C. Grefkes

PB7. Comparison of three different fMRI paradigms for language mapping

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 (pu202f 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.

P 146 Differences in processing of action and semantic tool knowledge – evidence from fMRI and dynamic causal modelling

Objective Whether processing of function knowledge about tools (i.e., knowing what a tool is used for) draws upon action or semantic knowledge remains controversial. Methods We investigated this issue using fMRI. 17 subjects performed three experimental tasks tapping into different aspects of tool knowledge. Data were analyzed using SPM and dynamic causal modeling (DCM). Results The behavioral data and fMRI activation pattern suggested that function knowledge about tools was processed similarly as non-motor-related semantic tool knowledge (here: the monetary value of a tool) and could therefore be classified as “motor-related semantic knowledge”, whereas action knowledge (i.e., how a tool is used) was processed differently. Processing of action knowledge activated areas of the ventro-dorsal stream (i.e., the lateral occipito-temporal cortex (LOTC) bilaterally, the left intraparietal sulcus (IPS), the left supramarginal gyrus (SMG), and the left inferior frontal gyrus (IFG)). In contrast, ventral stream areas were activated by the processing of semantic tool knowledge: the fusiform gyrus (FFG) bilaterally, the angular gyrus (ANG) bilaterally, and the medial prefrontal cortex (mPFC). Analyzing the effective connectivity between these areas with DCM revealed interactions between the processing streams (between LOTC and FFG as well as between SMG and ANG) and reciprocal modulatory effects. Conclusions This fMRI-study substantiates that action and semantic knowledge about tools are processed along two separate routes and that function knowledge (i.e., knowing what a tool is used for) draws upon the semantic system. In addition, connectivity analysis with DCM revealed relevant interactions between the processing streams at lower and higher levels.

P 14 Motor component of speech errors in rTMS language mapping

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: 2–5xa0days, long-term: 21–40xa0days) by 10xa0Hz-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, delayxa0=xa00xa0ms) with the rTMS. The rTMS bursts lasted for 1.5xa0s (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 (ICCxa0=xa00.45 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.

P 13 Congruency between speech-related areas investigated by fMRI and three rTMS protocols with different frequencies

Objective Recently, language mapping by repetitive transcranial magnetic stimulation (rTMS) has gained a lot of interest in preoperative planning to preserve language function. However, the improvement of rTMS protocols is still a matter of debate since rTMS-evoked speech-errors appear relatively widespread over the brain and are rather poorly reliable, depending on the type of the speech-errors. We, therefore, investigated how rTMS-evoked speech-errors of distinct categories are located relatively to speech-related functional MRI (fMRI) clusters (serving as a widely used method for language mapping). Moreover, we compared three different rTMS-protocols with varying frequencies (10, 30 and 50xa0Hz). Methods 13 right-handed, healthy volunteers were investigated using fMRI (3T) and navigated rTMS using the same picture naming-task. To control for speech-related movement artefacts in fMRI, a sparse-sampling design was used with the following parameters: TRxa0=xa011 000xa0ms, delay in TRxa0=xa09000xa0ms, TExa0=xa030xa0ms, flip anglexa0=xa090°, voxel size 3xa0×xa03xa0×xa03xa0mm3, FoVxa0=xa0192xa0mm2, 79 images. After preprocessing (SPM8), the clusters of the superior temporal gyrus (STG) and the inferior frontal gyrus (IFG) were extracted. In the rTMS-sessions, 10xa0Hz, 30xa0Hz and 50xa0Hz rTMS were applied in a randomized order over the left hemisphere, continuously covering facial (pre-)motor and language-related cortical areas. Bursts were triggered to picture presentation without delay (picture-to-trigger intervalxa0=xa00). Errors were rated by two independent raters using a post hoc video analysis and were categorized as follows: arrest, anomia, delayed term, complete delay, dysarthria, morphosyntactic errors, speech-motor disturbance, semantic and phonematic paraphasia (including neologisms). The coordinates of the sites (of maximal electrical field strength) corresponding to the speech-errors were extracted. Then the amount of rTMS-speech errors lying within the STG/IFG-clusters was calculated (relative to the total number of errors, “hit rate”) on an individual level using FSL. Results Overall, 17% of the rTMS-evoked speech-errors (“hit rate”) were located within the STG (10xa0Hz: 0.15xa0±xa00.05, 30xa0Hz: 0.19xa0±xa00.07, 50xa0Hz: 0.18xa0±xa00.07). In comparison, only 6% were located within the IFG (10xa0Hz: 0.06xa0±xa00.05, 30xa0Hz: 0.05xa0±xa00.02, 50xa0Hz: 0.07xa0±xa00.04). However, when corrected for the different cluster sizes (STGxa0>xa0IFG) this difference was not significant. Within the STG, a significantly higher rate of speech-errors could be found for 30xa0Hz as compared to10xa0Hz. Moreover, for motor-speech associated errors (e.g., delay) a tendency towards a higher rate of speech errors was found with higher rTMS-frequencies (30 & 50xa0Hz). Conclusion Our results suggest that rTMS language mapping is more sensitive for detecting language-relevant sites of the STG as compared to the IFG as identified via fMRI. This finding, however, results from the different cluster sizes. Within the STG, the number of speech-errors seems to increase with higher frequencies, especially for errors associated with motor-speech function. The results might differ for other speech related areas like the angular gyrus or primary motor areas, which needs to be further investigated.

