Machine Learning Algorithm Guides Catalyst Choices for Magnesium-Catalyzed Asymmetric Reactions.

Organic-chemical literature encompasses large numbers of catalysts and reactions they can effect. Many of these examples are published merely to document the catalysts' scope but do not necessarily guarantee that a given catalyst is "optimal" - in terms of yield or enantiomeric excess - for a particular reaction. This paper describes a Machine Learning model that aims to improve such catalyst-reaction assignments based on the carefully curated literature data. As we show here for the case of asymmetric magnesium catalysis, this model achieves relatively high accuracy and offers out of-the-box predictions successfully validated by experiment, e.g., in synthetically demanding asymmetric reductions or Michael additions.

MDM2-p53 Interaction Inhibitors: The Current State-of-Art and Updated Patent Review (2010-Present).

BACKGROUND: Mouse Double Minute 2 protein (MDM2) is a cellular regulator of p53 tumor suppressor (p53). Inhibition of the interaction between MDM2 and p53 proteins is a promising anticancer therapy. OBJECTIVE: This updated patent review is an attempt to compile the research and achievements of the various researchers working on small molecule MDM2 inhibitors from 2010 to date. We provide an outlook into the future for therapy based on MDM2 inhibition by presenting an overview of the most relevant patents which have recently appeared in the literature. METHODS: Literature and recent patents focusing on the anticancer potential of MDM2-p53 interaction inhibitors and its applications have been analyzed. We put the main emphasis on the most perspective compounds which are or were examined in clinical trials. RESULTS: Literature data indicated that MDM2 inhibitors are therapeutically effective in specific types of cancer or non-cancer diseases. A great number of patents and research work around new MDM2- p53 interaction inhibitors, possible combinations, new indications, clinical regimens in previous years prove that this targeted therapy is in the scope of interest for many business and academic research groups. CONCLUSION: Novel MDM2 inhibitors thanks to higher potency and better ADME properties have shown effectiveness in preclinical and clinical development however the final improvement of therapeutic potential for MDM2 inhibitors might depend on the useful combination therapy and exploring new cancer and non-cancer indications.

Neurogenesis upregulation on the healthy hemisphere after stroke enhances compensation for age-dependent decrease of basal neurogenesis.

Stroke is a leading cause of death and disability worldwide with no treatment for the chronic phase available. Interestingly, an endogenous repair program comprising inflammation and neurogenesis is known to modulate stroke outcome. Several studies have shown that neurogenesis decreases with age but the therapeutic importance of endogenous neurogenesis for recovery from cerebral diseases has been indicated as its ablation leads to stroke aggravation and worsened outcome. A detailed characterization of the neurogenic response after stroke related to ageing would help to develop novel and targeted therapies. In an innovative approach, we used the DCX-Luc mouse, a transgenic model expressing luciferase in doublecortin-positive neuroblasts, to monitor the neurogenic response following middle cerebral artery occlusion over three weeks in three age groups (2, 6, 12months) by optical imaging while the stroke lesion was monitored by quantitative MRI. The individual longitudinal and noninvasive time profiles provided exclusive insight into age-dependent decrease in basal neurogenesis and neurogenic upregulation in response to stroke which are not accessible by conventional BrdU-based measures of cell proliferation. For cortico-striatal strokes the maximal upregulation occurred at 4days post stroke followed by a continuous decrease to basal levels by three weeks post stroke. Older animals effectively compensated for reduced basal neurogenesis by an enhanced sensitivity to the cerebral lesion, resulting in upregulated neurogenesis levels approaching those measured in young mice. In middle aged and older mice, but not in the youngest ones, additional upregulation of neurogenesis was observed in the contralateral healthy hemisphere. This further substantiates the increased propensity of older brains to respond to lesion situation. Our results clearly support the therapeutic relevance of endogenous neurogenesis for stroke recovery and particularly in older brains.

Prenatally Diagnosed Vasa Previa: A Single-Institution Series of 96 Cases.

