Immunofluorescence analysis of DNA damage response protein p53-binding protein 1 in a case of uterine dedifferentiated leiomyosarcoma arising from leiomyoma.

AIMS: Genomic instability has been indicated during the dedifferentiation process from leiomyoma (LM) to leiomyosarcoma (LMS). Previously, we have described that nuclear expression pattern of DNA damage response protein p53-binding protein 1 (53BP1), detected by immunofluorescence, reflects the magnitude of genomic instability during malignancy. Here, we present a case of LMS arising from LM with molecular analysis of 53BP1, which showed transitional magnitude of DNA damage response within a tumor. METHODS AND RESULTS: A fifty-year-old female with abdominal mass underwent hysterectomy. Histologically, the tumor consisted of LMS with highly atypical multinucleated giant cells as well as an LM component with transitional atypical spindle cells in the border area. LMS showed diffuse nuclear staining of 53BP1 expression, which has been previously described as high DNA damage response pattern. In contrast, the LM component lacked 53BP1 immunoreactivity and focal expression was observed in transitional lesion. Furthermore, double-labelled immunofluorescence revealed co-localization of 53BP1 with p53 and Ki-67 in the LMS component, which indicated abnormal DNA damage response in proliferative state. CONCLUSIONS: This study revealed that diffuse-type 53BP1 expression may be beneficial to estimate genomic instability during dedifferentiation from LM to DLMS.

Malignant transformation from mature cystic teratoma of the ovary.

We present a case of malignant change of an ovarian mature cystic teratoma. Our patient was a 48-year-old woman and she visited a primary care doctor presenting with abdominal pain. At her first visit, her pelvic tumor measured 70 × 50 mm by ultrasonography. She was diagnosed as rupture of the malignant tumor occurred secondary to mature cystic teratoma and she took the surgery (abdominal total hysterectomy, bilateral oophorectomy and partial omentectomy). Pathologic diagnosis was squamous cell carcinoma (SCC) occurred secondary to mature cystic teratoma. Treatment with paclitaxel/carboplatin (TC chemotherapy) and gemcitabine hydrochloride/carboplatin (GC chemotherapy) after operation was not effective, and the refractory ileus resulting from rapid progression of the disease continued. She was died of disease progression 7 months after the diagnosis of ovarian cancer. We discuss about the clinical characteristics of malignant transformation of mature cystic teratoma and considered about the treatment of the ovarian SCC.

Novel recessive mutations in MSTO1 cause cerebellar atrophy with pigmentary retinopathy.

Misato 1, mitochondrial distribution and morphology regulator (encoded by the MSTO1 gene), is involved in mitochondrial distribution and morphology. Recently, MSTO1 mutations have been shown to cause clinical manifestations suggestive of mitochondrial dysfunction, such as muscle weakness, short stature, motor developmental delay, and cerebellar atrophy. Both autosomal dominant and recessive modes of inheritance have been suggested. We performed whole-exome sequencing in two unrelated patients showing cerebellar atrophy, intellectual disability, and pigmentary retinopathy. Three novel mutations were identified: c.836 G > A (p.Arg279His), c.1099-1 G > A (p.Val367Trpfs*2), and c.79 C > T (p.Gln27*). Both patients had compound heterozygous mutations with a combination of protein-truncation mutation and missense mutation, the latter shared by them both. This survey of two patients with recessive and novel MSTO1 mutations provides additional clinical and genetic information on the pathogenicity of MSTO1 in humans.

Rapid growth of mitotically active cellular fibroma of the ovary: a case report and review of the literature.

