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Hedgehog signaling is a highly conserved pathway that plays pivotal roles in morphogenesis, tumorigenesis, osteogenesis, and wound healing. Previous investigations in patients with Gorlin syndrome found low harm avoidance traits, and increased volumes in the cerebrum, cerebellum, and cerebral ventricles, suggesting the association between brain morphology and the constitutive hyperactivation of hedgehog signaling, while the changes of regional brain volumes in upregulated hedgehog signaling pathway remains unclear so far. Herein, we investigated comprehensive brain regional volumes using quantitative structural brain MRI, and identified increased volumes of amygdala, striatum, and pallidum on the global segmentation, and increased volumes of the lateral and medial parts of the central nucleus of the amygdala on the detail segmentation in Ptch heterozygous deletion mice. Our data may enhance comprehension of the association between brain morphogenic changes and hyperactivity in hedgehog signaling.

Abstract Background Somali Red Crescent Society (SRCS), supported by Norwegian Red Cross, has implemented community-based surveillance (CBS) in Somaliland. This methodology aims to reduce the high risk of epidemics by strengthening early warning and response from and at community level, particularly where there is a weak public health surveillance system. CBS is implemented through SRCS community volunteers, who report signals from the community via SMS to the software platform Nyss. This paper presents key findings from the CBS programme evaluation. Methods A retrospective observational mixed-methods approach to evaluate the CBS programme was conducted, using routine CBS data from 2021 for Awdal and Togdheer regions and qualitative interviews with stakeholders’ representatives. Results The usefulness of the CBS programme in preventing, detecting, and responding to disease outbreaks was acknowledged by the stakeholders’ representatives. 83% of the signals in Awdal region matched a Community Case Definition (CCD) and were escalated to the Ministry of Health and Development (MoHD)). For Togdheer region, 97% were escalated. Verification of signals by supervisors and escalation to the authorities was done timely.Alert outcome and response action was not well recorded, therefore there is limited evidence on sensitivity. The programme was shown to be simple and can be flexibly adjusted for new diseases and changing CCDs.Stakeholders appreciated being engaged, the good collaboration, their participation throughout the implementation and expressed high acceptance of the programme. Conclusion CBS can support early warning and response for a variety of public health risks. Improved documentation for alert outcomes could help to better evaluate the sensitivity of CBS. A participatory approach is vital to achieve successful community volunteer engagement. Software tools, such as the Nyss platform, can be useful to support effective and efficient CBS implementation.

Characterizing Alzheimer’s disease (AD) progression remains a significant clinical challenge. The initial stages of AD are marked by the accumulation of amyloid-beta plaques and Tau tangles, with cognitive functions often appearing normal, and clinical symptoms may not manifest until up to 20 years after the prodromal period begins. Comprehensive longitudinal studies analyzing brain-wide structural connectomics in the early stages of AD, especially those with large sample sizes, are scarce. In this study, we investigated a longitudinal diffusion-weighted imaging dataset of 264 subjects to assess the predictive potential of diffusion data for AD. Our findings indicate the potential of a simple prognostic biomarker for disease progression based on the hemispheric lateralization of mean tract volume for tracts originating from the supramarginal and paracentral regions, achieving an accuracy of 86%, a sensitivity of 86%, and a specificity of 93% when combined with other clinical indicators. However, diffusion-weighted imaging measurements alone did not provide strong predictive accuracy for clinical variables, disease classification, or disease conversion. By conducting a comprehensive tract-by-tract analysis of diffusion-weighted characteristics contributing to the characterization of AD and its progression, our research elucidates the potential of diffusion MRI as a tool for the early detection and monitoring of neurodegenerative diseases and emphasizes the importance of integrating multi-modal data for enhanced predictive analytics.

Down syndrome (DS) is a genetic disorder characterized by intellectual disability whose etiology includes an additional partial or full copy of chromosome 21. Brain surface morphometry analyses can potentially assist in providing a better understanding of structural brain differences, and may help characterize DS-specific neurodevelopment. We performed a retrospective surface morphometry study of 73 magnetic resonance imaging (MRI) examinations of DS patients (aged 1 day to 22 years) and compared them to a large cohort of 993 brain MRI examinations of neurotypical participants, aged 1 day to 32 years. Surface curvature measurements, absolute surface area measurements, and surface areas as a percentage of total brain surface area (%TBSA) were extracted from each brain region in each examination. Results demonstrate broad reductions in surface area and abnormalities of surface curvature measurements across the brain in DS. After adjusting our regional surface area measurements as %TBSA, abnormally increased presentation in DS relative to neurotypical controls was observed in the left precentral, bilateral entorhinal, left parahippocampal, and bilateral perirhinal cortices, as well as Brodmann’s area 44 (left), and the right temporal pole. Findings suggest the presence of developmental abnormalities of regional %TBSA in DS that can be characterized from clinical MRI examinations.

