Differential volume reductions in the subcortical, limbic, and brainstem structures associated with behavior in Prader-Willi syndrome.

Individuals with Prader-Willi syndrome (PWS) exhibit complex behavioral characteristics, including hyperphagia, autistic features, and subsequent age-related maladaptive behaviors. While this suggests functional involvements of subcortical, limbic, and brainstem areas, developmental abnormalities in such structures remain to be investigated systematically. Twenty-one Japanese individuals with PWS and 32 healthy controls with typical development were included. T1-weighted three-dimensional structural magnetic resonance images were analyzed for subcortical, limbic, and brainstem structural volumes, with age as a covariate, using a model-based automatic segmentation tool. Correlations were determined between each volume measurement and behavioral characteristics as indexed by questionnaires and block test scores for hyperphagia (HQ), autistic and obsessional traits, non-verbal intelligence (IQ), and maladaptive behavior (VABS_mal). Compared with the control group, the PWS group showed significantly reduced relative volume ratios per total intracranial volume (TIV) in thalamus, amygdala, and brainstem structures, along with TIV and native volumes in all substructures. While the brainstem volume ratio was significantly lower in all age ranges, amygdala volume ratios were significantly lower during early adulthood and negatively correlated to HQ and VABS_mal but positively correlated to Kohs IQ. Thus, limbic and brainstem volume alterations and differential volume trajectories may contribute to the developmental and behavioral pathophysiology of PWS.

Altered Functional Network Architecture of the Brain in Prader-Willi Syndrome.

Background: Prader-Willi syndrome (PWS) is a genetic syndrome with clinical behavioral phenotypes, including autistic characteristics. However, brain functional connectivity (Fc) remains underreported. This study aimed at investigating alterations in functional network architecture in the cortical and subcortical structures of brains in individuals with PWS. Methods: Twelve individuals with PWS (age range: 15-42 years; female 4, male 8), and 14 age- and sex-matched controls with typical development (TD), participated in a 3 Tesla resting-state functional magnetic resonance imaging study. Fc was analyzed: (1) voxel-based group independent component analysis and correlations with Autism-Spectrum Quotient (AQ) scores, (2) seed-based neuroanatomical region of interest (ROI) analysis. Results: In individuals with PWS, AQ showed a significant positive correlation with Fc in the right frontal area, and the ROI analysis exhibited enhanced dorsolateral prefrontal Fcs compared with those in TD controls; the frontopolar-parietotemporal Fcs were attenuated. Discussion: The observed Fc indicated altered Fc in specific brain regions, which is consistent with the behavioral features in individuals with PWS. The enhanced versus attenuated connectivity in distinct frontal regions may contribute to not only autistic features but also other behavioral characteristics, and it provides a clue for better understanding of the brain-behavior relationship in PWS.

Application of 7 tesla magnetic resonance imaging for pediatric neurological disorders: Early clinical experience.

Ultra-high field magnetic resonance imaging (MRI) has been introduced for use in pediatric developmental neurology. While higher magnetic fields have certain advantages, optimized techniques with specific considerations are required to ensure rational and safe use in children and those with pediatric neurological disorders (PNDs). Here, we summarize our initial experience with clinical translational studies that utilized 7 tesla (T)-MRI in the fields of developmental neurology. T2-reversed images and three-dimensional anisotropy contrast imaging enabled the depiction of targeted pathological brain structures with better spatial resolution. Diffusion imaging and susceptibility-weighted imaging enabled visualization of intracortical, subcortical, and intratumoral microstructures in vivo within highly limited scan times appropriate for patients with PNDs. 7T-MRI appears to have significant potential to enhance the depiction of the structural and functional properties of the brain, particularly those associated with atypical brain development.

Cerebellar Volumes Associate with Behavioral Phenotypes in Prader-Willi Syndrome.

