Improving the efficacy and reliability of rTMS language mapping by increasing the stimulation frequency.

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 <.01), whereas error rates were comparable between 30/50 and 10 Hz (18 ± 11%). Across all conditions, a significantly higher error rate was found in Session 1 (19 ± 13%) compared to Session 2 (13 ± 7%, p <.05). The error rate was poorly reliable between sessions for 10 (intraclass correlation coefficient, ICC = .315) and 30 Hz (ICC = .427), whereas 50 Hz showed a moderate reliability (ICC = .597). Spatial reliability of language errors was low to moderate with a tendency toward increased reliability for higher frequencies, for example, within frontal regions. Compared to 10 Hz, both, 30 and 50 Hz were rated as less painful. Taken together, our data favor the use of rTMS-protocols employing higher frequencies for evoking language errors reliably and with reduced discomfort, depending on the region of interest.

Invasive versus non-invasive mapping of the motor cortex.

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.

Modulation of I-wave generating pathways by theta-burst stimulation: a model of plasticity induction.

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.

Cortical Inhibition of Face and Jaw Muscle Activity and Discomfort Induced by Repetitive and Paired-Pulse TMS During an Overt Object Naming Task.

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 < 0.001). Also, cSPs with longest durations were induced by PP. Exploratory analyses of PP suggest that the trials with strongest motor inhibitory effects (presence of cSP) were associated with more articulatory naming errors, hence hinting at the utility of TMS-elicited, facial cSP for mapping of language production areas. Higher-frequency rTMS and PP evoked stronger inhibitory effects as compared to 10 Hz-rTMS during a language task, thus enabling a probably more efficient and tolerable routine for language mapping. The spatial distribution of cranial muscle cSPs implies that TMS might affect not only M1, but also distant parts of the language network.

Short- and long-term reliability of language fMRI.

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 (ICC<0.5) and moderate (ICC 0.5-0.74) reliability, highly reliable voxels (ICC>0.75) 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.

Network dynamics engaged in the modulation of motor behavior in stroke patients.

Stroke patients with motor deficits typically feature enhanced neural activity in several cortical areas when moving their affected hand. However, also healthy subjects may show higher levels of neural activity in tasks with higher motor demands. Therefore, the question arises to what extent stroke-related overactivity reflects performance-level-associated recruitment of neural resources rather than stroke-induced neural reorganization. We here investigated which areas in the lesioned brain enable the flexible adaption to varying motor demands compared to healthy subjects. Accordingly, eleven well-recovered left-hemispheric chronic stroke patients were scanned using functional magnetic resonance imaging. Motor system activity was assessed for fist closures at increasing movement frequencies performed with the affected/right or unaffected/left hand. In patients, an increasing movement rate of the affected hand was associated with stronger neural activity in ipsilesional/left primary motor cortex (M1) but unlike in healthy controls also in contralesional/right dorsolateral premotor cortex (PMd) and contralesional/right superior parietal lobule (SPL). Connectivity analyses using dynamic causal modeling revealed stronger coupling of right SPL onto affected/left M1 in patients but not in controls when moving the affected/right hand independent of the movement speed. Furthermore, coupling of right SPL was positively coupled with the "active" ipsilesional/left M1 when stroke patients moved their affected/right hand with increasing movement frequency. In summary, these findings are compatible with a supportive role of right SPL with respect to motor function of the paretic hand in the reorganized brain.

Dose-dependent effects of theta burst rTMS on cortical excitability and resting-state connectivity of the human motor system.