OBJECTIVE: To describe outcomes for a large cohort of women with prenatally diagnosed vasa previa, determine the percentage in patients without risk factors, and compare delivery timing and indications for singletons and twins. METHODS: This was a retrospective case series of women with prenatally diagnosed vasa previa delivered at a single tertiary center over 12 years. Potential participants were identified using hospital records and perinatal databases. Patients were included if vasa previa was confirmed at delivery and by pathologic examination. Maternal and newborn data were gathered from medical records. RESULTS: There were 77 singleton and 19 twin pregnancies with a prenatal diagnosis of vasa previa. There was one neonatal death from congenital heart disease. Perinatal management of recommended elective hospitalizations with corticosteroid administration and elective early delivery resulted in average gestational age for delivery in singletons at 34.7±1.6 weeks and 32.8±2.2 weeks for twins. Among the 77 singletons, delivery was elective in 48, as a result of contractions or labor in 21, bleeding in four, nonreassuring tracing in two, asymptomatic cervical shortening in one, and preeclampsia in one. Among 19 twins, delivery was elective in six and for contractions or labor in 13. Sixty-eight percent of twins compared with 37% of singletons had nonelective delivery (P<.05). Delivery occurred by 32 weeks of gestation in 6.4% of singletons and 26% of twins (P<.05) and by 34 weeks of gestation in 11% of singletons and 58% of twins (P<.001). Six neonates (5.2%) had major anomalies, all prenatally detected. Respiratory distress syndrome occurred in 57.1% of singletons and 65.7% of twins. Nineteen singletons (24.7%) had no risk factors for vasa previa. CONCLUSION: Planned preterm delivery for women with prenatally diagnosed vasa previa resulted in elective delivery for singletons in 62% and for twins 32%. Gestational age at birth on average was 34.7 weeks for singletons and 32.8 weeks of gestation for twins. Major anomalies were frequent as was respiratory distress syndrome. Elective delivery between 34 and 35 weeks of gestation for singletons is reasonable. As a result of the high rate of nonelective delivery in twins, delivery at 32-34 weeks of gestation may be risk-beneficial. The high rate of singletons without risk factors for vasa previa reinforces the recommendation to screen routinely for cord insertion site.

Dynamic Modulation of Microglia/Macrophage Polarization by miR-124 after Focal Cerebral Ischemia.

Mononuclear phagocytes respond to ischemic stroke dynamically, undergoing an early anti-inflammatory and protective phenotype followed by the pro-inflammatory and detrimental type. These dual roles of microglia/macrophages suggest the need of subtle adjustment of their polarization state instead of broad suppression. The most abundant brain-specific miRNA, miR-124, promotes neuronal differentiation but can also modulate microglia activation and keeps them in a quiescent state. We addressed whether the intracerebral injection of miR-124 in a mouse model of ischemic stroke before or after the peak phase of the pro-inflammatory polarization modifies the pro-/anti- inflammatory balance. In the sub-acute phase, 48 h after stroke, liposomated miR-124 shifted the predominantly pro-inflammatory polarized microglia/macrophages toward the anti-inflammatory phenotype. The altered immune response improved neurological deficit at day 6 after stroke. When miR-124 was injected 10 days after stroke, the pro-/anti- inflammatory ratio was still significantly reduced although to a lower degree and had no effect on recovery at day 14. This study indicates that miR-124 administration before the peak of the pro-inflammatory process of stroke is most effective in support of increasing the rehabilitation opportunity in the sub-acute phases of stroke. Our findings highlight the important role of immune cells after stroke and the therapeutic relevance of their polarization balance.

Human neural stem cell intracerebral grafts show spontaneous early neuronal differentiation after several weeks.

Human neural stem cells (hNSCs) hold great promise for the treatment of neurological diseases. Considerable progress has been made to induce neural differentiation in the cell culture in vitro and upon transplantation in vivo [2] in order to explore restoration of damaged neuronal circuits. However, in vivo conventional strategies are limited to post mortem analysis. Here, we apply our developed first fate mapping platform to monitor neuronal differentiation in vivo by magnetic resonance imaging, bioluminescence imaging, and fluorescence imaging. Ferritin, Luciferase and GFP under neuronal-specific promoters for immature and mature neurons, respectively, were used to generate transgenic hNSCs. Differentiation-linked imaging reporter expression was validated in vitro. The time profile of spontaneous neuronal maturation after transplantation into mouse brain cortex demonstrated early neuronal differentiation within 6 weeks. Fully mature neurons expressing synaptogenesis were observed only after three months or longer. Our trimodal fate mapping strategy represents a unique non-invasive tool to monitor the time course of neuronal differentiation of transplanted stem cells in vivo.

A review of novel optical imaging strategies of the stroke pathology and stem cell therapy in stroke.

