Kajo van der Marel

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.

Longitudinal in vivo MRI of alterations in perilesional tissue after transient ischemic stroke in rats

Spontaneous restoration of function after stroke is associated with remodelling of functional neuronal networks in and around the ischemic lesion. However, the spatiotemporal profile of structural alterations in (peri)lesional tissue in relation to post-stroke recovery of neuronal function remains largely to be elucidated. We performed neurological testing in combination with in vivo serial T(2)-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to assess functional recovery in relation to longitudinal changes in tissue integrity from 3 h up to 9 weeks after experimental unilateral stroke in rats (n=7). Subsequently, to evaluate perilesional neuronal connectivity, we conducted manganese-enhanced MRI after MnCl(2) injection in cortical tissue at the boundary of the lesion at 10 weeks post-stroke (n=5). All animals showed significant improvement of neurological function over time. Normalization of tissue T(2) and fractional diffusion anisotropy (FA) after significant subacute change was observed in cortical and subcortical lesion borderzones between 3 and 9 weeks post-stroke. Progressive FA increase above baseline levels was detected in perilesional white matter areas (n=4). In these animals particularly, significant manganese enhancement appeared within the neuronal network around the chronic lesion, including areas that were part of the lesion at day 3 post-stroke. This longitudinal multi-parametric MRI study suggests that resolution of early ischemic damage and reorganization of white matter in perilesional tissue is chronically accompanied by preservation or restoration of neuronal connectivity, which may significantly contribute to post-stroke functional recovery.

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.

Temporal scaling properties and spatial synchronization of spontaneous blood oxygenation level-dependent (BOLD) signal fluctuations in rat sensorimotor network at different levels of isoflurane anesthesia.

Spontaneous fluctuations in the blood oxygenation level‐dependent (BOLD) MRI signal during the resting state are increasingly being studied in healthy and diseased brain in humans and animal models. Yet, the relationship between functional brain status and the characteristics of spontaneous BOLD fluctuations remains poorly understood. In order to obtain more insights into this relationship and, in particular, the effects of anesthesia thereupon, we investigated the spatial and temporal correlations of spontaneous BOLD fluctuations in somatosensory and motor regions of rat brain at different inhalation levels of the frequently applied anesthetic isoflurane. We found that the temporal scaling, characterized by the Hurst exponent (H), showed persistent behavior (H > 0.5) at 0.5–1.0% isoflurane. Furthermore, low‐pass‐filtered spontaneous BOLD oscillations were correlated significantly in bilateral somatosensory and bilateral motor cortices, reflective of interhemispheric functional connectivity. Under 2.9% isoflurane anesthesia, the temporal scaling characteristics approached those of Gaussian white noise (H = 0.5), the relative amplitude of BOLD low‐frequency fluctuations declined, and cross‐correlations of these oscillations between functionally connected regions decreased significantly. Loss of interhemispheric functional connectivity at 2.9% isoflurane anesthesia was stronger between bilateral motor regions than between bilateral somatosensory regions, which points to distinct effects of anesthesia on differentially organized neuronal networks. Although we cannot completely rule out a possible contribution from hemodynamic signals with a non‐neuronal origin, our results emphasize that spatiotemporal characteristics of spontaneous BOLD fluctuations are related to the brains specific functional status and network organization, and demonstrate that these are largely preserved under light to mild anesthesia with isoflurane. Copyright

Stress-induced alterations in large-scale functional networks of the rodent brain

Stress-related psychopathology is associated with altered functioning of large-scale brain networks. Animal research into chronic stress, one of the most prominent environmental risk factors for development of psychopathology, has revealed molecular and cellular mechanisms potentially contributing to human mental disease. However, so far, these studies have not addressed the system-level changes in extended brain networks, thought to critically contribute to mental disorders. We here tested the effects of chronic stress exposure (10 days immobilization) on the structural integrity and functional connectivity patterns in the brain, using high-resolution structural MRI, diffusion kurtosis imaging, and resting-state functional MRI, while confirming the expected changes in neuronal dendritic morphology using Golgi-staining. Stress effectiveness was confirmed by a significantly lower body weight and increased adrenal weight. In line with previous research, stressed animals displayed neuronal dendritic hypertrophy in the amygdala and hypotrophy in the hippocampal and medial prefrontal cortex. Using independent component analysis of resting-state fMRI data, we identified ten functional connectivity networks in the rodent brain. Chronic stress appeared to increase connectivity within the somatosensory, visual, and default mode networks. Moreover, chronic stress exposure was associated with an increased volume and diffusivity of the lateral ventricles, whereas no other volumetric changes were observed. This study shows that chronic stress exposure in rodents induces alterations in functional network connectivity strength which partly resemble those observed in stress-related psychopathology. Moreover, these functional consequences of stress seem to be more prominent than the effects on gross volumetric change, indicating their significance for future research.

