Charlotte Nettekoven

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.

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.

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.

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.

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.

Shaping Early Reorganization of Neural Networks Promotes Motor Function after Stroke

Neural plasticity is a major factor driving cortical reorganization after stroke. We here tested whether repetitively enhancing motor cortex plasticity by means of intermittent theta-burst stimulation (iTBS) prior to physiotherapy might promote recovery of function early after stroke. Functional magnetic resonance imaging (fMRI) was used to elucidate underlying neural mechanisms. Twenty-six hospitalized, first-ever stroke patients (time since stroke: 1–16 days) with hand motor deficits were enrolled in a sham-controlled design and pseudo-randomized into 2 groups. iTBS was administered prior to physiotherapy on 5 consecutive days either over ipsilesional primary motor cortex (M1-stimulation group) or parieto-occipital vertex (control-stimulation group). Hand motor function, cortical excitability, and resting-state fMRI were assessed 1 day prior to the first stimulation and 1 day after the last stimulation. Recovery of grip strength was significantly stronger in the M1-stimulation compared to the control-stimulation group. Higher levels of motor network connectivity were associated with better motor outcome. Consistently, control-stimulated patients featured a decrease in intra- and interhemispheric connectivity of the motor network, which was absent in the M1-stimulation group. Hence, adding iTBS to prime physiotherapy in recovering stroke patients seems to interfere with motor network degradation, possibly reflecting alleviation of post-stroke diaschisis.

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.

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.

P 82. Dose-dependent effects of theta-burst rTMS on the cortical excitability and fMRI-connectivity of the primary motor cortex

Introduction Theta Burst Stimulation (TBS) is an effective rTMS-protocol to modulate the excitability of cortical motor regions (Huang et al., 2005). However, the effects between subjects are rather variable (Hamda et al., 2012). The reason for this variability is still unclear (Thickbroom, 2007). Recently, animal studies showed that there are dose-dependent effects of TBS on the expression of cellular proteins (Volz et al., 2010). In contrast, studies with human subjects did not find a consistent dose–effect after applying two TBS sessions serially at different intersession intervals (Gamboa et al., 2010, 2011). Objectives The aim of our study was to investigate the effect of a triple TBS session on the cortical excitability compared to a control-stimulation. By combining TBS with functional magnetic resonance imaging (fMRI) measurements we sought to reveal stimulation effects on cortical connectivity. Methods 15 healthy subjects received three stimulations according to the iTBS-protocol (600 pulses per stimulation, (Huang et al., 2005)). iTBS sessions were applied in a serial fashion spaced by intervals of 15min. Two different stimulation sites were tested at different days: primary motor cortex (M1) and the parieto-occipital cortex (control). Stimulation after-effects on cortical excitability were tested via stimulus–response curves. In separate stimulation sessions, the iTBS effects on fMRI-connectivity were tested for two conditions: (i) resting-state measurements and (ii) during thumb movements. The following motor areas were included in the network analysis: M1, supplementary motor area (SMA), dorsal and ventral premotor cortex (dPMC, vPMC), anterior intraparietal cortex, putamen, thalamus and cerebellum. Results We found a dose-dependent effect of iTBS on the height of the stimulus–response-curve with significantly higher MEPs after applying iTBS over M1 compared to the control-stimulation. The connectivity-analyses revealed that after M1 stimulation with 1800 pulses the effective connectivity of the ipsilateral dPMC to the stimulated M1 was significantly enhanced while the control-stimulation had no differential effect on cortical connectivity ( p Conclusions Our results suggest that the after-effects of iTBS are dose-dependent. Furthermore, our data show that iTBS of M1 leads to a higher integration of the stimulated area with premotor areas.

Short- and long-term reliability of language fMRI

ABSTRACT 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 Symbol 1.36mm) as compared to the CoGs (8.03 Symbol 2.01mm). 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. Symbol. No caption available. Symbol. No caption available. 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.