Heavily Gd-Doped Non-Toxic Cerium Oxide Nanoparticles for MRI Labelling of Stem Cells.

Recently, human mesenchymal stem cells (hMSc) have attracted a great deal of attention as potential therapeutic agents in the treatment of socially significant diseases. Despite substantial advances in stem-cell therapy, the biological mechanisms of hMSc action after transplantation remain unclear. The use of magnetic resonance imaging (MRI) as a non-invasive method for tracking stem cells in the body is very important for analysing their distribution in tissues and organs, as well as for ensuring control of their lifetime after injection. Herein, detailed experimental data are reported on the biocompatibility towards hMSc of heavily gadolinium-doped cerium oxide nanoparticles (Ce0.8Gd0.2O2-x) synthesised using two synthetic protocols. The relaxivity of the nanoparticles was measured in a magnetic field range from 1 mT to 16.4 T. The relaxivity values (r1 = 11 ± 1.2 mM-1 s-1 and r1 = 7 ± 1.2 mM-1 s-1 in magnetic fields typical of 1.5 and 3 T MRI scanners, respectively) are considerably higher than those of the commercial Omniscan MRI contrast agent. The low toxicity of gadolinium-doped ceria nanoparticles to hMSc enables their use as an effective theranostic tool with improved MRI-contrasting properties.

Real-time fMRI neurofeedback compared to cognitive behavioral therapy in a pilot study for the treatment of mild and moderate depression.

Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback was found to reduce depressive symptoms. However, no direct comparison of drug-free patients with an active psychotherapy control group is available. The present study compared rt-fMRI neurofeedback with cognitive behavioral therapy, as the standard treatment in patients declining anti-depressants. Twenty adult, drug-free patients with mild or moderate depression were non-randomly assigned either to a course of eight half-hour sessions of neurofeedback targeting the left medial prefrontal cortex (N = 12) or to a 16-session course of cognitive behavioral therapy (N = 8). Montgomery-Asberg Depression Rating Scale was introduced at baseline, mid-treatment, and end-treatment points. In each group, 8 patients each remained in the study to a mid-treatment evaluation and 6 patients each to the study end-point. ANOVA revealed a depression reduction with a significant effect of Time (F(3,6) = 19.0, p < 0.001, η2 = 0.76). A trend to greater improvement in the cognitive behavioral therapy group compared to neurofeedback emerged (Group × Time; p = 0.078). Percent signal change in the region of interest between up- and down-regulation conditions was significantly correlated with session number (Pearson's r = 0.85, p < 0.001) indicating a learning effect. As limitations, small sample size could lead to insufficient power and non-random allocation to selection bias. Both neurofeedback and cognitive behavioral therapy improved mild and moderate depression. Neurofeedback was not superior to cognitive behavioral therapy. Noteworthy, the neurofeedback training course was associated with continuous improvement in the self-regulation skill, without plateau. This study delivers data to plan clinical trials comparing neurofeedback with cognitive behavioral interventions.

Brain Networks Connectivity in Mild to Moderate Depression: Resting State fMRI Study with Implications to Nonpharmacological Treatment.

Network mechanisms of depression development and especially of improvement from nonpharmacological treatment remain understudied. The current study is aimed at examining brain networks functional connectivity in depressed patients and its dynamics in nonpharmacological treatment. Resting state fMRI data of 21 healthy adults and 51 patients with mild or moderate depression were analyzed with spatial independent component analysis; then, correlations between time series of the components were calculated and compared between-group (study 1). Baseline and repeated-measure data of 14 treated (psychotherapy or fMRI neurofeedback) and 15 untreated depressed participants were similarly analyzed and correlated with changes in depression scores (study 2). Aside from diverse findings, studies 1 and 2 both revealed changes in within-default mode network (DMN) and DMN to executive control network (ECN) connections. Connectivity in one pair, initially lower in depression, decreased in no treatment group and was inversely correlated with Montgomery-Asberg depression score change in treatment group. Weak baseline connectivity in this pair also predicted improvement on Montgomery-Asberg scale in both treatment and no treatment groups. Coupling of another pair, initially stronger in depression, increased in therapy though was unrelated to improvement. The results demonstrate possible role of within-DMN and DMN-ECN functional connectivity in depression treatment and suggest that neural mechanisms of nonpharmacological treatment action may be unrelated to normalization of initially disrupted connectivity.

