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Figure S5. Electrical field strength in action-related left pIPL was not associated with behavioral performance for sound judgments on low sound–low action words (i.e. accuracy change in % for pIPL-rTMS vs. sham stimulation). The Bayes Factor BF10=0.260, or equivalently BF01=1/0.260=3.847, means that the data were ~4 times more likely under the null hypothesis than alternative hypothesis.
Source publication
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 disrupte...
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Conceptual knowledge about objects, people and events in the world is central to human cognition, underlying core cognitive abilities such as object recognition and use, and word comprehension. Previous research indicates that concepts consist of perceptual and motor features represented in modality-specific perceptual-motor brain regions. In addit...
Citations
... Future studies could also benefit from performing computational simulations of the rhTMS-induced electrical field (Thielscher et al., 2015;Saturnino et al., 2019) to precisely map which areas of the parietal cortex are most strongly stimulated in each participant during training. Given that the IPS lies adjacent to and deep to the gyral crowns of the superior and inferior parietal lobes, it is possible that these superficial regions receive more intense stimulation than the sulcal cortex (Thielscher et al., 2011;Kuhnke et al., 2020). Modeling the direct effects of rhTMS-induced electrical fields by simulation would be potentially useful as a complement to the mixed effects that we have shown by source reconstruction of simultaneous TMS-EEG recordings. ...
Introduction
Rhythmic transcranial magnetic stimulation (rhTMS) has been shown to enhance auditory working memory manipulation, specifically by boosting theta oscillatory power in the dorsal auditory pathway during task performance. It remains unclear whether these enhancements (i) persist beyond the period of stimulation, (ii) if they can accelerate learning and (iii) if they would accumulate over several days of stimulation. In the present study, we investigated the lasting behavioral and electrophysiological effects of applying rhTMS over the left intraparietal sulcus (IPS) throughout the course of seven sessions of cognitive training on an auditory working memory task.
Methods
A limited sample of 14 neurologically healthy participants took part in the training protocol with an auditory working memory task while being stimulated with either theta (5 Hz) rhTMS or sham TMS. Electroencephalography (EEG) was recorded before, throughout five training sessions and after the end of training to assess to effects of rhTMS on behavioral performance and on oscillatory entrainment of the dorsal auditory network.
Results
We show that this combined approach enhances theta oscillatory activity within the fronto-parietal network and causes improvements in auditoryworking memory performance. We show that compared to individuals who received sham stimulation, cognitive training can be accelerated when combined with optimized rhTMS, and that task performance benefits can outlast the training period by ∼ 3 days. Furthermore, we show that there is increased theta oscillatory power within the recruited dorsal auditory network during training, and that sustained EEG changes can be observed ∼ 3 days following stimulation.
Discussion
The present study, while underpowered for definitive statistical analyses, serves to improve our understanding of the causal dynamic interactions supporting auditory working memory. Our results constitute an important proof of concept for the potential translational impact of non-invasive brain stimulation protocols and provide preliminary data for developing optimized rhTMS and training protocols that could be implemented in clinical populations.
... In contrast, stimulation strength refers to the cortical stimulation exposure, quantified by the e-field strength (e.g., 100 V/m). It is essential to note that the TMS-induced e-field shows limited focality, rendering the exclusive stimulation of a single cortical location, without any off-target stimulation, impossible (Kuhnke et al., 2020). In our prior discussions , we explored this limitation of TMS and other NIBS approaches and presented strategies to address these constraints. ...
... This approach was ideal to elucidate potential advantages and drawbacks of e-field based dosing in comparison to MT-based dosing (e.g., Kuhnke et al., 2020) and other dosing strategies (Stokes et al., 2005). ...
... The motor threshold measures the minimum cortical excitation (with single-pulse TMS of the primary motor region) necessary to elicit MEPs just above the EMG noise floor. However, it remains unknown if the same cortical excitation threshold can be applied to effectively modulate other (cognitive) functions, such as attentional reorienting (Jing et al., 2023), sentence processing (Meyer et al., 2018;Kuhnke et al., 2017;van der Burght, 2022) or conceptual-semantic processing (Kuhnke et al., 2020. As pre-activation of the motor cortex drastically lowers the cortical threshold to evoke MEPs (Rossi et al., 2009;see Holmes et al., 2023 for unintended side-effects), different (cognitive) brain states are also likely to affect stimulation effects within higher association cortices (Silvanto et al., 2008;Feurra et al., 2013;Krause et al., 2022;see Hartwigsen & Silvanto, 2022 for discussion). ...
