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This study aimed to investigate the alterations of cognition and functional connectivity post noise, and find the progress and neural substrates of noise induced hearing loss (NIHL)-associated cognitive impairment. We exposed rats to 122 dB broad-band noise for 2 h to induce hearing loss and the auditory function was assessed by measuring auditory brainstem response thresholds. Morris water maze test and resting state MRI were computed at 0 day, 1, 3, 6 months post noise to reveal cognitive ability and neural substrate. The interregional connections in the auditory network and default mode network, as well as the connections using the auditory cortex and cingulate cortex as seeds were also examined addtionally. The deficit in spatial learning/memory was only observed at 6 months after noise exposure. The internal connections in the auditory network and default mode network were enhanced at 0 day and decreased at 6 months post noise. The connectivity using the auditory cortex and cingulate cortex as seeds generally followed the rule of "enhancement-normal-decrease-widely decrease". A new model accounting for arousal, dementia, motor control of NIHL in is proposed. Our study highlights the fundamental flexibility of neural systems, and may also point toward novel therapeutic strategies for treating sensory disorders.

We aimed to find where and how noise-induced cochlear hearing loss affects the central nervous system during the early state and identify the neural substrate for aberrant patterns that mediating noise-related anxiety-/depression- like behaviors.Broad band noise with 122 dB for 2 hours was conducted to induce hearing loss. We defined 0 day (N0D) and 10 days (N10D) post noise as the acute and sub-acute period. Behavioral tests (Open field test and light/dark test) and resting-state fMRI were computed to evaluate emotional conditions and aberrant neural activity. Functional connectivity analysis using the anterior cingulate cortex as a seed was computed to reveal the spatial distribution beyond auditory network during both periods.Anxiety-/depression-like behaviors were found in rats with noise exposure. Between-group analysis revealed that N0D rats displayed widespread reductions in functional connectivity, spanning primary somatosensory cortex, medial geniculate body, inferior colliculus, cingulate cortex, cerebellar lobule comparing with N10D rats and a similar pattern was also occurred in comparison with the control group.Taken together, an "acoustic-causing" network accounting for distress and gating of noise exposure related anxiety/depression was proposed.

This study aimed at developing a radiomics signature (R score) as prognostic biomarkers based on penumbra quantification and to validate the radiomics nomogram to predict the clinical outcomes for thrombolysis for acute ischemic stroke (AIS) patients. In total, 168 patients collected from seven centers were retrospectively included. A score of mismatch was defined as MIS. Based on a short-term clinical label, 456 radiomics features were evaluated with feature selection methods. R score was constructed with the selected features. To compare the predictive capabilities of the clinical factors, MIS, and R score, three nomograms were developed and evaluated, according to the short-term clinical assessment on day 7. Finally, the radiomics nomogram was validated by predicting the 3-month clinical outcomes of AIS patients, in an external cohort. R scores were found to be significantly higher in patients with favorable clinical outcomes in both training and validation datasets. The predictive value of the radiomics nomogram estimating favorable clinical outcomes was modest, with a concordance index (C-index) of 0.695 [95% confidence interval (CI) 0.667–0.723) in an external validation dataset. In addition, the area under curve (AUC) of the radiomics nomogram predicting favorable clinical outcome reached 0.886 (95% CI 0.809–0.963) on day 7 and 0.777 (95% CI 0.666–0.888) at 3 months. The radiomics signature is an independent biomarker for estimating the clinical outcomes in AIS patients. By improving the individualized prediction of the clinical outcome for AIS patients 3 months after onset, the radiomics nomogram adds more value to the current clinical decision-making process.

BACKGROUND Type 2 diabetes mellitus (T2DM) is associated with cognitive decline and altered brain structure and function. However, the interhemispheric coordination of T2DM patients is unclear. PURPOSE To investigate interhemispheric functional and anatomic connectivity in T2DM, and their associations with cognitive performance and endocrine parameters. STUDY TYPE Prospective. SUBJECTS 38 T2DM patients and 42 matched controls. FIELD STRENGTH/SEQUENCES 3.0 T magnetic resonance imaging (MRI) scanner; magnetization-prepared rapid acquisition gradient echo sequence; fluid-attenuated inversion recovery sequence; single-shot, gradient-recalled echo-planar imaging sequence (resting-state functional MRI); and diffusion-weighted spin-echo-based echo-planar sequence (diffusion tensor imaging). ASSESSMENT Voxel-mirrored homotopic connectivity (VMHC) value was calculated based on the functional images. Fibers passing through the regions with significant VMHC differences were identified using an atlas-guided track recognition. The mean fractional anisotropy (FA), mean diffusivity (MD), and fiber length were extracted and compared between the two groups. Finally, correlational analyses were performed to examine the relationships between abnormal interhemispheric connectivity, cognitive performances, and endocrine parameters. STATISTICAL TESTS Two-sample t-tests were performed controlling for confounding factors, with partial correlation analysis. False discovery rate (FDR) correction was used for multiple comparisons. A P value

Objective: To assess the reproducibility of 3.0T high-resolution magnetic resonance imaging for the identification and quantification of atherosclerotic plaques in the middle cerebral artery. Methods: Sixty-nine consecutive patients with ischemic stroke or asymptomatic stenosis (>30%) of the middle cerebral artery underwent 3.0T high-resolution magnetic resonance imaging examinations. Two independent investigators reviewed all images with 1 investigator re-evaluating all images 4 weeks later. Wall characteristics of the middle cerebral artery, including plaque surface morphology, plaque location, plaque components, and burden were identified and measured. Results: Intraobserver and interobserver agreement were all substantial in identifying plaque surface irregularity (k = 0.741, 0.555-0.897; k = 0.685, 0.490-0.843; respectively) and intraplaque hemorrhage (k = 0.654, 0.446-0.838; k = 0.605, 0.369-0.792; respectively). Intraobserver agreement was substantial (k = 0.654) and interobserver agreement was moderate (k = 0.553) for the identification of plaque fibrous caps. The total intraobserver and interobserver reproducibility was almost excellent for the identification of plaque position. With regards to vessel area measurement at the site of maximal lumen narrowing, intraobserver and interobserver reproducibility was excellent (intraclass correlation coefficient was 0.886 and 0.885, respectively) and moderate for lumen area at the site of maximal lumen narrowing (intraclass correlation coefficient was 0.695 and 0.558, respectively). In addition, intraobserver and interobserver reproducibility was excellent for vessel area and lumen area measurements at the reference sites. Conclusions: The reproducibility of 3.0T high-resolution magnetic resonance imaging for the identification and quantification of artery wall characteristics was overall acceptable. However, the reliability for lumen area measurement at the maximum narrowing site and identification of the fibrous cap needs to be improved.

Abnormal neural activity in the cerebellum has been implicated in hearing impairments, but the effects of long-term hearing loss on cerebellar function are poorly understood. To further explore the role of long-term bilateral sensorineural hearing loss on cerebellar function, we investigated hearing loss-induced changes among neural networks within cerebellar subregions and the changes in cerebellar-cerebral connectivity patterns using resting-state functional MRI. Twenty-one subjects with long-term bilateral moderate-to-severe sensorineural hearing loss and 21 matched controls with clinically normal hearing underwent MRI scanning and a series of neuropsychological tests targeting cognition and emotion. Voxel-wise functional connectivity (FC) analysis demonstrated decreased couplings between the cerebellum and other cerebral areas, including the temporal pole (TP), insula, supramarginal gyrus, inferior frontal gyrus (IFG), medial frontal gyrus, and thalamus, in long-term bilateral sensorineural hearing loss patients. An ROI-wise FC analysis found weakened interregional connections within cerebellar subdivisions. Moreover, there was a negative correlation between anxiety and FC between the left cerebellar lobe VI and left insula. Hearing ability and anxiety scores were also correlated with FC between the left cerebellar lobe VI and left TP, as well as the right cerebellar lobule VI and left IFG. Our results suggest that sensorineural hearing loss disrupts cerebellar-cerebral circuits, some potentially linked to anxiety, and interregional cerebellar connectivity. The findings contribute to a growing body showing that auditory deprivation caused by cochlear hearing loss disrupts not only activity with the classical auditory pathway but also portions of the cerebellum that communicates with other cortical networks.