Theta burst stimulation (TBS), a specific protocol of repetitive transcranial magnetic stimulation (rTMS), induces changes in cortical excitability that last beyond stimulation. TBS-induced aftereffects, however, vary between subjects, and the mechanisms underlying these aftereffects to date remain poorly understood. Therefore, the purpose of this study was to investigate whether increasing the number of pulses of intermittent TBS (iTBS) (1) increases cortical excitability as measured by motor-evoked potentials (MEPs) and (2) alters functional connectivity measured using resting-state fMRI, in a dose-dependent manner. Sixteen healthy, human subjects received three serially applied iTBS blocks of 600 pulses over the primary motor cortex (M1 stimulation) and the parieto-occipital vertex (sham stimulation) to test for dose-dependent iTBS effects on cortical excitability and functional connectivity (four sessions in total). iTBS over M1 increased MEP amplitudes compared with sham stimulation after each stimulation block. Although the increase in MEP amplitudes did not differ between the first and second block of M1 stimulation, we observed a significant increase after three blocks (1800 pulses). Furthermore, iTBS enhanced resting-state functional connectivity between the stimulated M1 and premotor regions in both hemispheres. Functional connectivity between M1 and ipsilateral dorsal premotor cortex further increased dose-dependently after 1800 pulses of iTBS over M1. However, no correlation between changes in MEP amplitudes and functional connectivity was detected. In summary, our data show that increasing the number of iTBS stimulation blocks results in dose-dependent effects at the local level (cortical excitability) as well as at a systems level (functional connectivity) with a dose-dependent enhancement of dorsal premotor cortex-M1 connectivity.

Inter-individual variability in cortical excitability and motor network connectivity following multiple blocks of rTMS.

The responsiveness to non-invasive neuromodulation protocols shows high inter-individual variability, the reasons of which remain poorly understood. We here tested whether the response to intermittent theta-burst stimulation (iTBS) - an effective repetitive transcranial magnetic stimulation (rTMS) protocol for increasing cortical excitability - depends on network properties of the cortical motor system. We furthermore investigated whether the responsiveness to iTBS is dose-dependent. To this end, we used a sham-stimulation controlled, single-blinded within-subject design testing for the relationship between iTBS aftereffects and (i) motor-evoked potentials (MEPs) as well as (ii) resting-state functional connectivity (rsFC) in 16 healthy subjects. In each session, three blocks of iTBS were applied, separated by 15min. We found that non-responders (subjects not showing an MEP increase of ≥10% after one iTBS block) featured stronger rsFC between the stimulated primary motor cortex (M1) and premotor areas before stimulation compared to responders. However, only the group of responders showed increases in rsFC and MEPs, while most non-responders remained close to baseline levels after all three blocks of iTBS. Importantly, there was still a large amount of variability in both groups. Our data suggest that responsiveness to iTBS at the local level (i.e., M1 excitability) depends upon the pre-interventional network connectivity of the stimulated region. Of note, increasing iTBS dose did not turn non-responders into responders. The finding that higher levels of pre-interventional connectivity precluded a response to iTBS could reflect a ceiling effect underlying non-responsiveness to iTBS at the systems level.

Network connectivity and individual responses to brain stimulation in the human motor system.

The mechanisms driving cortical plasticity in response to brain stimulation are still incompletely understood. We here explored whether neural activity and connectivity in the motor system relate to the magnitude of cortical plasticity induced by repetitive transcranial magnetic stimulation (rTMS). Twelve right-handed volunteers underwent functional magnetic resonance imaging during rest and while performing a simple hand motor task. Resting-state functional connectivity, task-induced activation, and task-related effective connectivity were assessed for a network of key motor areas. We then investigated the effects of intermittent theta-burst stimulation (iTBS) on motor-evoked potentials (MEP) for up to 25 min after stimulation over left primary motor cortex (M1) or parieto-occipital vertex (for control). ITBS-induced increases in MEP amplitudes correlated negatively with movement-related fMRI activity in left M1. Control iTBS had no effect on M1 excitability. Subjects with better response to M1-iTBS featured stronger preinterventional effective connectivity between left premotor areas and left M1. In contrast, resting-state connectivity did not predict iTBS aftereffects. Plasticity-related changes in M1 following brain stimulation seem to depend not only on local factors but also on interconnected brain regions. Predominantly activity-dependent properties of the cortical motor system are indicative of excitability changes following induction of cortical plasticity with rTMS.

Mapping the hand, foot and face representations in the primary motor cortex - retest reliability of neuronavigated TMS versus functional MRI.

