Willem M. Otte

Recovery of Sensorimotor Function after Experimental Stroke Correlates with Restoration of Resting-State Interhemispheric Functional Connectivity

Despite the success of functional imaging to map changes in brain activation patterns after stroke, spatiotemporal dynamics of cerebral reorganization in correlation with behavioral recovery remain incompletely characterized. Here, we applied resting-state functional magnetic resonance imaging (rs-fMRI) together with behavioral testing to longitudinally assess functional connectivity within neuronal networks, in relation to changes in associated function after unilateral stroke in rats. Our specific goals were (1) to identify temporal alterations in functional connectivity within the bilateral cortical sensorimotor system and (2) to elucidate the relationship between those alterations and changes in sensorimotor function. Our study revealed considerable loss of functional connectivity between ipsilesional and contralesional primary sensorimotor cortex regions, alongside significant sensorimotor function deficits in the first days after stroke. The interhemispheric functional connectivity restored in the following weeks, but remained significantly reduced up to 10 weeks after stroke in animals with lesions that comprised subcortical and cortical tissue, whereas transcallosal neuroanatomical connections were preserved. Intrahemispheric functional connectivity between primary somatosensory and motor cortex areas was preserved in the lesion border zone and moderately enhanced contralesionally. The temporal pattern of changes in functional connectivity between bilateral primary motor and somatosensory cortices correlated significantly with the evolution of sensorimotor function scores. Our study (1) demonstrates that poststroke loss and recovery of sensorimotor function is associated with acute deterioration and subsequent retrieval of interhemispheric functional connectivity within the sensorimotor system and (2) underscores the potential of rs-fMRI to assess spatiotemporal characteristics of functional brain reorganization that may underlie behavioral recovery after brain injury.

Extent of bilateral neuronal network reorganization and functional recovery in relation to stroke severity.

Remodeling of neuronal structures and networks is believed to significantly contribute to (partial) restoration of functions after stroke. However, it has been unclear to what extent the brain reorganizes and how this correlates with functional recovery in relation to stroke severity. We applied serial resting-state functional MRI and diffusion tensor imaging together with behavioral testing to relate longitudinal modifications in functional and structural connectivity of the sensorimotor neuronal network to changes in sensorimotor function after unilateral stroke in rats. We found that gradual improvement of functions is associated with wide-ranging changes in functional and structural connectivity within bilateral neuronal networks, particularly after large stroke. Both after medium and large stroke, brain reorganization eventually leads to (partial) normalization of neuronal signal synchronization within the affected sensorimotor cortical network (intraregional signal coherence), as well as between the affected and unaffected sensorimotor cortices (interhemispheric functional connectivity). Furthermore, the bilateral network configuration shifts from subacutely increased “small-worldness,” possibly reflective of initial excessive neuronal clustering and wiring, toward a baseline small-world topology, optimal for global information transfer and local processing, at chronic stages. Cortical network remodeling was accompanied by recovery of initially disrupted structural integrity in corticospinal tract regions, which correlated positively with retrieval of sensorimotor functions. Our study demonstrates that the degree of functional recovery after stroke is associated with the extent of preservation or restoration of ipsilesional corticospinal tracts in combination with reinstatement of interhemispheric neuronal signal synchronization and normalization of small-world cortical network organization.

A meta-analysis of white matter changes in temporal lobe epilepsy as studied with diffusion tensor imaging.

Purpose:  Diffusion tensor imaging (DTI) is used increasingly to study white matter integrity in people with temporal lobe epilepsy (TLE). Most studies report fractional anisotropy (FA) decrease and mean diffusivity (MD) increase in multiple white matter regions. The disturbance of white matter integrity varies across studies and between regions. We aimed to obtain a more consistent estimate of white matter diffusion characteristics and relate these to the distance from the seizure focus.

