Imaging cortical plasticity in the human motor system

Intermittent theta-burst stimulation (iTBS) is a novel form of repetitive transcranial magnetic stimulation (rTMS) inducing increases in cortical excitability that last beyond stimulation. Compared to conventional rTMS protocols iTBS induces strong and long-lasting aftereffects with shorter stimulation time and less stimulation intensity. However, mechanisms underlying iTBS-induced aftereffects as well as factors contributing to a high inter-individual variability between subjects are still poorly understood. The aim of the present study was to gain some new insights into these mechanisms by combining non-invasive brain stimulation with neuroimaging and connectivity analyses of the human motor system. Previous studies suggested a link between rTMS aftereffects and activity as well as connectivity of the stimulated region. However, the mechanisms underlying iTBS-induced plasticity on the systems level are still incompletely understood. Hence, the aim of the first study of the present thesis was to investigate how neural activity and connectivity of the motor system are related to aftereffects of iTBS. Therefore, 12 healthy, right-handed volunteers underwent functional magnetic resonance imaging (fMRI) during rest (resting-state fMRI, rs-fMRI) and while performing a simple hand motor task. Based on this data, resting-state functional connectivity (rsFC) and task-induced activation as well as task-related effective connectivity were assessed. In separate sessions, aftereffects of iTBS applied over the left, primary motor cortex (M1) and the parieto-occipital vertex (sham) were tested for up to 25 min by measuring motor-evoked potentials (MEPs). High MEP increases post stimulation correlated with low movement-induced blood oxygenation level dependent (BOLD) activity in the stimulated M1. MEP changes also correlated positively with the effective connectivity between M1 and different premotor regions. However, no correlation could be found for rsFC. Therefore, our data suggest that changes in cortical plasticity induced by iTBS not only depend on local properties of the stimulated region, but also on activity-dependent properties of the cortical motor system. Furthermore, different studies recently aimed at enhancing iTBS aftereffects by increasing the dose. However, no additive aftereffects could be observed. This may result from the incomplete understanding of the mechanisms underlying the dose-dependent induction of cortical plasticity in humans. The second study, therefore, aimed at investigating the dose-dependency of iTBS aftereffects by applying multiple stimulation blocks within a short time-interval. Possible mechanisms underlying cortical plasticity should be revealed by combining iTBS with connectivity analyses of the motor system. 16 healthy, right-handed subjects received three serially applied blocks of iTBS with an interstimulus-interval of 15 min. Each subject underwent M1- and sham-iTBS in two separate sessions. Aftereffects were tested on both MEP amplitudes as well as rsFC leading to a total of four sessions: M1-iTBS_MEPs, sham-iTBS_MEPs, M1_rs-fMRI, sham_rs-fMRI. For the first time, a dose-dependent buildup of aftereffects after the third block could be found both on the local level (MEPs) as well as on the systems level (rsFC). These increases in MEP amplitudes and rsFC were not linearly correlated, thus, possibly representing two parallel mechanisms underlying iTBS-induced plasticity. Of note, similar dose-dependent alterations of cortical protein expression of distinct subgroups of GABAergic inhibitory interneurons were observed following multiple iTBS blocks in an animal model. Hence, possibly suggesting a similar mechanism to be involved in iTBS aftereffects in humans. Recently, a considerable number of studies addressing the variability of TBS aftereffects reported strong variations across subjects often resulting in no overall effects on the group level. The reasons for this variability remain poorly understood. Moreover, the question arises whether non-responders to iTBS can be turned into responders by increasing the dose. Therefore, in the third study, the data of the second study were re-analyzed with respect to the individual susceptibility to iTBS. Subjects were grouped into responders (n=7) and non-responders (n=9) according to their increase in MEP amplitudes after one iTBS block. When taking the individual responsiveness to iTBS into account a higher rsFC between M1 and premotor areas before stimulation could be found for non-responders compared to responders. Interestingly, non-responders to iTBS after one block could not be turned into responders by increasing the dose, i.e., applying a second or third block of iTBS. In contrast, responders after one block of iTBS featured a dose-dependent increase in MEP amplitudes as well as rsFC after all three iTBS blocks. Hence, our data suggest that responsiveness to iTBS at the local level (i.e., M1 excitability) is related to the capability of modulating network connectivity of the stimulated region (i.e., motor network). A ceiling effect at the systems level might underlie non-responsiveness to iTBS since higher levels of pre-interventional connectivity precluded a further increase upon iTBS. Taken together, the findings of the present thesis add to the understanding of the mechanisms underlying iTBS aftereffects as well as the factors contributing to the high inter-individual variability. Furthermore, our data might help to improve the usefulness of iTBS in both basic research and as a therapeutic intervention

tDCS induced GABA change is associated with the simulated electric field in M1, an effect mediated by grey matter volume in the MRS voxel

Background and objectiveTranscranial direct current stimulation (tDCS) has wide ranging applications in neuro-behavioural and physiological research, and in neurological rehabilitation. However, it is currently limited by substantial inter-subject variability in responses, which may be explained, at least in part, by anatomical differences that lead to variability in the electric field (E-field) induced in the cortex. Here, we tested whether the variability in the E-field in the stimulated cortex during anodal tDCS, estimated using computational simulations, explains the variability in tDCS induced changes in GABA, a neurophysiological marker of stimulation effect. MethdsData from five previously conducted MRS studies were combined. The anode was placed over the left primary motor cortex (M1, 3 studies, N = 24) or right temporal cortex (2 studies, N = 32), with the cathode over the contralateral supraorbital ridge. Single voxel spectroscopy was performed in a 2x2x2cm voxel under the anode in all cases. MRS data were acquired before and either during or after 1 mA tDCS using either a sLASER sequence (7T) or a MEGA-PRESS sequence (3T). sLASER MRS data were analysed using LCModel, and MEGA-PRESS using FID-A and Gannet. E-fields were simulated in a finite element model of the head, based on individual structural MR images, using SimNIBS. Separate linear mixed effects models were run for each E-field variable (mean and 95th percentile; magnitude, and components normal and tangential to grey matter surface, within the MRS voxel). The model included effects of time (pre or post tDCS), E-field, grey matter volume in the MRS voxel, and a 3-way interaction between time, E-field and grey matter volume. Additionally, we ran a permutation analysis using PALM to determine whether E-field anywhere in the brain, not just in the MRS voxel, correlated with GABA change. ResultsIn M1, higher mean E-field magnitude was associated with greater anodal tDCS-induced decreases in GABA (t(24) = 3.24, p = 0.003). Further, the association between mean E-field magnitude and GABA change was moderated by the grey matter volume in the MRS voxel (t(24) = -3.55, p = 0.002). These relationships were consistent across all E-field variables except the mean of the normal component. No significant relationship was found between tDCS-induced GABA decrease and E-field in the temporal voxel. No significant clusters were found in the whole brain analysis. ConclusionsOur data suggest that the electric field induced by tDCS within the brain is variable, and is significantly related to anodal tDCS-induced decrease in GABA, a key neurophysiological marker of stimulation. These findings strongly support individualised dosing of tDCS, at least in M1. Further studies examining E-fields in relation to other outcome measures, including behaviour, will help determine the optimal E-fields required for any desired effects

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 (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

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)

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

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

Data supporting "Learning to optimize perceptual decisions through suppressive interactions in the human brain"

Behavioural data. Resting state fMRI data. GABA measurements. For further information, see the associated Data Description file. Raw data can be provided upon request to the first and/or corresponding author