The objective of this study was to investigate lobule-specific cerebellar structural alterations relevant to clinical behavioral characteristics of Prader-Willi syndrome (PWS). We performed a case-control study of 21 Japanese individuals with PWS (age; median 21.0, range 13-50 years, 14 males, 7 females) and 40 age- and sex-matched healthy controls with typical development. Participants underwent 3-Tesla magnetic resonance imaging. Three-dimensional T1-weighted images were assessed for cerebellar lobular volume and adjusted for total intracerebellar volume (TIV) using a spatially unbiased atlas template to give a relative volume ratio. A region of interest analysis included the deep cerebellar nuclei. A correlation analysis was performed between the volumetric data and the clinical behavioral scores derived from the standard questionnaires (hyperphagia, autism, obsession, and maladaptive index) for global intelligence assessment in paired subgroups. In individuals with PWS, TIV was significantly reduced compared with that of controls (p < 0.05, family-wise error corrected; mean [standard deviation], 1014.1 [93.0] mm3). Decreased relative lobular volume ratios were observed in posterior inferior lobules with age, sex, and TIV as covariates (Crus I, Crus II, lobules VIIb, VIIIa, VIIIb, and IX). However, increased ratios were found in the dentate nuclei bilaterally in individuals with PWS (p < 0.01); the mean (standard deviation) × 10-3 was as follows: left, 1.58 (0.26); right, 1.67 (0.30). The altered lobular volume ratios showed negative correlations with hyperphagic and autistic characteristics and positive correlations with obsessive and intellectual characteristics. This study provides the first objective evidence of topographic patterns of volume differences in cerebellar structures consistent with clinical behavioral characteristics in individuals with PWS and strongly suggests a cerebellar contribution to altered functional brain connectivity in PWS.

MRI characteristics of the glia limitans externa: A 7T study.

PURPOSE: To perform a systematic analysis of the intrinsic contrast parameters of the FLAIR hyperintense rim (FHR), a thin layer of high intensity covering the entire surface of the cerebral cortex detected on fluid-attenuated inversion recovery (FLAIR) sequence T2 weighted imaging performed on a 7T system, in an attempt to identify its anatomical correlate. METHODS: Fast spin echo inversion recovery (FSE-IR) and cardiac-gated fast spin echo (FSE) images were obtained with defined parameters in eight normal volunteers on a 7 T MRI system to determine T2 and proton density, T1 characteristics. K-means clustering analysis of parameter sets was performed using MATLAB version R2015b for the purpose of identifying the cluster reflecting FHR. The results were subsequently confirmed by independent component analysis (ICA) based on T1 behavior on FSE-IR using a MATLAB script of FastICA algorithm. RESULTS: The structure giving rise to FHR was found to have a unique combination of intrinsic contrast parameters of low proton density, long T2, and disproportionally short T1. The findings are in strong agreement with the functional and structural specifics of the glia limitans externa (GLE), a structure composed of snuggled endfeet of astrocytes containing abundant aquaporin-4 (AQP-4), the main water channel of the brain. CONCLUSION: Intrinsic contrast parameters of FHR reflect structural and functional specifics of the GLE, and their values are highly dependent on the physiologic functionality of AQP-4. Microscopic imaging on a 7T system and analysis of GLE contrast parameters can be developed into a method for evaluating AQP-4 functionality.

The Posterior Limb of the Internal Capsule as the Subcortical Transitional Zone of the Anterior and Posterior Circulations: Insights from Human 7T MRI.

BACKGROUND: In patients with cerebral infarction, identifying the distribution of infarction and the relevant artery is essential for ascertaining the underlying vascular pathophysiological mechanisms and preventing subsequent stroke. However, visualization of the basal perforating arteries (BPAs) has had limited success, and simultaneous viewing of background anatomical structures has only rarely been attempted in living human brains. Our study aimed at identifying the BPAs with 7T MRI and evaluating their distribution in the subcortical structures, thereby showing the clinical significance of the technique. METHODS: Twenty healthy subjects and 1 patient with cerebral infarction involving the posterior limb of the internal capsule (ICpost) and thalamus underwent 3-dimensional fast spoiled gradient-echo sequence as time-of-flight magnetic resonance angiography (MRA) at 7T with a submillimeter resolution. The MRA was modified to detect inflow signals from BPAs, while preserving the background anatomical signals. BPA stems and branches in the subcortical structures and their origins were identified on images, using partial maximum intensity projection in 3 dimensions. RESULTS: A branch of the left posterior cerebral artery (PCA) in the patient ran through both the infarcted thalamus and ICpost and was clearly the relevant artery. In 40 intact hemispheres in healthy subjects, 571 stems and 1,421 branches of BPAs were detected in the subcortical structures. No significant differences in the numbers of stems and branches were observed between the intact hemispheres. The numbers deviated even less across subjects. The distribution analysis showed that the subcortical structures of the telencephalon, such as the caudate nucleus, anterior limb of the internal capsule, and lenticular nucleus, were predominantly supplied by BPAs from the anterior circulation. In contrast, the thalamus, belonging to the diencephalon, was mostly fed by BPAs from the posterior circulation. However, compared with other subcortical structures, the ICpost, which marks the anatomical boundary between the telencephalon and the diencephalon, was supplied by BPAs with significantly more diverse origins. These BPAs originated from the internal carotid artery (23.1%), middle cerebral artery (38.5%), PCA (17.3%), and the posterior communicating artery (21.1%). CONCLUSIONS: The modified MRI method allowed the detection of the relevant BPA within the infarcted area in the stroke survivor as well as the BPAs in the subcortical structures of living human brains. Based on in vivo BPA distribution analyses, the ICpost is the transitional zone of the anterior and posterior cerebral circulations.