BACKGROUND: Mitotically active cellular fibroma (MACF) of the ovary, characterized by relatively high mitotic activity without severe atypia, represents a relatively new disease entity. MACF is categorized as a benign ovarian tumor. However, due to a limited number of case reports, its clinical and pathological features and optimum management remains largely undetermined. Herein, we report on a rare case of MACF that grew rapidly in size and was diagnosed on detailed pathological examination. CASE PRESENTATION: A 44-year-old Japanese woman, who detected a myoma-like lesion 1-year earlier, was referred to our hospital when the follow-up examination demonstrated that the mass had increased in size. Magnetic resonance imaging revealed a T1 isointense and T2 hyperintense tumor (11 cm in diameter) in the right pelvic cavity. Laparoscopy confirmed the presence of a right ovarian tumor and laparoscopic right adnexectomy was performed. The tumor cells consisted of dense cellular proliferations of spindle fibroblast-like cells without significant cytological atypia. The mitotic activity index was estimated at >15 mitotic figures per 10 high-power fields. Reticulin staining and FOXL2 mutation analysis excluded the possibility of an adult granulosa cell tumor, and the patient was diagnosed with a MACF of the ovary. CONCLUSIONS: To the best of our knowledge, we are the first to report on a case of rapid growth of a MACF of the ovary during follow-up. When an increase in the size of a solid ovarian mass is detected, a MACF should be considered as a differential diagnosis.

The Associations between Regional Gray Matter Structural Changes and Changes of Cognitive Performance in Control Groups of Intervention Studies.

In intervention studies of cognitive training, the challenging cognitive tests, which were used as outcome measures, are generally completed in more than a few hours. Here, utilizing the control groups' data from three 1-week intervention studies in which young healthy adult subjects underwent a wide range of cognitive tests and T1-weighted magnetic resonance imaging (MRI) before and after the intervention period, we investigated how regional gray matter (GM) density (rGMD) of the subjects changed through voxel-based morphometry (VBM). Statistically significant increases in rGMD were observed in the anatomical cluster that mainly spread around the bilateral dorsal anterior cingulate cortex (dACC) and the right superior frontal gyrus (rSFG). Moreover, mean rGMD within this cluster changes were significantly and positively correlated with performance changes in the Stroop task, and tended to positively correlate with performance changes in a divergent thinking task. Affected regions are considered to be associated with performance monitoring (dACC) and manipulation of the maintained information including generating associations (rSFG), and both are relevant to the cognitive functions measured in the cognitive tests. Thus, the results suggest that even in the groups of the typical "control group" in intervention studies including those of the passive one, experimental or non-experimental factors can result in an increase in the regional GM structure and form the association between such neural changes and improvements related to these cognitive tests. These results suggest caution toward the experimental study designs without control groups.

Regional gray matter volume is associated with empathizing and systemizing in young adults.

Empathizing is defined as the drive to identify the mental states of others for predicting their behavior and responding with an appropriate emotion. Systemizing is defined as the drive to analyze a system in terms of the rules that govern the system in order to predict its behavior. Using voxel-based morphometry and questionnaires in a large sample of normal, right-handed young adults, we investigated the regional gray matter volume (rGMV) correlates of empathizing and systemizing and additionally those of the D score, which is the difference between systemizing and empathizing, to reveal the comprehensive picture of those correlates. Negative rGMV correlates of empathizing and positive rGMV correlates of the D score (formed by the negative correlation between rGMV and empathizing), were found primarily in nodes in the default mode network, mirror neuron system, dorsal anterior cingulate cortex, and the lateral part of the prefrontal cortex together with other areas. Positive rGMV correlates of systemizing and of the D score (formed by the positive correlation between rGMV and systemizing) were found primarily in nodes in the external attention system, middle cingulate cortex, and other regions. Negative rGMV correlates of systemizing were found in an area close to the left posterior insula and putamen. These findings reconcile some previously inconsistent findings, provide other new findings and suggest that these areas contribute to empathizing-systemizing. Furthermore, the negative/positive rGMV correlates of empathizing and positive/negative rGMV correlates of systemizing overlapped substantially. This may be in line with the notion that empathizing and systemizing compete neurally in the brain.

White matter structures associated with empathizing and systemizing in young adults.