Transplanted stem cells can induce and enhance functional recovery in experimental stroke. Invasive analysis has been extensively used to provide detailed cellular and molecular characterization of the stroke pathology and engrafted stem cells. But post mortem analysis is not appropriate to reveal the time scale of the dynamic interplay between the cell graft, the ischemic lesion and the endogenous repair mechanisms. This review describes non-invasive imaging techniques which have been developed to provide complementary in vivo information. Recent advances were made in analyzing simultaneously different aspects of the cell graft (e.g., number of cells, viability state, and cell fate), the ischemic lesion (e.g., blood-brain-barrier consistency, hypoxic, and necrotic areas) and the neuronal and vascular network. We focus on optical methods, which permit simple animal preparation, repetitive experimental conditions, relatively medium-cost instrumentation and are performed under mild anesthesia, thus nearly under physiological conditions. A selection of recent examples of optical intrinsic imaging, fluorescence imaging and bioluminescence imaging to characterize the stroke pathology and engrafted stem cells are discussed. Special attention is paid to novel optimal reporter genes/probes for genetic labeling and tracking of stem cells and appropriate transgenic animal models. Requirements, advantages and limitations of these imaging platforms are critically discussed and placed into the context of other non-invasive techniques, e.g., magnetic resonance imaging and positron emission tomography, which can be joined with optical imaging in multimodal approaches.

In vivo bioluminescence imaging of vascular remodeling after stroke.

Thrombolysis remains the only beneficial therapy for ischemic stroke, but is restricted to a short therapeutic window following the infarct. Currently research is focusing on spontaneous regenerative processes during the sub-acute and chronic phase. Angiogenesis, the formation of new blood vessels from pre-existing ones, was observed in stroke patients, correlates with longer survival and positively affects the formation of new neurons. Angiogenesis takes place in the border zones of the infarct, but further insight into the temporal profile is needed to fully apprehend its therapeutic potential and its relevance for neurogenesis and functional recovery. Angiogenesis is a multistep process, involving extracellular matrix degradation, endothelial cell proliferation, and, finally, new vessel formation. Interaction between vascular endothelial growth factor and its receptor 2 (VEGFR2) plays a central role in these angiogenic signaling cascades. In the present study we investigated non-invasively the dynamics of VEGFR2 expression following cerebral ischemia in a mouse model of middle cerebral artery occlusion (MCAO). We used a transgenic mouse expressing firefly luciferase under the control of the VEGFR2 promotor to non-invasively elucidate the temporal profile of VEGFR2 expression after stroke as a biomarker for VEGF/VEGFR2 signaling. We measured each animal repetitively up to 2 weeks after stroke and found increased VEGFR2 expression starting 3 days after the insult with peak values at 7 days. These were paralleled by increased VEGFR2 protein levels and increased vascular volume in peri-infarct areas at 14 days after the infarct, indicating that signaling via VEGFR2 leads to successful vascular remodeling. This study describes VEGFR2-related signaling is active at least up to 2 weeks after the infarct and results in increased vascular volume. Further, this study presents a novel strategy for the non-invasive evaluation of angiogenesis-based therapies.

Transient antiangiogenic treatment improves delivery of cytotoxic compounds and therapeutic outcome in lung cancer.

Extensive oncologic experience argues that the most efficacious applications of antiangiogenic agents rely upon a combination with cytotoxic drugs. Yet there remains a lack of clarity about how to optimize scheduling for such drug combinations. Prudent antiangiogenic therapy might transiently normalize blood vessels to improve tumor oxygenation and drug exposure. Using [(15)O]H2O positron emission tomography imaging in a preclinical mouse model of non-small cell lung cancer, we observed that short-term treatment with the vascular endothelial growth factor receptor/platelet-derived growth factor receptor inhibitor PTK787 licensed a transient window of improved tumor blood flow. The improvement observed was associated with a reduced leakiness from tumor vessels, consistent with induction of a vascular normalization process. Initiation of a cytotoxic treatment in this window of tumor vessel normalization resulted in increased efficacy, as illustrated by improved outcomes of erlotinib administration after initial PTK787 treatment. Notably, intermittent PTK787 treatment also facilitated long-term tumor regression. In summary, our findings offer strong evidence that short-term antiangiogenic therapy can promote a transient vessel normalization process that improves the delivery and efficacy of a targeted cytotoxic drug.

A multi-modality platform to image stem cell graft survival in the naïve and stroke-damaged mouse brain.