Hydrophilic-interaction liquid chromatography-tandem mass spectrometric determination of erythrocyte 5-phosphoribosyl 1-pyrophosphate in patients with hypoxanthine-guanine phosphoribosyltransferase deficiency.

Mutations in the gene encoding hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause Lesch-Nyhan disease (LND) and its variants (LNV). Due to the technical problems for measuring the HPRT activity in vitro, discordances between the residual HPRT activity and the clinical severity were found. 5-Phosphoribosyl 1-pyrophosphate (PRPP) is a substrate for HPRT. Since increased PRPP concentrations were observed in erythrocytes from patients with LND and LNV, we have turned our attention to erythrocyte PRPP as a biomarker for the phenotype classification. In the present work, a method for determination of PRPP concentration in erythrocyte was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with multiple reaction monitoring (MRM). Packed erythrocyte samples were deproteinized by heating and the supernatants were injected into the LC-MS/MS system. All measurement results showed good precision with RSD <6%. PRPP concentrations of nine normal male subjects, four male patents with LND and six male patients with LNV were compared. The PRPP concentrations in erythrocyte from patients with LND were markedly increased compared with those from normal subjects, and those from patients with LNV were also increased but the degree was smaller than those with LND. The increase pattern of PRPP concentration in erythrocyte from patients with HPRT deficiency was consistent with the respective phenotypes and was correlated with the disease severity. PRPP concentration was suggested to give us supportive information for the diagnosis and the phenotype classification of LND and LNV.

Ligand-based molecular MRI: O-17 JJVCPE amyloid imaging in transgenic mice.

BACKGROUND: Development of molecular MR imaging (MRI) similar to PET imaging using contrast agents such as gadolinium as probe have been inherently hampered by incompatibility between potential probe (charged molecules) and membrane permeability. Nevertheless, considering the inherent spatial resolution limit for PET of 700µ, the superior microscopic resolution of MRI of 4 µ presents a strong incentive for research into ligand-based molecular MRI. METHODS: (17) O exhibits JJ vicinal coupling with a covalently bound proton in a hydroxyl group. This (17) O coupled proton can be ionized in water solution and interexchange with other water protons. This property can be utilized as "probe" in T2-weighted imaging and developed into ligand-based molecular MRI. We examined ß-amyloid distribution in human APP overexpressed transgenic mice in vivo following injection of (17) O labeled Pittsburg compound B ((17) O-PiB). RESULTS: JJVCPE imaging successfully imaged (17) O-PiB, unequivocally establishing that (17) O JJVCPE imaging can be developed into PET-like molecular MRI in clinical medicine. CONCLUSIONS: The study represents the first successful ligand-based molecular MRI in vivo. This is also the first in vivo amyloid imaging using MRI. High-resolution molecular MRI with high specificity under clinical settings, such as in vivo microscopic imaging of senile plaque, is a foreseeable aim.

Separation of perfusion signals from diffusion-weighted image series enabled by independent component analysis.

