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.

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 level.

Handedness denotes the individual predisposition to consistently use the left or right hand for most types of skilled movements. A putative neurobiological mechanism for handedness consists in hemisphere-specific differences in network dynamics that govern unimanual movements. We, therefore, used functional magnetic resonance imaging and dynamic causal modeling to investigate effective connectivity between key motor areas during fist closures of the dominant or non-dominant hand performed by 18 right- and 18 left-handers. Handedness was assessed employing the Edinburgh-Handedness-Inventory (EHI). The network of interest consisted of key motor regions in both hemispheres including the primary motor cortex (M1), supplementary motor area (SMA), ventral premotor cortex (PMv), motor putamen (Put) and motor cerebellum (Cb). The connectivity analysis revealed that in right-handed subjects movements of the dominant hand were associated with significantly stronger coupling of contralateral (left, i.e., dominant) SMA with ipsilateral SMA, ipsilateral PMv, contralateral motor putamen and contralateral M1 compared to equivalent connections in left-handers. The degree of handedness as indexed by the individual EHI scores also correlated with coupling parameters of these connections. In contrast, we found no differences between right- and left-handers when testing for the effect of movement speed on effective connectivity. In conclusion, the data show that handedness is associated with differences in effective connectivity within the human motor network with a prominent role of SMA in right-handers. Left-handers featured less asymmetry in effective connectivity implying different hemispheric mechanisms underlying hand motor control compared to right-handers.

Cerebral ischemia triggers a cascade of cellular processes, which induce neuroprotection, inflammation, apoptosis and regeneration. At the neural network level, lesions concomitantly induce cerebral plasticity. Yet, many stroke survivors are left with a permanent motor deficit, and only little is known about the neurobiological factors that determine functional outcome after stroke. Transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) are non-invasive approaches that allow insights into the functional (re-) organization of the cortical motor system. We here combined neuronavigated TMS, MRI and analyses of connectivity to investigate to which degree recovery of hand function depends on corticospinal tract (CST) damage and biomarkers of cerebral plasticity like cortical excitability and motor network effective connectivity. As expected, individual motor performance of 12 stroke patients with persistent motor deficits was found to depend upon the degree of CST damage but also motor cortex excitability and interhemispheric connectivity. In addition, the data revealed a strong correlation between reduced ipsilesional motor cortex excitability and reduced interhemispheric inhibition in severely impaired patients. Interindividual differences in ipsilesional motor cortex excitability were stronger related to the motor deficit than abnormal interhemispheric connectivity or CST damage. Multivariate linear regression analysis combining the three factors accounted for more than 80 % of the variance in functional impairment. The inter-relation of cortical excitability and reduced interhemispheric inhibition provides direct multi-modal evidence for the disinhibition theory of the contralesional hemisphere following stroke. Finally, our data reveal a key mechanism (i.e., the excitability-related reduction in interhemispheric inhibition) accounting for the rehabilitative potential of novel therapeutic approaches which aim at modulating cortical excitability in stroke patients.

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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.

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Cerebral plasticity-inducing approaches like repetitive transcranial magnetic stimulation (rTMS) are of high interest in situations where reorganization of neural networks can be observed, e.g., after stroke. However, an increasing number of studies suggest that improvements in motor performance of the stroke-affected hand following modulation of primary motor cortex (M1) excitability by rTMS shows a high interindividual variability. We here tested the hypothesis that in stroke patients the interindividual variability of behavioral response to excitatory rTMS is related to interindividual differences in network connectivity of the stimulated region. Chronic stroke patients (n = 14) and healthy controls (n = 12) were scanned with functional magnetic resonance imaging (fMRI) while performing a simple hand motor task. Dynamic causal modeling (DCM) was used to investigate effective connectivity of key motor regions. On two different days after the fMRI experiment, patients received either intermittent theta-burst stimulation (iTBS) over ipsilesional M1 or control stimulation over the parieto-occipital cortex. Motor performance and TMS parameters of cortical excitability were measured before and after iTBS. Our results revealed that patients with better motor performance of the affected hand showed stronger endogenous coupling between supplemental motor area (SMA) and M1 before starting the iTBS intervention. Applying iTBS to ipsilesional M1 significantly increased ipsilesional M1 excitability and decreased contralesional M1 excitability as compared to control stimulation. Individual behavioral improvements following iTBS specifically correlated with neural coupling strengths in the stimulated hemisphere prior to stimulation, especially for connections targeting the stimulated M1. Combining endogenous connectivity and behavioral parameters explained 82% of the variance in hand motor performance observed after iTBS. In conclusion, the data suggest that the individual susceptibility to iTBS after stroke is influenced by interindividual differences in motor network connectivity of the lesioned hemisphere.