Abstract Introduction There has been little documentation of the large networks of community health workers that contributed to Ebola Virus Disease (EVD) surveillance during the 2018–2020 Democratic Republic of Congo (DRC) epidemic in the form of community-based surveillance (CBS). These networks, comprised entirely of local community members, were a critical and mostly unrecognized factor in ending the epidemic. Challenges with collection, compilation, and analysis of CBS data have made their contribution difficult to quantify. From November 2019 to March 2020, the DRC Ministry of Health (MoH), the World Health Organization (WHO), and Médecins Sans Frontières (MSF) worked with communities to strengthen existing EVD CBS in two key health areas in Ituri Province, DRC. We describe CBS strengthening activities, detail collaboration with communities and present results of these efforts. We also provide lessons learned to inform future outbreak responses. Methods As the foundation of CBS, community health workers (CHW) completed training to identify and report patients who met the EVD alert definitions. Alerts were investigated and if validated, the patient was sent for isolation and EVD testing. Community members provided early and ongoing input to the CBS system. We established a predefined ratio of community- elected CHW, allocated by population, to assure equal and adequate coverage across areas. Strong performing CHW or local leaders managed the CHWs, providing a robust supervision structure. We made additional efforts to integrate rural villages, revised tools to lighten the reporting burden and focused analysis on key indicators. Phased roll-out of activities ensured time for community discussion and approval. An integrated treatment center (ITC) combined EVD testing and isolation with free primary health care (PHC), referral services, and an ambulance network. Results A total of 247 CHW and supervisors completed training. CBS had a retention rate of 94.3% (n = 233) with an average daily reporting rate of 97.4% (range 75.0-100.0%). Local chiefs and community leaders participated in activities from the early stages. Community feedback, including recommendations to add additional CHW, run separate meetings in rural villages, and strengthen PHC services, improved system coverage and performance. Of 6,711 community referrals made, 98.1% (n = 6,583) were classified as alerts. Of the alerts, 97.4% (n = 6,410) were investigated and 3.0% (n = 190) were validated. Of the community referrals, 73.1% (n = 4,905) arrived for care at the ITC. The contribution of CBS to total alerts in the surveillance system increased from an average of 47.3% in the four weeks prior to system strengthening to 69.0% after. In one of the two health areas, insufficient reporting in rural villages suggested inadequate coverage, with 8.3% of the total population contributing 6.1% of alerts. Discussion CBS demonstrated the capacity of community networks to improve early disease detection and expand access to healthcare. Early and consistent community involvement proved vital to CBS, as measured by system performance, local acceptance of EVD activities, and health service provision. The CBS system had high reporting rates, number of alerts signaled, proportion of alerts investigated, and proportion of community referrals that arrived for care. The change in contribution of CBS to total alerts may have been due in part to system strengthening, but also to the expansion in the EVD suspect case definition. Provision of PHC, referral services, and an ambulance network linked EVD response activities to the existing health system and facilitated CBS performance. More importantly, these activities provided a continuum of care that addressed community prioritized health needs. The involvement of local health promotion teams was vital to the CBS and other EVD and PHC activities. Lessons learned include the importance of early and consistent community involvement in surveillance activities and the recommendation to assure local representation in leadership positions.

In this interventional pilot study, we investigated the effects of a modified ketogenic diet (KD) on children with autism spectrum disorder (ASD). We previously observed improved behavioral symptoms in this cohort following the KD; this trial was registered with Clinicaltrials.gov (NCT02477904). This report details the alterations observed in the microbiota, inflammation markers, and microRNAs of seven children following a KD for a duration of 4 months. Our analysis included blood and stool samples, collected before and after the KD. After 4 months follow up, we found that the KD led to decreased plasma levels of proinflammatory cytokines (IL-12p70 and IL-1b) and brain-derived neurotrophic factor (BDNF). Additionally, we observed changes in the gut microbiome, increased expression of butyrate kinase in the gut, and altered levels of BDNF-associated miRNAs in the plasma. These cohort findings suggest that the KD may positively influence ASD sociability, as previously observed, by reducing inflammation, reversing gut microbial dysbiosis, and impacting the BDNF pathway related to brain activity.