Transcranial magnetic stimulation (TMS) is an invaluable non-invasive brain stimulation (NIBS) technique to modulate cortical activity and behavior, but high within- and between-participant variability limits its efficacy and reliability. Here, we explore the potential of electric field (e-field) based TMS dosing to reduce its variability and discuss current challenges as well as future pathways. In contrast to previous dosing approaches, e-field dosing better matches the stimulation strength across cortical areas, both within and across individuals. Challenges include methodological uncertainties of the e-field simulation, target definitions, and comparability of different stimulation thresholds across cortical areas and NIBS protocols. Despite these challenges, e-field dosing promises to substantially improve NIBS applications in neuroscientific research and personalized medicine.
... Although the different localizer tasks in the present study allowed us to functionally characterize the experiential brain areas contributing to processing abstract mental state concepts, fMRI measurements only provide correlative evidence. A causal relevance of identified neural brain circuits for processing MST concepts thus needs to be verified in studies using transcranial magnetic stimulation (Kuhnke et al., 2020a) or investigation of brain-lesioned patients (Dreyer et al., 2015;Trumpp et al., 2013). ...
Abstract concepts like mental state concepts lack a physical referent, which can be directly perceived. Classical theories therefore claim that abstract concepts require amodal representations detached from experiential brain systems. However, grounded cognition approaches suggest an involvement of modal experiential brain regions in the processing of abstract concepts. In the present functional magnetic resonance imaging study, we investigated the relation of the processing of abstract mental state concepts to modal experiential brain systems in a fine-grained fashion. Participants performed lexical decisions on abstract mental state as well as on verbal association concepts as control category. Experiential brain systems related to the processing of mental states, generating verbal associations, automatic speech as well as hand and lip movements were determined by corresponding localizer tasks. Processing of abstract mental state concepts neuroanatomically overlapped with activity patterns associated with processing of mental states, generating verbal associations, automatic speech and lip movements. Hence, mental state concepts activate the mentalizing brain network, complemented by perceptual-motor brain regions involved in simulation of visual or action features associated with social interactions, linguistic brain regions as well as face-motor brain regions recruited for articulation. The present results provide compelling evidence for the rich grounding of abstract mental state concepts in experiential brain systems related to mentalizing, verbal communication and mouth action.
... However, we wish to emphasize that subdomain-specific clusters for syntax in temporal regions did not survive our conservative threshold and we thus did not find one specific area in the STS/pMTG region that engaged more for syntax than all other subdomains. Last, the bilateral medial frontal cortex/anterior cingulate region has been related to various cognitive processes, including inferential temporal control, task flexibility and adaptation, and abstract action chunking (Rouault & Koechlin, 2018) as well as conceptual (semantic) processing (e.g., Binder et al., 2009;Kuhnke et al., 2020). While we cannot provide evidence for the role of this region in these processes, we believe that the consistently observed activation of these regions shows high reliance of all language tasks on domain-general cognitive skills and mechanisms. ...
... It seems that the left ITG/pMTG cluster with high semantic specificity in our meta-analysis largely overlapped with the semantic control area found in Hodgson et al.'s (2021) metaanalysis. Left pMTG has also been characterized as a multimodal region for conceptual-semantic knowledge in previous work (Kuhnke et al., 2020. The left frontal pole/orbitofrontal cortex is not a classical semantic region but is connected to the left anterior temporal lobe, an amodal hub region for semantic representation (Kuhnke et al., 2021;Lambon Ralph et al., 2017) via the ventral stream for semantic processing (Dick et al., 2014). ...
