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Repetitive TMS (rTMS) with a frequency of 5–10 Hz is widely used for language mapping. However, it may be accompanied by discomfort and is limited in the number and reliability of evoked language errors. We, here, systematically tested the influence of different stimulation frequencies (i.e., 10, 30, and 50 Hz) on tolerability, number, reliability, and cortical distribution of language errors aiming at improved language mapping. 15 right‐handed, healthy subjects (m = 8, median age: 29 yrs) were investigated in two sessions, separated by 2–5 days. In each session, 10, 30, and 50 Hz rTMS were applied over the left hemisphere in a randomized order during a picture naming task. Overall, 30 Hz rTMS evoked significantly more errors (20 ± 12%) compared to 50 Hz (12 ± 8%; p, The use of repetitive transcranial magnetic stimulation (rTMS) for language mapping is still hampered by a limited sensitivity and specificity, by an overall poor reliability and by stimulation‐associated discomfort. We, here, found that increasing the stimulation intensity up to 30 and 50 Hz can improve language mapping results as compared to the most commonly used protocol of 10 Hz rTMS.

Key points Mechanisms underlying plasticity induction by repetitive transcranial magnetic stimulation protocols such as intermittent theta-burst stimulation (iTBS) remain poorly understood. Individual response to iTBS is associated with recruitment of late indirect wave (I-wave) generating pathways that can be probed by the onset latency of transcranial magnetic stimulation applied to primary motor cortex (M1) at different coil orientations. We found an association between late I-wave recruitment [reflected by anterior-posterior (AP)-lateromedial (LM) latency; i.e. the excess latency of motor-evoked potentials generated by transcranial magnetic stimulation with an AP orientation over the latency of motor-evoked potentials evoked by direct activation of corticospinal axons using LM stimulation] and changes in cortical excitability following iTBS, confirming previous studies. AP-LM latency significantly decreased following iTBS, and this decrease correlated with the iTBS-induced increase in cortical excitability across subjects. Plasticity in the motor network may in part derive from a modulation of excitability and the recruitment of late I-wave generating cortical pathways. Abstract Plasticity-induction following theta burst transcranial stimulation (TBS) varies considerably across subjects, and the underlying neurophysiological mechanisms remain poorly understood, representing a challenge for scientific and clinical applications. In human motor cortex (M1), recruitment of indirect waves (I-waves) can be probed by the excess latency of motor-evoked potentials elicited by transcranial magnetic stimulation with an anterior-posterior (AP) orientation over the latency of motor-evoked potentials evoked by direct activation of corticospinal axons using lateromedial (LM) stimulation, referred to as the 'AP-LM latency' difference. Importantly, AP-LM latency has been shown to predict individual responses to TBS across subjects. We, therefore, hypothesized that the plastic changes in corticospinal excitability induced by TBS are the result, at least in part, of changes in excitability of these same I-wave generating pathways. In 20 healthy subjects, we investigated whether intermittent TBS (iTBS) modulates I-wave recruitment as reflected by changes in the AP-LM latency. As expected, we found that AP-LM latencies before iTBS were associated with iTBS-induced excitability changes. A novel finding was that iTBS reduced AP-LM latency, and that this reduction significantly correlated with changes in cortical excitability observed following iTBS: subjects with larger reductions in AP-LM latencies featured larger increases in cortical excitability following iTBS. Our findings suggest that plasticity-induction by iTBS may derive from the modulation of I-wave generating pathways projecting onto M1, accounting for the predictive potential of I-wave recruitment. The excitability of I-wave generating pathways may serve a critical role in modulating motor cortical excitability and hence represent a promising target for novel repetitive transcranial magnetic stimulation protocols.