Objective To observe the migration characteristics of neural stem cells (NSCs) labeled with the MRI contrast agent superparamagnetic iron oxide (SPIO) in the brain of APP/PS1 transgenic mice with Alzheimer's disease (AD) by 7.0 T high resolution MRI. Methods C57BL/6 mouse NSCs were cultured, amplified, labeled with Feridex and Poly- l -lysine (FE-PLL) and evaluated by transmission electron microscopy (TEM). Using the random number table method, 24 APP/PS1 transgenic AD mice aged 12 months were equally assigned to two groups: animals in group A were transplanted with FE-PLL labeled NSCs and those in group B were transplanted with non-labeled NSCs in the right hippocampus. Twelve wild-type mice of the same age and born from the same litter were used as the control group (group C) and transplanted with FE-PLL labeled NSCs. Using the 7.0 T high resolution MR scanner, the transplanted NSCs were traced in vivo at 1 day, 1 and 2 weeks after cell transplantation. The MRI findings were compared with the histopathological findings. Results C57BL/6 mouse NSCs were cultured and amplified successfully. TEM showed large amounts of iron-containing particles in the cytoplasm of transplanted cells. MRI in group A showed the presence of spheroid low signals at the injection point of the hippocampus on T2*WI one day after transplantation; one weeks later, the low signals were seen diffusing to the surroundings along the injection point, and covering almost the whole hippocampal area but the intensity of the low signals became weaker gradually; two weeks after transplantation, almost all low signals disappeared. In group B, no significant change in low signals was observed in the transplantation area at all designated time points. Although low signals were also observed in the hippocampus after transplantation of FE-PLL labeled NSCs in group C, their size and location remained almost unchanged. Prussian blue staining showed that migration of the FE-PLL labeled NSCs in the hippocampus of the AD mice was consistent with the MRI findings at all designated time points. Conclusion NSCs underwent diffuse and non-directional migration to the surroundings after they were transplanted to the hippocampus of APP/PS1 transgenic AD mice, and this migration pattern could be traced in vivo by MRI when they were labeled with magnet.

The protracted nature of development makes the cerebellum vulnerable to a broad spectrum of pathologic conditions, especially during the early fetal period. This study aims to characterize normal cerebellar growth in human fetuses during the early second trimester. We manually segmented the fetal cerebellum using 7.0-T high-resolution MR images obtained in 35 specimens with gestational ages ranging from 15 to 22 weeks. Volume measurements and shape analysis were performed to quantitatively evaluate global and regional cerebellar growth. The absolute volume of the fetal cerebellum showed a quadratic growth with increasing gestational age, while the pattern of relative volume changes revealed that the cerebellum grew at a greater pace than the cerebrum after 17 gestational weeks. Shape analysis was used to examine the distinctive development of subregions of the cerebellum. The extreme lateral portions of both cerebellar hemispheres showed the lowest rate of growth. The anterior lobe grew faster than most of the posterior lobe. These findings expand our understanding of the early growth pattern of the human cerebellum and could be further used to assess the developmental conditions of the fetal brain.

Depression, anxiety and apathy are 'common neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD). We aimed to find regional gray matter (GM) volume difference of these symptoms, in AD patients compared to AD control, and investigate possible associations of GM atrophy with cognitive covariant. Study subjects were retrieved from the Alzheimer's Disease Neuroimaging Initiative database. Thirty-five participants are AD control, 27 AD patients with anxiety, 19 with depression and 24 with apathy, ages ≥ 55.1 years. Recruited subjects had an assessment of their clinical and structural MRI data. GM differences and clinical data were analyzed using voxel-based morphometry and ANOVA with Scheffe post hoc test, respectively. We found significant GM volumes differences in the left insula, left parahippocampal, posterior cingulate and the bilateral putamen in the anxiety group. The results also revealed that the right parahippocampal, Brodmann area 38 and the middle frontal gyrus were significant in patients with depression. Significant results were with a p 0.05, corrected with AlphaSim program for multiple comparisons. The left insula had a strong negative association with Clinical Dementia Rate Sum of Boxes and Alzheimer's Disease Assessment Scale-cognitive subscale-13 items in anxiety and apathy groups. The difference in GM density in the left insula and hippocampus plays a crucial role in depression, anxiety and apathy NPS and outline precise approaches to test these symptoms.

PURPOSE To prospectively investigate age- and gender-related changes in the fast-twitch (tibialis anterior, TA) and slow-twitch (soleus, SOL) skeletal muscle of healthy rats and volunteers and to compare the exercise-related difference in health volunteers with T1 ρ magnetic resonance imaging (MRI). MATERIALS AND METHODS In all, 18 rats and 70 humans were involved in this study. For the animal study, T1 ρ relaxation times were measured in the TA and SOL rat muscle with a 3.0T MRI scanner and compared to histological data. For the human study, three groups (young, middle-aged, and elderly) of volunteers underwent T1 ρ MRI scans (3.0T) of their calves. To further differentiate the human scans, 18 volunteers were recruited, half of them (n = 9) routinely trained with high-intensity sports, while the other half (n = 9) with no physical training. Statistical analysis was performed via paired t-test, independent-sample t-test, and analysis of variance (ANOVA). Correlations between T1 ρ and age/gender/physical endurance were calculated. RESULTS The average T1 ρ relaxation times of the TA and SOL of female rats were higher than that of male rats (P < 0.001). The T1 ρ relaxation time of TA was significantly lower compared to SOL (P < 0.001). A significant linear correlation was observed between T1 ρ and the type I slow-twitch fiber proportion (%) in SOL (R2 = 0.837, P < 0.001). Similarly, in human studies the average T1 ρ relaxation times of TA were significantly lower than SOL for all age groups (P < 0.001). The higher T1 ρ relaxation times of TA and SOL in the elderly volunteers (P < 0.001) and in the females (P < 0.05) indicated significant age- and gender-dependent differences. In high-intensity sports groups, the higher T1 ρ in SOL (P < 0.01) and lower in TA (P < 0.05) were observed compared with the control group. CONCLUSION This study demonstrated that T1 ρ MRI can be used to display the differences in fast- and slow-twitch skeletal muscle as well as potentially age-, gender-, and exercise-related differences. LEVEL OF EVIDENCE 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:61-70.

Aims Stroke is a refractory cerebral blood circulation disorder. Endothelial progenitor cells (EPCs) participate in the repair and regeneration of vascular injury through the combination of cell replacement and bystander effects. Here, we evaluated the biological function of EPCs in treating a mouse model of cerebral ischaemic stroke, using dual-mode bioluminescence and magnetic resonance imaging to trace EPCs in vivo. Main methods We constructed a viral vector with a luciferase-enhanced green fluorescent protein (Luc-eGFP) reporter gene for bioluminescence imaging (BLI) detection, and simultaneously synthesized the magnetic resonance imaging (MRI) contrast agent, nano-sized superparamagnetic iron oxide (USPIO), to co-label human umbilical cord blood-derived EPCs (hEPCs). The labelled hEPCs were transplanted into mice with stroke, and the biological behaviours of the cells in-vivo were studied using BLI and MRI, and methods of molecular biology and histology. Key findings Comparing the two cell transplantation routes by BLI confirmed that many cells transplanted via the left ventricular route homed to ischaemic brain tissue. The dual-modality-imaging showed the prognosis of in-vivo tracking cells after transplantation in ischaemic tissues at different time points. Histological staining and neurological function scores confirmed that EPC transplantation can improve the symptoms of nerve deficit in the mouse stroke model. Histological staining revealed that cell transplantation can lead to recovery of neurological function after stroke, via various processes. These include reduced blood brain barrier permeability, recovery of white matter and of myelin, and the enhancement of neuroneogenesis. Significance Dual-modality imaging revealed EPCs as potential candidates for the treatment of ischaemic stroke.