Direct comparison between apparent diffusion coefficient and macromolecular proton fraction as quantitative biomarkers of the human fetal brain maturation.

BACKGROUND: Apparent diffusion coefficient (ADC) is known as a quantitative biomarker of prenatal brain maturation. Fast macromolecular proton fraction (MPF) mapping is an emerging method for quantitative assessment of myelination that was recently adapted to fetal MRI. PURPOSE: To compare the capability of ADC and MPF to quantify the normal fetal brain development. STUDY TYPE: Prospective. POPULATION: Forty-two human fetuses in utero (gestational age [GA] = 27.7 ± 6.0, range 20-38 weeks). FIELD STRENGTH/SEQUENCE: 1.5 T; diffusion-weighted single-shot echo-planar spin-echo with five b-values for ADC mapping; spoiled multishot echo-planar gradient-echo with T1 , proton density, and magnetization transfer contrast weightings for single-point MPF mapping. ASSESSMENT: Two operators measured ADC and MPF in the medulla, pons, cerebellum, thalamus, and frontal, occipital, and temporal cerebral white matter (WM). STATISTICAL TESTS: Mixed repeated-measures analysis of variance (ANOVA) with the factors of pregnancy trimester and brain structure; Pearson correlation coefficient (r); Hotelling-Williams test to compare strengths of correlations. RESULTS: From the 2nd to 3rd trimester, ADC significantly decreased in the thalamus and cerebellum (P < 0.005). MPF significantly increased in the medulla, pons, thalamus, and cerebellum (P < 0.005). Cerebral WM had significantly higher ADC and lower MPF compared with the medulla and pons in both trimesters. MPF (r range 0.83, 0.89, P < 0.001) and ADC (r range -0.43, -0.75, P ≤ 0.004) significantly correlated with GA and each other (r range -0.32, -0.60, P ≤ 0.04) in the medulla, pons, thalamus, and cerebellum. No significant correlations or distinctions between regions and trimesters were observed for cerebral WM (P range 0.1-0.75). Correlations with GA were significantly stronger for MPF compared with ADC in the medulla, pons, and cerebellum (Hotelling-Williams test, P < 0.003) and similar in the thalamus. Structure-averaged MPF and ADC values strongly correlated (r = 0.95, P < 0.001). DATA CONCLUSION: MPF and ADC demonstrated qualitatively similar but quantitatively different spatiotemporal patterns. MPF appeared more sensitive to changes in the brain structures with prenatal onset of myelination. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:52-61.

Congenital medulloblastoma: Fetal and postnatal longitudinal observation with quantitative MRI.

Congenital medulloblastoma is extremely rare. MRI appearance of this tumor in the fetal brain has not been described. A case of congenital medulloblastoma initially observed by antenatal MRI with postnatal follow-up and treatment is presented. A pregnant female underwent fetal MRI on the 31st gestational week for routine indications. Midline cerebellar lesion of ≤2 cm in size with minor T2 hypointensity and T1 hyperintensity was identified. Additionally, quantitative MRI including apparent diffusion coefficient (ADC) and fast macromolecular proton fraction (MPF) mapping was performed. The lesion showed a marked ADC decrease and MPF increase. MPF maps depicted the lesion most conspicuously. After term delivery, a male neonate presented with symptoms of increased intracranial pressure. Postnatal MRI identified obstructive hydrocephalus caused by a large posterior fossa mass. The child was treated by cerebrospinal fluid shunt placement. Follow-up quantitative MRI on the fifth month revealed tumor growth and vivid changes of its tissue contrast associated with brain maturation. The tumor appeared nearly isointense on T1- and T2-weighted images and slightly hypointense on the ADC map. MPF contrast showed the most remarkable change from hyper- to hypointensity due to brain myelination with stable MPF in the tumor. Subsequently, the child underwent partial tumor resection, and currently continues treatment with chemotherapy. The pathological diagnosis was desmoplastic/nodular medulloblastoma. The described case illustrates evolution of the tumor contrast in the course of fetal and postnatal brain development and highlights the added diagnostic value of MPF mapping in fetal and neonatal neuroimaging.