Background Functional magnetic resonance imaging (fMRI) is a useful method for noninvasive presurgical functional mapping. However, the scanner environment is inherently unsuitable for the examination of auditory and language functions, due to the loud acoustic noise produced by the scanner. Interleaved acquisition methods alleviate this problem by providing a silent period for stimulus presentation and/or response control (sparse sampling) but at the expense of a diminished amount of data collected. There are possible improvements to these sparse acquisition methods that increase the amount of data by acquiring several images per event (clustered sampling). We tested accelerated clustered fMRI acquisition in comparison with conventional sparse sampling in a pilot study. Methods The clustered and sparse acquisition techniques (7.4 minutes scanning time per protocol) were directly compared in 15 healthy subjects (8 men; mean age: 24 ± 3 years) using both a motor (tongue movement) and a language (overt picture-naming) task. Functional imaging data were analyzed using Statistical Parametric Mapping software (SPM12 Wellcome Department of Imaging Neuroscience, London, UK). For both tasks, activation levels were compared and Euclidean distances (EDs) between cluster centers (i.e., local activation maxima and centers of gravity) were calculated. Overlaps and laterality indices were computed for the picture-naming task. In addition, the feasibility of the clustered acquisition protocol in a clinical setting was assessed in one pilot patient. Results For both tasks, activation levels were higher using the clustered acquisition protocol, reflected by bigger cluster sizes (p Conclusion Despite some drawbacks inherent to the acquisition technique, the clustered sparse sampling protocol showed increased sensitivity for activation in language-related cortical regions with short scanning times. Such scanning techniques may be particularly advantageous for investigating patients with contraindications for long scans (e.g., reduced attention span).

Language assessment using a picture naming task crucially relies on the interpretation of the given verbal response by the rater. To avoid misinterpretations, a language-specific and linguistically controlled set of unambiguous, clearly identifiable and common object–word pairs is mandatory. We, here, set out to provide an open-source set of black and white object drawings, particularly suited for language mapping and monitoring, e.g., during awake brain tumour surgery or transcranial magnetic stimulation, in German language. A refined set of 100 black and white drawings was tested in two consecutive runs of randomised picture order and was analysed in respect of correct, prompt, and reliable object recognition and naming in a series of 132 healthy subjects between 18 and 84 years (median 25 years, 64% females) and a clinical pilot cohort of 10 brain tumour patients (median age 47 years, 80% males). The influence of important word- and subject-related factors on task performance and reliability was investigated. Overall, across both healthy subjects and patients, excellent correct object naming rates (97 vs. 96%) as well as high reliability coefficients (Goodman–Kruskal's gamma = 0.95 vs. 0.86) were found. However, the analysis of variance revealed a significant, overall negative effect of low word frequency (p < 0.05) and high age (p < 0.0001) on task performance whereas the effect of a low educational level was only evident for the subgroup of 72 or more years of age (p < 0.05). Moreover, a small learning effect was observed across the two runs of the test (p < 0.001). In summary, this study provides an overall robust and reliable picture naming tool, optimised for the clinical use to map and monitor language functions in patients. However, individual familiarisation before the clinical use remains advisable, especially for subjects that are comparatively prone to spontaneous picture naming errors such as older subjects of low educational level and patients with clinically apparent word finding difficulties.

Modulatory effects of transcranial magnetic stimulation (TMS) strongly depend on the stimulation parameters. Here, we compared the immediate, task-locked inhibitory effects on speech-related muscles and the tolerability of different TMS protocols during a language production task. Repetitive TMS (rTMS) and paired-pulse TMS (PP) were applied in 13 healthy subjects over the primary motor cortex (M1) during a finger-tapping/tongue-twisting tasks. The lowest subject-specific TMS intensity leading to movement disruptions was used for TMS over left-sided speech-related areas during picture naming. Here, time-locked PP and rTMS (10/30/50 Hz; randomized sequence) were applied. Cortical silent periods (cSPs) were analyzed from electromyography obtained from various face muscles. 30 Hz- and 50 Hz-rTMS reliably evoked tongue movement disruption (ICC = 0.65) at lower rTMS intensities compared to 10 Hz-rTMS or PP. CSPs were elicited from the left hemisphere by all TMS protocols, most reliably by PP (p