Wide-ranging functional remodeling is involved in sensorineural hearing loss (SNHL), which has been demonstrated to have accumulated risk of cognitive and emotional dysfunction. Anterior cingulate cortex (ACC) has close connections with the auditory area and plays a vital role in regulating the cognitive, emotional and auditory processing. However, the functional reorganization of the ACC and its associations with potential cognitive and emotional impairments involved in SNHL have never been explored. Thirty-five patients with long-term bilateral SNHL and thirty-five well-matched healthy controls were recruited for this study. We analyzed resting-state functional MRI data and neuropsychological test scores from these participants. Functional connectivity of the ACC subdivisions, voxel-wise degree centrality (DC) and intra-/internetwork connectivity were computed to evaluate the functional changes related to cognitive, emotional and multiple sensory functions. ANCOVA and post hoc analyses were conducted to identify differences between normal controls and patients for each measure. Widespread alterations of functional coupling with the subdivisions of the ACC were observed in regions involved in cognitive, emotional and multiple sensory processing, particularly within the cingulo-opercular network (CON), default mode network (DMN) and auditory network (AN) in the SNHL patients. Outstandingly increased DC was found in the ACC. Network analyses showed significant intra- and inter-network hypo-synchronization in the SNHL patients. Importantly, the functional alterations were associated with the anxiety states and the processing speed. The functional reorganization in the ACC and the disturbance of intrinsic multiple network functional connectivity among the CON, DMN, and AN were found in the SNHL patient, which might shed more lights on potential substrates underlying the cognitive and emotional impairments related to the SNHL.

The thalamus is an integrative hub conveying sensory information between cortical areas and related to cognition. However, alterations of the thalamus following partial hearing deprivation remains unknown.To investigate the modifications of the thalamus and its seven subdivisions in terms of structure, function, and perfusion in subjects with sensorineural hearing loss (SNHL), as well as their associations with SNHL-induced cognitive impairments.Cross-sectional study.Thirty-seven bilateral long-term SNHL patients and 38 well-matched controls.3 T/BOLD, TQuantitative measurements in the thalamus and subdivisions were obtained, including the relative volume, fractional amplitude of low-frequency fluctuation (fALFF) within slow 5 (0.01-0.027 Hz), slow 4 (0.027-0.073 Hz), and combined frequency (0.01-0.073 Hz), as well as the whole-brain functional connectivity. Twenty-five SNHL patients and 20 controls underwent ASL scanning. Then correlation analysis was computed between all significant changes and cognition tests.Continuous and categorical variables were compared by independent-sample t-test and chi-square test, respectively. Quantitative MRI measurement comparisons were corrected for multiple comparison, and functional connectivity (FC) analysis used two-sample t-test with false-discovery rate correction. Area under the curve (AUC) in receiver operating characteristic curve analysis was applied to evaluate the power of alterations in differentiating SNHL and controls.No significant difference in the relative volume and perfusion of seven thalamus subdivisions were observed, but a decrease in fALFF in SNHL. SNHL showed reduced thalamic connectivity with the cerebellum lobule VIII, ventral anterior cingulate cortex, insula, superior temporal gyrus, media temporal gyrus, medial frontal gyrus, Heschl's gyrus, and temporal pole. And some FC abnormalities exhibited positive correlations with cognitive tests and high discriminative power (0.8 AUC 1) in two groups.SNHL led to decreased thalamic activity and widespread weakened connectivity with other brain areas.2 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2019;50:787-797.

Background & Aims Noninvasive and accurate methods are needed to identify patients with clinically significant portal hypertension (CSPH). We investigated the ability of deep convolutional neural network (CNN) analysis of computed tomography (CT) or magnetic resonance (MR) to identify patients with CSPH. Methods We collected liver and spleen images from patients who underwent contrast-enhanced CT or MR analysis within 14 days of transjugular catheterization for hepatic venous pressure gradient measurement. The CT cohort comprised participants with cirrhosis in the CHESS1701 study, performed at 4 university hospitals in China from August 2016 through September 2017. The MR cohort comprised participants with cirrhosis in the CHESS1802 study, performed at 8 university hospitals in China and 1 in Turkey from December 2018 through April 2019. Patients with CSPH were identified as those with a hepatic venous pressure gradient of 10 mm Hg or higher. In total, we analyzed 10,014 liver images and 899 spleen images collected from 679 participants who underwent CT analysis, and 45,554 liver and spleen images from 271 participants who underwent MR analysis. For each cohort, participants were shuffled and then sampled randomly and equiprobably for 6 times into training, validation, and test data sets (ratio, 3:1:1). Therefore, a total of 6 deep CNN models for each cohort were developed for identification of CSPH. Results The CT-based CNN analysis identified patients with CSPH with an area under the receiver operating characteristic curve (AUC) value of 0.998 in the training set (95% CI, 0.996–1.000), an AUC of 0.912 in the validation set (95% CI, 0.854–0.971), and an AUC of 0.933 (95% CI, 0.883–0.984) in the test data sets. The MR-based CNN analysis identified patients with CSPH with an AUC of 1.000 in the training set (95% CI, 0.999–1.000), an AUC of 0.924 in the validation set (95% CI, 0.833–1.000), and an AUC of 0.940 in the test data set (95% CI, 0.880–0.999). When the model development procedures were repeated 6 times, AUC values for all CNN analyses were 0.888 or greater, with no significant differences between rounds (P > .05). Conclusions We developed a deep CNN to analyze CT or MR images of liver and spleen from patients with cirrhosis that identifies patients with CSPH with an AUC value of 0.9. This provides a noninvasive and rapid method for detection of CSPH ( ClincialTrials.gov numbers: NCT03138915 and NCT03766880 ).

Tumor metastasis to brain is the main clinical manifestation of patients with advanced breast cancer, leading to poor survival prognosis. In order to detect the early incidence of brain metastasis, it is urgent to develop hypersensitive contrast agents for multimode imaging. In this study, PEG-phospholipids coated, a phage play derived peptide, BRBP1 peptide modified ultra-small iron oxide nanoparticles were prepared for targeted NIRF and MR imaging of breast cancer brain metastasis. The nanoparticles showed 10 nm core-shell, high relaxivity values and photon emission efficiency in vitro. The nanoparticles offered a T2 contrast imaging effect and near-infrared fluorescent signal enhancement. Compared with control peptide modified nanoparticles, the MR/NIRF imaging signal of BRBP1-modified nanoparticles in tumor tissue was significantly enhanced, which should be induced by the targeting ability of BRBP1 peptide. These results indicated that BRBP1-SPIO@mPEG (DiR) nanoparticles could be applied as an effective targeted delivery system for diagnosis of breast cancer brain metastasis.

To explore the effect of T2DM on cerebral perfusion, and the relationship between cerebral perfusion changes and cognitive impairment as well as diabetic variables, by using a whole-brain arterial spin-labeling (ASL) MRI technique. This prospective study was approved by the local institutional review board and was performed between November 2012 and October 2013. All subjects provided informed consent. Forty T2DM patients and 41 age-, sex- and education-matched healthy controls were included. Cerebral blood flow (CBF) map was obtained by pulsed ASL perfusion imaging at 3 T MRI. Voxel-wise comparisons on CBF maps with and without partial volume effects (PVEs) correction were performed between groups. Associations between CBF and cognitive functioning, and between CBF and diabetic variables were investigated by using voxel-wise, whole-brain correlation analyses. In T2DM patients, PVEs uncorrected CBF was decreased in the posterior cingulate cortex (PCC), precuneus and bilateral occipital lobe, and increased in the anterior cingulate cortex (corrected P

Background People exposed to stressful experience are at increased risk of the development of depression. A number of functional imaging studies have found disturbances in the mood-regulating circuit of the stress-exposed depressed patients, although few animal imaging studies have been undertaken addressing the brain functional changes of depression. Methods Two rat models of depression: maternal separation (MS) and chronic unpredictable mild stress (CUMS), imitating early life stress and adult stress respectively, were administered with escitalopram. The differences in functional brain changes were determined by blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI). Results Increased BOLD activation was observed in some brain regions of MS and CUMS animals, such as the bilateral hypothalamus, limbic system, hippocampus and frontal lobe, which were parts of mood-regulating circuit. Furthermore, the MS- and CUMS-induced increases in BOLD activation were partially attenuated by chronic escitalopram treatment. Conclusions These results suggested hyperactivation of mood-regulating circuit at baseline in the depressed animals exposed to stressful experience, and escitalopram can at least partially reverse these effects.