Neural stem cell implantations have been extensively investigated for treatment of brain diseases such as stroke. In order to follow the localization and functional status of cells after implantation noninvasive imaging is essential. Therefore, we developed a comprehensive multi-modality platform for in vivo imaging of graft localization, density, and survival using 19F magnetic resonance imaging in combination with bioluminescence imaging. We quantitatively analyzed cell graft survival over the first 4 weeks after transplantation in both healthy and stroke-damaged mouse brain and correlated our findings of graft vitality with the host innate immune response. The multi-modality imaging platform will help to improve cell therapy also in context other than stroke and to gain indispensable information for clinical translation.

Vascular changes after stroke in the rat: a longitudinal study using optimized magnetic resonance imaging.

During stroke, the reduction of blood flow leads to undersupply of oxygen and nutrients and, finally, to cell death, but also to upregulation of pro-angiogenic molecules and vascular remodeling. However, the temporal profile of vascular changes after stroke is still poorly understood. Here, we optimized steady-state contrast-enhanced magnetic resonance imaging (SSCE MRI) and followed the dynamic changes in vascular architecture for up to 4 weeks after transient middle cerebral artery occlusion (MCAO) in rats. Using MRI diffusion measurements and the changes of transversal relaxation rates ΔR2 and ΔR2* after injection of a superparamagnetic contrast agent, SSCE MRI provided several hemodynamic parameters: relative cerebral blood volume (rCBV), rCBV in small vessels, microvascular density, and relative vessel size. Six rats underwent SSCE MRI before MCAO and at 7, 14, 21 and 28 days after surgery. 5-Bromo-2'deoxyuridine (BrdU) was injected between days 2 and 7 to label proliferating cells during this time. SSCE MRI depicted a decrease in microvessel density and an increase in vessel size in the ischemic striatum after stroke. A persistently decreased MRI vessel density was confirmed with histology at 28 days. BrdU + endothelial cells were found in regions close to the infarct indicating endothelial cell proliferation during the first week after MCAO; however, late-stage angiogenesis, as would be reflected by increased vessel density, was not detected. The optimized SSCE MRI protocol was used to follow spatio-temporal changes of important vessel characteristics, which may contribute to a better understanding of the role of angiogenesis at different stages after stroke.

Noninvasive multimodal imaging of stem cell transplants in the brain using bioluminescence imaging and magnetic resonance imaging.

Transplantation of stem cells represents a promising approach for the therapy of different brain diseases, including stroke, Parkinson's, and Huntington's disease. Tracking of stem cells with noninvasive imaging technologies provides insight into location, migration, and proliferation of the cells-key features for a possible clinical translation. This chapter describes a multimodal and noninvasive approach employing magnetic resonance imaging (MRI) and bioluminescence imaging (BLI), both of which offer the opportunity for repetitive measurements on the same individual, revealing the full temporal profile of cell dynamics. The combination of these modalities allows the simultaneous investigation of different aspects of the graft fate. We will present the detailed protocol for noninvasive multimodal tracking of labeled and transplanted neural stem cells, specifically optimized for brain applications, which allows repetitive assessment of localization as well as identification of cell viability and cell quantity after transplantation.

Boosting bioluminescence neuroimaging: an optimized protocol for brain studies.

Bioluminescence imaging is widely used for optical cell tracking approaches. However, reliable and quantitative bioluminescence of transplanted cells in the brain is highly challenging. In this study we established a new bioluminescence imaging protocol dedicated for neuroimaging, which increases sensitivity especially for noninvasive tracking of brain cell grafts. Different D-Luciferin concentrations (15, 150, 300 and 750 mg/kg), injection routes (i.v., i.p., s.c.), types of anesthesia (Isoflurane, Ketamine/Xylazine, Pentobarbital) and timing of injection were compared using DCX-Luc transgenic mice for brain specific bioluminescence. Luciferase kinetics was quantitatively evaluated for maximal photon emission, total photon emission and time-to-peak. Photon emission followed a D-Luciferin dose-dependent relation without saturation, but with delay in time-to-peak increasing for increasing concentrations. The comparison of intravenous, subcutaneous and intraperitoneal substrate injection reflects expected pharmacokinetics with fastest and highest photon emission for intravenous administration. Ketamine/Xylazine and Pentobarbital anesthesia showed no significant beneficial effect on maximal photon emission. However, a strong difference in outcome was observed by injecting the substrate pre Isoflurane anesthesia. This protocol optimization for brain specific bioluminescence imaging comprises injection of 300 mg/kg D-Luciferin pre Isoflurane anesthesia as an efficient and stable method with a signal gain of approx. 200% (compared to 150 mg/kg post Isoflurane). Gain in sensitivity by the novel imaging protocol was quantitatively assessed by signal-to-noise calculations of luciferase-expressing neural stem cells grafted into mouse brains (transplantation of 3,000-300,000 cells). The optimized imaging protocol lowered the detection limit from 6,000 to 3,000 cells by a gain in signal-to-noise ratio.