Precise and comprehensive mapping of somatotopic representations in the motor cortex is clinically essential to achieve maximum resection of brain tumours whilst preserving motor function, especially since the current gold standard, that is, intraoperative direct cortical stimulation (DCS), holds limitations linked to the intraoperative setting such as time constraints or anatomical restrictions. Non‐invasive techniques are increasingly relevant with regard to pre‐operative risk‐assessment. Here, we assessed the congruency of neuronavigated transcranial magnetic stimulation (nTMS) and functional magnetic resonance imaging (fMRI) with DCS. The motor representations of the hand, the foot and the tongue regions of 36 patients with intracranial tumours were mapped pre‐operatively using nTMS and fMRI and by intraoperative DCS. Euclidean distances (ED) between hotspots/centres of gravity and (relative) overlaps of the maps were compared. We found significantly smaller EDs (11.4 ± 8.3 vs. 16.8 ± 7.0 mm) and better spatial overlaps (64 ± 38% vs. 37 ± 37%) between DCS and nTMS compared with DCS and fMRI. In contrast to DCS, fMRI and nTMS mappings were feasible for all regions and patients without complications. In summary, nTMS seems to be the more promising non‐invasive motor cortex mapping technique to approximate the gold standard DCS results., The motor representations of the hand, the foot and the tongue regions were mapped pre‐operatively using neuronavigated transcranial magnetic stimulation (nTMS) and functional magnetic resonance imaging (fMRI) in thirty six patients with intracranial tumours and were compared with intraoperative direct cortex stimulation (DCS). We found significantly smaller Euclidean distances and better spatial overlaps between DCS and nTMS compared with DCS and fMRI. In summary, nTMS seems to be the more promising non‐invasive motor cortex mapping technique to approximate the gold standard DCS results.

When using functional magnetic resonance imaging (fMRI) for mapping important language functions, a high test-retest reliability is mandatory, both in basic scientific research and for clinical applications. We, therefore, systematically tested the short- and long-term reliability of fMRI in a group of healthy subjects using a picture naming task and a sparse-sampling fMRI protocol. We hypothesized that test-retest reliability might be higher for (i) speech-related motor areas than for other language areas and for (ii) the short as compared to the long intersession interval. 16 right-handed subjects (mean age: 29 years) participated in three sessions separated by 2-6 (session 1 and 2, short-term) and 21-34 days (session 1 and 3, long-term). Subjects were asked to perform the same overt picture naming task in each fMRI session (50 black-white images per session). Reliability was tested using the following measures: (i) Euclidean distances (ED) between local activation maxima and Centers of Gravity (CoGs), (ii) overlap volumes and (iii) voxel-wise intraclass correlation coefficients (ICCs). Analyses were performed for three regions of interest which were chosen based on whole-brain group data: primary motor cortex (M1), superior temporal gyrus (STG) and inferior frontal gyrus (IFG). Our results revealed that the activation centers were highly reliable, independent of the time interval, ROI or hemisphere with significantly smaller ED for the local activation maxima (6.45 ± 1.36 mm) as compared to the CoGs (8.03 ± 2.01 mm). In contrast, the extent of activation revealed rather low reliability values with overlaps ranging from 24% (IFG) to 56% (STG). Here, the left hemisphere showed significantly higher overlap volumes than the right hemisphere. Although mean ICCs ranged between poor (ICC0.5) and moderate (ICC 0.5-0.74) reliability, highly reliable voxels (ICC0.75) were found for all ROIs. Voxel-wise reliability of the different ROIs was influenced by the intersession interval. Taken together, we could show that, despite of considerable ROI-dependent variations of the extent of activation over time, highly reliable centers of activation can be identified using an overt picture naming paradigm.