Long-term oral methylphenidate treatment in adolescent and adult rats: differential effects on brain morphology and function.

Methylphenidate is a widely prescribed psychostimulant for treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents, which raises questions regarding its potential interference with the developing brain. In the present study, we investigated effects of 3 weeks oral methylphenidate (5 mg/kg) vs vehicle treatment on brain structure and function in adolescent (post-natal day [P]25) and adult (P65) rats. Following a 1-week washout period, we used multimodal magnetic resonance imaging (MRI) to assess effects of age and treatment on independent component analysis-based functional connectivity (resting-state functional MRI), D-amphetamine-induced neural activation responses (pharmacological MRI), gray and white matter tissue volumes and cortical thickness (postmortem structural MRI), and white matter structural integrity (postmortem diffusion tensor imaging (DTI)). Many age-related differences were found, including cortical thinning, white matter development, larger dopamine-mediated activation responses and increased striatal functional connectivity. Methylphenidate reduced anterior cingulate cortical network strength in both adolescents and adults. In contrast to clinical observations from ADHD patient studies, methylphenidate did not increase white matter tissue volume or cortical thickness in rat. Nevertheless, DTI-based fractional anisotropy was higher in the anterior part of the corpus callosum following adolescent treatment. Furthermore, methylphenidate differentially affected adolescents and adults as evidenced by reduced striatal volume and myelination upon adolescent treatment, although we did not observe adverse treatment effects on striatal functional activity. Our findings of small but significant age-dependent effects of psychostimulant treatment in the striatum of healthy rats highlights the importance of further research in children and adolescents that are exposed to methylphenidate.

MRI of ICAM-1 Upregulation After Stroke: the Importance of Choosing the Appropriate Target-Specific Particulate Contrast Agent

PurposeMagnetic resonance imaging (MRI) with targeted contrast agents provides a promising means for diagnosis and treatment monitoring after cerebrovascular injury. Our goal was to demonstrate the feasibility of this approach to detect the neuroinflammatory biomarker intercellular adhesion molecule-1 (ICAM-1) after stroke and to establish a most efficient imaging procedure.ProceduresWe compared two types of ICAM-1-functionalized contrast agent: T1-shortening gadolinium chelate-containing liposomes and T2(*)-shortening micron-sized iron oxide particles (MPIO). Binding efficacy and MRI contrast effects were tested in cell cultures and a mouse stroke model.ResultsBoth ICAM-1-targeted agents bound effectively to activated cerebrovascular cells in vitro, generating significant MRI contrast-enhancing effects. Direct in vivo MRI-based detection after stroke was only achieved with ICAM-1-targeted MPIO, although both contrast agents showed similar target-specific vascular accumulation.ConclusionsOur study demonstrates the potential of in vivo MRI of post-stroke ICAM-1 upregulation and signifies target-specific MPIO as most suitable contrast agent for molecular MRI of cerebrovascular inflammation.

MRI of bilateral sensorimotor network activation in response to direct intracortical stimulation in rats after unilateral stroke

Reinstatement of perilesional activation and connectivity may underlie functional recovery after stroke. To measure activation responsiveness in perilesional cortex in relation to white matter integrity, we performed functional functional magnetic resonance imaging during stimulation of the contralesional cortex, together with diffusion tensor imaging, 3 and 28 days after stroke in rats. Despite disturbed sensorimotor function and abnormal callosal appearance at day 3, activation amplitudes were preserved in the perilesional sensorimotor cortex, although time-to-peak was significantly delayed. This indicates that in spite of dysfunction, perilesional cortical tissue can be activated subacutely after stroke, while delay of the hemodynamic activation response suggests impaired neurovascular coupling.