... NEUROBIOLOGY OF LANGUAGE the right cerebellum during semantic processing is in line with a few neurostimulation studies that point toward a role of this area for semantic processing and prediction (D'Mello et al., 2017;Gatti et al., 2020), as well as neuroimaging work that revealed multimodal semantic effects in the right cerebellum (crus I/II; Kuhnke et al., 2020). ...
Language is a key human faculty for communication and interaction that provides invaluable insight into the human mind. Previous work has dissected different linguistic operations, but the large-scale brain networks involved in language processing are still not fully uncovered. Particularly, little is known about the subdomain-specific engagement of brain areas during semantic, syntactic, phonological, and prosodic processing and the role of subcortical and cerebellar areas. Here, we present the largest coordinate-based meta-analysis of language processing including 403 experiments. Overall, language processing primarily engaged bilateral fronto-temporal cortices, with the highest activation likelihood in the left posterior inferior frontal gyrus (IFG). Whereas we could not detect any syntax-specific regions, semantics specifically engaged left posterior temporal areas (left fusiform and occipitotemporal cortex) and the left frontal pole. Phonology showed highest subdomain-specificity in bilateral auditory and left postcentral regions, whereas prosody engaged specifically the right amygdala and the right IFG. Across all subdomains and modalities, we found strong bilateral subcortical and cerebellar contributions. Especially the right cerebellum was engaged during various processes, including speech production, visual, and phonological tasks. Collectively, our results emphasize consistent recruitment and high functional modularity for general language processing in bilateral domain-specific (temporo-frontal) and domain-general (medial frontal/anterior cingulate cortex) regions but also a high specialization of different subareas for different linguistic subdomains. Our findings refine current neurobiological models of language by adding novel insight into the general sensitivity of the language network and subdomain-specific functions of different brain areas and highlighting the role of subcortical and cerebellar regions for different language operations.
... Similarly, novel analysis techniques with respect to the use of TMS have recently used modeling of the TMS-induced electric field in each individual subject. The magnitude of the electric field in a certain ROI can, in turn, be used to explain modulations in behavior in a number of language tasks van der Burght, Numssen, Schlaak, Goucha, & Hartwigsen, 2023;Maran, Numssen et al., 2022;Kuhnke et al., 2020). In this case, the auxiliary assumptions again imply that the process of interest can be localized to one or multiple ROIs and that stimulation and task performance are linearly related. ...
The capacity for language is a defining property of our species, yet despite decades of research, evidence on its neural basis is still mixed and a generalized consensus is difficult to achieve. We suggest that this is partly caused by researchers defining “language” in different ways, with focus on a wide range of phenomena, properties, and levels of investigation. Accordingly, there is very little agreement among cognitive neuroscientists of language on the operationalization of fundamental concepts to be investigated in neuroscientific experiments. Here, we review chains of derivation in the cognitive neuroscience of language, focusing on how the hypothesis under consideration is defined by a combination of theoretical and methodological assumptions. We first attempt to disentangle the complex relationship between linguistics, psychology, and neuroscience in the field. Next, we focus on how conclusions that can be drawn from any experiment are inherently constrained by auxiliary assumptions, both theoretical and methodological, on which the validity of conclusions drawn rests. These issues are discussed in the context of classical experimental manipulations as well as study designs that employ novel approaches such as naturalistic stimuli and computational modeling. We conclude by proposing that a highly interdisciplinary field such as the cognitive neuroscience of language requires researchers to form explicit statements concerning the theoretical definitions, methodological choices, and other constraining factors involved in their work.
... For the lexical decision task, a pseudoword was generated for each word matched in length, syllable structure and transition frequencies using the Wuggy software (Keuleers and Brysbaert, 2010; htt ps://crr.ugent.be/Wuggy). For the full stimulus set, see the Supplementary Material of Kuhnke et al. (2020a). ...
... Finally, it should be noted that evidence for a causal role of multimodal conceptual areas is currently weak. For example, we previously found that transcranial magnetic stimulation (TMS) over left IPL selectively impairs action judgments, but not sound judgments, on written words (Kuhnke et al., 2020a). These findings suggest that left IPL might be specialized for action knowledge retrieval, challenging the view of left IPL as a multimodal conceptual hub (also see Ishibashi et al., 2011;Pobric et al., 2010). ...
