, rTMS, and intensities calibrated to the individual resting motor threshold are more prone to induce robust TMS effects. As for stimulation frequencies and timing, both high and low frequencies, online and offline stimulation elicited significant effects; (d) for experimental designs, studies adopting sham TMS or no TMS as the control condition and within-subject design obtained more significant effects.DiscussionOverall, the results show that TMS may robustly modulate healthy adults’ language performance and scrutinize the brain-and-language relation in a profound fashion. However, due to limited sample size and constraints in the current meta-analysis approach, analyses at a more comprehensive level were not conducted and results need to be confirmed by future studies.Systematic review registration[https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=366481], identifier [CRD42022366481].

Categorical predictions have been proposed as the key mechanism supporting the fast pace of syntactic composition in language. Accordingly, grammar-based expectations are formed—e.g., the determiner “a” triggers the prediction for a noun—and facilitate the analysis of incoming syntactic information, which is then checked against a single or few other word categories. Previous functional neuroimaging studies point towards Broca’s area in the left inferior frontal gyrus (IFG) as one fundamental cortical region involved in categorical prediction during incremental language processing. Causal evidence for this hypothesis is however still missing. In this study, we combined Electroencephalography (EEG) and Transcranial Magnetic Stimulation (TMS) to test whether Broca’s area is functionally relevant in predictive mechanisms for language. We transiently perturbed Broca’s area during the first word in a two-word construction, while simultaneously measuring the Event-Related Potential (ERP) correlates of syntactic composition. We reasoned that if Broca’s area is involved in predictive mechanisms for syntax, disruptive TMS during the first word would mitigate the difference in the ERP responses for predicted and unpredicted categories in basic two-word constructions. Contrary to this hypothesis, perturbation of Broca’s area at the predictive stage did not affect the ERP correlates of basic composition. The correlation strength between the electrical field induced by TMS and the ERP responses further confirmed this pattern. We discuss the present results considering an alternative account of the role of Broca’s area in syntactic composition, namely the bottom-up integration of words into constituents, and of compensatory mechanisms within the language predictive network.

Background: The COVID-19 pandemic has broadly disrupted biomedical treatment and research including non-invasive brain stimulation (NIBS). Moreover, the rapid onset of societal disruption and evolving regulatory restrictions may not have allowed for systematic planning of how clinical and research work may continue throughout the pandemic or be restarted as restrictions are abated. The urgency to provide and develop NIBS as an intervention for diverse neurological and mental health indications, and as a catalyst of fundamental brain research, is not dampened by the parallel efforts to address the most life-threatening aspects of COVID-19; rather in many cases the need for NIBS is heightened including the potential to mitigate mental health consequences related to COVID-19. Objective: To facilitate the re-establishment of access to NIBS clinical services and research operations during the current COVID-19 pandemic and possible future outbreaks, we develop and discuss a framework for balancing the importance of NIBS operations with safety considerations, while addressing the needs of all stakeholders. We focus on Transcranial Magnetic Stimulation (TMS) and low intensity transcranial Electrical Stimulation (tES) - including transcranial Direct Current Stimulation (tDCS) and transcranial Alternating Current Stimulation (tACS). Methods: The present consensus paper provides guidelines and good practices for managing and reopening NIBS clinics and laboratories through the immediate and ongoing stages of COVID-19. The document reflects the analysis of experts with domain-relevant expertise spanning NIBS technology, clinical services, and basic and clinical research – with an international perspective. We outline regulatory aspects, human resources, NIBS optimization, as well as accommodations for specific demographics. Results: A model based on three phases (early COVID-19 impact, current practices, and future preparation) with an 11-step checklist (spanning removing or streamlining in-person protocols, incorporating telemedicine, and addressing COVID-19-associated adverse events) is proposed. Recommendations on implementing social distancing and sterilization of NIBS related equipment, specific considerations of COVID-19 positive populations including mental health comorbidities, as well as considerations regarding regulatory and human resource in the era of COVID-19 are outlined. We discuss COVID-19 considerations specifically for clinical (sub-)populations including pediatric, stroke, addiction, and the elderly. Numerous case-examples across the world are described. Conclusion: There is an evident, and in cases urgent, need to maintain NIBS operations through the COVID-19 pandemic, including anticipating future pandemic waves and addressing effects of COVID-19 on brain and mind. The proposed robust and structured strategy aims to address the current and anticipated future challenges while maintaining scientific rigor and managing risk.