INTRODUCTION: Functional magnetic resonance imaging (fMRI) is a frequently used non-invasive mapping technique for investigating the human motor system. Recently, neuronavigated transcranial magnetic stimulation (nTMS) has been established as an alternative approach. We here compared the test-retest reliability of both mapping techniques with regard to the cortical representations of the hand, leg, face and tongue areas. METHODS: Ten healthy subjects were examined three times (intervals: 3-5days/21-35days) with fMRI and nTMS. Motor-evoked potentials were recorded from the abductor pollicis brevis, plantaris, mentalis and the tongue muscles. The same muscles were activated in an fMRI motor task. Euclidean distances (ED) between hotspots and centers of gravity (CoG) were computed for the respective somatotopic representations. Furthermore, spatial reliability was tested by intersession overlap volumes (OV) and voxel-wise intraclass correlations (ICC). RESULTS: Feasibility of fMRI was 100% for all body parts and sessions. In contrast, nTMS was feasible in all sessions and subjects only for the hand area, while mappings of the foot (90%), face (70%) and tongue representations (40%) remained incomplete in several subjects due to technical constraints and co-stimulation artifacts. On average, the mean ED of the hotspots was better for fMRI (6.2±1.1mm) compared to nTMS (10.8±1.9mm) while stability of CoG was similar for both methods. Peak voxel reliability (ICC) was high for both methods (>0.8), and there was no influence of inter-session intervals. In contrast, the reliability of mapping the spatial extent of the hand, foot, lips and tongue representations was poor to moderate for both fMRI and nTMS (OVs and ICC<50%). Especially nTMS mappings of the face and tongue areas yielded poor reliability estimates. CONCLUSION: Both methods are highly reliable when mapping the core region of a given target muscle, especially for the hand representation area. In contrast, mapping the spatial extent of a cortical representation area was only little reliable for both nTMS and fMRI. In summary, fMRI was better suited when mapping motor representations of the head, while nTMS showed equal reliability for mapping the hand and foot representation areas. Hence, both methods may well complement each other.

Impact of the SARS-CoV-2 pandemic on the survival of patients with high-grade glioma and best practice recommendations.

The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has changed the clinical day-to-day practice. The aim of this study was to evaluate the impact of the pandemic on patients with high-grade glioma (HGG) as well as to derive best practice recommendations. We compared a multi-institutional cohort with HGG (n = 251) from 03/2020 to 05/2020 (n = 119) to a historical cohort from 03/2019 to 05/2019 (n = 132). The endpoints were outcome (progression-free survival (PFS) and overall survival (OS)) as well as patterns of care and time intervals between treatment steps. The median OS for WHO grade 4 gliomas was 12 months in 2019 (95% Confidence Interval 9.7-14.3 months), and not reached in 2020 (p = .026). There were no other significant differences in the Kaplan-Meier estimates for OS and PFS between cohorts of 2019 and 2020, neither did stratification by WHO grade reveal any significant differences for OS, PFS or for patterns of care. The time interval between cranial magnetic resonance imaging (cMRI) and biopsy was significantly longer in 2020 cohort (11 versus 21 days, p = .031). Median follow-up was 10 months (range 0-30 months). Despite necessary disease containment policies, it is crucial to ensure that patients with HGG are treated in line with the recent guidelines and standard of care (SOC) algorithms. Therefore, we strongly suggest pursuing no changes to SOC treatment, a timely diagnosis and treatment with short time intervals between first symptoms, initial diagnosis, and treatment, as well as a guideline-based cMRI follow-up.

Surgery of Motor Eloquent Glioblastoma Guided by TMS-Informed Tractography: Driving Resection Completeness Towards Prolonged Survival.