Conceptual knowledge is central to human cognition. Neuroimaging studies suggest that conceptual processing involves modality-specific and multimodal brain regions in a task-dependent fashion. However, it remains unclear (1) to what extent conceptual feature representations are also modulated by the task, (2) whether conceptual representations in multimodal regions are indeed cross-modal, and (3) how the conceptual system relates to the large-scale functional brain networks. To address these issues, we conducted multivariate pattern analyses on fMRI data. 40 participants performed three tasks-lexical decision, sound judgment, and action judgment-on written words. We found that (1) conceptual feature representations are strongly modulated by the task, (2) conceptual representations in several multimodal regions are cross-modal, and (3) conceptual feature retrieval involves the default, frontoparietal control, and dorsal attention networks. Conceptual representations in these large-scale networks are task-dependent and cross-modal. Our findings support theories that assume conceptual processing to rely on a flexible, multi-level architecture.
... This approach was ideal to elucidate potential advantages and drawbacks of e-field based dosing in comparison to MT-based dosing (e.g., Kuhnke et al., 2020) and other dosing strategies (Stokes et al., 2005). ...
... The motor threshold measures the minimum cortical excitation (with single-pulse TMS of the primary motor region) necessary to elicit MEPs just above the EMG noise floor. However, it remains unknown if the same cortical excitation threshold can be applied to effectively modulate other (cognitive) functions, such as attentional reorienting (Jing et al. 2023) or conceptual-semantic processing (Kuhnke et al., 2020. As pre-activation of the motor cortex drastically lowers the cortical threshold to evoke MEPs (Rossi et al., 2009), different (cognitive) brain states are also likely to affect stimulation effects within higher association cortices (Silvanto et al., 2008;Feurra et al., 2013;Krause et al., 2022;see Hartwigsen & Silvanto, 2022 for discussion). ...
Non-invasive brain stimulation (NIBS) methods, such as transcranial magnetic stimulation (TMS), are invaluable tools to modulate cortical activity and behavior, but high within- and between-subject variability limit their efficacy and reliability. Here, we explore the potential of electrical field (e-field) based NIBS dosing to reduce its variability and discuss current challenges as well as future pathways. In contrast to previous dosing approaches, e-field dosing optimally matches the stimulation strength across cortical areas, both within and across individuals. Challenges include methodological uncertainties of the e-field calculation, target definitions, and comparability of different stimulation thresholds across cortical areas and NIBS protocols. Despite these challenges, e-field dosing promises to substantially improve NIBS applications in neuroscientific research and personalized medicine.
Outstanding Questions Box
Outstanding Questions
Does the cortical threshold for effective stimulation differ between primary regions and higher-level association areas? How large is the impact of cytoarchitectonic differences between regions on a stimulation threshold?
Do cortical stimulation thresholds differ across individuals? Are thresholds stable within an individual across the lifespan? What are the physiological factors influencing these thresholds?
Can a cortical stimulation threshold measured with single-pulse TMS be transferred to repetitive TMS protocols for the study of cognition?
How does the cortical stimulation threshold interact with the current brain state?
Graphical abstract
... For example, we previously found that transcranial magnetic stimulation (TMS) over left IPL selectively impairs action judgments, but not sound judgments, on written words (Kuhnke et al., 2020a). These findings suggest that left IPL might be specialized for action knowledge retrieval, challenging the view of left IPL as a multimodal conceptual hub (also see Ishibashi et al., 2011;Pobric et al., 2010). ...
Conceptual knowledge is central to human cognition. Neuroimaging studies suggest that conceptual processing involves modality-specific and multimodal brain regions in a task-dependent fashion. However, it remains unclear (1) whether conceptual representations within these regions are also modulated by the task, (2) whether conceptual representations in multimodal areas are indeed cross-modal, and (3) how the conceptual system relates to the large-scale functional brain networks. To address these issues, we conducted multivariate pattern analyses on fMRI data. 40 participants performed three tasks-lexical decision, sound judgment, and action judgment-on written words. We found that (1) conceptual representations are strongly modulated by the task, (2) conceptual representations in several multimodal regions are cross-modal, and (3) conceptual feature retrieval involves the default, frontoparietal control, and dorsal attention networks. Conceptual representations in these large-scale networks are task-dependent and cross-modal. Our findings support theories that assume conceptual processing to rely on a flexible, multi-level architecture.