Hypoglycemia has not been previously reported as a postoperative complication of mitral valve repair (MVR) in dogs; however, the authors have encountered cases of hypoglycemia after MVR. This study aimed to determine the incidence of hypoglycemia in dogs after MVR and investigate its causes. Blood glucose levels were measured at multiple timepoints in dogs undergoing MVR. Simultaneously, insulin and glucagon blood concentrations in dogs with hypoglycemia preoperatively and postoperatively were compared to verify the physiological responses to hypoglycemia. Furthermore, risk factors for hypoglycemia, using variables selected based on the characteristics of MVR and dogs undergoing MVR, were examined prospectively. The incidence of hypoglycemia after MVR was 14.2%, and plasma glucagon concentrations increased in these dogs (mean: 260 pg/mL and 644 pg/mL pre- and postoperatively, p < 0.001), whereas serum insulin concentrations decreased (median: 0.50 ng/mL and 0.29 ng/mL pre- and postoperatively, p = 0.002). Therefore, hyperinsulinemia or hypoglucagonemia is unlikely to be the cause of postoperative hypoglycemia. The identified risk factors for hypoglycemia included low body weight and asymptomatic myxomatous mitral valve disease. Monitoring blood glucose levels after MVR should be included in the standard hospitalization plan to prevent hypoglycemic emergencies in dogs.

Diffusion magnetic resonance imaging (MRI) tractography is a powerful tool for non-invasively studying brain architecture and structural integrity by inferring fiber tracts based on water diffusion profiles. This study provided a thorough set of baseline data of structural connectomics biomarkers for 809 healthy participants between the ages of 1 and 35 years. The data provided can help to identify potential biomarkers that may be helpful in characterizing physiological and anatomical neurodevelopmental changes linked with healthy brain maturation and can be used as a baseline for comparing abnormal and pathological development in future studies. Our results demonstrate statistically significant differences between the sexes, representing a potentially important baseline from which to establish healthy growth trajectories. Biomarkers that correlated with age, potentially representing useful methods for assessing brain development, are also presented. This baseline information may facilitate studies that identify abnormal brain development associated with a variety of pathological conditions as departures from healthy sex-specific age-dependent neural development. Our findings are the result of combining the use of mainstream analytic methods with in-house-developed open-source software to help facilitate reproducible analyses, inclusive of many potential biomarkers that cannot be derived from existing software packages. Assessing relationships between our identified regional tract measurements produced by our technology and participant characteristics/phenotypic data in future analyses has tremendous potential for the study of human neurodevelopment.

Lissencephaly (LIS) is a rare neurodevelopmental disorder with severe symptoms caused by abnormal neuronal migration during cortical development. It is caused by both genetic and non-genetic factors. Despite frequent studies about the cortex, comprehensive elucidation of structural abnormalities and their effects on the white matter is limited. The main objective of this study is to analyze abnormal neuronal migration pathways and white matter fiber organization in LIS1-associated LIS using diffusion MRI (dMRI) tractography. For this purpose, slabs of brain specimens with LIS (n = 3) and age and sex-matched controls (n = 4) were scanned with 3T dMRI. Our high-resolution ex vivo dMRI successfully identified common abnormalities across the samples. The results revealed an abnormal increase in radially oriented subcortical fibers likely associated with radial migration pathways and u-fibers and a decrease in association fibers in all LIS specimens.

IntroductionAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, communication and repetitive, restrictive behaviors, features supported by cortical activity. Given the importance of the subventricular zone (SVZ) of the lateral ventrical to cortical development, we compared molecular, cellular, and structural differences in the SVZ and linked cortical regions in specimens of ASD cases and sex and age-matched unaffected brain.MethodsWe used magnetic resonance imaging (MRI) and diffusion tractography on ex vivo postmortem brain samples, which we further analyzed by Whole Genome Bisulfite Sequencing (WGBS), Flow Cytometry, and RT qPCR.ResultsThrough MRI, we observed decreased tractography pathways from the dorsal SVZ, increased pathways from the posterior ventral SVZ to the insular cortex, and variable cortical thickness within the insular cortex in ASD diagnosed case relative to unaffected controls. Long-range tractography pathways from and to the insula were also reduced in the ASD case. FACS-based cell sorting revealed an increased population of proliferating cells in the SVZ of ASD case relative to the unaffected control. Targeted qPCR assays of SVZ tissue demonstrated significantly reduced expression levels of genes involved in differentiation and migration of neurons in ASD relative to the control counterpart. Finally, using genome-wide DNA methylation analyses, we identified 19 genes relevant to neurological development, function, and disease, 7 of which have not previously been described in ASD, that were significantly differentially methylated in autistic SVZ and insula specimens.ConclusionThese findings suggest a hypothesis that epigenetic changes during neurodevelopment alter the trajectory of proliferation, migration, and differentiation in the SVZ, impacting cortical structure and function and resulting in ASD phenotypes.

Regional anatomical structures of the brain are intimately connected to functions corresponding to specific regions and the temporospatial pattern of genetic expression and their functions from the fetal period to old age. Therefore, quantitative brain morphometry has often been employed in neuroscience investigations, while controlling for the scanner effect of the scanner is a critical issue for ensuring accuracy in brain morphometric studies of rare orphan diseases due to the lack of normal reference values available for multicenter studies. This study aimed to provide across-site normal reference values of global and regional brain volumes for each sex and age group in children and adolescents. We collected magnetic resonance imaging (MRI) examinations of 846 neurotypical participants aged 6.0–17.9 years (339 male and 507 female participants) from 5 institutions comprising healthy volunteers or neurotypical patients without neurological disorders, neuropsychological disorders, or epilepsy. Regional-based analysis using the CIVET 2.1.0. pipeline provided regional brain volumes, and the measurements were across-site combined using ComBat-GAM harmonization. The normal reference values of global and regional brain volumes and lateral indices in our study could be helpful for evaluating the characteristics of the brain morphology of each individual in a clinical setting and investigating the brain morphology of ultra-rare diseases.

Introduction Community-based surveillance may improve early detection and response to disease outbreaks by leveraging the capacity of community members to carry out surveillance activities within their communities. In 2021, the WHO published a report detailing the evidence gaps and research priorities around community-centred approaches to health emergencies. In response, we carried out a systematic review and narrative synthesis of the evidence describing the drivers of success of community-based surveillance systems.Methods We included grey literature and peer-reviewed sources presenting empirical findings of the drivers of success of community-based surveillance systems for the detection and reporting of infectious disease-related events. We searched for peer-reviewed literature via MEDLINE, EMBASE, Global Health, SCOPUS and ReliefWeb. We carried out grey literature searches using Google Search and DuckDuckGo. We used an evaluation quality checklist to assess quality.Results Nineteen sources (17 peer-reviewed and 2 grey literature) met our inclusion criteria. Included sources reported on community-based surveillance for the detection and reporting of a variety of diseases in 15 countries (including three conflict settings). The drivers of success were grouped based on factors relating to: (1) surveillance workers, (2) the community, (3) case detection and reporting, (4) and integration.Discussion The drivers of success were found to map closely to principles of participatory community engagement with success factors reflecting high levels of acceptability, collaboration, communication, local ownership, and trust. Other factors included: strong supervision and training, a strong sense of responsibility for community health, effective engagement of community informants, close proximity of surveillance workers to communities, the use of simple and adaptable case definitions, quality assurance, effective use of technology, and the use of data for real-time decision-making. Our findings highlight strategies for improving the design and implementation of community-based surveillance. We suggest that investment in participatory community engagement more broadly may be a key surveillance preparedness activity.PROSPERO registration number CRD42022303971.

We have performed a morphological analysis of patients with schizophrenia and compared them with healthy controls. Our analysis includes the use of publicly available automated extraction tools to assess regional cortical thickness (inclusive of within region cortical thickness variability) from structural magnetic resonance imaging (MRI), to characterize group-wise abnormalities associated with schizophrenia based on a publicly available dataset. We have also performed a correlation analysis between the automatically extracted biomarkers and a variety of patient clinical variables available. Finally, we also present the results of a machine learning analysis. Results demonstrate regional cortical thickness abnormalities in schizophrenia. We observed a correlation (rho = 0.474) between patients’ depression and the average cortical thickness of the right medial orbitofrontal cortex. Our leading machine learning technology evaluated was the support vector machine with stepwise feature selection, yielding a sensitivity of 92% and a specificity of 74%, based on regional brain measurements, including from the insula, superior frontal, caudate, calcarine sulcus, gyrus rectus, and rostral middle frontal regions. These results imply that advanced analytic techniques combining MRI with automated biomarker extraction can be helpful in characterizing patients with schizophrenia.