In vivo imaging of cell transplants in experimental ischemia.

The therapeutic potential of stem cells for regeneration after cerebral lesion has become of great interest. This is particularly so for neurodegenerative diseases as well as for stroke. Contrary to more conventional, cerebroprotective treatment approaches, the focus of regeneration lies in a longer time window during the chronic phase of the lesion evolution. Thus, in order to assess the true potential of a treatment strategy and to investigate the underlying mechanisms, observation of the temporal profile of both the cell dynamics as well as the organ response to the treatment is of paramount importance. This need for intraindividual longitudinal studies can be optimally met by the application of noninvasive imaging modalities. This chapter presents in breadth the potential of noninvasive imaging modalities for cell tracking with application focus to experimental stroke. While the lion's share of discussed studies is based on MRI, we have also included the contributions of positron emission tomography and of the increasingly important optical imaging modality.

The soluble receptor for advanced glycation end products can prospectively identify patients at greatest risk for preterm birth.

OBJECTIVE: Our primary objective was to determine whether there was an association between levels of antenatal maternal serum soluble RAGE (sRAGE), drawn at the time of presentation with preterm labor (PTL), and subsequent preterm birth (PTB). Secondary objectives were to determine whether levels of sRAGE - analyzed from both antenatal maternal serum (MS) and postpartum umbilical cord serum (CS) - were associated with neonatal sepsis. METHODS: Nested case-control analyses were performed within a prospective cohort of patients at risk for PTB. MS was obtained at enrollment and CS at delivery. The sRAGE levels were analyzed. Non-parametric calculations and receiver-operator analyses were performed. RESULTS: Overall, 39.8% of patients delivered < 37 weeks (n=498) and 15% had neonatal sepsis (n=193). In comparing cases and controls, sRAGE was significantly lower in those with than those without an adverse event (PTB: median MS-sRAGE 771.79 versus 948.485 pg/mL, p=0.004; neonatal sepsis: 25-centile CS-sRAGE 1220.49 versus 2244.41 pg/mL, p=0.0013). Adding MS-sRAGE to models of clinical variables significantly enhanced the ability of the model to predict both PTB (area under the curve [AUC] 0.71 versus 0.79, p=0.004) and neonatal sepsis (AUC 0.65 versus 0.75, p=0.04). The negative predictive value of CS-sRAGE for neonatal sepsis was very strong (NPV=0.91). CONCLUSIONS: The sRAGE can be used to help predict adverse perinatal outcomes. Patients with higher levels of sRAGE - who therefore may have an enhanced capability to regulate their immune response - appear less likely to experience PTB and neonatal sepsis.

Antenatal corticosteroids for late-preterm infants: a decision-analytic and economic analysis.

Objectives. Antenatal corticosteroids (ACS) are not routinely administered to patients at risk for delivery between 34 and 36 6/7 weeks. Our objective was to determine whether ACS are cost-effective for late-preterm infants at risk for imminent preterm delivery. We hypothesized that the preferred strategy <36 weeks would include ACS while the preferred strategy ≥36 weeks would not. Methods. We performed decision-analytic and cost-effectiveness analyses to determine whether ACS was cost-effective at 34, 35, and 36 weeks. We conducted a literature review to determine probability, utility, and cost estimates absent of patient-level data. Base-case cost-effectiveness analysis, univariable sensitivity analysis, and Monte Carlo simulation were performed. A threshold of $100,000/QALY was considered cost-effective. Results. The incremental cost-effectiveness ratio favored the administration of a full course of ACS at 34, 35, and 36 weeks ($62,888.25/QALY, $64,425.67/QALY, and $64,793.71/QALY, resp.). A partial course of ACS was not cost-effective. While ACS was the consistently dominant strategy for acute respiratory outcomes, all models were sensitive to changes in variables associated with chronic respiratory disease. Conclusions. Our findings suggest that the administration of ACS to patients at risk of imminent delivery 34-36 weeks could significantly reduce the cost and acute morbidity associated with late-preterm birth.

Trends in prematurity: what do changes at an urban institution suggest about the public health impact of 17-alpha hydroxyprogesterone caproate?