Functional MRI and Diffusion Tensor Imaging of Brain Reorganization After Experimental Stroke

The potential of the adult brain to reorganize after ischemic injury is critical for functional recovery and provides a significant target for therapeutic strategies to promote brain repair. Despite the accumulating evidence of brain plasticity, the interaction and significance of morphological and physiological modifications in post-stroke brain tissue remain mostly unclear. Neuroimaging techniques such as functional MRI (fMRI) and diffusion tensor imaging (DTI) enable in vivo assessment of the spatial and temporal pattern of functional and structural changes inside and outside ischemic lesion areas. This can contribute to the elucidation of critical aspects in post-stroke brain remodeling. Task/stimulus-related fMRI, resting-state fMRI, or pharmacological MRI enables direct or indirect measurement of neuronal activation, functional connectivity, or neurotransmitter system responses, respectively. DTI allows estimation of the structural integrity and connectivity of white matter tracts. Together, these MRI methods provide an unprecedented means to (a) measure longitudinal changes in tissue structure and function close by and remote from ischemic lesion areas, (b) evaluate the organizational profile of neural networks after stroke, and (c) identify degenerative and restorative processes that affect post-stroke functional outcome. Besides, the availability of MRI in clinical institutions as well as research laboratories provides an optimal basis for translational research on stroke recovery. This review gives an overview of the current status and perspectives of fMRI and DTI applications to study brain reorganization in experimental stroke models.

Correspondence between altered functional and structural connectivity in the contralesional sensorimotor cortex after unilateral stroke in rats: a combined resting-state functional MRI and manganese-enhanced MRI study

This study shows a significant correlation between functional connectivity, as measured with resting-state functional magnetic resonance imaging (MRI), and neuroanatomical connectivity, as measured with manganese-enhanced MRI, in rats at 10 weeks after unilateral stroke and in age-matched controls. Reduced interhemispheric functional connectivity between the contralesional primary motor cortex (M1) and ipsilesional sensorimotor cortical regions was accompanied by a decrease in transcallosal manganese transfer from contralesional M1 to the ipsilesional sensorimotor cortex after a large unilateral stroke. Increased intrahemispheric functional connectivity in the contralesional sensorimotor cortex was associated with locally enhanced neuroanatomical tracer uptake, which underlines the strong link between functional and structural reorganization of neuronal networks after stroke.

REKINDLE: Robust extraction of kurtosis INDices with linear estimation

Recent literature shows that diffusion tensor properties can be estimated more accurately with diffusion kurtosis imaging (DKI) than with diffusion tensor imaging (DTI). Furthermore, the additional non‐Gaussian diffusion features from DKI can be sensitive markers for tissue characterization. Despite these benefits, DKI is more susceptible to data artifacts than DTI due to its increased model complexity, higher acquisition demands, and longer scanning times. To increase the reliability of diffusion tensor and kurtosis estimates, we propose a robust estimation procedure for DKI.

Longitudinal assessment of blood-brain barrier leakage during epileptogenesis in rats. A quantitative MRI study.

The blood-brain barrier (BBB) plays an important role in the homeostasis of the brain. BBB dysfunction has been implicated in the pathophysiology of various neurological disorders, including epilepsy in which it may contribute to disease progression. Precise understanding of BBB dynamics during epileptogenesis may be of importance for the assessment of future therapies, including BBB leakage blocking-agents. Longitudinal changes in BBB integrity can be studied with in vivo magnetic resonance imaging (MRI) in combination with paramagnetic contrast agents. Although this approach has shown to be suitable to detect major BBB leakage during the acute phase in experimental epilepsy models, so far no studies have provided information on dynamics of the extent of BBB leakage towards later phases. Therefore a sensitive and quantitative approach was used in the present study, involving fast T1 mapping (dynamic approach) during a steady-state infusion of gadobutrol, as well as pre- and post-contrast T1-weighted MRI (post-pre approach). This was applied in an experimental epilepsy model in which previous MRI studies failed to detect BBB leakage during epileptogenesis. Adult male Sprague-Dawley rats were injected with kainic acid to induce status epilepticus (SE). MRI experiments were performed before SE (control) and during the acute (1 day) and chronic epileptic phases (6 weeks after SE). BBB leakage was quantified by fast T1 mapping (Look-Locker gradient echo MRI) with a time resolution of 48 s from 5 min before up to 45 min after 20 min step-down infusion of 0.2M gadobutrol. In addition, T1-weighted MRI was acquired before and 45 min after infusion. MRI data were compared to post-mortem microscopic analysis using the BBB tracer fluorescein. Our MRI data showed BBB leakage, which was evident at 1 day and 6 weeks after SE in the hippocampus, entorhinal cortex, amygdala and piriform cortex. These findings were confirmed by microscopic analysis of fluorescein leakage. Furthermore, our MRI data revealed non-uniform BBB leakage throughout epileptogenesis. This study demonstrates BBB leakage in specific brain regions during epileptogenesis, which can be quantified using MRI. Therefore, MRI may be a valuable tool for experimental or clinical studies to elucidate the role of the BBB in epileptogenesis.

