Motor recovery and cortical reorganization after constraint-induced movement therapy in stroke patients: a preliminary study.

Constraint-induced movement therapy (CIMT) is a physical rehabilitation regime that has been previously shown to improve motor function in chronic hemiparetic stroke patients. However, the neural mechanisms supporting rehabilitation-induced motor recovery are poorly understood. The goal of this study was to assess motor cortical reorganization after CIMT using functional magnetic resonance imaging (fMRI). In a repeated-measures design, 4 incompletely recovered chronic stroke patients treated with CIMT underwent motor function testing and fMRI. Five age-matched normal subjects were also imaged. A laterality index (LI) was determined from the fMRI data, reflecting the distribution of activation in motor cortices contralateral compared with ipsilateral to the moving hand. Pre-intervention fMRI showed a lower LI during affected hand movement of stroke patients (LI = 0.23+/-0.07) compared to controls (LI unaffected patient hand = 0.65+/-0.10; LI dominant normal hand = 0.65+/-0.11; LI nondominant normal hand = 0.69+/-0.11; P < 0.05) due to trends toward increased ipsilateral motor cortical activation. Motor function testing showed that patients made significant gains in functional use of the stroke-affected upper extremity (detected by the Motor Activity Log) and significant reductions in motor impairment (detected by the Fugl-Meyer Stroke Scale and the Wolf Motor Function Test) immediately after CIMT, and these effects persisted at 6-month follow-up. The behavioral effects of CIMT were associated with a trend toward a reduced LI from pre-intervention to immediately post-intervention (LI = -0.01+/-0.06, P = 0.077) and 6 months post-intervention (LI = -0.03+/-0.15). Stroke-affected hand movement was not accompanied by mirror movements during fMRI, and electromyographic measures of mirror recruitment under simulated fMRI conditions were not correlated with LI values. These data provide preliminary evidence that gains in motor function produced by CIMT in chronic stroke patients may be associated with a shift in laterality of motor cortical activation toward the undamaged hemisphere

Interferon-β attenuates lung inflammation following experimental subarachnoid hemorrhage

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (SAH) affects relatively young people and carries a poor prognosis with a case fatality rate of 35%. One of the major systemic complications associated with SAH is acute lung injury (ALI) which occurs in up to one-third of the patients and is associated with poor outcome. ALI in SAH may be predisposed by neurogenic pulmonary edema (NPE) and inflammatory mediators. The objective of this study was to assess the immunomodulatory effects of interferon-β (IFN-β) on inflammatory mediators in the lung after experimental SAH. METHODS: Male Wistar rats were subjected to the induction of SAH by means of the endovascular filament method. Sham-animals underwent sham-surgery. Rats received IFN-β for four consecutive days starting at two hours after SAH induction. After seven days, lungs were analyzed for the expression of inflammatory markers. RESULTS: SAH induced the influx of neutrophils into the lung, and enhanced expression of the pulmonary adhesion molecules E-selectin, inter-cellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 compared to sham-animals. In addition, SAH increased the expression of the chemokines macrophage inflammatory protein (MIP)-1α, MIP-2, and cytokine-induced neutrophil chemoattractant (CINC)-1 in the lung. Finally, tumor necrosis factor-α (TNF-α) was significantly increased in lungs from SAH-animals compared to sham-animals. IFN-β effectively abolished the SAH-induced expression of all pro-inflammatory mediators in the lung. CONCLUSIONS: IFN-β strongly reduces lung inflammation after experimental SAH and may therefore be an effective drug to prevent SAH-mediated lung injury

The effect of adipose tissue-derived stem cells in a middle cerebral artery occlusion stroke model depends on their engraftment rate