Diaschisis is a phenomenon observed in stroke that is defined as neuronal dysfunction in regions spared by the infarction but connected to the lesion site.We combined lesion network mapping and task-based functional MRI in 71 patients with post-stroke aphasia to investigate, whether diaschisis and its resolution contribute to early loss and recovery of language functions. Language activation acquired in the acute, subacute and chronic phase was analyzed in compartments with high and low normative resting-state functional connectivity to the lesion site on an individual basis.Regions with high compared to regions with low lesion connectivity showed a steeper increase in language reactivation from the acute to the subacute phase. This finding is compatible with the assumption of resolution of diaschisis. Additionally, language performance in the subacute phase and improvement from the subacute to the chronic phase significantly correlated with the diaschisis effect and its resolution, respectively, suggesting a behavioral relevance of this effect.We therefore assume that undamaged but functionally connected regions become dysfunctional due to missing input from the lesion contributing to the aphasic deficit. Since these regions are structurally intact, dysfunction resolves over time contributing to the rapid early behavioral improvement observed in aphasic stroke patients. Our results demonstrate that diaschisis and its resolution might be a relevant mechanism of early loss and recovery of language function in acute stroke patients.

The cerebellum and its interaction with cortical areas play a key role in our ability to flexibly adapt a motor program in response to sensory input. Current knowledge about specific neural mechanisms underlying the process of visuomotor adaptation is however lacking. Using a novel placement of EEG electrodes to record electric activity from the cerebellum, we studied local cerebellar activity, as well as its coupling with neocortical activity to obtain direct neurophysiological markers of visuomotor adaptation in humans. We found increased theta (4–8 Hz) power in “cerebellar” as well as cortical electrodes, when subjects first encountered a visual manipulation. Theta power decreased as subjects adapted to the perturbation, and rebounded when the manipulation was suddenly removed. This effect was observed in two distinct locations: a cerebellar cluster and a central cluster, which were localized in left cerebellar crus I (lCB) and right supplementary motor area (rSMA) using linear constrained minimum variance beamforming. Importantly, we found that better adaptation was associated with increased theta power in left cerebellar electrodes and a right sensorimotor cortex electrode. Finally, increased rSMA -> lCB connectivity was significantly decreased with adaptation. These results demonstrate that: (1) cerebellar theta power is markedly modulated over the course of visuomotor adaptation and (2) theta oscillations could serve as a key mechanism for communication within a cortico-cerebellar loop.

Language is a cognitive function that is asymmetrically distributed across both hemispheres, with left dominance for most linguistic operations. One key question of interest in cognitive neuroscience studies is related to the contribution of both hemispheres in bilingualism. Previous work shows a difference of both hemispheres for auditory processing of emotional and non-emotional words in bilinguals and monolinguals. In this study, we examined the differences between both hemispheres in the processing of emotional and non-emotional words of mother tongue language and foreign language. Sixty university students with Persian mother tongue and English as their second language were included. Differences between hemispheres were compared using the dichotic listening test. We tested the effect of hemisphere, language and emotion and their interaction. The right ear (associated with the left hemisphere) showed an advantage for the processing of all words in the first language, and positive words in the second language. Overall, our findings support previous studies reporting left-hemispheric dominance in late bilinguals for processing auditory stimuli.

Transcranial magnetic stimulation (TMS) is a powerful tool to investigate causal structure-function relationships in the human brain. However, a precise delineation of the effectively stimulated neuronal populations is notoriously impeded by the widespread and complex distribution of the induced electric field.Here, we propose a method that allows rapid and feasible cortical localization at the individual subject level. The functional relationship between electric field and behavioral effect is quantified by combining experimental data with numerically modeled fields to identify the cortical origin of the modulated effect. Motor evoked potentials (MEPs) from three finger muscles were recorded for a set of random stimulations around the primary motor area. All induced electric fields were nonlinearly regressed against the elicited MEPs to identify their cortical origin.We could distinguish cortical muscle representation with high spatial resolution and localized them primarily on the crowns and rims of the precentral gyrus. A post-hoc analysis revealed exponential convergence of the method with the number of stimulations, yielding a minimum of about 180 random stimulations to obtain stable results.Establishing a functional link between the modulated effect and the underlying mode of action, the induced electric field, is a fundamental step to fully exploit the potential of TMS. In contrast to previous approaches, the presented protocol is particularly easy to implement, fast to apply, and very robust due to the random coil positioning and therefore is suitable for practical and clinical applications.