BACKGROUND AND PURPOSE: An important task in diagnostic imaging of acute ischemic stroke is to identify the so-called diffusion-perfusion mismatch area. We aimed to investigate the possibility of facilitating the identification process by combining independent component analysis (ICA) and diffusion-weighted MRI (DWI), with the expectation that this would eliminate the need for additional perfusion imaging to delineate perfusion lesion. METHODS: Simulations were performed to confirm the utility of an intuitively determined sequence of 14 b-factors ranging from 0 to 1,000 seconds/mm(2) for ICA separation of perfusion lesion. Corresponding DWI data from 2 stroke patients, 1 in the acute and 1 in the subacute phase, were decomposed into independent component (IC) maps, and their b-dependent amplitude decay profiles were subjected to multiexponential fitting. RESULTS: Low-perfusion areas were successfully delineated on IC maps in both patients. Comparison with the areas of diffusion lesion identifiable on relatively high b-factor images in the DWI data, for example, those at b= 1,000 seconds/mm(2) , allowed the mismatch to be identified. CONCLUSION: This study demonstrates that combining ICA and DWI enables noninvasive mapping of sluggish perfusion provided an appropriate b-sequence is applied, and that it thereby facilitates the identification of diffusion-perfusion mismatch.

Evaluation of psychological effect of prosthetic treatment using Emotion Spectrum Analysis Method (ESAM).

PURPOSE: The aim of this pilot study was to consider evaluation of the psychological effects of dental prosthetic treatments using ESAM. METHOD: We examined gum chewing with and without an occlusal interference device that simulated a negative change in oral sensation in four subjects. First, we analyzed the temporal components of mandibular movement trajectories as indices for evaluating the degree to which chewing is actually impaired by occlusal interference. Subsequently, we measured brain activity before and after chewing for each of the two conditions (with or without the occlusal interference device). For brain activity, we used the four emotional indices of stress, sadness, joy and relaxation based on ESAM to estimate psychological states before and after chewing, and made a comparison between the two conditions. Statistical analyses were performed with Mann-Whitney's U-test (p<0.05). RESULTS: The opening phase and chewing cycle were shorter when wearing the occlusal interference device in every subject. There was a significant difference for all subjects (p<0.05) in the closing cycle. Therefore, because a significant difference occurred for at least one temporal component of the mandibular movement trajectory for every subject, we concluded that normal chewing in subjects was impaired by wearing the occlusal interference device. Similarly, in ESAM analyses using EEG, stress tended to increase due to occlusal interference in every subject. In addition, relaxation decreased due to occlusal interference in three subjects. CONCLUSION: The results suggested the potential for evaluating the psychological effects of dental prostheses using emotional indices based on ESAM.

The response of bovine beta-lactoglobulin-specific T-cell clones to single amino acid substitution of T-cell core epitope.

Cow's milk is one of the most common food allergens in the first year of life, with approximately 2.5% of infants experiencing an allergic reaction to it. Beta-lactoglobulin (BLG) is one of the major allergens in cow's milk. Previously, we reported that four of six T-cell clones (TCC) which were established from cow's milk allergy patients recognized BLGp97-117 as the core sequence and also recognized BLG in association with the human leucocyte antigen (HLA)-DRB1*0405 allele. Using two of these four TCCs, we evaluated the T-cell response to BLG peptides with single amino acid substitution or deletion and identified BLGp102-112 as the minimum essential region in BLGp97-117. In the alanine-scan assay, the proliferative responses of TCCs to pE108A disappeared, and the proliferative responses of TCCs to pC106A decreased. In the analog peptide proliferation assay, pY102S had retained some T-cell response to the two TCCs. Collecting these results, we propose a motif for the interaction between the HLA-DRB1*0405 allele and antigen peptide, and suggest that BLGp105-108 are important residues to retain the TCR/BLG-peptide/HLA complex. pY102A and pY102S are partial agonists for the T-cell receptor. These peptides might be considered as candidate peptides for the modification of the T-cell response to BLG in cow's milk allergy.

Natural preference in luminosity for frame composition.