Empathizing is defined as the drive to identify the mental states of others in order to predict their behavior and respond with an appropriate emotion. Systemizing is defined as the drive to analyze a system in terms of the rules that govern it to predict its behavior. We undertook voxel-by-voxel investigations of regional white matter volume (rWMV) and fractional anisotropy (FA) of diffusion tensor imaging to discover the WM structural correlates of empathizing, systemizing, and their difference (D score: systemizing-empathizing). Whole brain analyses of covariance revealed that across both sexes, the D score was negatively correlated with rWMV in the WM area in the bilateral temporal lobe, near the right inferior frontal gyrus, near the ventral medial prefrontal cortex, and near the posterior cingulate cortex and positively correlated with FA in an area involving the superior longitudinal fasciculus. Post-hoc analyses revealed that these associations were generally formed by both the correlation between WM structures and empathizing as well as the opposite correlation between WM structures and systemizing. A significant effect of interaction between sex and the D score on rWMV, which was mainly observed because of a positive correlation between rWMV and empathizing in females and a negative correlation between rWMV and systemizing in females, was found in an area close to the right inferior parietal lobule and temporoparietal junction. Our results suggest that WM structures involving the default mode network and the mirror neuron system support empathizing, and that a WM structure relating to the external attention system supports systemizing. Further, our results revealed an overlap between positive/negative WM structural correlates of empathizing and negative/positive WM structural correlates of systemizing despite little correlation between empathizing and systemizing, which supports the previously held idea that there is a trade-off between empathizing and systemizing in the brain.

Brain structures associated with executive functions during everyday events in a non-clinical sample.

Executive functions involve control processes such as goal-oriented planning, flexible strategy generation, sustaining set maintenance, self-monitoring, and inhibition. Executive functions during everyday events (EFEEs) are distinct from those measured under laboratory settings; the former can be severely impaired while the latter remain intact. Non-routine everyday problems due to executive dysfunctions affect individual functioning in everyday life and are of great clinical interest. Despite the importance of anatomical bases underlying better EFEEs, such bases have never been investigated among non-clinical samples. Using voxel-based morphometry to measure regional gray matter volume (rGMV) and regional white matter volume (rWMV) and diffusion tensor imaging to determine fractional anisotropy values, we identified the anatomical correlates of better EFEEs using the Dysexecutive Questionnaire in 303 normal young subjects (168 men and 135 women). Better EFEEs were associated with a smaller rGMV in the orbitofrontal cortex (OFC) spread across Brodmann areas (BA) 25, 11, and 12 and larger rWMV in the WM area of OFC adjacent to BA 11. Furthermore, individual EFEEs were positively associated with rWMV in the temporal areas, primarily the inferior longitudinal fasciculus and inferior fronto-occipital fasciculus, the latter of which connects OFC and posterior regions. Thus, our findings suggest that brain structures involving OFC, together with other regions, contribute to the maintenance of effective EFEEs among non-clinical subjects.

White matter structures associated with emotional intelligence: evidence from diffusion tensor imaging.

Previous studies of brain lesions, functional activity, and gray matter structures have suggested that emotional intelligence (EI) is associated with regions involved in the network of social cognition (SCN) and in somatic marker circuitry (SMC). Our new study is the first to investigate the association between white matter (WM) integrity and EI. We examined this relationship in the brain of healthy young adult men [n = 74, mean age = 21.5 years, standard deviation (SD) = 1.6] and women (n = 44, mean age = 21.9 years, SD = 1.4). We performed a voxel-based analysis of fractional anisotropy, which is an indicator of WM integrity, using diffusion tensor imaging and used a questionnaire (EI Scale) for measuring EI to identify the correlation of WM integrity with individual EI factor (intrapersonal, interpersonal, and situation management factors). Our results showed that (a) the intrapersonal factor of EI was positively correlated with WM integrity in the right anterior insula, and (b) the interpersonal factor of EI was associated with WM integrity in a part of the right inferior longitudinal fasciculus (ILF). The right anterior insula is one of the important nodes of the SMC, whereas the ILF connects the visual cortex and areas related to SCN, and thus, is a part of the SCN. Our findings further support the notion that the brain regions involved in the SCN and in the SMC are associated with EI.

A new mother-child play activity program to decrease parenting stress and improve child cognitive abilities: a cluster randomized controlled trial.