The inferior parietal lobe (IPL) is a key neural substrate underlying diverse mental processes, from basic attention to language and social cognition, that define human interactions. Its putative domain-global role appears to tie into poorly understood differences between cognitive domains in both hemispheres. Across attentional, semantic, and social cognitive tasks, our study explored functional specialization within the IPL. The task specificity of IPL subregion activity was substantiated by distinct predictive signatures identified by multivariate pattern-learning algorithms. Moreover, the left and right IPL exerted domain-specific modulation of effective connectivity among their subregions. Task-evoked functional interactions of the anterior and posterior IPL subregions involved recruitment of distributed cortical partners. While anterior IPL subregions were engaged in strongly lateralized coupling links, both posterior subregions showed more symmetric coupling patterns across hemispheres. Our collective results shed light on how under-appreciated hemispheric specialization in the IPL supports some of the most distinctive human mental capacities.

Motor and cognitive functions are organized in large-scale networks in the human brain that interact to enable flexible adaptation of information exchange to ever-changing environmental conditions. In this review, we discuss the unique potential of the consecutive combination of repetitive transcranial magnetic stimulation (rTMS) and functional neuroimaging to probe network organization and reorganization in the healthy and lesioned brain. First, we summarize findings highlighting the flexible (re-)distribution and short-term reorganization in motor and cognitive networks in the healthy brain. Plastic after-effects of rTMS result in large-scale changes on the network level affecting both local and remote activity within the stimulated network as well as interactions between the stimulated and distinct functional networks. While the number of combined rTMS-fMRI studies in patients with brain lesions remains scarce, preliminary evidence suggests that the lesioned brain flexibly (re-)distributes its computational capacities to functionally reorganize impaired brain functions, using a similar set of mechanisms to achieve adaptive network plasticity compared to short-term reorganization observed in the healthy brain after rTMS. In general, both short-term reorganization in the healthy brain and stroke-induced reorganization seem to rely on three general mechanisms of adaptive network plasticity that allow to maintain and recover function: i) interhemispheric changes, including increased contribution of homologous regions in the contralateral hemisphere and increased interhemispheric connectivity, ii) increased interactions between differentially specialized networks and iii) increased contributions of domain-general networks after disruption of more specific functions. These mechanisms may allow for computational flexibility of large-scale neural networks underlying motor and cognitive functions. Future studies should use complementary approaches to address the functional relevance of adaptive network plasticity and further delineate how these general mechanisms interact to enable network flexibility. Besides furthering our neurophysiological insights into brain network interactions, identifying approaches to support and enhance adaptive network plasticity may result in clinically relevant diagnostic and treatment approaches.

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

Conceptual knowledge is central to human cognition. The left posterior inferior parietal lobe (pIPL) is implicated by neuroimaging studies as a multimodal hub representing conceptual knowledge related to various perceptual–motor modalities. However, the causal role of left pIPL in conceptual processing remains unclear. Here, we transiently disrupted left pIPL function with transcranial magnetic stimulation (TMS) to probe its causal relevance for the retrieval of action and sound knowledge. We compared effective TMS over left pIPL with sham TMS, while healthy participants performed three different tasks—lexical decision, action judgment, and sound judgment—on words with a high or low association to actions and sounds. We found that pIPL-TMS selectively impaired action judgments on low sound–low action words. For the first time, we directly related computational simulations of the TMS-induced electrical field to behavioral performance, which revealed that stronger stimulation of left pIPL is associated with worse performance for action but not sound judgments. These results indicate that left pIPL causally supports conceptual processing when action knowledge is task-relevant and cannot be compensated by sound knowledge. Our findings suggest that left pIPL is specialized for the retrieval of action knowledge, challenging the view of left pIPL as a multimodal conceptual hub.