We investigated whether or not frame composition spontaneously selected by individuals exhibit a natural left shift in preference of luminosity, as previously suggested, by examining biases in luminosity imprinted in photographs taken under three different conditions: (i) daytime pictures taken outside without determination of frame composition (N=4153); (ii) daytime pictures taken outside with determination of frame composition (N=4035); and (iii) pictures taken inside with determination of frame composition (N=4045). As anticipated, there was a strong vertical gradient of luminance grayscale intensity, reflecting natural day light distribution, for pictures of categories (i) and (ii). Similarly, a minor vertical gradient was detected for pictures of category (iii), indicating common room lighting conditions. To our great interest, there was a consistent leftward tilt of ca. 2 and 9 degrees found in the vertical gradients for pictures of categories (ii) and (iii), respectively, but not for pictures of category (i). The result provides clear-cut evidence that there is indeed a natural preference for a leftward bias in luminosity for frame composition.

Human primary motor cortex shows hemispheric specialization for speech.

Hemispheric specialization is a prominent characteristic of the human brain. Should the 'dominant' hemisphere possess differential neural organization for language production in the 'higher order' cortex, it would be rational to consider that the primary motor cortex may also show similar hemispheric specialization for speech production. In order to test this hypothesis, we investigated the spatial distribution of neural activities associated with phonation (M1p), silent tongue motion (M1t), and vocalization (M1v) within the primary motor cortex, utilizing independent component-cross correlation-sequential epoch analysis of high-field functional magnetic resonance imaging time series. While M1t showed no significant differences between the two hemispheres, M1p and M1v exhibited significant hemispheric differences. The study demonstrated direct evidence that human primary motor cortex possesses clear-cut hemispheric specialization similar to that observed for the higher order cortices.

[Study on the number of denture adjustments in complete denture wearers--relationship to mandibular ridge shape].

PURPOSE: This study investigated the relationship between the degree of mandibular alveolar ridge resorption and the number of denture adjustments after insertion of dentures in complete denture wearers. METHODS: The subjects were 77 complete denture patients (34 males, 43 females, mean age 69.1+/-8.1 years). Using bite plates of Gothic arch tracing for new denture production, the width, height, and inclination toward the tentative occlusal plane of the mandibular alveolar ridge corresponding to the canine areas (C), first premolar areas (P1), second premolar areas (P2), and first molar areas (M1) were measured bilaterally, and the relationship with the number of denture adjustment was evaluated. RESULTS: The mean of number of denture adjustments was 4.4+/-1.8 times (male 3.8 times, female 5.0 times), showing a significant difference between males and females (p<0.01). The alveolar ridge mean width was C: 9.7 mm, P1: 10.4 mm, P2: 11.5 mm, and M1: 13.0 mm respectively. The alveolar ridge mean height was C: 4.3 mm, P1: 4.6 mm, P2: 4.9 mm, and M1: 5.2 mm. The alveolar ridge mean inclination was C: 11.2 degrees, P1: 13.5 degrees, P2: 15.4 degrees, and M1: 18.8 degrees. The width and height of the mandibular alveolar ridge in C, P1, P2, and M1 were significantly larger in males than in females (p<0.05). The height of mandibular alveolar ridge was significantly lower in high number of denture adjustment than in low number of denture adjustment (p<0.05). CONCLUSION: Complete denture wearers showed a high relation between the number of denture adjustment and the mandibular alveolar ridge height.

The primary motor area for voluntary diaphragmatic motion identified by high field fMRI.

In order to identify the precise location of the primary motor area for the diaphragm with respect to the classical motor homunculus, functional magnetic resonance imaging (fMRI) experiments were performed utilizing independent component-cross correlation- sequential epoch (ICS) analysis on a high-field (3.0 Tesla) system. Activations which correlated with voluntary diaphragmatic motion mapped onto the area anterolateral to that for voluntary hand motion (internal control in ICS analysis). Multiple subject analysis yielded the primary motor cortex for the diaphragm to be (+/-48, -4, 47) in the Talairach and Tournoux coordinates. The results were highly consistent with the previously reported cortical area for the diaphragm determined by transcranial electrical/magnetic stimulation.

A novel single-nucleotide substitution, Leu 467 Pro, in the interferon-gamma receptor 1 gene associated with allergic diseases.