Xingui Peng,1 Cong Li,2 Yingying Bai,1 Xinyi Wang,1 Yi Zhang,1 Yanli An,1 Gao-Jun Teng,1 Shenghong Ju1 1Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 2Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China Background: Endothelial progenitor cells (EPCs) play an important role in repairing ischemia tissues. However, the survival, migration and therapeutic efficacy of EPCs after transplantation need to be better understood for further cell therapy. Purpose: This study investigated the migration effect of EPCs labeled with a multimodal imaging agent in a murine ischemic hindlimb model, using magnetic resonance imaging (MRI) and optical imaging after transplantation. Methods: EPCs derived from mouse bone marrow were labeled with a multimodal imaging agent and were administered through intracardiac delivery to mice with ischemic hindlimbs. The injected EPCs and their migration effect were observed via MRI and optical imaging in vivo, and then compared to a reference standard based on histological data. The quantification of gadolinium in tissue samples was done using inductively coupled plasma mass spectrometry (ICP-MS). Results: Using in vivo MRI and optical imaging, the labeled EPCs were observed to migrate to ischemic muscle on days 3–5 after injection, while ex vivo, the EPCs were observed in the capillary vessels of the injured tissue. There were significant linear correlations between the Gd contents measured using ICP-MS in samples from the ischemic hindlimbs and livers and T1 relaxation times calculated using MRI, as well as the average fluorescence signal intensities recorded in optical images (T1 relaxation time: r=0.491; average signal from optical imaging: r=0.704, P

Mucin-1 (MUC1), a transmembrane glycoprotein is aberrantly expressed on ∼90% of breast cancer and is an excellent target for nanoparticulate targeted imaging. In this study, the development of a dye-doped NIR emitting mesoporous silica nanoparticles platform conjugated to tumor-specific MUC1 antibody (ab-tMUC1-NIR-MSN) for in vivo optical detection of breast adenocarcinoma tissue is reported. The structural properties, the in vitro and in vivo performance of this nanoparticle-based probe were evaluated. In vitro studies showed that the MSN-based optical imaging nanoprobe is non-cytotoxic and targets efficiently mammary cancer cells overexpressing human tMUC1 protein. In vivo experiments with female C57BL/6 mice indicated that this platform accumulates mainly in the liver and did not induce short-term toxicity. In addition, we demonstrated that the ab-tMUC1-NIR-MSN nanoprobe specifically detects mammary gland tumors overexpressing human tMUC1 in a human MUC1 transgenic mouse model.

Endothelial progenitor cell (EPC)-based therapy has brought potential benefits to stroke patients as an important restorative therapeutics. However, its efficacy is limited by poor migration and survival ability. Here, we found out that hif-prolyl hydroxylase 2 (PHD2) silencing could enhance the migration and survival ability of EPCs which could improve the therapy efficacy for ischemic stroke. We successfully developed a siRNA delivery system, which could achieve siRNA delivery and EPCs tracking with magnetic resonance imaging (MRI) simultaneously. Besides, combining MRI and bioluminescence imaging (BLI), we successfully observed full temporal profile of EPCs dynamics in vivo. Furthermore, we found out that PHD2 silencing in EPCs elevated the expression of C-X-C chemokine receptor type 4 (CXCR4) and hypoxia-inducible factor 1α (HIF-1α), which enhanced the migration and survival ability of EPCs respectively. Significantly decreased infarct volume, functional deficits and increased fractional anisotrophy (FA) value, fiber counts were observed in the siPHD2-EPCs (EPCs transfected with siRNA targeting PHD2) group. What's more, higher level of BNDF, CD31, DCX, NeuN and MBP were also observed in the siPHD2-EPCs group. Altogether, our study provides an effective method to improve EPC-based therapy efficacy for ischemic stroke.

Background Ischemic stroke is a complex disease with multiple etiologies and clinical manifestations. Paired immunoglobulin‐like receptor B (PirB), which is originally thought to function exclusively in the immune system, is now also known to be expressed by neurons. A growing number of studies indicate that PirB can inhibit neurite outgrowth and restrict neuronal plasticity. The aim of the study is to investigate whether PirB can be an attractive theranostic target for ischemic stroke. Methods and Results First, we investigated the spatial‐temporal expression of PirB in multiple ischemic stroke models, including transient middle cerebral artery occlusion, photothrombotic cerebral cortex ischemia, and the neuronal oxygen glucose deprivation model. Then, anti‐PirB immunoliposome nanoprobe was developed by thin‐film hydration method and investigated its specific targeting in vitro and in vivo. Finally, soluble PirB ectodomain ( sP irB) protein delivered by polyethylene glycol–modified nanoliposome was used as a therapeutic reagent for ischemic stroke by blocking PirB binding to its endogenous ligands. These results showed that PirB was significantly upregulated after cerebral ischemic injury in ischemic stroke models. Anti‐PirB immunoliposome nanoprobe was successfully developed and specifically bound to PirB in vitro. There was accumulation of anti‐PirB immunoliposome nanoprobe in the ischemic hemisphere in vivo. Soluble PirB ectodomains remarkably improved ischemic stroke model recovery by liposomal delivery system. Conclusions These data indicated that PirB was a significant element in the pathological process of cerebral ischemia. Therefore, PirB may act as a novel theranostic target for ischemic stroke.

Background: Ischemic stroke caused severe damages to patients, mostly treatments for ischemic stroke focused recovery on the peri-infarct areas. In this study, we found that focal ischemic stroke caused damages to whole brain, endothelial progenitor cells (EPCs) treatment could significantly promote the recovery of the whole brain after ischemic stroke. Methods: EPCs were infected with lentivirus carrying luc2 and eGFP cassette for bioluminescence imaging (BLI) and labeled with Alkyl-PEI-SPIO for magnetic resonance imaging (MRI). 5×10^5 EPCs were transplanted intracardially 24 hours after photothrombotic ischemic stroke onset. BLI, MRI and behavior test were carried out at different time points. Expression of BDNF, VEGF in the ipsilateral and contralateral hemisphere and infarct volume were analyzed 7 days after EPCs transplantation. Expression of myelin basic protein (MBP) and NeuN in the ipsilateral and contralateral hemisphere were detected 14 days after EPCs transplantation. Findings: EPCs transplantation significantly increased the expression of BDNF, MBP and NeuN in both ipsilateral and contralateral hemisphere, while no significant differences were found in VEGF expression. Also, in vivo MRI results showed that fiber counts and FA values in both ipsilateral and contralateral corpus callosum increased 14 days after EPCs transplantation. No significant differences were found in the infarct volume 7 days after EPCs transplantation. mNSS scores and foot-faults test indicated better functional recovery 14 days after EPCs transplantation. Interpretation: Studies should focus on the whole brain recovery after stroke onset. EPCs treatment offered a powerful therapy method for whole brain recovery after ischemic stroke which may associated with elevated BDNF expression. Funding Statement: This work was supported by the National Key Basic Research Program of China (NOs. 2013CB733800 and 2013CB733803), the National Natural Science Foundation of China (NOs. 81230034 and 81520108015), the National Natural Science Foundation of Jiangsu Province (NO. BK20130057), the National Science Foundation for Youths of China (NOs. 81601544 and 81501522), the Fundamental Research Funds for the Central Universities (NO. 2242018k30004). C. Wang acknowledged the financial support from the China Scholarship Council for his joint PhD scholarship (NO. 201706090204). The funder had no role in the study design, data analysis, write-up or in the writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Declaration of Interest: The authors have no conflicts of interest to disclose. Ethics Approval Statement: This study was approved by the Institutional Animal Care and Use Committee (IACUC) of Southeast University (approval ID: SYXK-2010.4987). BALB/c nude female mice (8 weeks, 20-23 g, Comparative Medicine Centre of Yangzhou University [SCXK (SU) 2012-0004], Yangzhou, China) were used in this study. Briefly, EPCs were isolated from newborns with all mothers’ informed consent and with the approval of the local hospital ethics committee.

Purpose The phantom sound of tinnitus is believed to arise from abnormal functional coupling between the thalamus and cerebral cortex. To explore this hypothesis, we used resting-state functional magnetic resonance imaging (fMRI) to compare the degree of thalamocortical functional connectivity in chronic tinnitus patients and controls. Materials and methods Resting-state fMRI scans were obtained from 31 chronic tinnitus patients and 33 well-matched healthy controls. Thalamocortical functional connectivity was characterized using a seed-based whole-brain correlation method. The resulting thalamic functional connectivity measures were correlated with other clinical data. Results We found decreased functional connectivity between the seed region in left thalamus and right middle temporal gyrus (MTG), right middle orbitofrontal cortex, left middle frontal gyrus, right precentral gyrus, and bilateral calcarine cortex. Decreased functional connectivity was detected between the seed in the right thalamus and the left superior temporal gyrus (STG), left amygdala, right superior frontal gyrus, left precentral gyrus, and left middle occipital gyrus. Tinnitus distress correlated negatively with thalamic functional connectivity in right MTG; tinnitus duration correlated negatively with thalamic functional connectivity in left STG. Increased functional connectivity between the bilateral thalamus and a set of regions were also observed. Conclusions Chronic tinnitus patients have disrupted thalamocortical functional connectivity to selected brain regions which is associated with specific tinnitus characteristics. Resting-state thalamic functional connectivity disturbances may play an important role in neuropathological features of tinnitus.