Rett syndrome (RTT) is a severe progressive neurodevelopmental disorder characterized by various neurological symptoms. Almost all RTT cases are caused by mutations in the X-linked methyl-CpG-binding protein 2 (MeCP2) gene, and several mouse models have been established to understand the disease. However, the neuroanatomical abnormalities in each brain region of RTT mouse models have not been fully understood. Here, we investigated the global and local neuroanatomy of the Mecp2 gene-deleted RTT model (Mecp2-KO) mouse brain using T2-weighted 3D magnetic resonance imaging with different morphometry to clarify the brain structural abnormalities that are involved in the pathophysiology of RTT. We found a significant reduction in global and almost all local volumes in the brain of Mecp2-KO mice. In addition, a detailed comparative analysis identified specific volume reductions in several brain regions in the Mecp2-deficient brain. Our analysis also revealed that the Mecp2-deficient brain shows changes in hemispheric asymmetry in several brain regions. These findings suggest that MeCP2 affects not only the whole-brain volume but also the region-specific brain structure. Our study provides a framework for neuroanatomical studies of a mouse model of RTT.

Schizophrenia is a pathological condition characterized by delusions, hallucinations, and a lack of motivation. In this study, we performed a morphological analysis of regional biomarkers in early-onset schizophrenia, including cortical thicknesses, surface areas, surface curvature, and volumes extracted from T1-weighted structural magnetic resonance imaging (MRI) and compared these findings with a large cohort of neurotypical controls. Results demonstrate statistically significant abnormal presentation of the curvature of select brain regions in early-onset schizophrenia with large effect sizes, inclusive of the pars orbitalis, pars triangularis, posterior cingulate cortex, frontal pole, orbital gyrus, lateral orbitofrontal gyrus, inferior occipital gyrus, as well as in medial occipito-temporal, lingual, and insular sulci. We also observed reduced regional volumes, surface areas, and variability of cortical thicknesses in early-onset schizophrenia relative to neurotypical controls in the lingual, transverse temporal, cuneus, and parahippocampal cortices that did not reach our stringent standard for statistical significance and should be confirmed in future studies with higher statistical power. These results imply that abnormal neurodevelopment associated with early-onset schizophrenia can be characterized with structural MRI and may reflect abnormal and possibly accelerated pruning of the cortex in schizophrenia.

Background: Accurate range of motion (ROM) assessment is an essential component of clinical practice to identify underlying deficits at the hip joint. Hip joint active ROM has been measured by goniometric methods in the clinical setting. More recently, the Clinometer Smartphone Application has gained attention for ROM measures. However, minimal research has been identified for the use of the Clinometer Smartphone Application™ for hip ROM. Therefore, the purpose of this study was to determine intrarater and interrater reliability of the Clinometer Smartphone Application™ as well as establishing its validity for active hip internal rotation (IR) and external rotation (ER). Methods: A concurrent test-retest reliability study was conducted using a convenience sample at three different sites. This study included 46 males and 30 females (n = 76) with an average age of 23.93 (5.37) years. Five clinicians measured each participant’s active prone hip rotation at three different sites. Three trials were measured with the goniometer and with the Clinometer Smartphone Application™. Intrarater reliability was assessed within one week for the five clinicians. Interrater reliability was assessed between three clinicians located at the same site. Results: The intrarater reliability of goniometer was moderate to excellent (ICC > .73 - .96) for hip IR and moderate to good (ICC > .76 - .89) for ER. Similarly, smartphone intrarater reliability was good to excellent for IR (ICC > .81 - .96) and ER (ICC > .77 - .90). The validity of the Clinometer Smartphone Application™ when compared to the goniometer and had a very strong relationship for IR (r = .94 - .96) and ER (r = .84 - .89). Conclusion: The results of this study suggest this application may be a valid and reliable alternative to the goniometer for clinicians when measuring active hip rotation in clinical practice.

