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

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

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 15 min.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 lev

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

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

Modulation of I‐wave generating pathways by TBS: a model of plasticity induction

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

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

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