Background: In the field of experimental stem cell therapy, intra-arterial (IA) delivery yields the best results concerning, for example, migrated cell number at the targeted site. However, IA application also appears to be associated with increased mortality rates and infarction. Since many rodent studies systemically apply 1 × 106 cells, this could also be a consequence of engrafted cell number. The aim of this study was therefore to investigate the effect of different doses of adipose tissue-derived stem cells (ASCs) on engraftment rates and stroke outcome measured in vivo using 9.4-T high-field magnetic resonance imaging (MRI). Methods: Male Wistar rats (n = 43) underwent a middle cerebral artery occlusion (MCAo) for 45 or 90 min, followed by IA delivery of either saline or 1 × 106, 3 × 105, or 5 × 104 ASCs pre-labelled with very small superparamagnetic iron oxide particles (VSOPs). MRI (9.4-T) analysis was performed 48 h and 9 days post-MCAo. Lesion volumes were assessed by analysis of T2-weighted images and cell signal tracking showing cell engraftment and active cell migration by an improved T2*-analysis. Results: The ASC-derived signal intensity increased in the affected hemisphere 48 h post MCAo with injected cell number (p < 0.05). The analysis of stroke volumes revealed an increased infarction after injection of 1 × 106 ASCs compared to controls or application of 5 × 104 ASCs (p < 0.05). At 9 days post-MCAo, injection of 3 × 105 ASCs resulted in reduced infarct volumes (p < 0.05). Correspondingly, MRI analysis revealed no changes in cell numbers between both MRI examinations but showed active ASC migration to the site of infarction. Conclusion: Our results confirm that IA injection is an efficient way of targeting damaged brain tissue but its usefulness strongly depends on the right dose of delivered stem cells since this factor has a strong influence on migration rate and infarct volume, with better results for doses below 1 × 106 cells. Future challenges will include the determination of therapeutic doses for best cellular engraftment and stroke outcome

Glutamatergic medication in the treatment of obsessive compulsive disorder (OCD) and autism spectrum disorder (ASD) - study protocol for a randomised controlled trial

BACKGROUND: Compulsivity is a cross-disorder trait underlying phenotypically distinct psychiatric disorders that emerge in childhood or adolescence. Despite the effectiveness of serotonergic compounds in the treatment of obsessive-compulsive disorder, treatment-resistant symptoms remaining in 40 to 60 % of patients present a pressing clinical problem. There are currently no medications that effectively treat the core impairments of autism spectrum disorder. There is an urgent need for the development of conceptually novel pharmacological strategies. Agents targeting glutamate neurotransmission, such as memantine, represent promising candidates. This proof-of-concept clinical study will allow pilot-testing of memantine for both clinical effectiveness and tolerability/safety. Memantine is an N-methyl-D-aspartate receptor antagonist, approved for the treatment of Alzheimer's dementia in a number of countries. METHODS/DESIGN: This 12-week study has an add-on, randomised, double-blind, placebo-controlled design of treatment with memantine, including an up-titration phase (forced flexible dose design, 5-15 mg/day), in patients aged 6-17 years and 9 months with obsessive-compulsive disorder or autism spectrum disorder. It is planned to include patients with obsessive-compulsive disorder (N = 50) or autism spectrum disorder (N = 50) across four centres in three European countries. Patients will be randomly assigned to memantine or placebo in a 1:1 ratio. Primary objectives are the investigation of the effectiveness of memantine in paediatric patients for improving symptoms of compulsivity (primary outcome measure: total score on the Children's Yale-Brown Obsessive-Compulsive Scale) and to explore its tolerability and safety. Secondary objectives are to explore the effects of memantine at the level of structure, function and biochemistry of the fronto-striatal circuits, and to collect blood for genetic analyses and biomarkers. Tertiary objectives are to explore the role of new candidate genes and pathways for compulsivity by linking genes to clinical phenotypes, response to treatment, neurocognitive test performance, and key structural and functional neuroimaging measures of the fronto-striatal circuits and to explore biomarkers/proteomics for compulsivity traits. DISCUSSION: This study is part of the large, translational project TACTICS ( http://www.tactics-project.eu/ ) that is funded by the European Union and investigates the neural, genetic and molecular factors involved in the pathogenesis of compulsivity. Its results will provide clinically relevant solid information on potential new mechanisms and medication treatment in obsessive-compulsive and autism spectrum disorders. TRIAL REGISTRATION: EudraCT Number: 2014-003080-38 , date of registration: 14 July 2014