Proper brain development requires the precise coordination and orchestration of various molecular and cellular processes and dysregulation of these processes can lead to neurological diseases. In the past decades, post-transcriptional regulation of gene expression has been shown to contribute to various aspects of brain development and function in the central nervous system. MicroRNAs (miRNAs), short non-coding RNAs, are emerging as crucial players in post-transcriptional gene regulation in a variety of tissues, such as the nervous system. In recent years, miRNAs have been implicated in multiple aspects of brain development, including neurogenesis, migration, axon and dendrite formation, and synaptogenesis. Moreover, altered expression and dysregulation of miRNAs have been linked to neurodevelopmental and psychiatric disorders. Magnetic resonance imaging (MRI) is a powerful imaging technology to obtain high-quality, detailed structural and functional information from the brains of human and animal models in a non-invasive manner. Because the spatial expression patterns of miRNAs in the brain, unlike those of DNA and RNA, remain largely unknown, a whole-brain imaging approach using MRI may be useful in revealing biological and pathological information about the brain affected by miRNAs. In this review, we highlight recent advancements in the research of miRNA-mediated modulation of neuronal processes that are important for brain development and their involvement in disease pathogenesis. Also, we overview each MRI technique, and its technological considerations, and discuss the applications of MRI techniques in miRNA research. This review aims to link miRNA biological study with MRI analytical technology and deepen our understanding of how miRNAs impact brain development and pathology of neurological diseases.

Down syndrome (DS) is a genetic disorder caused by the presence of an extra full or partial copy of chromosome 21 and characterized by intellectual disability. We hypothesize that performing a retrospective analysis of 73 magnetic resonance imaging (MRI) examinations of participants with DS (aged 0 to 22 years) and comparing them to a large cohort of 993 brain MRI examinations of neurotypical participants (aged 0 to 32 years), will assist in better understanding what brain differences may explain phenotypic developmental features in DS, as well as to provide valuable confirmation of prospective literature findings clinically. Measurements for both absolute volumes and volumes corrected as a percentage of estimated total intracranial volume (%ETIV) were extracted from each examination. Our results presented novel findings such as volume increases (%ETIV) in the perirhinal cortex, entorhinal cortex, choroid plexus, and Brodmann’s areas (BA) 3a, 3b, and 44, as well as volume decreases (%ETIV) in the white matter of the cuneus, the paracentral lobule, the postcentral gyrus, and the supramarginal gyrus. We also confirmed volumetric brain abnormalities previously discussed in the literature. Findings suggest the presence of volumetric brain abnormalities in DS that can be detected clinically with MRI.

The development of cortical convolutions, gyri and sulci, is a complex process that takes place during prenatal development. Lissencephaly, a rare genetic condition characterized by the lack of cortical convolutions, offers a model to look into biological processes that lead to the development of convolutions. Retrospective, qualitative, and quantitative analyses of structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were performed in patients with lissencephaly (N = 10) and age-/sex-matched controls (N = 10). In order to identify microstructural correlates of structural MRI and DTI findings, postmortem brains of patients with lissencephaly (N = 4) and age-matched controls (N = 4) were also examined with histology. Patients with lissencephaly had significantly smaller gyrification index and volumes of hemispheric white and gray matter, compared to the age-/sex-matched control group. However, there was no significant difference between groups in the subcortical gray matter volumes. Although the majority of patients with lissencephaly had a preserved normal-like appearance of major fissures and primary sulci, the spatial distribution of agyric cortical regions was different in patients with lissencephaly-1 (LIS1) and doublecortin (DCX) mutations. Lastly, in patients with lissencephaly, the spatiotemporal distribution of projection pathways was preserved while short- to medium-range cortico-cortical pathways were absent or fewer in number. Our results indicate that in the patients with lissencephaly cortical system is affected more than the subcortical one.

Autism is a group of complex neurodevelopmental disorders characterized by impaired social interaction and restricted/repetitive behavior. We performed a large-scale retrospective analysis of 1,996 clinical neurological structural magnetic resonance imaging (MRI) examinations of 781 autistic and 988 control subjects (aged 0–32 years), and extracted regionally distributed cortical thickness measurements, including average measurements as well as standard deviations which supports the assessment of intra-regional cortical thickness variability. The youngest autistic participants (

