Transcranial magnetic stimulation combined with functional magnetic resonance imaging: From target identification to prediction of therapeutic effects in stroke patients

Repetitive transcranial magnetic stimulation (rTMS), particularly theta-burst stimulation (TBS), can be applied to modulate cortical excitability beyond the period of stimulation (Huang et al., 2005). Consequently, rTMS is regarded to have high therapeutic potential for treatment of various psychiatric and neurological diseases related to cortical hypo- or hyperexcitability such as stroke (Ridding & Rothwell, 2007). Whether rTMS induced effects are sufficiently robust to be useful in clinical settings is currently under intense investigation. The most challenging problem appears to be considerably high variability in rTMS induced effects both, across studies (Hoogendam et al., 2010) and individual patients (Ameli et al., 2009). Hence, the major goal of the present thesis was to improve rTMS intervention strategies in stroke patients suffering from chronic motor hand deficits by multimodal uses of (repetitive) TMS with state-of-the-art neuroimaging techniques. Sources of variance across studies are likely to be methodological in origin. They might result from different strategies to identify the cortical rTMS target position. Individual functional magnetic resonance (fMRI) data have been demonstrated to yield best spatial approximations of the most excitable TMS position compared to other techniques (Sparing et al., 2008). However, there is still a considerably large spatial mismatch between the cortical position showing highest movement-related fMRI signal and the cortical position yielding highest muscle responses when stimulated with TMS of up to 14 mm (Bastings et al., 1998; Boroojerdi et al., 1999; Herwig et al., 2002; Krings et al., 1997; Lotze et al., 2003; Sparing et al., 2008; Terao et al., 1998). The underlying cause of this spatial mismatch is unknown. Hence, the aim of the first study (Study I) of the present thesis was to test the hypothesis that the spatial mismatch between positions with highest fMRI signal change and positions with highest TMS excitability might be caused by the widely-used Gradient-Echo blood oxygenation level dependent (GRE-BOLD) fMRI technique. GRE-BOLD signal has been demonstrated to occur further downstream from the site of neural activity in large veins running on the cerebral surface (Uludag et al., 2009). Consequently, we tested the hypothesis that alternative fMRI sequences may localize neural activity (i) closer to the anatomical motor hand area, i.e. Brodmann Area 4 (BA4), and (ii) closer to the optimal TMS position than GRE-BOLD. The following alternative fMRI techniques were tested: (i) Spin-Echo (SE-BOLD) assessing blood oxygenation level dependent signal changes with decreased sensitivity for the macrovasculature at high magnetic fields (≥ 3 Tesla, Uludag et al., 2009) and (ii) arterial spin labelling (ASL), assessing local changes in cerebral blood flow (ASL-CBF) which have been shown to occur in close proximity to synaptic activity (Duong et al., 2000). GRE-BOLD, SE-BOLD, and ASL-CBF signal changes during right thumb abductions were obtained from 15 healthy young subjects at 3 Tesla. In 12 subjects, brain tissue at fMRI peak voxel coordinates was stimulated with neuronavigated TMS to investigate whether spatial differences between fMRI techniques are functionally relevant, i.e. impact on motor-evoked potentials (MEPs) recorded from a contralateral target muscle, which is involved in thumb abductions. A systematic TMS motor mapping was performed to identify the most excitable TMS position (i.e. the TMS hotspot) and the centre-of-gravity (i.e. the TMS CoG), which considers the spatial distribution of excitability in the pericentral region. Euclidean distances between TMS and fMRI positions were calculated for each fMRI technique. Results indicated that highest SE-BOLD and ASL-CBF signal changes occurred in the anterior wall of the central sulcus (BA4), whereas highest GRE-BOLD signal changes occurred significantly closer to the gyral surface where most large draining veins are located. fMRI techniques were not significantly different from each other in Euclidean distances to optimal TMS positions since optimal TMS positions were located considerably more anterior (and slightly surprisingly in premotor cortex (BA6) and not BA4). Stimulation of brain tissue at GRE-BOLD peak voxel coordinates with TMS resulted in significantly higher MEPs (compared to SE-BOLD and ASL-CBF coordinates). This was probably the case because GRE-BOLD positions tended to be located at the gyral crown, which was slightly (but not significantly) closer to the TMS hotspot position. Taken together, findings of Study I suggest that spatial differences between fMRI and TMS positions are not caused by spatial unspecificity of the widely-used GRE-BOLD fMRI technique. Hnece, other factors such as complex interactions between brain tissue and the TMS induced electric field (Opitz et al., 2011), could be the underlying cause. Identification of the cortical rTMS target position is particularly challenging in stroke patients since reorganization processes after stroke may shift both, fMRI and TMS positions in unknown direction and extend (Rossini et al., 1998). In the second study (Study II) of the present thesis, we therefore tested whether findings obtained from healthy young subjects in Study I do also apply to chronic stroke patients and older (i.e. age-matched) healthy control subjects. In this study, arterial spin labelling (ASL) was used to assess CBF and BOLD signal changes simultaneously during thumb abductions with the affected/non-dominant and the unaffected/dominant hand in 15 chronic stroke patients and 13 age-matched healthy control subjects at 3 Tesla. Brain tissue at fMRI peak voxel coordinates was stimulated with neuronavigated TMS to test whether