EP 110. Phase-locking as a neurophysiological marker of movement execution in young and elderly subjects

Motor actions are generated by complex interactions of various brain regions. The same brain regions can build various functional networks depending on the action. Identifying the neural signals that encode an action’s component (selection, preparation, execution) remains a difficult task. In the current study, EEG data were recorded continuously from 18 young (22–35xa0years) and 16 elderly (60–71xa0years) right-handed healthy subjects as they performed a simple motor task. The task required participants to execute a left or right index finger tapping triggered by a visual cue or by an uncued voluntary choice. We found that voluntary and visually triggered movements exhibit significant phase locking in the delta-theta frequency band (2–7xa0Hz) around movement onset both in young and old subjects. However, significant differences in movement and processing time between the two groups of subjects were observed as well. Moreover, there was a negative correlation between the movement time and the maximal value of the phase-locking index (PLI) in young subjects. This indicates that the aforementioned changes in behavioral performance result from a decrease of PLI in the respective motor regions. In summary, we suggest that this enhanced intra-regional synchrony, which seems to be impaired in the elderly, helps the simultaneously active pathways of distinct cortical networks that initiate voluntary and stimulus-triggered movements, converge to a common motor output and activate the appropriate muscles to perform the movement. This mechanism may thus be regarded as a prototype for organizing more complex motor activities.

EP 8. The role of contralesional motor areas in early motor recovery – evidence from event-related (“online”) TMS

Background TMS studies examining the role of the unaffected hemisphere in motor function after stroke have mainly focused on the contralesional primary motor cortex (M1), revealing both supporting ( Lotze et al., 2006 , Rehme et al., 2011 ) as well as disturbing ( Vollmer et al., 2015 , Nowak et al., 2008 ) influence for recovery of function. However, the relevance of other contralesional motor areas for paretic hand function has rarely been examined, especially with respect to motor recovery in the first days and weeks after stroke. Therefore, we tested the effects of online-TMS applied to contralesional primary motor cortex, anterior intraparietal sulcus (aIPS) and dorsal premotor cortex (dPMC) while stroke patients performed different motor tasks with their paretic hand. Methods Patients with first-ever ischemic left hemispheric stroke performed motor tasks of different complexities with their paretic right hand while being stimulated with ‘online TMS’: (i) index finger tapping, (ii) hand tapping, (iii) visuomotor pointing task (pointing back and forth between two defined targets) and (iv) simple reaction time task. Performance was measured using a three-dimensional motion analyzer system (Zebris). Patients were measured in the acute stage after stroke. Results Compared to healthy controls, acute stroke patients showed reduced finger tapping amplitudes during TMS interference with ipsilateral (=contralesional) aIPS. Likewise, reaction times deteriorated upon contralesional aIPS stimulation in stroke patients but not in controls. Finally, accuracy in the 3D pointing task not only deteriorated upon aIPS stimulation (like in controls) but in addition also during interference with contralesional M1, which was exclusively found in the stroke patients group. Conclusion We here found evidence that especially anterior intraparietal cortex –an area critically engaged in hand motor function by means of parieto-frontal loops– has a relevant influence on motor performance of the paretic hand early after stroke. Therefore, aIPS might constitute an interesting stimulation target for excitability enhancing brain stimulation protocols in order to support recovery of function after stroke.