Objective Functional magnetic resonance imaging (fMRI) is widely used for mapping of language areas. However, depending on the task design and the region of interest, a clear identification of language relevant areas can be challenging. We, therefore, compared three different fMRI task designs, i.e., picture naming and listening to simple vs. complex sentences followed by a non-verbal semantic decision task, for delineating cortical language areas. Methods 20 right-handed, healthy volunteers were investigated using fMRI (3T) with a sparse-sampling design (controlling for speech-related movement artefacts). In the first task, subjects were asked to name objects which were presented as black-white drawings by speaking out loudly a whole sentence introduced by the phrase ‘That is a/an…’. In the other paradigms, subjects were listening to simple or complex sentences (spoken by a male or female voice) followed by a semantic decision task. Here, three pictures were presented 5s after the sentences and subjects were asked to choose the corresponding item via button press. FMRI activation levels corresponding to the semantic decision after listening to meaningful sentences were compared to a control condition (i.e., listening to reverse sentences). fMRI data were analyzed using SPM12. Results The three language tasks differently activated regions engaged in the language network. Of note, listening to complex sentences led to a significantly higher activation during the semantic decision within the inferior frontal gyrus (IFG) as compared to simple sentences (p Conclusion Our results show that the activation of language-relevant areas depends strongly on the design of the fMRI task and indicate that activation within Broca’s area (IFG) increases with the complexity of the semantic decision.

INTRODUCTION: Imaging of the primary motor representation (M1) prior to brain tumour surgery is helpful to achieve a maximum extent of resection whilst preserving motor functions. To date, functional magnetic resonance imaging (fMRI) has been the most commonly used localizer technique for primary motor functioning. However, navigated transcranial magnetic stimulation (nTMS) gains increasing acceptance due to its high resolution and little dependence on the patients' compliance. We compared the congruency of nTMS vs. fMRI results with the gold standard method of direct cortical simulation (DCS). METHODS: 32 patients with intracerebral tumours underwent nTMS and fMRI prior to surgery. The cortical hot spots (HS) and Centres of Gravity (CoG) of M1 of the hand, the foot and the tongue representation were determined for each localizer technique and controlled by DCS. Euclidean distances (ED) between nTMS / fMRI and the respective DCS HS / CoG's were computed in 3D. Feasibility of both fMRI and nTMS were assessed in relation to the DCS results. RESULTS: Regarding the hand and the tongue representation, the CoG's of the nTMS maps were located significantly closer to the respective DCS-CoG's as compared to fMRI (hand [nTMS-DCS/ fMRI-DCS]: 9.7 ± 6.0 / 17.3 ± 9.6; p = 0.001; tongue: 9.4 ± 4.9 / 16.9 ± 5.9; p < 0.001 ). For the foot representation, a similar statistical trend was observed (12.2 ± 6.5 / 19.2 ± 12.9; p = 0.1). However, comparison of hot-spots did not reveal statistically significant differences. The feasibility of non-invasive localizer methods (fMRI: 100% / nTMS: 99%) was superior to DCS (71%). CONCLUSIONS: NTMS is a highly robust method for M1 mapping and seems to be superior to fMRI for mapping areas adjacent to brain tumours. Probably due to the limited depth of nTMS stimulation effects, nTMS is less clearly favourable for localizing the foot representation.

Objective The preservation of important white matter tracts is extremely important to optimize the functional long-term outcome after brain tumour surgery. The integration of functional localizer data such as navigated transcranial magnetic stimulation (nTMS) as starting region of interest (ROI) within the primary motor cortex (M1) into diffusion-tensor-imaging- (DTI-) tractography algorithms represents a recent advancement of the methodology with regard to the reconstruction of the corticospinal tract (CST). We here studied the use of a single nTMS-derived seeding ROI of M1 of the tongue to reconstruct connected fibres of the motor-speech network. Methods 13 healthy volunteers were investigated by nTMS mapping of M1. The hotspot, i.e. the cortical site of the highest motor evoked potential (MEP) amplitude, of the tongue representation was localized. The 3D-coordinate of the respective voxel (site of maximum calculated electrical-field strength) was obtained and was enlarged by a radius of 5 mm. This spheric ROI, representing M1 of the tongue, served as origin for probabilistic fibre tracking (FSL). The reconstructed fibres were segmented according to anatomical knowledge. Moreover, the tractography result was compared to the ”traditional” approach using and anatomical seeding-ROI of equivalent size and depth. Tracts were visualized using MRIcron and Slicer (3D). Results Segments of the arcuate fasciculus (AF) could be reconstructed in all subjects using the single M1-tongue-ROI. Most prominently, the anterior segment of the AF was observed, linking the triangular and opercular part of the inferior frontal gyrus (IFG), i.e., Broca’s territory, with the inferior parietal lobule (85% of cases). Moreover, also the long segment of the AF, connecting the IFG to the angular and dorsal superior temporal gyrus, could be displayed in most cases (92% of cases). Besides several motor pathways like the CST, other tracts involved in language/speech processing were reconstructed using this approach, e.g., the left frontal aslant tract (85% of cases) for which a crucial involvement in speech production (verbal fluency) has been described. Preliminary results regarding diffusion metrics and numbers of aberrant fibres point towards the use of nTMS for seeding-ROI determination being more specific as compared anatomical ROI-seeding. Conclusions Implementing the M1 hotspot of the tongue as a unique seeding-ROI for probabilistic diffusion tractography allows for depiction of motor-speech associated fibres, particularly the anterior segment of the AF. In comparison to anatomical ROI-seeding, this approach may offer a higher specificity and thus avoid aberrant fibre reconstruction, particularly in areas of unfavorable signal-to-noise-ratio.