Despite the widespread use of transcranial magnetic stimulation (TMS), the precise cortical locations underlying the resulting physiological and behavioral effects are still only coarsely known. To date, mapping strategies have relied on projection approaches (often termed “center of gravity” approaches) or maximum electric field value evaluation, and therefore localize the stimulated cortical site only approximately and indirectly. Focusing on the motor cortex, we present and validate a novel method to reliably determine the effectively stimulated cortical site at the individual subject level. The approach combines measurements of motor evoked potentials (MEPs) at different coil positions and orientations with numerical modeling of induced electric fields. We identify sharply bounded cortical areas, around the gyral crowns and rims of the motor hand area, as the origin of MEPs and show that the magnitude of the tangential component and the overall magnitude of the electric field are most relevant for the observed effect. To validate our approach, we identified the coil location and orientation that produces the maximal electric field at the predicted stimulation site, and then experimentally show that this location produces MEPs more efficiently than other tested locations/orientations. Moreover, we used extensive uncertainty and sensitivity analyses to verify the robustness of the method and identify the most critical model parameters. Our generic approach improves the localization of the cortical area effectively stimulated by TMS and may be transferred to other modalities such as language mapping.

The left inferior frontal gyrus (IFG) is a key region for language comprehension and production. Previous studies point to a preferential involvement of left anterior IFG (aIFG) in lexical and semantic processes, while the posterior IFG (pIFG) has been implicated in supporting syntactic and phonological processes. Here we used focal neuronavigated transcranial magnetic stimulation (TMS) to probe the functional involvement of left IFG in lexical and grammatical processing at the sentence level. We applied 10 Hz TMS effective or sham bursts to left aIFG and pIFG, while healthy volunteers performed an adjective-noun production task contrasting grammatical and lexical determiners. For each trial, we measured the time from the stimulus onset to the moment of articulation (response time) and the time from articulation onset to the end of articulation (duration). Focal TMS of IFG generally delayed response times. The TMS-induced delay in response times was relatively stronger for the grammatical condition compared to the lexical condition, when TMS targeted aIFG. Articulation of the determiner was generally shorter in trials presenting grammatical determiners relative to lexical determiners. The shorter articulation time for grammar determiners was facilitated by effective TMS to pIFG. Together, the effects of TMS on task performance provide novel evidence for a joint involvement of anterior and posterior parts of left IFG in implementing grammatical determiners during language production, suggesting an involvement of aIFG in the initiation and pIFG in the production of grammatically appropriate verbal responses at the sentence level.

Language is sustained by large-scale networks in the human brain. Stroke often severely affects function and network dynamics. However, the adaptive potential of the brain to compensate for lesions is poorly understood. A key question is whether upregulation of the right hemisphere is adaptive for language recovery. Targeting the potential for short-term reorganization in the lesioned brain, we applied 'virtual lesions' over left anterior or posterior inferior frontal gyrus (IFG) in post-stroke patients with left temporo-parietal lesions prior to functional neuroimaging. Perturbation of the posterior IFG selectively delayed phonological decisions and decreased phonological activity. The individual response delay was correlated with the upregulation of the lesion homologue, likely reflecting compensation. Moreover, stronger individual tract integrity of the right superior longitudinal fascicle was associated with lesser disruption. Our results provide evidence for functional and structural underpinnings of plasticity in the lesioned language network, and a compensatory role of the right hemisphere.

Word-production theories argue that during language production, a concept activates multiple lexical candidates in left temporal cortex, and the intended word is selected from this set. Evidence for theories on spoken-word production comes, for example, from the picture-word interference task, where participants name pictures superimposed by congruent (e.g., picture: rabbit, distractor "rabbit"), categorically related (e.g., distractor "sheep"), or unrelated (e.g., distractor "fork") words. Typically, whereas congruent distractors facilitate naming, related distractors slow down picture naming relative to unrelated distractors, resulting in semantic interference. However, the neural correlates of semantic interference are debated. Previous neuroimaging studies have shown that the left mid-to-posterior STG (pSTG) is involved in the interference associated with semantically related distractors. To probe the functional relevance of this area, we targeted the left pSTG with focal repetitive transcranial magnetic stimulation (rTMS) while subjects performed a picture-word interference task. Unexpectedly, pSTG stimulation did not affect the semantic interference effect but selectively increased the congruency effect (i.e., faster naming with congruent distractors). The facilitatory TMS effect selectively occurred in the more difficult list with an overall lower name agreement. Our study adds new evidence to the causal role of the left pSTG in the interaction between picture and distractor representations or processing streams, only partly supporting previous neuroimaging studies. Moreover, the observed unexpected condition-specific facilitatory rTMS effect argues for an interaction of the task- or stimulus-induced brain state with the modulatory TMS effect. These issues should be systematically addressed in future rTMS studies on language production.