BACKGROUND: We propose a new play activity intervention program for mothers and children. Our interdisciplinary program integrates four fields of child-related sciences: neuroscience, preschool pedagogy, developmental psychology, and child and maternal psychiatry. To determine the effect of this intervention on child and mother psychosocial problems related to parenting stress and on the children's cognitive abilities, we performed a cluster randomized controlled trial. METHODOLOGY/PRINCIPAL FINDINGS: Participants were 238 pairs of mothers and typically developing preschool children (ages 4-6 years old) from Wakakusa kindergarten in Japan. The pairs were asked to play at home for about 10 min a day, 5 days a week for 3 months. Participants were randomly assigned to the intervention or control group by class unit. The Parenting Stress Index (PSI) (for mothers), the Goodenough Draw-a-Man intelligence test (DAM), and the new S-S intelligence test (NS-SIT) (for children) were administered prior to and 3 months after the intervention period. Pre-post changes in test scores were compared between the groups using a linear mixed-effects model analysis. The primary outcomes were the Total score on the child domain of the PSI (for child psychosocial problems related to parenting stress), Total score on the parent domain of the PSI (for maternal psychosocial problems related to parenting stress), and the score on the DAM (for child cognitive abilities). The results of the PSI suggested that the program may reduce parenting stress. The results of the cognitive tests suggested that the program may improve the children's fluid intelligence, working memory, and processing speed. CONCLUSIONS/SIGNIFICANCE: Our intervention program may ameliorate the children's psychosocial problems related to parenting stress and increase their cognitive abilities. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000002265.

Regional gray and white matter volume associated with Stroop interference: evidence from voxel-based morphometry.

During Stroop tasks, subjects experience cognitive interference when they resolve interferences such as identifying the ink color of a printed word while ignoring the word's identity. Stroop paradigms are commonly used as an index of attention deficits and a tool for investigating the functions of the frontal lobes and other associated structures. Despite these uses and the vast amount of attention given to Stroop paradigms, the regional gray matter volume/regional white matter volume (rGMV/rWMV) correlates of Stroop interference have not yet been identified at the whole brain level in normal adults. We examined this issue using voxel-based morphometry in right-handed healthy young adults. We found significant negative relationships between the Stroop interference rate and rGMV in the anterior cingulate cortex (ACC), right inferior frontal gyrus, and cerebellum. Furthermore, we found relationships between the Stroop interference rate and rWMV in bilateral anatomical clusters that extended around extensive WM regions in the dorsal part of the frontal lobe. These findings are the first to reveal rGMV/rWMV that underlie the performance of the Stroop task, a widely used psychological paradigm at the whole brain level. Of note, our findings support the notion that ACC contributes to Stroop performance and show the involvement of regions that have been implicated in response inhibition and attention.

Working memory training using mental calculation impacts regional gray matter of the frontal and parietal regions.

Training working memory (WM) improves performance on untrained cognitive tasks and alters functional activity. However, WM training's effects on gray matter morphology and a wide range of cognitive tasks are still unknown. We investigated this issue using voxel-based morphometry (VBM), various psychological measures, such as non-trained WM tasks and a creativity task, and intensive adaptive training of WM using mental calculations (IATWMMC), all of which are typical WM tasks. IATWMMC was associated with reduced regional gray matter volume in the bilateral fronto-parietal regions and the left superior temporal gyrus. It improved verbal letter span and complex arithmetic ability, but deteriorated creativity. These results confirm the training-induced plasticity in psychological mechanisms and the plasticity of gray matter structures in regions that have been assumed to be under strong genetic control.

Verbal working memory performance correlates with regional white matter structures in the frontoparietal regions.

Working memory is the limited capacity storage system involved in the maintenance and manipulation of information over short periods of time. Previous imaging studies have suggested that the frontoparietal regions are activated during working memory tasks; a putative association between the structure of the frontoparietal regions and working memory performance has been suggested based on the analysis of individuals with varying pathologies. This study aimed to identify correlations between white matter and individual differences in verbal working memory performance in normal young subjects. We performed voxel-based morphometry (VBM) analyses using T1-weighted structural images as well as voxel-based analyses of fractional anisotropy (FA) using diffusion tensor imaging. Using the letter span task, we measured verbal working memory performance in normal young adult men and women (mean age, 21.7 years, SD=1.44; 42 men and 13 women). We observed positive correlations between working memory performance and regional white matter volume (rWMV) in the frontoparietal regions. In addition, FA was found to be positively correlated with verbal working memory performance in a white matter region adjacent to the right precuneus. These regions are consistently recruited by working memory. Our findings suggest that, among normal young subjects, verbal working memory performance is associated with various regions that are recruited during working memory tasks, and this association is not limited to specific parts of the working memory network.