EPV 9. The role of ipsilateral motor areas in hand motor function in healthy ageing – Insights from online TMS

Background Event-related (“online”) transcranial magnetic stimulation (TMS) allows to interfere with neural processing of distinct cortical areas. While we have a rather good knowledge on the role of frontoparietal areas for motor performance of the contralateral hand, the contribution of areas in the hemisphere ipsilateral to the moving hand is far less understood ( [Davare et al., 2007] , [Vollmer et al., 2015] ). For example, neuroimaging studies found an increasing ipsilateral recruitment of motor regions in healthy eldery subjects, implying a supportive influence during normative ageing ( [Hutchinson et al., 2002] , [Riecker et al., 2006] ). To test this hypothesis, we used online-TMS to investigate the role of ipsilateral primary motor cortex (M1), premotor cortex (dPMC) and anterior intraparietal sulcus (aIPS) in motor tasks of different complexity in young and elderly subjects. Methods Young (range: 20–30xa0years) and elderly (range: 50–70xa0years) healthy, right-handed subjects conducted four motor tasks of different complexity with their right hand: (i) simple reaction time, (ii) maximum finger and (iii) hand tapping frequencies and (iv) rapid pointing between two defined targets. Tapping and pointing tasks were measured with kinematic, three-dimensional recordings using an ultrasound motion analyzer system (Zebris). TMS pulses were applied as 10xa0Hz-trains time-locked to task execution. Stimulation was applied at 90% of resting motor threshold (rMT) to ipsilateral M1, dPMC and aIPS. Sham-stimulation at 90% of rMT to parieto-occipital vertex served as control condition. Results Online-TMS applied to ipsilateral M1 led to a significant response slowing and to a significantly increased coeffcient of variation in the simple reaction time task in elderly subjects. In contrast, performance of more complex motor tasks was not affected by ipsilateral M1-stimulation. TMS applied to the ipsilateral dPMC or aIPS affected the more complex motor tasks. DPMC-stimulation caused a reduction of tapping amplitude and a significant reduction of overall performance in the finger tapping task. TMS applied to the aIPS led to a significant reduction of tapping amplitude and tended to reduce overall performance in the hand tapping task. Furthermore, subjects showed a significant decrease of aiming accuracy in the pointing task, upon TMS interference with ipsilateral dPMC as well as aIPS in elderly subjects. Finally, within the group of elderly subjects, age strongly correlated with a frequency reduction of hand tapping induced by both M1- and aIPS-stimulation. Conclusion Consistent with previous work ( Vollmer et al., 2015 ), our findings underline the impact of ipsilateral M1 on simple motor task. We also show that in eldery subjects ipsilateral dPMC as well as ipsilateral aIPS seem to be causally engaged in maintaining performance in more complex motor tasks. These findings agree with neuroimaging studies indicating the IPS’ particular involvement in visuomotor tasks ( Grefkes et al., 2006 ). Of note, our results support the notion of age-dependent recruitment of ipsilateral M1 in motor tasks ( [Hutchinson et al., 2002] , [Riecker et al., 2006] ) and suggest a similar relevance of aIPS for motor performance in healthy ageing individuals.

P157. Incidence and predictability of motor functioning after resection of pre-centrally located brain tumours

Objective In addition to a maximum extent of resection the preservation of important functions such as motor control are the major objectives in brain tumour surgery, not least with respect to consecutive treatments such as radio- or chemotherapy which require a good clinical state of the patients. Brain mapping techniques such as functional MRI and navigated transcranial magnetic stimulation (nTMS) have facilitated a lot the preoperative planning of the resection of eloquent brain tumours. However, the clinical course after resection of precentrally located brain tumours is often associated with hardly predictable, at least transient deterioration of motor functions. Methods A case series of 10 patients (7M/3F, mean age 57.8xa0yrs) with precentrally located brain tumours was collected within a prospective clinical trial between 2012 and 2014. All of them underwent preoperative nTMS mapping of the tumour-adjacent M1 areas (Nexstim eXimia 4.2). Tumour volume, oedema volume, the minimal distance between tumour/ oedema and the adjacent primary motor (M1) representation (hot spot, margin of map; iPlanNet) and the resting motor threshold (RMT) were compared to the neurological outcome which was evaluated before surgery, immediately after surgery (ICU), at discharge and 3–6xa0months later (follow-up). Results 7/10 of the patients deteriorated immediately after surgery (ICU). At discharge, 5 patients showed an improved motor status compared to admission (example: Fig. 1 ) and 3 patients had deteriorated of which at least one patient continued with slightly deteriorated motor functioning 3xa0months after surgery. In 4 of these patients, the neurological symptoms were totally reversible ( Table 1 ). The preliminary analysis revealed a weak correlation ( p Conclusion Aiming at the total resection of brain tumours located anteriorly to the M1 representation, a transient motor deficit should be expected in a high percentage (70% in this study). However, the deficit usually recovers well during the first week after surgery. Mapping techniques for the supplementary and pre-motor area may improve the predictability of transient motor deficits which is not only important for diagnostic decisions but also for the patient management with respect to presurgical consultancy. A novel protocol for non-invasive SMA-mapping by repetitive nTMS is currently under pre-clinical investigation by our group and showed promising preliminary results.