... These e-field estimations have been used to map cortical muscle representations accurately in M1 (Opitz et al., 2013;Bungert et al., 2016;Aonuma et al., 2018;Weise et al., 2020). Moreover, studies from our lab have used e-field strength in cortical regions of interest to explain performance differences in a wide range of cognitive tasks (Kuhnke et al., 2020;van der Burght et al., 2023;Maran et al., 2022). Likewise, simulations have underlined that the stimulation spread is highly dependent on macro-anatomical The effective electric field is shaped by individual-specific factors, such as gyrification patterns and distribution of various tissue types (shown here: grey matter). ...
... multiple stimulations sites or across-subjects, comparing the e-field distributions between various brain and head anatomies. Within-subject modelling has recently been implemented for the motor cortex (Weise et al., 2022;Numssen et al., 2021) and adapted to map spatial attention (Jing et al., 2023), while the analysis of between-subject variation is a promising path for studies on cognition: e-field strengths across subjects within a region of interest are used to explain the TMS modulation of task performance and thus, identify causally involved areas (Kuhnke et al., 2020;van der Burght et al., 2023;Maran et al., 2022). As such, the between-subject variability in e-field strength turns into an advantage and can be used to explain between-subject variability in behaviour. ...
Non-invasive brain stimulation techniques are popular tools to investigate brain function in health and disease. Although transcranial magnetic stimulation (TMS) is widely used in cognitive neuroscience research to probe causal structure-function relationships, studies often yield inconclusive results. To improve the effectiveness of TMS studies, we argue that the cognitive neuroscience community needs to revise the stimulation focality principle - the spatial resolution with which TMS can differentially stimulate cortical regions. In the motor domain, TMS can differentiate between cortical muscle representations of adjacent fingers. However, this high degree of spatial specificity cannot be obtained in all cortical regions due to the influences of cortical folding patterns on the TMS-induced electric field. The region-dependent focality of TMS should be assessed a priori to estimate the experimental feasibility. Post-hoc simulations allow modeling of the relationship between cortical stimulation exposure and behavioral modulation by integrating data across stimulation sites or subjects.
... Similarly, novel analysis techniques with respect to the use of TMS have recently used modeling of the TMSinduced electric field in each individual subject. The magnitude of the electric field in a certain ROI can, in turn, be used to explain modulations in behavior in a number of language tasks (Kuhnke et al., 2020;Maran, Numssen, et al., 2022;van der Burght et al., 2022). In this case, the auxiliary assumptions again imply that the process of interest can be localized to one or multiple ROIs, and that stimulation and task performance are linearly related. ...
The capacity for language is a defining property of our species, yet despite decades of research, evidence on its neural basis is still mixed and a generalized consensus is difficult to achieve. We suggest that this is partly caused by researchers defining “language” in radically different ways, with focus on a wide range of phenomena, properties, and levels of investigation. Accordingly, there is very little agreement amongst cognitive neuroscientists of language on the operationalization of fundamental concepts to be investigated in neuroscientific experiments. This paper reviews chains of derivation in the cognitive neuroscience of language, focusing on how the hypothesis under consideration is defined by a combination of theoretical and methodological assumptions. We first attempt to disentangle the complex relationship between linguistics, psychology, and neuroscience in the field. We then focus on how conclusions that can be drawn from any experiment are inherently constrained not just by the research techniques and analyses adopted, but also by the theoretical starting point of the study: auxiliary assumptions, both theoretical and methodological, on which the validity of conclusions drawn rely. These issues are discussed in the context of classical experimental manipulations, as well as study designs that employ novel approaches such as naturalistic stimuli and computational methods. We conclude by proposing that a highly interdisciplinary field such as the cognitive neuroscience of language requires researchers to form explicit statements concerning the theoretical definitions, methodological choices, and other constraining factors involved in their work.