Regional gray matter density associated with emotional intelligence: evidence from voxel-based morphometry.

Emotional Intelligence (EI) is the ability to monitor one's own and others' emotions and the ability to use the gathered information to guide one's thinking and action. EI is thought to be important for social life making it a popular subject of research. However, despite the existence of previous functional imaging studies on EI, the relationship between regional gray matter morphology and EI has never been investigated. We used voxel-based morphometry (VBM) and a questionnaire (Emotional Intelligence Scale) to measure EI to identify the gray matter correlates of each factor of individual EI (Intrapersonal factor, Interpersonal factor, Situation Management factor). We found significant negative relationships between the Intrapersonal factor and regional gray matter density (rGMD) (1-a) in an anatomical cluster that included the right anterior insula, (1-b) in the right cerebellum, (1-c) in an anatomical cluster that extends from the cuneus to the precuneus, (1-d) and in an anatomical cluster that extends from the medial prefrontal cortex to the left lateral fronto-polar cortex. We also found significant positive correlations between the Interpersonal factor and rGMD in the right superior temporal sulcus, and significant negative correlations between the Situation Management factor and rGMD in the ventromedial prefrontal cortex. These findings suggest that each factor of EI in healthy young people is related to the specific brain regions known to be involved in the networks of social cognition and self-related recognition, and in the somatic marker circuitry.

Regional gray matter volume of dopaminergic system associate with creativity: evidence from voxel-based morphometry.

Creativity has been essential to the development of human civilization and plays a crucial role in cultural life. However, despite a number of functional imaging studies on creativity, the relationship between regional gray matter morphology and creativity has never been investigated in subcortical regions. We used voxel-based morphometry (VBM) to identify the gray matter correlates of individual creativity as measured by the divergent thinking test. We found positive correlations between regional gray matter volume and individual creativity in several regions such as the right dorsolateral prefrontal cortex, bilateral striata and in an anatomical cluster which included areas such as the substantia nigra, tegmental ventral area and periaqueductal gray. These findings suggest that individual creativity, as measured by the divergent thinking test, is mainly related to the regional gray matter of brain regions known to be associated with the dopaminergic system, congruent with the idea that dopaminergic physiological mechanisms are associated with individual creativity.

White matter structures associated with creativity: evidence from diffusion tensor imaging.

Creativity has been essential to the development of human civilization and plays a crucial role in cultural life. However, despite literature that has proposed the importance of structural connectivity in the brain for creativity, the relationship between regional white matter integrity and creativity has never been directly investigated. In this study, we used diffusion tensor imaging and a behavioral creativity test of divergent thinking to investigate the relationship between creativity and structural connectivity. We examined associations between creativity and fractional anisotropy across the brain in healthy young adult (mean age, 21.7 years old; [SD]=1.44) men (n=42) and women (n=13). After controlling for age, sex, and score on Raven's advanced progressive matrices, a test for psychometric measures of intelligence, significant positive relationships between fractional anisotropy and individual creativity as measured by the divergent thinking test were observed in the white matter in or adjacent to the bilateral prefrontal cortices, the body of the corpus callosum, the bilateral basal ganglia, the bilateral temporo-parietal junction and the right inferior parietal lobule. As a whole, these findings indicate that integrated white matter tracts underlie creativity. These pathways involve the association cortices and the corpus callosum, which connect information in distant brain regions and underlie diverse cognitive functions that support creativity. Thus, our results are congruent with the ideas that creativity is associated with the integration of conceptually distant ideas held in different brain domains and architectures and that creativity is supported by diverse high-level cognitive functions, particularly those of the frontal lobe.