CHARGE syndrome (CS) is a rare congenital syndrome characterized by coloboma, heart anomaly, choanal atresia, retardation of growth and development, and genital and ear anomalies. While several neuroimaging studies have revealed abnormalities such as hypoplasia of the semicircular canal, olfactory nerve, cerebellum, and brainstem, no quantitative analysis of brain morphology in CS has been reported. We quantitatively investigated brain morphology in CS participants using structural magnetic resonance imaging (MRI) (N = 10, mean age 14.7 years old) and high-angular resolution diffusion MRI (HARDI) tractography (N = 8, mean age 19.4 years old) comparing with gender- and age-matched controls. Voxel-based analyses revealed decreased volume of the bilateral globus pallidus (left and right; p = 0.021 and 0.029), bilateral putamen (p = 0.016 and 0.011), left subthalamic nucleus (p = 0.012), bilateral cerebellum (p = 1.5 × 10−6 and 1.2 × 10−6), and brainstem (p = 0.031), and the enlargement of the lateral ventricles (p = 0.011 and 0.0031) bilaterally in CS. Surface-based analysis revealed asymmetrically increased cortical thickness in the right hemisphere (p = 0.013). The group-wise differences observed in global cortical volume, gyrification index, and left cortical thickness were not statistically significant. HARDI tractography revealed reduced volume, elongation, and higher ADC values in multiple fiber tracts in patients in CS compared to the controls, but FA values were not statistically significantly different between the two groups. Facial features are known to be asymmetric in CS, which has been recognized as an important symptom in CS. Our results revealed that the cortex in CS has an asymmetric appearance similar to the facial features. In addition, the signal pattern of high ADC with statistically unchanged FA values of tractography pathways indicated the presence of other pathogenesis than vasogenic edema or myelination dysfunction in developmental delay in CS. Keywords: CHARGE syndrome, Structural brain MRI, HARDI

Down syndrome (DS) is a genetic disorder caused by an extra copy of all or part of chromosome 21 and is characterized by intellectual disability. We performed a retrospective analysis of 47 magnetic resonance imaging (MRI) examinations of participants with DS (aged 5 to 22 years) and compared them with a large cohort of 854 brain MRIs obtained from neurotypical participants (aged 5 to 32 years) with the objective of assessing the clinical presentation of Down syndrome, towards better understanding the neurological development associated with the condition. An additional cohort of 26 MRI exams from patients with DS and 139 exams from neurotypical participants (aged 0–5 years) are included as part of a supplementary analysis. Regionally distributed cortical thickness measurements, including average measurements as well as standard deviations (intra-regional cortical thickness variability) were extracted from each examination. The largest effect sizes observed were associated with increased average cortical thickness in the postcentral gyrus with specific abnormalities observed in Brodmann's areas 1 and 3b in DS, which was observed across all age ranges. We also observed strong effect sizes associated with decreased cortical thickness variability in the lateral orbitofrontal gyrus, the postcentral gyrus and more in DS participants. Findings suggest regionally irregular gray matter development in DS that can be detected with MRI. Keywords: Down syndrome, Cortical thickness, Development, Neuroanatomy, Variability

Multivariate analysis (MVA) is a class of statistical and pattern recognition methods that involve the processing of data that contains multiple measurements per sample. MVA can be used to address a wide variety of medical neuroimaging-related challenges including identifying variables associated with a measure of clinical importance (i.e. patient outcome), creating diagnostic tests, assisting in characterizing developmental disorders, understanding disease etiology, development and progression, assisting in treatment monitoring and much more. Compared to adults, imaging of developing immature brains has attracted less attention from MVA researchers. However, remarkable MVA research growth has occurred in recent years. This paper presents the results of a systematic review of the literature focusing on MVA technologies applied to neurodevelopmental disorders in fetal, neonatal and pediatric magnetic resonance imaging (MRI) of the brain. The goal of this manuscript is to provide a concise review of the state of the scientific literature on studies employing brain MRI and MVA in a pre-adult population. Neurological developmental disorders addressed in the MVA research contained in this review include autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, schizophrenia and more. While the results of this review demonstrate considerable interest from the scientific community in applications of MVA technologies in pediatric/neonatal/fetal brain MRI, the field is still young and considerable research growth remains ahead of us.