Objective Using neuronavigated repetitive transcranial magnetic stimulation (rTMS) to disrupt language function during an online-task (e.g., picture naming) is a novel mapping technique which has recently been introduced for presurgical diagnostics in brain tumor patients. However, the method has some limitations due to its rather low specificity. Beyond its dependency on the task, the distinct error categories may have a major effect on the mapping results. We, here, studied the reliability and the spatial localization of rTMS-induced naming errors related to motor-speech function in contrast to semantic language errors. Methods 13 right-handed, healthy volunteers were investigated in 3 consecutive sessions (short-term: 2–5 days, long-term: 21–40 days) by 10 Hz-rTMS. First, the primary motor representation of the face (M1) was mapped by single-pulse TMS. Then, the minimal stimulation intensity which was required to disrupt rhythmic tongue movements by at least three out of five consecutive stimulations over the M1 hotspot was assessed by two independent observers. The “motor inhibition threshold” (MIT) determined the stimulation intensity for the following rTMS language mapping. Online-rTMS was then applied during a picture-naming task using black-and-white drawings of everyday objects which were presented simultaneously (triggered, delay = 0 ms) with the rTMS. The rTMS bursts lasted for 1.5 s (15 pulses). The continuous stimulated area of the left hemisphere had the following anatomical boundaries: middle temporal sulcus (caudal), angular gyrus/ middle parietal sulcus (mediodorsal), hand knob and middle frontal sulcus (medial), triangular part of the inferior frontal gyrus (rostral). Errors were rated by two independent raters by post hoc video analysis. The error frequency (number of errors per 100 TMS trains) as well as the spatial representation and the reliability of distinct motor-speech-related errors, i.e., speech arrest and dysarthria, were compared to language errors associated with semantic processing, i.e., anomia and semantic paraphasia. Test-retest-reliability was assessed by the average intraclass correlation coefficient for a fixed rater (ICC). Results Overall, speech/ language errors were rare events. Amongst the four analyzed error categories, dysarthria represented the most frequent error ( 4.0 ± 2.5 % ) whereas only very few semantic paraphasias were induced ( 0.5 ± 0.4 % ). Motor-speech errors were found significantly more often than semantic language errors ( p 0.01 ). In comparison to semantic errors, the test-retest-reliability of the error rates was lower for motor-speech errors (ICC = 0.45 vs. 0.64). By contrast, the spatial reliability was higher for motor speech errors and showed a strong clustering over M1 and the premotor cortex, especially for the category “arrest”. Conclusion RTMS language mapping is a promising novel technique but the results are still hard to interpret and highly variable. The great majority of errors seems to be at least partially due to motor network disruption rather than being induced by interference with language processing. Further studies, combining different neuroimaging techniques and online-EEG, are mandatory to gain further insight into the underlying mechanisms and the brain-state-dependency of rTMS during language tasks.