The neural basis of agency: an fMRI study.

Agency, a feeling that the self is the cause of action, has a strong relationship to the processing of discrepancies between the predicted multi-sensory feedback from one's intended action and its actual outcome (hereafter, agency error). Although previous studies have explored the neural basis of agency by assessing the brain's response to agency error, the effects found are confounded by two types of error irrelevant to agency: a mismatch between different sensory inputs in general (sensory mismatch, SM error) and a basic response to any type of prediction error (oddball error). In this functional magnetic resonance imaging study, we identified the neural response specific to agency error by dissociating it from responses to SM and oddball errors. Subjects played a game in which they controlled an on-screen character. Neural responses to rare events of violated control and congruency between types of audio-visual feedback were compared to dissociate agency from SM error. In a separate session, subjects viewed repetitive motions of the character, and neural responses to rare events of unpredictable change in movement were identified as related to oddball error. Agency-error-specific activation was observed in the supplementary motor area (SMA), left cerebellum, right posterior parietal cortex (PPC), and right extrastriate body area (EBA). Oddball errors also activated areas near the PPC and EBA peaks. SM errors activated the pre-SMA and the right posterior superior temporal sulcus. Our results suggest that the SMA, cerebellum, and some parts of the PPC and EBA serve as the neural bases of agency.

Abnormal cerebral glucose metabolism in alternating hemiplegia of childhood.

Alternating hemiplegia of childhood (AHC) is a rare and intractable disorder of unknown cause. To determine cerebral neuronal function in five patients with AHC (two adults and three children), we analyzed brain glucose metabolism by positron emission tomography (PET) using 2-deoxy-2 [(18)F] fluoro-d-glucose (FDG), performed between hemiplegic attacks. Interictal FDG-PET revealed abnormal cerebral glucose metabolism; all patients showed low glucose metabolism in the frontal lobes with some laterality, and three had low glucose metabolism in the ipsilateral putamen. The adult patients also showed low glucose metabolism and mild atrophy in the cerebellum. Glucose metabolism in the brainstem was virtually normal for all patients. The areas of low glucose metabolism indicated local or regional neuronal damage, possible reflecting progressive neurological symptoms. AHC might therefore result from focal abnormal glucose metabolism in the brain occurring progressively or permanently, particularly in the frontal lobes and the cerebellum.

Somatotopical relationships between cortical activity and reflex areas in reflexology: a functional magnetic resonance imaging study.

We examined the somatotopical relationship between cortical activity and sensory stimulation of reflex areas in reflexology using functional magnetic resonance imaging. Three reflex areas on the left foot, relating to the eye, shoulder, and small intestine were stimulated during the experiment. A statistical analysis showed that reflexological stimulation of the foot reflex areas corresponding to the eye, shoulder, and small intestine activated not only the somatosensory areas corresponding to the foot, but also the somatosensory areas corresponding to the eye, shoulder, and small intestine or neighboring body parts. Thus, the findings showed that reflexological stimulation induced a somatosensory process corresponding to the stimulated reflex area and that a neuroimaging approach can be used to examine the basis of reflexology effects.

[Case of 12-year-old boy with idiopathic recurrent neuralgic amyotrophy].

Here we report a 12-year-old boy with idiopathic neuralgic amyotrophy who had two episodes of shoulder pain followed by shoulder muscle atrophy and weakness at the age of 7 and 11 years, respectively. These symptoms were self-limited and disappeared within 9 months. During the second episode, electromyograph (EMG) revealed neurogenic changes in the deltoid muscle. Muscle imaging showed the right deltoid muscle atrophy with slightly high intensity areas on T1 and T2 weighted images in MRI. Muscle biopsy from the right deltoid muscle revealed neurogenic changes with denervating and reinnervating processes. Neuralgic amyotrophy is characterized by neuralgic pain followed by weakness and atrophy at a unilateral extremity and is usually self-limited. EMG and imaging studies showed focal neurogenic abnormalities, which were confirmed by muscle biopsy. Neuralgic amyotrophy usually occurs in young adults and it is very rare in children.