To explore the disrupted thalamic functional connectivity and its relationships with cognitive dysfunction in type 2 diabetes mellitus (T2DM) by using resting-state functional magnetic resonance imaging (fMRI). A total of 38 T2DM patients and 39 well-matched healthy controls participated in the resting-state fMRI and T1-weighted imaging scans. The thalamic functional connectivity was characterized by using a seed-based whole-brain correlation method and compared T2DM patients with healthy controls. Pearson correlation analysis was performed between thalamic functional connectivity and clinical data. When compared with healthy controls, T2DM showed significantly decreased functional connectivity of the thalamus mainly in the right middle temporal gyrus (MTG), right precentral gyrus and bilateral occipital cortex; Increased functional connectivity of the thalamus was detected in the left cerebellum, bilateral middle frontal gyrus and middle cingulate gyrus (p

Objectives Type 2 diabetes mellitus is associated with increased risk for dementia. Patients with impaired cognition often show default-mode network disruption. We aimed to investigate the integrity of a default-mode network in diabetic patients by using independent component analysis, and to explore the relationship between network abnormalities, neurocognitive performance and diabetic variables. Methods Forty-two patients with type 2 diabetes and 42 well-matched healthy controls were included and underwent resting-state functional MRI in a 3 Tesla unit. Independent component analysis was adopted to extract the default-mode network, including its anterior and posterior components. Z-maps of both sub-networks were compared between the two groups and correlated with each clinical variable. Results Patients showed increased connectivity around the medial prefrontal cortex in the anterior sub-network, but decreased connectivity around the posterior cingulate cortex in the posterior sub-network. The decreased connectivity in the posterior part was significantly correlated with the score on Complex Figure Test-delay recall test (r = 0.359, p = 0.020), the time spent on Trail-Making Test-part B (r = -0.346, p = 0.025) and the insulin resistance level (r = −0.404, p = 0.024). Conclusion Dissociation pattern in the default-mode network was found in diabetic patients, which might provide powerful new insights into the neural mechanisms that underlie the diabetes-related cognitive decline. Key points • Type 2 diabetes mellitus is associated with impaired cognition • Default- mode network plays a central role in maintaining normal cognition • Network connectivity within the default mode was disrupted in type 2 diabetes patients • Decreased network connectivity was correlated with cognitive performance and insulin resistance level • Disrupted default-mode network might explain the impaired cognition in diabetic population Electronic supplementary material The online version of this article (doi:10.1007/s00330-015-3746-8) contains supplementary material, which is available to authorized users.

Hearing impairment contributes to cognitive dysfunction. Previous studies have found changes of functional connectivity in the default mode network (DMN) associated with cognitive processing in individuals with sensorineural hearing loss (SNHL). Whereas the changes in the DMN in patients with long-term unilateral SNHL (USNHL) is still not entirely clear. In this work, we analyzed resting-state functional magnetic resonance imaging (fMRI) data and neuropsychological test scores from normal hearing subjects (n = 11) and patients (n = 21) with long-term USNHL. Functional connectivity and nodal topological properties were computed for every brain region in the DMN. Analysis of covariance (ANCOVA) and post hoc analyses were conducted to identify differences between normal controls and patients for each measure. Results indicated that the left USNHL presented enhanced connectivity (p < 0.05, false discovery rate (FDR) corrected), and significant changes (p < 0.05, Bonferroni corrected) of the nodal topological properties in the DMN compared with the control. More changes in the DMN have been found in the left than right long-term USNHL (RUSNHL). However, the neuropsychological tests did not show significant differences between the USNHL and the control. These findings suggest that long-term USNHL contributes to changes in the DMN, and these changes might affect cognitive abilities in patients with long-term USNHL. Left hearing loss affects the DMN more than the right hearing loss does. The fMRI measures might be more sensitive for observing cognitive changes in patients with hearing loss than clinical neuropsychological tests. This study provides some insights into the mechanisms of the association between hearing loss and cognitive function.

We aimed to find the most representative connectivity patterns for minimal hepatic encephalopathy (MHE) using large-scale intrinsic connectivity networks (ICNs) and machine learning methods. Resting-state fMRI was administered to 33 cirrhotic patients with MHE and 43 cirrhotic patients without MHE (NMHE). The connectivity maps of 20 ICNs for each participant were obtained by dual regression. A Bayesian machine learning technique, called Graphical Model-based Multivariate Analysis, was applied to determine ICN regions that characterized group differences. The most representative ICNs were evaluated by the performance of three machine learning methods (support vector machines (SVMs), multilayer perceptrons (MLP), and C4.5). The clinical significance of these potential biomarkers was further tested. The temporal lobe network (TLN), and subcortical network (SCN), and sensorimotor network (SMN) were selected as representative ICNs. The distinct functional integration patterns of the representative ICNs were significantly correlated with behavior criteria and Child-Pugh scores. Our findings suggest the representative ICNs based on GAMMA can distinguish MHE from NMHE and provide supplementary information to current MHE diagnostic criteria.

This study explored connective tissue growth factor (CTGF)-targeted ultrasmall superparamagnetic iron oxides (USPIOs) for noninvasive MRI of CTGF within carotid atherosclerotic lesions in apoE-deficient (apoE-/-) mice. Anti-CTGF polyclonal and nonspecific IgG antibodies were conjugated to polyethylene glycol-coated USPIOs, and apoE-/- carotid partial ligation-model mice were imaged via MRI before and after contrast administration. ApoE-/- mice were treated with CTGF-neutralizing antibodies for 3 weeks. Carotid artery diameter and plaque volume were measured via MRI in IgG and CTGF antibody-treated groups. Anti-CTGF-USPIO-treated macrophages showed the greatest iron uptake. MRI signal loss was observed in carotid atherosclerotic lesions 24 h after anti-CTGF-USPIO administration, consistent with the presence of nanoparticles, as indicated by pathological examinations. Atheromata in anti-CTGF-treated mice showed reduced macrophage deposition, CTGF expression, and plaque volume. Anti-CTGF-USPIOs can be used for the direct detection of CTGF and imaging of atherosclerotic lesions in vivo. CTGF is a potential therapeutic target for treating atherosclerosis.

Background Penumbra salvage from infarction by early reperfusion within the time window is the target of acute ischemic stroke therapies. Although the penumbral imaging is potently usable in clinic trial, additional work needs to be performed to advancing the field with better-defined, evaluated, and validated imaging measures. Methods Mice were subjected to permanent stroke by right middle cerebral artery (MCA) occlusion. Multimodel magnetic resonance imaging (MRI) method was assessed to define the penumbra as that brain region in which the perfusion and diffusion-weighted MR images are mismatched (perfusion-weighted imaging [PWI]-diffusion-weighted imaging [DWI] mismatch). MRI measurements were performed at 1 hour after MCA occlusion (MCAO). Sigma-1 receptor expression was assessed by immunoblotting and immunostaining in PWI-DWI–defined penumbra and core compared with sham or contralateral slice. Penumbral sigma-1 receptor identified the correlation with the neuron, astrocyte, and microglia by immuno-colocalization. Results Sigma-1 receptor was significantly upregulated in penumbra or peri-infarct compared with sham and core tissue at 1 hour and 24 hours after MCAO. There was a colocalization of sigma-1 receptor and neuron in penumbra at 1 hour after stroke. Sigma-1 receptor is specifically increased in ischemic penumbral neuron at 1 hour after MCAO. Conclusions Sigma-1 receptor may act as an endogenous marker of penumbra after acute ischemic stroke.

