Functional connectivity in relation to motor performance and recovery after stroke.

Plasticity after stroke has traditionally been studied by observing changes only in the spatial distribution and laterality of focal brain activation during affected limb movement. However, neural reorganization is multifaceted and our understanding may be enhanced by examining dynamics of activity within large-scale networks involved in sensorimotor control of the limbs. Here, we review functional connectivity as a promising means of assessing the consequences of a stroke lesion on the transfer of activity within large-scale neural networks. We first provide a brief overview of techniques used to assess functional connectivity in subjects with stroke. Next, we review task-related and resting-state functional connectivity studies that demonstrate a lesion-induced disruption of neural networks, the relationship of the extent of this disruption with motor performance, and the potential for network reorganization in the presence of a stroke lesion. We conclude with suggestions for future research and theories that may enhance the interpretation of changing functional connectivity. Overall findings suggest that a network level assessment provides a useful framework to examine brain reorganization and to potentially better predict behavioral outcomes following stroke

Locally embedded presages of global network bursts

Spontaneous, synchronous bursting of neural population is a widely observed phenomenon in nervous networks, which is considered important for functions and dysfunctions of the brain. However, how the global synchrony across a large number of neurons emerges from an initially non-bursting network state is not fully understood. In this study, we develop a new state-space reconstruction method combined with high-resolution recordings of cultured neurons. This method extracts deterministic signatures of upcoming global bursts in "local" dynamics of individual neurons during non-bursting periods. We find that local information within a single-cell time series can compare with or even outperform the global mean field activity for predicting future global bursts. Moreover, the inter-cell variability in the burst predictability is found to reflect the network structure realized in the non-bursting periods. These findings demonstrate the deterministic mechanisms underlying the locally concentrated early-warnings of the global state transition in self-organized networks

Causal evidence that intrinsic beta frequency is relevant for enhanced signal propagation in the motor system as shown through rhythmic TMS

Correlative evidence provides support for the idea that brain oscillations underpin neural computations. Recent work using rhythmic stimulation techniques in humans provide causal evidence but the interactions of these external signals with intrinsic rhythmicity remain unclear. Here, we show that sensorimotor cortex precisely follows externally applied rhythmic TMS (rTMS) stimulation in the beta-band but that the elicited responses are strongest at the intrinsic individual beta-peak-frequency. While these entrainment effects are of short duration, even subthreshold rTMS pulses propagate through the network and elicit significant cortico-spinal coupling, particularly when stimulated at the individual beta-frequency. Our results show that externally enforced rhythmicity interacts with intrinsic brain rhythms such that the individual peak frequency determines the effect of rTMS. The observed downstream spinal effect at the resonance frequency provides evidence for the causal role of brain rhythms for signal propagation

Reorganization of cerebral networks after stroke: new insights from neuroimaging with connectivity approaches

The motor system comprises a network of cortical and subcortical areas interacting via excitatory and inhibitory circuits, thereby governing motor behaviour. The balance within the motor network may be critically disturbed after stroke when the lesion either directly affects any of these areas or damages-related white matter tracts. A growing body of evidence suggests that abnormal interactions among cortical regions remote from the ischaemic lesion might also contribute to the motor impairment after stroke. Here, we review recent studies employing models of functional and effective connectivity on neuroimaging data to investigate how stroke influences the interaction between motor areas and how changes in connectivity relate to impaired motor behaviour and functional recovery. Based on such data, we suggest that pathological intra- and inter-hemispheric interactions among key motor regions constitute an important pathophysiological aspect of motor impairment after subcortical stroke. We also demonstrate that therapeutic interventions, such as repetitive transcranial magnetic stimulation, which aims to interfere with abnormal cortical activity, may correct pathological connectivity not only at the stimulation site but also among distant brain regions. In summary, analyses of connectivity further our understanding of the pathophysiology underlying motor symptoms after stroke, and may thus help to design hypothesis-driven treatment strategies to promote recovery of motor function in patients

Neutral coding - A report based on an NRP work session

Neural coding by impulses and trains on single and multiple channels, and representation of information in nonimpulse carrier

Tracking dynamic interactions between structural and functional connectivity : a TMS/EEG-dMRI study

Transcranial magnetic stimulation (TMS) in combination with neuroimaging techniques allows to measure the effects of a direct perturbation of the brain. When coupled with high-density electroencephalography (TMS/hd-EEG), TMS pulses revealed electrophysiological signatures of different cortical modules in health and disease. However, the neural underpinnings of these signatures remain unclear. Here, by applying multimodal analyses of cortical response to TMS recordings and diffusion magnetic resonance imaging (dMRI) tractography, we investigated the relationship between functional and structural features of different cortical modules in a cohort of awake healthy volunteers. For each subject, we computed directed functional connectivity interactions between cortical areas from the source-reconstructed TMS/hd-EEG recordings and correlated them with the correspondent structural connectivity matrix extracted from dMRI tractography, in three different frequency bands (alpha, beta, gamma) and two sites of stimulation (left precuneus and left premotor). Each stimulated area appeared to mainly respond to TMS by being functionally elicited in specific frequency bands, that is, beta for precuneus and gamma for premotor. We also observed a temporary decrease in the whole-brain correlation between directed functional connectivity and structural connectivity after TMS in all frequency bands. Notably, when focusing on the stimulated areas only, we found that the structure-function correlation significantly increases over time in the premotor area controlateral to TMS. Our study points out the importance of taking into account the major role played by different cortical oscillations when investigating the mechanisms for integration and segregation of information in the human brain

Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation

Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration

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