Memantine treatment does not affect compulsive behavior or frontostriatal connectivity in an adolescent rat model for quinpirole-induced compulsive checking behavior

RATIONALE: Compulsivity often develops during childhood and is associated with elevated glutamate levels within the frontostriatal system. This suggests that anti-glutamatergic drugs, like memantine, may be an effective treatment. OBJECTIVE: Our goal was to characterize the acute and chronic effect of memantine treatment on compulsive behavior and frontostriatal network structure and function in an adolescent rat model of compulsivity. METHODS: Juvenile Sprague-Dawley rats received repeated quinpirole, resulting in compulsive checking behavior (n = 32; compulsive) or saline injections (n = 32; control). Eight compulsive and control rats received chronic memantine treatment, and eight compulsive and control rats received saline treatment for seven consecutive days between the 10th and 12th quinpirole/saline injection. Compulsive checking behavior was assessed, and structural and functional brain connectivity was measured with diffusion MRI and resting-state fMRI before and after treatment. The other rats received an acute single memantine (compulsive: n = 12; control: n = 12) or saline injection (compulsive: n = 4; control: n = 4) during pharmacological MRI after the 12th quinpirole/saline injection. An additional group of rats received a single memantine injection after a single quinpirole injection (n = 8). RESULTS: Memantine treatment did not affect compulsive checking nor frontostriatal structural and functional connectivity in the quinpirole-induced adolescent rat model. While memantine activated the frontal cortex in control rats, no significant activation responses were measured after single or repeated quinpirole injections. CONCLUSIONS: The lack of a memantine treatment effect in quinpirole-induced compulsive adolescent rats may be partly explained by the interaction between glutamatergic and dopaminergic receptors in the brain, which can be evaluated with functional MRI

Hyperperfusion profiles after recanalization differentially associate with outcomes in a rat ischemic stroke model

Futile recanalization hampers prognoses of ischemic stroke after successful mechanical thrombectomy, hypothetically through post-recanalization perfusion deficits, onset-to-groin delays and sex effects. Clinically, acute multiparametric imaging studies remain challenging. We assessed possible relationships between these factors and disease outcome after experimental cerebral ischemia-reperfusion, using translational MRI, behavioral testing and multi-model inference analyses. Male and female rats (N = 60) were subjected to 45-/90-min filament-induced transient middle cerebral artery occlusion. Diffusion, T2- and perfusion-weighted MRI at occlusion, 0.5 h and four days after recanalization, enabled tracking of tissue fate, and relative regional cerebral blood flow (rrCBF) and -volume (rrCBV). Lesion areas were parcellated into core, salvageable tissue and delayed injury, verified by histology. Recanalization resulted in acute-to-subacute lesion volume reductions, most apparently in females (n = 19). Hyperacute normo-to-hyperperfusion in the post-ischemic lesion augmented towards day four, particularly in males (n = 23). Tissue suffering delayed injury contained higher ratios of hypoperfused voxels early after recanalization. Regressed against acute-to-subacute lesion volume change, increased rrCBF associated with lesion growth, but increased rrCBV with lesion reduction. Similar relationships were detected for behavioral outcome. Post-ischemic hyperperfusion may develop differentially in males and females, and can be beneficial or detrimental to disease outcome, depending on which perfusion parameter is used as explanatory variable.</p

Recent advances in arterial spin labeling perfusion MRI in patients with vascular cognitive impairment