Lectin-like Oxidized Low-Density Lipoprotein Receptor 1 (LOX-1) plays a key role in atherosclerotic plaque initiation, formation and rupture, as well as in hyperlipidemia-induced glomerular disease. Here we report a sensitive, specific and biocompatible LOX-1-targeted-USPIO for the noninvasive MR imaging of LOX-1 within carotid atherosclerotic lesions and glomerular disease in apoE-deficient mice. In vitro analysis showed the highest uptake of targeted USPIOs in only activated RAW264.7 macrophages, and in vivo MRI studies showed signal loss in carotid atherosclerotic lesions after administration of targeted USPIOs at 8 h and 24 h. These areas of signal loss were correlated with the presence of nanoparticles in the atherosclerotic lesions, and immunohistochemistry and Perl’s staining confirmed the co-localization of the LOX-1/macrophages/MMP-9 and targeted nanoparticles. Finally, additional studies suggest that this targeted probe may have potential to noninvasively image early glomerular disease. This finding may provide important methods for characterizing vulnerable atherosclerotic plaques and hyperlipidemia-induced glomerular diseases. From the Clinical Editor A functionalized USPIO-based negative contrast material was used in this study, demonstrating feasibility of sensitive MRI-based detection of atherosclerotic plaque formation in the carotid arteries and in the renal cortex, paving the way to potential future clinical applications.

Aberrant brain functional connectivity has been considered as the important mechanism underlying minimal hepatic encephalopathy (MHE); however, little is known about the change in interhemispheric connection in MHE patients. Twenty patients with HBV-related cirrhosis and MHE and 15 healthy controls were included in this study and underwent the resting-state fMRI scanning and diffusion tensor imaging. The functional connectivity between symmetric interhemispheric voxels was computed by a technique called voxel-mirrored homotopic connectivity (VMHC), in which the time series for each voxel in one hemisphere was correlated with that of its homotopic voxel. Diffusion tensor imaging was conducted to measure the mean diffusivity (MD) and fractional anisotropy (FA) values in corpus callosum (CC). Compared with controls, MHE patients showed decreased regional VMHC in medial frontal gyrus, superior frontal gryus, anterior cingulate gyrus, inferior parietal lobule, postcentral gyrus, lingual gyrus, and middle occipital gyrus. MHE patients had significant decreased FA value in CC genu and CC splenium and increased MD value in CC genu. Pearson correlation analyses showed that the VMHC in anterior cingulate gyrus/medial frontal gyrus was correlated with FA/MD values of CC genu. These findings may suggest aberrant interhemispheric coordination in MHE and may provide new insight into the disease-related mechanisms.

Endothelial progenitor cells (EPCs) serve as cellular vehicles for targeting cancer cells and are a powerful tool for delivery of therapeutic genes. Cytosine deaminase (CD), a kind of frequent suicide gene which can kill carcinoma cells by converting a non-poisonous pro-drug 5-flucytosine (5-FC) into a poisonous cytotoxic 5-fluorouracil (5-FU). We combined super-paramagnetic iron oxide (SPIO) nanoparticles labeled EPCs with CD gene to treat grafted liver carcinomas and tracked them with 7.0 T Magnetic resonance imaging (MRI). Results showed that the therapeutic EPCs loaded with CD plus 5-Fc provided stronger carcinoma growth suppression compared with treatment using CD alone. The CD/5-Fc significantly inhibited the growth of endothelial cells and induced carcinoma cells apoptosis. These results indicate that EPCs transfected with anti-carcinoma genes can be used in carcinoma therapy as a novel therapeutic modality.

Blood-brain barrier (BBB) damage during ischemia may induce devastating consequences like cerebral edema and hemorrhagic transformation. This study presents a novel strategy for dynamically imaging of BBB damage with PEGylated supermagnetic iron oxide nanoparticles (SPIONs) as contrast agents. The employment of SPIONs as contrast agents made it possible to dynamically image the BBB permeability alterations and ischemic lesions simultaneously with T2-weighted MRI, and the monitoring could last up to 24 h with a single administration of PEGylated SPIONs in vivo. The ability of the PEGylated SPIONs to highlight BBB damage by MRI was demonstrated by the colocalization of PEGylated SPIONs with Gd-DTPA after intravenous injection of SPION-PEG/Gd-DTPA into a mouse. The immunohistochemical staining also confirmed the leakage of SPION-PEG from cerebral vessels into parenchyma. This study provides a novel and convenient route for imaging BBB alteration in the experimental ischemic stroke model.

Few investigators have analyzed fetal ocular growth with Magnetic Resonance Imaging (MRI) of high magnetic strength. Our purpose is to obtain normative biometrics for fetal ocular development in the second trimester of pregnancy. Sixty specimens with a gestational age (GA) of 12-23 weeks were scanned using a 7.0 T MRI scanner. The linear interocular and binocular distances (IOD and BOD, respectively), globe diameter (GD) and lens diameter (LD) were measured on the transverse section of the largest diameter of the eyeballs. The three dimensional (3D) visualization model of the eyeball was reconstructed with Amira software. Then, the globe and lens volumes (GV and LV, respectively) were obtained. All the measurements were plotted as a function of GA. The fetal ocular structures in the second trimester of pregnancy could be clearly delineated on 7.0 T postmortem MRI images. All the linear measurements logarithmically increased with GA, while, the volumetric measurements linearly increased with GA. Postmortem MRI of high magnetic strength can clearly document fetal ocular growth in the second trimester of pregnancy. These quantitative data may be a valuable reference for the assessment of normal fetal eyeball development in clinical settings and may be considered a supplement to anatomical investigations.

During the second trimester, the human fetal brain undergoes numerous changes that lead to substantial variation in the neonatal in terms of its morphology and tissue types. As fetal MRI is more and more widely used for studying the human brain development during this period, a spatiotemporal atlas becomes necessary for characterizing the dynamic structural changes. In this study, 34 postmortem human fetal brains with gestational ages ranging from 15 to 22 weeks were scanned using 7.0 T MR. We used automated morphometrics, tensor-based morphometry and surface modeling techniques to analyze the data. Spatiotemporal atlases of each week and the overall atlas covering the whole period with high resolution and contrast were created. These atlases were used for the analysis of age-specific shape changes during this period, including development of the cerebral wall, lateral ventricles, Sylvian fissure, and growth direction based on local surface measurements. Our findings indicate that growth of the subplate zone is especially striking and is the main cause for the lamination pattern changes. Changes in the cortex around Sylvian fissure demonstrate that cortical growth may be one of the mechanisms for gyration. Surface deformation mapping, revealed by local shape analysis, indicates that there is global anterior–posterior growth pattern, with frontal and temporal lobes developing relatively quickly during this period. Our results are valuable for understanding the normal brain development trajectories and anatomical characteristics. These week-by-week fetal brain atlases can be used as reference in in vivo studies, and may facilitate the quantification of fetal brain development across space and time.

To investigate whether resting-state brain functional connectivity (FC) differed among cirrhotic patients without overt hepatic encephalopathy (HE) (OHE), those who currently had minimal HE (MHE), or those who had recovered from previous OHE and to investigate whether previous bouts of OHE rather than current MHE predominantly contributed to brain dysfunction in patients without current OHE.This study was approved by the institutional ethics committee, and informed consent was obtained. Resting-state functional magnetic resonance (MR) data were compared between healthy controls and the following groups of cirrhotic patients: (a) patients without MHE and without previous OHE, (b) patients with current MHE and without previous OHE, and (c) patients with previous OHE. Independent component analysis was applied to identify the best-fit component for the default-mode network (DMN). One-way analysis of variance was performed to detect different FC among groups. Pearson correlation analyses were conducted to determine the relationships between FC and neurocognitive performance.Two important regions within the DMN, including the precuneus and posterior cingulate cortex and left medial frontal gyrus, showed significantly different FC among the four groups. A trend of gradually reduced FC in two regions was observed from controls, to patients without HE, and to patients with current MHE, while patients with previous OHE showed remarkably reduced FC in these two regions. Significant correlations were found between FC and neurocognitive performance in cirrhotic patients.The reduced resting-state FC within DMN was associated with neurocognitive impairments in MHE and after clinical resolution of OHE. Previous OHE rather than current MHE might be primarily related to brain dysfunction in patients with latent OHE.http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120026/-/DC1.

To prospectively investigate age- and gender-related changes in the fast-twitch (tibialis anterior, TA) and slow-twitch (soleus, SOL) skeletal muscle of healthy rats and volunteers and to compare the exercise-related difference in health volunteers with TIn all, 18 rats and 70 humans were involved in this study. For the animal study, TThe average TThis study demonstrated that T2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:61-70.