The adaptive potential of the language network to compensate for lesions remains elusive. We show that perturbation of a semantic region in the healthy brain induced suppression of activity in a large semantic network and upregulation of neighbouring phonological areas. After perturbation, the disrupted area increased its inhibitory influence on another semantic key node. The inhibitory influence predicted the individual delay in response speed, indicating that inhibition at remote nodes is functionally relevant. Individual disruption predicted the upregulation of semantic activity in phonological regions. In contrast, perturbation over a phonological region suppressed activity in the network and disrupted behaviour without inducing upregulation. The beneficial contribution of a neighbouring network might thus depend on the level of functional disruption and may be interpreted to reflect a differential compensatory potential of distinct language networks. These results might reveal generic mechanisms of plasticity in cognitive networks and inform models of language reorganization.

Semantic cognition, i.e. processing of meaning is based on semantic representations and their controlled retrieval. Semantic control has been shown to be implemented in a network that consists of left inferior frontal (IFG), and anterior and posterior middle temporal gyri (a/pMTG). We aimed to disrupt semantic control processes with continuous theta burst stimulation (cTBS) over left IFG and pMTG and to study whether behavioral effects are moderated by induced alterations in resting-state functional connectivity. To this end, we applied real cTBS over left IFG and left pMTG as well as sham stimulation on 20 healthy participants in a within-subject design. Stimulation was followed by resting-state functional magnetic resonance imaging and a semantic priming paradigm. Resting-state functional connectivity of regions of interest in left IFG, pMTG and aMTG revealed highly interconnected left-lateralized fronto-temporal networks representing the semantic system. We did not find any significant direct modulation of either task performance or resting-state functional connectivity by effective cTBS. However, after sham cTBS, functional connectivity between IFG and pMTG correlated with task performance under high semantic control demands in the semantic priming paradigm. These findings provide evidence for the functional relevance of interactions between IFG and pMTG for semantic control processes. This interaction was functionally less relevant after cTBS over aIFG which might be interpretable in terms of an indirect disruptive effect of cTBS.

Sensitivity to regularities plays a crucial role in the acquisition of various linguistic features from spoken language input. Artificial grammar (AG) learning paradigms explore pattern recognition abilities in a set of structured sequences (i.e. of syllables or letters). In the present study, we investigated the functional underpinnings of learning phonological regularities in auditorily presented syllable sequences. While previous neuroimaging studies either focused on functional differences between the processing of correct vs. incorrect sequences or between different levels of sequence complexity, here the focus is on the neural foundation of the actual learning success. During functional magnetic resonance imaging (fMRI), participants were exposed to a set of syllable sequences with an underlying phonological rule system, known to ensure performance differences between participants. We expected that successful learning and rule application would require phonological segmentation and phoneme comparison. As an outcome of four alternating learning and test fMRI sessions, participants split into successful learners and non-learners. Relative to non-learners, successful learners showed increased task-related activity in a fronto-parietal network of brain areas encompassing the left lateral premotor cortex as well as bilateral superior and inferior parietal cortices during both learning and rule application. These areas were previously associated with phonological segmentation, phoneme comparison and verbal working memory. Based on these activity patterns and the phonological strategies for rule acquisition and application, we argue that successful learning and processing of complex phonological rules in our paradigm is mediated via a fronto-parietal network for phonological processes.

Across the last three decades, the application of noninvasive brain stimulation (NIBS) has substantially increased the current knowledge of the brain’s potential to undergo rapid short-term reorganization on the systems level. A large number of studies applied transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) in the healthy brain to probe the functional relevance and interaction of specific areas for different cognitive processes. NIBS is also increasingly being used to induce adaptive plasticity in motor and cognitive networks and shape cognitive functions. Recently, NIBS has been combined with electrophysiological techniques to modulate neural oscillations of specific cortical networks. In this review, we will discuss recent advances in the use of NIBS to modulate neural activity and effective connectivity in the healthy language network, with a special focus on the combination of NIBS and neuroimaging or electrophysiological approaches. Moreover, we outline how these results can be transferred to the lesioned brain to unravel the dynamics of reorganization processes in poststroke aphasia. We conclude with a critical discussion on the potential of NIBS to facilitate language recovery after stroke and propose a phase-specific model for the application of NIBS in language rehabilitation.