We identified a novel heterozygous single-nucleotide substitution 1400 T right curved arrow C (Leu 467 Pro) in the seventh exon of the interferon-gamma receptor 1 (IFNGR1) gene. This substitution was detected in 6 of the 89 allergic patients but not in the 72 non-allergic subjects. There was a difference in the L467P frequency between the allergic patients and the non-allergic subjects (Fisher's exact test: p=0.033). The 6 patients with L467P have allergic diseases such as bronchial asthma and/or allergic rhinitis. Furthermore, a familial analysis for L467P revealed a linkage between allergic diseases and L467P. Serum IgE levels of the patients with L467P were higher than those of the non-allergic subjects (p=0.001). Our previous studies have been shown that interferon-gamma (IFN-gamma) production by PBMCs in the allergic patients was lower than that in the non-allergic subjects. In this study, although IFN-gamma production in the allergic patients with L467P was equivalent to that in the non-allergic subjects, their serum IgE levels were high and they had allergic diseases. Our results suggest that some allergic patients have IFNGR dysfunction, and that L467P in the IFNGR1 gene is one of candidate susceptibility genes for allergic diseases.

All-phase MR angiography using independent component analysis of dynamic contrast enhanced MRI time series: phi-MRA.

Dynamic contrast enhanced magnetic resonance imaging (dynamic MRI) represents a MRI version of non-diffusible tracer methods, the main clinical use of which is the physiological construction of what is conventionally referred to as perfusion images. The raw data utilized for constructing MRI perfusion images are time series of pixel signal alterations associated with the passage of a gadolinium containing contrast agent. Such time series are highly compatible with independent component analysis (ICA), a novel statistical signal processing technique capable of effectively separating a single mixture of multiple signals into their original independent source signals (blind separation). Accordingly, we applied ICA to dynamic MRI time series. The technique was found to be powerful, allowing for hitherto unobtainable assessment of regional cerebral hemodynamics in vivo.

[Evaluation before and after pranlukast administration with the QOL questionnaire (revised version 2001) for pediatric patients with bronchial asthma and their parents or caregivers].

We conducted a longitudinal investigation with the QOL questionnaire (revised version 2001) before and after the 4-week-administration of a leukotriene receptor antagonist pranlukast. A significant improvement in the < 4 yrs group was observed at week 1, and that in > or = 4 yrs group at week 2. Under these conditions, the overall QOL score, physical domains and mental domains, significantly improved in both the < 4 yrs group and the > or = 4 yrs group. Overall, a slight correlation was observed between ratio changes in QOL scores and differences in symptom scores. However, no correlation was found in part of patients, suggesting that the QOL questionnaire allows measurement of mental changes in the patients themselves and their parents or caregivers for therapeutic effects which cannot be determined with ordinary physical findings only. In "event present" group, a significant difference in physical and mental domains was revealed by the comparison of QOL scores before and after administration. And furthermore in "event absence" group, the p-value for physical domain and mental domain was 0.0505 and 0.0912 in the < 4 yrs group, respectively, 0.0101 and 0.0446 in the > or = 4 yrs group, respectively. The above results led us to consider the QOL questionnaire (revised version 2001) useful for routine medical care. Furthermore, pranlukast was considered useful for improvement not only of physical symptoms of bronchial asthma but also of the patient's QOL, although the placebo effects in this open trial must be considered.

Fast and precise independent component analysis for high field fMRI time series tailored using prior information on spatiotemporal structure.

Independent component analysis (ICA) has been shown as a promising tool for the analysis of functional magnetic resonance imaging (fMRI) time series. Each of these studies, however, used a general-purpose algorithm for performing ICA and the computational efficiency and accuracy of elicited neuronal activations have not been discussed in much detail. We have previously proposed a direct search method for improving computational efficiency. The method, which is based on independent component-cross correlation-sequential epoch (ICS) analysis, utilizes a form of the fixed-point ICA algorithm and considerably reduces the time required for extracting desired components. At the same time, it is shown that the accuracy of detecting physiologically meaningful components is much improved by tailoring the contrast function used in the algorithm. In this study, further improvement was made to this direct search method by integrating an optimal contrast function. Functional resolution of activation maps could be controlled with a suitable selection of the contrast function derived from prior knowledge of the spatial patterns of physiologically desired components. A simple skewness-weighted contrast function was verified to extract sufficiently precise activation maps from the fMRI time series acquired using a 3.0 Tesla MRI system.