The high performance and increased tumor-targeting accumulation of magnetic nanocrystals (MNCs) are the most important considerations in cancer targeted magnetic hyperthermia (TMH). To achieve these goals, our study was firstly done using well-established fluorescence/magnetic Mn-Zn ferrite MNCs (core size: 14 nm) as multi-modal imaging contrast agents and highly-efficient "heat generators", which were coated with a biocompatible PEG-phospholipid (DSPE-PEG2000) and further modified by a cyclic tripeptide of arginine-glycine-aspartic acid (RGD). By using a mouse model bearing breast carcinoma (4T1), we then systematically compared PEGylated MNCs (MNCs@PEG)- and RGD-PEGylated MNCs (MNCs@RGD)-mediated tumor targeting abilities by intravenous administration. The MNCs@PEG-based passive targeting could successfully accumulate at the tumor due to the enhanced permeability and retention (EPR) effects, but the non-targeted localization might make the MNCs@PEG "leaking" from larger pores of tumor fenestrated vascular networks. Our designed MNCs@RGD, simultaneously functionalized with PEG and RGD ligands, might promote a synergistic effect including efficient tumor vasculature active targeting and EPR-mediated passive targeting, improving total MNC concentration and retention time in tumor tissues. By combining fluorescence/magnetic resonance (MR)/thermal multi-modal imaging-guided diagnostics and continuous TMH treatment under an alternating current magnetic field (ACMF, 2.58 kA m(-1), 390 kHz), the tumor surface could be heated to approximately 43-44 °C based on the MNC-mediated repeated injections. Sufficient temperature elevation induced the apoptosis of tumor cells, and inhibited the tumor angiogenesis. Compared with MNCs@PEG, the active MNCs@RGD-based tumor targeting MR image was significantly more efficient due to both the higher and long-lasting tumor accumulation, but its antitumor efficacy was not obviously improved in the TMH treatments. To achieve a singularly promising tumor TMH therapy, a greatly increased MNC content in tumor was needed. This insight indicated that not only the tumor vasculature targeting, but also the active tumor cells targeting of MNCs should receive considerable attention in future clinical TMH therapy application.

Objectives Post-stroke cognitive dysfunction greatly influences patients’ quality of life after stroke. However, its neurophysiological basis remains unknown. This study utilized resting-state functional magnetic resonance imaging (fMRI) to investigate the alterations in regional coherence in patients after subcortical stroke. Methods Resting-state fMRI measurements were acquired from 16 post-stroke patients with poor cognitive function (PSPC), 16 post-stroke patients with good cognitive function (PSGC) and 30 well-matched healthy controls (HC). Regional homogeneity (ReHo) was used to detect alterations in regional coherence. Abnormalities in regional coherence correlated with scores on neuropsychological scales. Results Compared to the HC and the PSGC, the PSPC showed remarkably decreased ReHo in the bilateral anterior cingulate cortex and the left posterior cingulate cortex/precuneus. ReHo in the bilateral anterior cingulate cortex positively correlated with the scores on the Symbol Digit Modalities Test (r = 0.399, P = 0.036) and the Complex Figure Test-delayed recall subtest (r = 0.397, P = 0.036) in all post-stroke patients. Moreover, ReHo in the left posterior cingulate cortex/precuneus positively correlated with the scores on the Forward Digit Span Test (r = 0.485, P = 0.009) in all post-stroke patients. Conclusions Aberrant regional coherence was observed in the anterior and posterior cingulate cortices in post-stroke patients with cognitive dysfunction. ReHo could represent a promising indicator of neurobiological deficiencies in post-stroke patients.

This study aims to obtain the signal intensity changes and quantitative measurements of the subcortical brain structures of 12-22 weeks gestational age (GA).Sixty-nine fetal specimens were selected and scanned by 7.0-T MR. The signal intensity changes of the subcortical brain structures were analyzed. The three-dimensional visualization models of the germinal matrix, caudate nucleus, lentiform nucleus, and dorsal thalamus were rebuilt with Amira 4.1, and the developmental trends between the measurements and GA were analyzed.The germinal matrix was delineated on 7.0-T MR images at 12 weeks GA, with high signals on T1-weighted images (WI). While at 16 weeks GA, the caudate nucleus, lentiform nucleus, and internal and external capsules could be distinguished. The caudate nucleus was high signal intensity on T1WI. The signal intensity of the putamen was high on T1WI during 15-17 weeks GA and was delineated as an area with uneven signal intensities. The signal intensity of the peripheral area of the putamen became higher after 18 weeks GA. The signal intensity of the globus pallidus was high on T1WI and low on T2WI after 20 weeks GA. At 18 weeks GA, the claustrum was delineated with low signals on T2WI. Measurements of the germinal matrix, caudate nucleus, lentiform nucleus, and dorsal thalamus linearly increased with the GA.Development of the subcortical brain structures during 12-22 weeks GA could be displayed with 7.0-T MRI. The measurement provides significant reference beneficial to the clinical evaluation of fetal brain development.

Resting-state functional magnetic resonance imaging (fMRI) has been used to detect the alterations of spontaneous neuronal activity in various neuropsychiatric diseases, but rarely in low-grade hepatic encephalopathy (HE), a common neuropsychiatric complication of liver cirrhosis. We conducted a resting-state fMRI in 19 healthy controls, 18 cirrhotic patients without HE, and 22 cirrhotic patients with low-grade HE. The amplitude of low-frequency fluctuations (ALFF) of fMRI signal was computed to measure the spontaneous neuronal activity. Several regions showing significant ALFF differences among three groups were the precuneus, occipital lobe, left frontal lobe and anterior/middle cingulate cortex, and left cerebellum posterior lobe. Compared to controls or patients without HE, patients with low-grade HE showed decreased ALFF in the precuneus and adjacent cuneus, visual cortex, and left cerebellum posterior lobe. Compared to controls, patients with low-grade HE showed higher ALFF in both cortical and subcortical regions, including the right middle cingulate gyrus, and left anterior/middle cingulate gyrus, inferior frontal gyrus, insula lobe, parahippocampal gyrus, middle temporal gyrus and lentiform nucleus; compared to patients without HE, patients with low-grade HE showed higher ALFF in the left medial frontal gyrus and anterior cingulate gyrus, bilateral superior frontal gyrus, and right middle frontal gyrus. Moreover, correlations between ALFF changes and poor neurocognitive performances were found in patients with low-grade HE. These results suggested the existence of aberrant brain activity at the baseline state in low-grade HE, which may be implicated in the neurological pathophysiology underlying HE.

Atherosclerotic disease is a leading cause of morbidity and mortality in developed countries, and oxidized LDL (OxLDL) plays a key role in the formation, rupture, and subsequent thrombus formation in atherosclerotic plaques. In the current study, anti-mouse OxLDL polyclonal antibody and nonspecific IgG antibody were conjugated to polyethylene glycol-coated ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, and a carotid perivascular collar model in apolipoprotein E-deficient mice was imaged at 7.0 Tesla MRI before contrast administration and at 8 h and 24 h after injection of 30 mg Fe/kg. The results showed MRI signal loss in the carotid atherosclerotic lesions after administration of targeted anti-OxLDL-USPIO at 8 h and 24 h, which is consistent with the presence of the nanoparticles in the lesions. Immunohistochemistry confirmed the colocalization of the OxLDL/macrophages and iron oxide nanoparticles. The nonspecific IgG-USPIO, unconjugated USPIO nanoparticles, and competitive inhibition groups had limited signal changes (p < 0.05). This report shows that anti-OxLDL-USPIO nanoparticles can be used to directly detect OxLDL and image atherosclerotic lesions within 24 h of nanoparticle administration and suggests a strategy for the therapeutic evaluation of atherosclerotic plaques in vivo.