Despite the introduction of 17-alpha-hydroxyprogesterone caproate (17P), the national preterm birth (PTB) rate remains unchanged. Our objectives were to determine whether the overall rate of PTB has decreased and whether there has been a shift in the trends of prematurity at our institution since the initiation of 17P use. We performed a cross sectional study of the PTB rate and gestational age distribution at delivery (GA-del) at our institution over two, 2-year time periods: TP1 (pre 17P, 1 Jan 2004-31 Dec 2005) and TP2 (post 17P, 1 Jan 2008-31 Dec 2009). Statistical analyses included χ(2) tests for categorical data, t-tests for continuous data, and multivariable logistic regression to control for confounders. Overall (n = 15,421), there was no difference in the rate of PTB from TP1 to TP2 (16.65 vs 16.95%, p = 0.62). Among those with a history of prior PTB (n = 2,141), the mean preterm GA-del was 10 days later in TP2 than in TP1 (33.13 vs 31.64 weeks, p < 0.01) and significantly more preterm infants in TP2 delivered between 34-36 6/7 weeks than in TP1 (65.00 vs 45.63%, p < 0.01). The odds of a preterm infant delivering in the late preterm period was 2.3-fold higher in TP2 than TP1 (95% CI 1.49-3.54) after controlling for confounders. The significant shift in GA-del towards the late preterm period in TP2 may be due to the introduction of 17P use at our institution. Additional studies are needed to determine whether these trends persist on a nationwide level.

The significance of a positive second trimester serum screen for trisomy 18.

OBJECTIVES: We designed this study to estimate the proportion of fetuses in pregnancies with positive second trimester serum screens for trisomy 18 who actually have trisomy 18, to estimate the proportion of women with trisomy 18 who have a negative serum screen, and to assess the role of ultrasound in the diagnosis of trisomy 18. METHODS: Retrospective study of two cohorts of pregnant women in 2004 and 2005: (1) those with a second trimester serum screen positive for trisomy 18 and (2) those with fetuses having trisomy 18. RESULTS: There were 93 women with positive serum screens for trisomy 18. Of these, only three had a fetus with trisomy 18. There were five other cases of trisomy 18, three of which had a negative second trimester serum screen for trisomy 18. All fetuses with trisomy 18 had multiple major structural abnormalities detected on targeted genetic sonography. CONCLUSIONS: A positive second trimester serum screen has a poor sensitivity and poor prediction for trisomy 18. Trisomy 18 is highly unlikely if a woman with a positive screen for trisomy 18 has no fetal abnormalities detected on targeted genetic sonography. Women with a positive second trimester serum screen for trisomy 18 should be offered genetic sonography, and the practice of routine amniocentesis for all women with a positive screen should be discouraged when targeted genetic sonography is available.

High field BOLD response to forepaw stimulation in the mouse.

We have established a robust protocol for longitudinal fMRI in mice at high field MRI using a medetomidine anesthesia. Electrical forepaw stimulation in anesthetized animals is widely used to produce BOLD contrast in the primary somatosensory cortex. To preserve neuronal activity, most fMRI experiments used alpha-chloralose to produce sedation, but severe side effects make this procedure unsuitable for survival experiments. As advantageous alternative, the alpha(2)-adrenergic receptor agonist medetomidine has been applied successfully to permit longitudinal fMRI studies in rats. With the advent of transgenic technology, mouse models have become increasingly attractive raising the demand for implementation of a suitable fMRI protocol for mice. Therefore, we investigated the use of medetomidine for repetitive fMRI experiments in C57BL/6 mice. We evaluated the optimal medetomidine dose for subcutaneous application. Somatosensory evoked potentials (SSEPs) in the contralateral somatosensory cortex were recorded to assess brain activity under medetominidine following forepaw stimulation. Repetitive administration of medetomidine, the requirement for longitudinal brain activation studies, was well tolerated. Using the forepaw stimulation paradigm, we observed BOLD contrast in the contralateral somatosensory cortex in approximately 50% of the performed scans using gradient echo-echo planar imaging (GE-EPI). However, imaging the small mouse brain at high field strength is challenging and we observed strong susceptibility artifacts in GE-EPI images in the cortex. We have developed an agar gel cap for successful compensation of these artifacts as prerequisite for successful mouse fMRI at 11.7T. The established protocol will be suitable for brain activation studies in transgenic animals and for studies of functional deficit and recovery after brain injury in mice.