Background: Surgical treatment of patients with glioblastoma affecting motor eloquent brain regions remains critically discussed given the risk-benefit dilemma of prolonging survival at the cost of motor-functional damage. Tractography informed by navigated transcranial magnetic stimulation (nTMS-informed tractography, TIT) provides a rather robust estimate of the individual location of the corticospinal tract (CST), a highly vulnerable structure with poor functional reorganisation potential. We hypothesised that by a more comprehensive, individualised surgical decision-making using TIT, tumours in close relationship to the CST can be resected with at least equal probability of gross total resection (GTR) than less eloquently located tumours without causing significantly more gross motor function harm. Moreover, we explored whether the completeness of TIT-aided resection translates to longer survival. Methods: A total of 61 patients (median age 63 years, m = 34) with primary glioblastoma neighbouring or involving the CST were operated on between 2010 and 2015. TIT was performed to inform surgical planning in 35 of the patients (group T; vs. 26 control patients). To achieve largely unconfounded group comparisons for each co-primary outcome (i.e., gross-motor functional worsening, GTR, survival), (i) uni- and multivariate regression analyses were performed to identify features of optimal outcome prediction; (ii), optimal propensity score matching (PSM) was applied to balance those features pairwise across groups, followed by (iii) pairwise group comparison. Results: Patients in group T featured a significantly higher lesion-CST overlap compared to controls (8.7 ± 10.7% vs. 3.8 ± 5.7%; p = 0.022). The frequency of gross motor worsening was higher in group T, albeit non-significant (n = 5/35 vs. n = 0/26; p = 0.108). PSM-based paired-sample comparison, controlling for the confounders of preoperative tumour volume and vicinity to the delicate vasculature of the insula, showed higher GTR rates in group T (77% vs. 69%; p = 0.025), particularly in patients with a priori intended GTR (87% vs. 78%; p = 0.003). This translates into a prolonged PFS in the same PSM subgroup (8.9 vs. 5.8 months; p = 0.03), with GTR representing the strongest predictor of PFS (p = 0.001) and OS (p = 0.0003) overall. Conclusion: The benefit of TIT-aided GTR appears to overcome the drawbacks of potentially elevated motor functional risk in motor eloquent tumour localisation, leading to prolonged survival of patients with primary glioblastoma close to the CST.

The Cologne Picture Naming Test for Language Mapping and Monitoring (CoNaT): An Open Set of 100 Black and White Object Drawings.

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.

Accelerated Clustered Sparse Acquisition to Improve Functional MRI for Mapping Language Functions.

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 < 0.05). Mean ED between cluster centers ranged between 9.9 ± 5.4 mm (left superior temporal gyrus; centers of gravity) and 16.6 ± 13.2 mm (left inferior frontal gyrus; local activation maxima) for the picture-naming task. Overlaps between sparse and clustered acquisition reached 88% (Simpson overlap coefficient). A similar activation pattern for both acquisition methods was also confirmed in the clinical case. 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).

Effect of early palliative care for patients with glioblastoma (EPCOG): a randomised phase III clinical trial protocol.

​INTRODUCTION: Randomised controlled trials (RCTs) have shown a positive effect of early integration of palliative care (EIPC) in various advanced cancer entities regarding patients' quality of life (QoL), survival, mood, caregiver burden and reduction of aggressiveness of treatment near the end of life. However, RCTs investigating the positive effect of EIPC for patients suffering from glioblastoma multiforme (GBM) are lacking. After modelling work identifying the specific needs of GBM patients and their caregivers, the aim of this study is to investigate the impact of EIPC in this particular patient group. ​METHODS AND ANALYSIS: The recruitment period of this multicenter RCT started in May 2019. GBM patients (n=214) and their caregivers will be randomly assigned to either the intervention group (receiving proactive EIPC on a monthly basis) or the control group (receiving treatment according to international standards and additional, regular assessment of QoL ('optimised' standard care)).The primary outcome is QoL assessed by subscales of the Functional Assessment of Cancer Therapy for brain tumour (FACT-Br) from baseline to 6 months of treatment. Secondary outcomes are changes in QoL after 12 (end of intervention), 18 and 24 months (end of follow-up), the full FACT-Br scale, patients' palliative care needs, depression/anxiety, cognitive impairment, caregiver burden, healthcare use, cost-effectiveness and overall survival. ​ETHICS AND DISSEMINATION: The study will be conducted in accordance with the Declaration of Helsinki and has been approved by the local ethics committees of the University Clinics of Cologne, Aachen, Bonn, Freiburg and Munich (LMU). Results of the trial will be submitted for publication in a peer-reviewed, open access journal and disseminated through presentations at conferences. TRIAL REGISTRATION NUMBER: German Register for Clinical Studies (DRKS) (DRKS00016066); Pre-results.

Functional MRI vs. navigated TMS to optimize M1 seed volume delineation for DTI tractography. A prospective study in patients with brain tumours adjacent to the corticospinal tract.