Recently it was shown that the magnetic resonance imaging (MRI) T1ρ value increased with the severity of liver fibrosis in rats with bile duct ligation. Using a rat carbon tetrachloride (CCl(4)) liver injury model, this study further investigated the merit of T1ρ relaxation for liver fibrosis evaluation.Male Sprague-Dawley rats received intraperitoneal injection of 2 ml/kg CCl(4) twice weekly for up to 6 weeks. Then CCl(4) was withdrawn and the animals were allowed to recover. Liver T1ρ MRI and conventional T2-weighted images were acquired. Animals underwent MRI at baseline and at 2 days, 2 weeks, 4 weeks and 6 weeks post CCl(4) injection, and they were also examined at 1 week and 4 weeks post CCl(4) withdrawal. Liver histology was also sampled at these time points.Liver T1ρ values increased slightly, though significantly, on day 2, and then increased further and were highest at week 6 post CCl(4) insults. The relative liver signal intensity change on T2-weighted images followed a different time course compared with that of T1ρ. Liver T1ρ values decreased upon the withdrawal of the CCl(4) insult. Histology confirmed the animals had typical CCl(4) liver injury and fibrosis progression and regression processes.MR T1ρ imaging can monitor CCl(4)-induced liver injury and fibrosis.• MR T1ρ is a valuable imaging biomarker for liver injury/fibrosis. • Liver T1ρ was only mildly affected by oedema and acute inflammation. • Liver MR T1ρ decreased when liver fibrosis and injury regressed.

The objective of this study was to noninvasively measure the volume of myocardial infarction in rats, using delayed enhancement magnetic resonance imaging (MRI) in a coronary occlusion/reperfusion model on a 7-T scanner.At 24 h after cardiac ischemia, contrast-enhanced MRI was performed. Two distinct experimental groups were compared: one was subjected to permanent ischemia (PL) and the other was subjected to 30 min of ischemia followed by 24 h of reperfusion (IR). The sizes of enhanced regions were compared to triphenyltetrazolium chloride (TTC)-stained sections of the excised rat heart. Cardiomyocyte apoptosis was analyzed by TUNEL methods, and neutrophils and macrophages were quantitated after histology and immunohistochemical staining.Twenty-four hours after ischemia, delayed hyperenhancement imaging was clearly visualized in the anterior left ventricular walls corresponding to the infarcted myocardium. In the PL group, infarct size was 37.2±9.8% (LV %) as measured by MRI and 38.8±9% (LV %) by TTC (P=NS). In the IR group, infarct size was 23.2±8.8% (LV %) as measured by MRI and 24.4±9.2% (LV %) by TTC (P=NS). Infarction volume measured with MRI was strongly correlated to TTC staining (R=0.82 for PL, R=0.973 for IR). Increased inflammatory cell infiltration was detected in the infarct area of the heart after reperfusion compared to permanent ligation (P.01). The ratio of TUNEL-positive cardiomyocytes to total number of cardiomyocytes in the IR group was significantly reduced as compared to the PL group (P.01).MRI can accurately assess infarct size in intact rats early after MI. After transient arterial occlusion, the size of the myocardial infarct was found to be significantly smaller as compared to permanent occlusion.

To investigate fluctuations in the amplitude of low-frequency blood oxygenation level-dependent (BOLD) fMRI during acute brain ischemia, and to evaluate the use of amplitude of low-frequency fluctuations (ALFFs) in resting state fMRI for assessing super-acute focal cerebral ischemic stroke. A super-acute stroke model with middle cerebral artery occlusion (MCAO) in the rat was employed. Spontaneous fluctuations were recorded using a series of gradient echo-planar imaging (EPI) images before and 30 min, 60 min, 2 h, 6 h, 12 h, and 24 h after MCAO. After preprocessing, serial fMRI data were obtained by fast Fourier transformation to calculate the ALFFs. Statistical parametric mapping software was used for the statistical analysis of ALFFs. T2-weighted images and diffusion weighted images (DWI) were also performed to detect the ischemic lesion. The signal intensities of abnormal ALFFs increased and migrated from the core of the ischemic lesion areas to the edge of lesion following MCAO. The dynamic changes in the ALFF maps demonstrated that the sizes of the ALFF regions exceeded beyond the borderline of the DWI lesions during the super-acute ischemic stroke stage. There was a significant difference in the ALFFs maps between the ischemic stroke group and the control group (P 10 voxels), which mainly occurred in the periphery of the ischemic region in the cortex. These data suggest that ALFF maps provide hemodynamic BOLD information on neural activity, and have potential for predicting survival and prognosis of acute ischemic brain tissues. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

This study constructs a rat brain T2-weighted magnetic resonance imaging template including olfactory bulb and a compatible digital atlas. The atlas contains 624 carefully delineated brain structures based on the newest (2005) edition of rat brain atlas by Paxinos and Watson. An automated procedure, as an SPM toolbox, was introduced for spatially normalizing individual rat brains, conducting statistical analysis and visually localizing the results in the Atlas coordinate space. The brain template/atlas and the procedure were evaluated using functional images between rats with the right side middle cerebral artery occlusion (MCAO) and normal controls. The result shows that the brain region with significant signal decline in the MCAO rats was consistent with the occlusion position. Hum Brain Mapp, 2013. (c) 2012 Wiley Periodicals, Inc.

Developing ultrasensitive contrast agents for the early detection of malignant tumors in liver is highly demanded. Constructing hepatic tumors specific targeting probes could provide more sensitive imaging information but still faces great challenges. Here we report a novel approach for the synthesis of ultra-small Fe3O4 nanoparticles conjugated with c(RGDyK) and their applications as active-target T1-weighted magnetic resonance imaging (MRI) contrast agent (T1-Fe3O4) for imaging tiny hepatic tumors in vivo. RGD-modified T1-Fe3O4 nanoprobes exhibited high r1 of 7.74 mM(-1)s(-1) and ultralow r2/r1 of 2.8 at 3 T, reflecting their excellent T1 contrast effect at clinically relevant magnetic field. High targeting specificity together with favorable biocompatibility and strong ability to resist against non-specific uptake were evaluated through in vitro studies. Owing to the outstanding properties of tumor angiogenesis targeting with little phagocytosis in liver parenchyma, hepatic tumor as small as 2.2 mm was successfully detected via the T1 contrast enhancement of RGD-modified T1-Fe3O4. It is emphasized that this is the first report on active-target T1 imaging of hepatic tumors, which could not only significantly improve diagnostic sensitivity, but also provide post therapeutic assessments for patients with liver cancer.

Background The 20th week gestational age (GA) is at mid-gestation and corresponds to the age at which the termination of pregnancy in several countries and the first Magnetic Resonance Imaging (MRI) can be performed, and at which the premature babies may survive. However, at present, very little is known about the exact anatomical character at this GA. Objective To delineate the developing fetal brain of 20 weeks GA and obtain the three dimensional visualization model. Materials and methods 20 fetal specimens were scanned by 3.0 T and 7.0 T post-mortem MRI, and the three dimensional visualization model was obtained with Amira 4.1. Results Most of the sulci or their anlage, except the postcentral sulcus and intraparietal sulcus, were present. The laminar organization, described as layers with different signal intensities, was most clearly distinguished at the parieto-occipital lobe and peripheral regions of the hippocampus. The basal nuclei could be clearly visualized, and the brain stem and cerebellum had formed their common shape. On the visualization model, the shape and relative relationship of the structures could be appropriately delineated. The ranges of normal values of the brain structures were obtained, but no sexual dimorphisms or cerebral asymmetries were found. Conclusions The developing fetal brain of 20 weeks GA can be clearly delineated on 3.0 T and 7.0 T post-mortem MRIs, and the three dimensional visualization model supplies great help in precise cognition of the immature brain. These results may have positive influences on the evaluation of the fetal brain in the uterus.

We evaluated dual-echo Dixon in-phase and out-of-phase (IP-OP), chemical shift imaging (CSI), and (1)H MRS (hydrogen MR spectroscopy) in estimating fat content (FC) in phantoms and in livers of mice. Phantoms were made according to the volume percentage of fat ranging from 0% to 100%. The three MR methods were performed to measure FC in phantoms and in livers of obese leptin-deficient (ob/ob), human BSCL2/seipin gene knockout (SKO), and wild-type (WT) mice. The results were compared with known FC in phantoms and to a reference standard from mice by histological semiautomatic vacuole segmentation (HIS-S) procedure and liver lipid (LL) chemical analysis. In phantoms, CSI underestimated FC from 50% to 100%, to a lesser extent than IP-OP. In vivo, liver FC in ob/ob and SKO mice measured by the three MR methods were all significantly higher than that in WT mice. Liver FC measured by IP-OP were significantly lower than that measured by CSI and MRS, with no significant difference between CSI and MRS. CSI and MRS showed a linear correlation with LL analysis and with each other. IP-OP underestimated FC, whereas CSI and MRS were more accurate for quantifying FC in both phantoms and liver. CSI and MRS have the potential to replace HIS-S and LL analysis in longitudinal studies.