INTRODUCTION: Imaging of the course of the corticospinal tract (CST) by diffusion tensor imaging (DTI) is useful for function-preserving tumour surgery especially of gliomas infiltrating the white matter. The integration of functional data such as functional MRI (fMRI) or navigated transcranial magnetic stimulation (nTMS) for the delineation of starting Regions of Interest (ROI) can improve the fibre tracking results in a multiple-ROI approach. Here, both functional localizer methods are compared for the plausibility of the resulting fibre course. METHODS: 32 patients with intracerebral tumours were allocated to the prospective study. The cortical seeding ROIs were defined by the nTMS hot-spots or by the fMRI local-activation-maximum representing the primary motor area (M1) of the hand, the foot and the tongue. The CST originating from the contralesional M1 hand area was mapped as intra-individual reference. As subcortical ROI, we used the anterior inferior pontine region (aiP). The plausibility of the fibre trajectories was assessed by a-priori defined anatomical criteria by two independent raters. As potential co-factors i.a. the franctional anisotropy threshold (FAT) was analysed. RESULTS: Both methods revealed excellent plausibility results for the contralesional hand-CST (100%). NTMS seems to be favourable to construct the hand-CST on the lesional side (NTMS/fMRI: 97%/81%) whereas no significant difference could be observed for the foot- and the tongue-CST. Plausibility rates were significantly deteriorated at low FAT values (ROC-cut-off: FAT = 0.105) for both nTMS- and fMRI-derived CST (p < 0.001). The interrater reliability was excellent (Cohen's k = 0.96). CONCLUSIONS: In summary, we found excellent plausibility rates using a deterministic multiple-ROI approach with a cortical ROI defined by functional localizer methods. In comparison, nTMS was advantageous for the hand-CST tractography whereas both localizer methods revealed adequate results for the foot- and the tongue-CST. In general, tractography results at FAT lower than 0.105 should be interpreted with particular caution.

Introduction Intermittent theta-burst stimulation (iTBS) effectively increases cortical excitability within the human brain (Huang et al., 2005). However, individual after-effects of iTBS vary between subjects, with a large proportion not responding at all in terms of changes in excitability (Ridding and Ziemann, 2010; Hamada et al., 2013). We here investigated whether subjects responding to iTBS show differential changes in resting-state functional connectivity (rsFC) within the cortical motor system compared to subjects with no response and whether the application of multiple iTBS-blocks can alter responsiveness. Methods We used a sham-stimulation controlled, single-blinded within-subject design to test for iTBS after-effects on (i) motor evoked potentials (MEPs) and (ii) resting-state functional connectivity (rsFC) in 16 healthy, right-handed subjects ( m =7, 27±3years). iTBS was applied over the left primary motor cortex (M1-iTBS) and over the parieto-occipital vertex (sham-iTBS) in separate sessions. In each stimulation session three iTBS blocks were applied, separated by 15min. Seed-based whole-brain rsFC was computed for the stimulated M1. Results Subjects were divided into groups of responders ( n =7) and non-responders ( n =9) according to iTBS-induced changes in MEPs (criterion: increase of at least 10% compared to baseline; Hinder et al., 2014). Increases in MEP-amplitudes following all three M1-iTBS blocks compared to sham-iTBS could exclusively be found for responders. Likewise, rsFC between M1 and premotor areas was significantly higher in responders after all three iTBS blocks ( p ⩽0.05, cluster-level FWE-corrected), whereas no significant increases could be found for the non-responder group. Dose-dependent increases in MEP-amplitudes and rsFC could also only be found for responders. Importantly, non-responders featured higher levels of pre-interventional rsFC compared to responders ( p ⩽0.01, cluster-level FWE-corrected). Individual changes in MEPs and rsFC did not correlate. Discussion Significant iTBS-induced modulations of rsFC and MEP-amplitudes were exclusively found for the responder group, suggesting that responsiveness to iTBS is paralleled by differential changes in motor network connectivity. However, there was no linear correlation between changes in MEP-amplitudes and rsFC. Additional iTBS blocks did not cause a conversion from non-responders to responders, but rather enhanced cortical excitability and rsFC in responders. Furthermore, lower levels of pre-interventional rsFC might contribute to better effectiveness of iTBS.