Neuroimaging Study of Alpha and Beta EEG Biofeedback Effects on Neural Networks.

Neural networks interaction was studied in healthy men (20-35 years old) who underwent 20 sessions of EEG biofeedback training outside the MRI scanner, with concurrent fMRI-EEG scans at the beginning, middle, and end of the course. The study recruited 35 subjects for EEG biofeedback, but only 18 of them were considered as "successful" in self-regulation of target EEG bands during the whole course of training. Results of fMRI analysis during EEG biofeedback are reported only for these "successful" trainees. The experimental group (N = 23 total, N = 13 "successful") upregulated the power of alpha rhythm, while the control group (N = 12 total, N = 5 "successful") beta rhythm, with the protocol instructions being as for alpha training in both. The acquisition of the stable skills of alpha self-regulation was followed by the weakening of the irrelevant links between the cerebellum and visuospatial network (VSN), as well as between the VSN, the right executive control network (RECN), and the cuneus. It was also found formation of a stable complex based on the interaction of the precuneus, the cuneus, the VSN, and the high level visuospatial network (HVN), along with the strengthening of the interaction of the anterior salience network (ASN) with the precuneus. In the control group, beta enhancement training was accompanied by weakening of interaction between the precuneus and the default mode network, and a decrease in connectivity between the cuneus and the primary visual network (PVN). The differences between the alpha training group and the control group increased successively during training. Alpha training was characterized by a less pronounced interaction of the network formed by the PVN and the HVN, as well as by an increased interaction of the cerebellum with the precuneus and the RECN. The study demonstrated the differences in the structure and interaction of neural networks involved into alpha and beta generating systems forming and functioning, which should be taken into account during planning neurofeedback interventions. Possibility of using fMRI-guided biofeedback organized according to the described neural networks interaction may advance more accurate targeting specific symptoms during neurotherapy.

A Female Patient with FMR1 Premutation and Mosaic X Chromosome Aneuploidy and Two Sons with Intellectual Disability.

In this report, we describe a molecular cytogenetic study of a family burdened with intellectual disability (ID) and suicide. Our study revealed that the mother has a heterozygous premutation in the FMR1 gene and supernumerary X chromosomes as well as X-derived marker chromosomes. Both of her sons have ID and a normal chromosome number. One of the sons has fragile X syndrome, and the other has ID of an unclear nature.

Proton magnetic resonance spectroscopy of brain metabolic shifts induced by acute administration of 2-deoxy-d-glucose and lipopolysaccharides.

In vivo proton magnetic resonance spectroscopy ((1) H MRS) of outbred stock ICR male mice (originating from the Institute of Cancer Research) was used to study the brain (hippocampus) metabolic response to the pro-inflammatory stimulus and to the acute deficiency of the available energy, which was confirmed by measuring the maximum oxygen consumption. Inhibition of glycolysis by means of an injection with 2-deoxy-d-glucose (2DG) reduced the levels of gamma-aminobutyric acid (GABA, p < 0.05, in comparison with control, least significant difference (LSD) test), N-acetylaspartate (NAA, p < 0.05, LSD test) and choline compounds, and at the same time increased the levels of glutamate and glutamine. An opposite effect was found after injection with bacterial lipopolysaccharide (LPS) - a very common pro-inflammatory inducer. An increase in the amounts of GABA, NAA and choline compounds in the brain occurred in mice treated with LPS. Different metabolic responses to the energy deficiency and the pro-inflammatory stimuli can explain the contradictory results of the brain (1) H MRS studies under neurodegenerative pathology, which is accompanied by both mitochondrial dysfunction and inflammation. The prevalence of the excitatory metabolites such as glutamate and glutamine in 2DG treated mice is in good agreement with excitation observed during temporary reduction of the available energy under acute hypoxia or starvation. In turn, LPS, as an inducer of the sickness behavior, which was manifested as depression, sleepiness, loss of appetite etc., shifts the brain metabolic pattern toward the prevalence of the inhibitory neurotransmitter GABA.