Characterization of Functional and Structural Integrity in Experimental Focal Epilepsy: Reduced Network Efficiency Coincides with White Matter Changes

Background Although focal epilepsies are increasingly recognized to affect multiple and remote neural systems, the underlying spatiotemporal pattern and the relationships between recurrent spontaneous seizures, global functional connectivity, and structural integrity remain largely unknown. Methodology/Principal Findings Here we utilized serial resting-state functional MRI, graph-theoretical analysis of complex brain networks and diffusion tensor imaging to characterize the evolution of global network topology, functional connectivity and structural changes in the interictal brain in relation to focal epilepsy in a rat model. Epileptic networks exhibited a more regular functional topology than controls, indicated by a significant increase in shortest path length and clustering coefficient. Interhemispheric functional connectivity in epileptic brains decreased, while intrahemispheric functional connectivity increased. Widespread reductions of fractional anisotropy were found in white matter regions not restricted to the vicinity of the epileptic focus, including the corpus callosum. Conclusions/Significance Our longitudinal study on the pathogenesis of network dynamics in epileptic brains reveals that, despite the locality of the epileptogenic area, epileptic brains differ in their global network topology, connectivity and structural integrity from healthy brains.

Use of positive and negative words in scientific PubMed abstracts between 1974 and 2014: retrospective analysis

Objective To investigate whether language used in science abstracts can skew towards the use of strikingly positive and negative words over time. Design Retrospective analysis of all scientific abstracts in PubMed between 1974 and 2014. Methods The yearly frequencies of positive, negative, and neutral words (25 preselected words in each category), plus 100 randomly selected words were normalised for the total number of abstracts. Subanalyses included pattern quantification of individual words, specificity for selected high impact journals, and comparison between author affiliations within or outside countries with English as the official majority language. Frequency patterns were compared with 4% of all books ever printed and digitised by use of Google Books Ngram Viewer. Main outcome measures Frequencies of positive and negative words in abstracts compared with frequencies of words with a neutral and random connotation, expressed as relative change since 1980. Results The absolute frequency of positive words increased from 2.0% (1974-80) to 17.5% (2014), a relative increase of 880% over four decades. All 25 individual positive words contributed to the increase, particularly the words “robust,” “novel,” “innovative,” and “unprecedented,” which increased in relative frequency up to 15 000%. Comparable but less pronounced results were obtained when restricting the analysis to selected journals with high impact factors. Authors affiliated to an institute in a non-English speaking country used significantly more positive words. Negative word frequencies increased from 1.3% (1974-80) to 3.2% (2014), a relative increase of 257%. Over the same time period, no apparent increase was found in neutral or random word use, or in the frequency of positive word use in published books. Conclusions Our lexicographic analysis indicates that scientific abstracts are currently written with more positive and negative words, and provides an insight into the evolution of scientific writing. Apparently scientists look on the bright side of research results. But whether this perception fits reality should be questioned.

Evaluation of HIV/AIDS secondary school peer education in rural Nigeria

In this study, we assessed whether peer education is an effective method of HIV/AIDS awareness, in terms of knowledge, misconception and behavior, among adolescents in the rural area of Nigeria. A comparative case series (n = 250), cross-sectional structured survey (n = 135) and focus group discussions (n = 80) were undertaken among adolescents. In both the case series and structured survey, a questionnaire was used which addresses the following issues: socio-demography, knowledge on transmission and prevention of HIV/AIDS, accessibility to different sources of HIV/AIDS information, stigmatization and sexual behavior. Binary logistic regression was applied to compare responses from the peer-educated and not peer-educated populations. The model was adjusted for confounders. We demonstrated increased knowledge and decreased misconception and sexual risk behavior in adolescents receiving peer education as compared to adolescents not receiving peer education. These differences are apparent both over time (2005-2007) and cross-sectional (2007). In conclusion, peer education in rural areas can be effective in HIV/AIDS prevention. Knowledge and behavior can be influenced positively.