Cognitive impairment (CI) is a major health concern in aging populations. It impairs patients’ independent life and may progress to dementia. Vascular cognitive impairment (VCI) encompasses all cerebrovascular pathologies that contribute to cognitive impairment (CI). Moreover, the majority of CI subtypes involve various aspects of vascular dysfunction. Recent research highlights the critical role of reduced cerebral blood flow (CBF) in the progress of VCI, and the detection of altered CBF may help to detect or even predict the onset of VCI. Arterial spin labeling (ASL) is a non-invasive, non-ionizing perfusion MRI technique for assessing CBF qualitatively and quantitatively. Recent methodological advances enabling improved signal-to-noise ratio (SNR) and data acquisition have led to an increase in the use of ASL to assess CBF in VCI patients. Combined with other imaging modalities and biomarkers, ASL has great potential for identifying early VCI and guiding prediction and prevention strategies. This review focuses on recent advances in ASL-based perfusion MRI for identifying patients at high risk of VCI

Thermosensitive Biodegradable Hydrogels for Local and Controlled Cerebral Delivery of Proteins: MRI-Based Monitoring of In Vitro and In Vivo Protein Release

Hydrogels have been suggested as novel drug delivery systems for sustained release of therapeutic proteins in various neurological disorders. The main advantage these systems offer is the controlled, prolonged exposure to a therapeutically effective dose of the released drug after a single intracerebral injection. Characterization of controlled release of therapeutics from a hydrogel is generally performed in vitro, as current methods do not allow for in vivo measurements of spatiotemporal distribution and release kinetics of a loaded protein. Importantly, the in vivo environment introduces many additional variables and factors that cannot be effectively simulated under in vitro conditions. To address this, in the present contribution, we developed a noninvasive in vivo magnetic resonance imaging (MRI) method to monitor local protein release from two injected hydrogels of the same chemical composition but different initial water contents. We designed a biodegradable hydrogel formulation composed of low and high concentration thermosensitive polymer and thiolated hyaluronic acid, which is liquid at room temperature and forms a gel due to a combination of physical and chemical cross-linking upon injection at 37 °C. The in vivo protein release kinetics from these gels were assessed by MRI analysis utilizing a model protein labeled with an MR contrast agent, i.e. gadolinium-labeled albumin (74 kDa). As proof of principle, the release kinetics of the hydrogels were first measured with MRI in vitro. Subsequently, the protein loaded hydrogels were administered in male Wistar rat brains and the release in vivo was monitored for 21 days. In vitro, the thermosensitive hydrogels with an initial water content of 81 and 66% released 64 ± 3% and 43 ± 3% of the protein loading, respectively, during the first 6 days at 37 °C. These differences were even more profound in vivo, where the thermosensitive hydrogels released 83 ± 16% and 57 ± 15% of the protein load, respectively, 1 week postinjection. Measurement of volume changes of the gels over time showed that the thermosensitive gel with the higher polymer concentration increased more than 4-fold in size in vivo after 3 weeks, which was substantially different from the in vitro behavior where a volume change of 35% was observed. Our study demonstrates the potential of MRI to noninvasively monitor in vivo intracerebral protein release from a locally administered in situ forming hydrogel, which could aid in the development and optimization of such drug delivery systems for brain disorders

Recent progress in translational research on neurovascular and neurodegenerative disorders

The already established and widely used intravenous application of recombinant tissue plasminogen activator as a re-opening strategy for acute vessel occlusion in ischemic stroke was recently added by mechanical thrombectomy, representing a fundamental progress in evidence-based medicine to improve the patient’s outcome. This has been paralleled by a swift increase in our understanding of pathomechanisms underlying many neurovascular diseases and most prevalent forms of dementia. Taken together, these current advances offer the potential to overcome almost two decades of marginally successful translational research on stroke and dementia, thereby spurring the entire field of translational neuroscience. Moreover, they may also pave the way for the renaissance of classical neuroprotective paradigms. This review reports and summarizes some of the most interesting and promising recent achievements in neurovascular and dementia research. It highlights sessions from the 9th International Symposium on Neuroprotection and Neurorepair that have been discussed from April 19th to 22nd in Leipzig, Germany. To acknowledge the emerging culture of interdisciplinary collaboration and research, special emphasis is given on translational stories ranging from fundamental research on neurode- and -regeneration to late stage translational or early stage clinical investigations