BACKGROUND: DTI-based tractography is an increasingly important tool for planning brain surgery in patients suffering from brain tumours. However, there is an ongoing debate which tracking approaches yield the most valid results. Especially the use of functional localizer data such as navigated transcranial magnetic stimulation (nTMS) or functional magnetic resonance imaging (fMRI) seem to improve fibre tracking data in conditions where anatomical landmarks are less informative due to tumour-induced distortions of the gyral anatomy. We here compared which of the two localizer techniques yields more plausible results with respect to mapping different functional portions of the corticospinal tract (CST) in brain tumour patients. METHODS: The CSTs of 18 patients with intracranial tumours in the vicinity of the primary motor area (M1) were investigated by means of deterministic DTI. The core zone of the tumour-adjacent hand, foot and/or tongue M1 representation served as cortical regions of interest (ROIs). M1 core zones were defined by both the nTMS hot-spots and the fMRI local activation maxima. In addition, for all patients, a subcortical ROI at the level of the inferior anterior pons was implemented into the tracking algorithm in order to improve the anatomical specificity of CST reconstructions. As intra-individual control, we additionally tracked the CST of the hand motor region of the unaffected, i.e., non-lesional hemisphere, again comparing fMRI and nTMS M1 seeds. The plausibility of the fMRI-ROI- vs. nTMS-ROI-based fibre trajectories was assessed by a-priori defined anatomical criteria. Moreover, the anatomical relationship of different fibre courses was compared regarding their distribution in the anterior-posterior direction as well as their location within the posterior limb of the internal capsule (PLIC). RESULTS: Overall, higher plausibility rates were observed for the use of nTMS- as compared to fMRI-defined cortical ROIs (p < 0.05) in tumour vicinity. On the non-lesional hemisphere, however, equally good plausibility rates (100%) were observed for both localizer techniques. fMRI-originated fibres generally followed a more posterior course relative to the nTMS-based tracts (p < 0.01) in both the lesional and non-lesional hemisphere. CONCLUSION: NTMS achieved better tracking results than fMRI in conditions when the cortical tract origin (M1) was located in close vicinity to a brain tumour, probably influencing neurovascular coupling. Hence, especially in situations with altered BOLD signal physiology, nTMS seems to be the method of choice in order to identify seed regions for CST mapping in patients.

Improved nTMS- and DTI-derived CST tractography through anatomical ROI seeding on anterior pontine level compared to internal capsule.

Imaging of the course of the corticospinal tract (CST) by diffusion tensor imaging (DTI) is useful for function-preserving tumour surgery. The integration of functional localizer data into tracking algorithms offers to establish a direct structure-function relationship in DTI data. However, alterations of MRI signals in and adjacent to brain tumours often lead to spurious tracking results. We here compared the impact of subcortical seed regions placed at different positions and the influences of the somatotopic location of the cortical seed and clinical co-factors on fibre tracking plausibility in brain tumour patients. The CST of 32 patients with intracranial tumours was investigated by means of deterministic DTI and neuronavigated transcranial magnetic stimulation (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 posterior limb of the internal capsule (PLIC) and/or the anterior inferior pontine region (aiP). The plausibility of the fibre trajectories was assessed by a-priori defined anatomical criteria. The following potential co-factors were analysed: Karnofsky Performance Scale (KPS), resting motor threshold (RMT), T1-CE tumour volume, T2 oedema volume, presence of oedema within the PLIC, the fractional anisotropy threshold (FAT) to elicit a minimum amount of fibres and the minimal fibre length. The results showed a higher proportion of plausible fibre tracts for the aiP-ROI compared to the PLIC-ROI. Low FAT values and the presence of peritumoural oedema within the PLIC led to less plausible fibre tracking results. Most plausible results were obtained when the FAT ranged above a cut-off of 0.105. 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. In summary, we found that the aiP-ROI yielded better tracking results compared to the IC-ROI when using deterministic CST tractography in brain tumour patients, especially when the M1 hand area was tracked. In case of FAT values lower than 0.10, the result of the respective CST tractography should be interpreted with caution with respect to spurious tracking results. Moreover, the presence of oedema within the internal capsule should be considered a negative predictor for plausible CST tracking.