spatial differences are functionally relevant and impact on MEPs. Systematic TMS motor mappings were performed for both hemispheres in overall 12 subjects (6 stroke patients and 6 healthy subjects). Euclidean distances between fMRI and TMS positions were calculated for each hemisphere and fMRI technique. In line with results of Study I, highest ASL-CBF signal changes were located in the anterior wall of the central sulcus (BA4), whereas highest ASL-BOLD signal changes occurred significantly closer to the gyral surface. In contrast to Study I, there were no significant differences between ASL-CBF and ASL-BOLD positions in MEPs when stimulated with neuronavigated TMS, which suggests that spatial differences (in depth) were not functionally relevant for TMS applications. In line with Study I, there were no significant differences between fMRI techniques in Euclidean distances to optimal TMS positions, since optimal TMS positions were located considerably more anterior than fMRI positions (in premotor cortex, i.e. BA6). Stroke patients showed overall larger displacements (between fMRI and TMS positions) on the ipsilesional (but not the contralesional) hemisphere compared to healthy subjects. However, none of the fMRI techniques yielded positions significantly closer to the optimal TMS position. Hence, functional reorganization may impact on spatial congruence between fMRI and TMS, but the effect is similar for ASL-CBF and ASL-BOLD. Pathomechanisms underlying stroke induced motor deficits are still poorly understood but a simplified model of hemispheric competition has been suggested, which proposes relative hypoexcitability of the ipsilesional hemisphere and hyperexcitability of the contralesional hemisphere leading to pathologically increased interhemispheric inhibition from the contralesional onto the ipsilesional hemisphere during movements of the paretic hand (Duque et al., 2005; Grefkes et al., 2008b, 2010; Murase et al., 2004). In line with the model of hemispheric competition, both increasing excitability of the ipsilesional hemisphere (Khedr et al., 2005; Talelli et al., 2007) as well as decreasing excitability of the contralesional hemisphere (Fregni et al., 2006; Di Lazzaro et al., 2008a) have been demonstrated to normalize cortical excitability towards physiological levels and/or ameliorate motor performance of the stroke affected hand. However, there is considerably high inter-individual variance and some patients may even show deteriorations of motor performance after rTMS (Ameli et al., 2009). Therefore, the aim of the third study (Study III) was to identify reliable predictors for TBS effects on motor performance of the affected hand in stroke patients, which appears essential for successful implementation of TBS in neurorehabilitation. Overall, 13 chronic stroke patients with unilateral motor hand deficit and 12 age-matched healthy control subjects were included in the study. All patients received 3 different TBS interventions on 3 different days: (i) intermittent TBS (iTBS, facilitatory) over the primary motor cortex (M1) of the ipsilesional hemisphere, (ii) continuous TBS (cTBS, inhibitory) over M1 of the contralesional hemisphere, and (iii) either iTBS or cTBS over a control stimulation site (to control for placebo effects). Motor performance was measured before and after each TBS session with 3 different motor tasks and an overall motor improvement score was calculated. All subjects participated in an fMRI experiment, in which they performed rhythmic fist closures with their affected/non-dominant and unaffected/dominant hand. A laterality index (LI), reflecting laterality of fMRI signal in cortical motor areas was calculated. Effective connectivity, i.e. the direct or indirect causal influence that activity in one area exerts on activity of another area (Friston et al., 1993a), was inferred from fMRI data by means of dynamic causal modelling (DCM). Due to relatively high inter-individual variance, neither iTBS nor cTBS was significantly different from control TBS in terms of average behavioural (or electrophysiological) changes over the group of patients. However, beneficial effects of iTBS over the ipsilesional hemisphere were predicted by a unilateral fMRI activation pattern during movements of the affected hand and by the integrity of the cortical motor network. The more pronounced the promoting influence from the ipsilesional supplementary motor area (SMA) onto ipsilesional M1 and the more pronounced the inhibitory effect originating from ipsilesional M1 onto contralesional M1, the better was the behavioural response to facilitatory iTBS applied to the ipsilesional hemisphere. No significant correlations were found for behavioural improvements following cTBS or behavioural changes of the unaffected hand. Taken together, Study III yielded promising results indicating that laterality of fMRI signal and integrity of the motor network architecture constitute promising predictors for response to iTBS. In patients in whom the connectivity pattern of the ipsilesional motor network resembled physiological network connectivity patterns (i.e. preserved inhibition of the contralesional hemisphere and supportive role of the SMA of the ipsilesional hemisphere), beneficial effects of iTBS over the ipsilesional hemisphere could be observed. In contrast, patients with severely disturbed motor networks did not respond to iTBS or even deteriorated

Degeneration of corpus callosum and recovery of motor function after stroke: A multimodal magnetic resonance imaging study

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Interindividual differences in motor network connectivity and behavioral response to iTBS in stroke patients

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

Motor cortex excitability and connectivity in chronic stroke: a multimodal model of functional reorganization

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