P156. Good long-term error rate retest reliability of 10 Hz neuronavigated repetitive TMS speech/language mapping in healthy volunteers

Introduction Maximizing the extent of resection whilst preserving important brain functions is a major goal in the surgical treatment of brain tumours. For primary motor functions, the presurgical diagnostic techniques such as functional MRI (fMRI) and navigated transcranial magnetic stimulation (TMS) have improved a lot over the last decades and are extremely useful for preoperative risk evaluation and planning of the surgical approach. By contrast, presurgical mapping techniques for language-relevant areas are regarded poorly reliable (fMRI) and/or rather unspecific (repetitive TMS, rTMS). Methods We investigated the retest reliability of neuronavigated rTMS for speech/language mapping in 11 right-handed healthy volunteers in 3 consecutive sessions, spaced by 2–5 (short term) and 21–40 (long term) days. Navigated 10xa0Hz rTMS (Nexstim eXimia 4.2) was applied over the dominant hemisphere after determination of the individual inhibition threshold over the primary motor representation of the face/tongue. The bursts were triggered to picture presentation (naming task) without delay (picture-to-trigger intervalxa0=xa00). Errors were categorised as follows: arrest, delay, anomia, dysarthria, semantic and phonematic paraphasia. Results As shown in Table 1 , a good feasibility in terms of the evocation of errors was observed. Per session, speech delays occurred most frequently (9.2xa0±xa02.1), followed by dysarthria (5.1xa0±xa02.4) and speech arrests (3.8xa0±xa01.8) whilst paraphasias were rather rare. There was a high variability in the distribution and the frequency of speech errors between the subjects. The reliability of the error frequency was rather good regarding long-term comparisons (Cohen’s weighted Kappa kxa0=xa00.41 [session 1–3]/kxa0=xa00.42 [session 2–3]) and still fair for the short-term (kxa0=xa00.29 [session 1–2]). Analyses of the spatial reliability of error representation are ongoing. Conclusions Presurgical speech/language mapping by neuronavigated rTMS is a promising tool to improve the risk evaluation and the planning of the surgical approach. In this preclinical study a rather satisfactory retest reliability of rTMS mapping at 10xa0Hz could be shown. However, since the method is still young, optimisation of the stimulation protocol and further intraoperative validation in clinical trials are required.

P115. The predictive value of FAT and MFL for deterministic, NTMS-based fibre tracking using a multiple-ROI approach

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 navigated transcranial magnetic stimulation (nTMS) for the delineation of starting ROIs has improved the fibre tracking results in a multiple-ROI approach. However, alterations of MRI signals in and adjacent to brain tumours often lead to spurious tracking results. Parameters such as the minimal fibre track length (MFL) and the fractional anisotropy threshold (FAT) may reflect an unfavourable signal-to-noise ratio and, thus, the risk for non-plausible tractography results. Methods The CST of 32 patients with intracranial tumours was investigated by deterministic DTI (iPlanNet) and nTMS. The cortical seeds were defined by the nTMS hot spots of the primary motor area (M1) of the hand, the foot and the tongue representation. The CST originating from the contralesional M1 hand area was mapped as intra-individual reference. As subcortical region of interests (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 FAT and the MFL were analysed. Results Low FAT values (cut-off of 0.105) and long MFL (cut-off 121.5xa0mm) led to less plausible fibre tracking results ( Figure ). In addition, there was a strong effect of somatotopic location of the seed ROI; best plausibility was obtained for the contralateral hand CST (100%), followed by the ipsilesional hand CST (>95%), the ipsilesional foot (>85%) and tongue (>75%) CST. Conclusions In summary, we found excellent plausibility rates using a deterministic multiple-ROI approach with a cortical, nTMS-derived ROI and an additional ROI in the anterior pontine region. However, due to the technical limitations of the method, the results should always be interpreted with caution, especially when dealing with the FAT values lower than 0.105 or the MFL exceeding 121.5xa0mm.