There has been evidence that during brain development, emerging thalamocortical (TC) and corticothalamic (CT) pathways converge in some brain regions and follow each other's trajectories to their final destinations. Corpus callosal (CC) pathways also emerge at a similar developmental stage, and are known to converge with TC pathways in specific cortical regions in mature brains. Given the functional relationships between TC and CC pathways, anatomical convergence of the two pathways are likely important for their functional integration. However, it is unknown (1) where TC and CT subcortically converge in the human brain, and (2) where TC and CC converge in the cortex of the human brain, due to the limitations of non-invasive methods. The goals of this study were to describe the spatio-temporal relationships in the development of the TC/CT and CC pathways in the human brain, using high-angular resolution diffusion MR imaging (HARDI) tractography. Emerging cortical, TC and CC pathways were identified in postmortem fetal brains ranging from 17 gestational weeks (GW) to 30 GW, as well as in vivo 34–40 GW newborns. Some pathways from the thalami were found to be converged with pathways from the cerebral cortex as early as 17 GW. Such convergence was observed mainly in anterior and middle regions of the brain until 21 GW. At 22 GW and onwards, posterior pathways from the thalami also converged with cortical pathways. Many CC pathways reached the full length up to the cortical surface as early as 17 GW, while pathways linked to thalami (not only TC axons but also including pathways linked to thalamic neuronal migration) reached the cortical surface at and after 20 GW. These results suggest that CC pathways developed earlier than the TC pathways. The two pathways were widespread at early stages, but by 40 GW they condensed and formed groups of pathways that projected to specific regions of the cortex and overlapped in some brain regions. These results suggest that HARDI tractography has the potential to identify developing TC/CT and CC pathways with the timing and location of their convergence in fetal stages persisting in postnatal development.

Fractional anisotropy (FA) threshold is commonly used to perform diffusion MRI tractography. However, FA threshold may be one aspect of tractography that needs additional scrutiny in accurately assessing pathways in immature, developing brains, as well as in adult brains. Using high-angular resolution diffusion MRI (HARDI) tractography without an FA threshold, we identified the arcuate fasciculus (AF) of 83 healthy subjects ranging in age from 40 gestational weeks (GW) (newborns) to 28-year-old adults. The AF was identified in both hemispheres in all subjects with high inter-rater reliability. The detected AF included regions with very low FA values. The entire AF was segmented into anterior, posterior, and long tracts. Growth and laterality patterns were investigated using tract count (number of detected streamlines), total volume of imaging voxels (touched by the detected streamlines), mean length, mean FA, and mean apparent diffusion coefficient (ADC). Comparison of subjects under 3 years old, to those that were older, revealed the three AF tracts that took different developmental courses. As expected, the anterior and long tracts showed lower ADC values in subjects over 3 years old, while the posterior tract showed higher ADC in that same age range. The posterior tract did not show age-related effect in terms of FA, tract count, length, and volume. These results suggest that the posterior AF tract shows a matured state, indexed by most of the used measurements in early postnatal developmental ages, and ADC is a measurement that can detect further maturation of the posterior tract. Interestingly, in all tracts, hemispheric asymmetries were found in raw (leftright) tract count, as well as in raw volume (left

In this study, we aimed to identify major fiber pathways and their spatiotemporal relationships within transient fetal zones in the human fetal brain by comparing postmortem high-angular resolution diffusion MR imaging (HARDI) in combination with deterministic streamline tractography and histology. Diffusion weighted imaging was performed on postmortem human fetal brains [N = 9, age = 18–34 post-conceptual weeks (PCW)] that were grossly normal with no pathologic abnormalities. After HARDI was performed, the fibers were reconstructed using Q-ball algorithm and deterministic streamline tractography. The position of major fiber pathways within transient fetal zones was identified both on diffusion weighted images and on histological sections. Our major findings include: (1) the development of massive projection fibers by 18 PCW, as compared to most association fibers (with the exception of limbic fibers) which have only begun to emerge, (2) the characteristic laminar distribution and sagittal plane geometry of reconstructed fibers throughout development, (3) the protracted prenatal development shown of the corpus collosum and its' associated fibers, as well as the association fibers, and (4) the predomination of radial coherence in the telencephalon (i.e., majority of streamlines in the telencephalic wall were radially oriented) during early prenatal period (24 PCW). In conclusion, correlation between histology and HARDI (in combination with Q-ball reconstruction and deterministic streamline tractography) allowed us to detect sequential development of fiber systems (projection, callosal, and association), their spatial relations with transient fetal zones, and their geometric properties.

Little is known about the excess mortality caused by multidrug-resistant (MDR) bacterial infection in low- and middle-income countries (LMICs). We retrospectively obtained microbiology laboratory and hospital databases of nine public hospitals in northeast Thailand from 2004 to 2010, and linked these with the national death registry to obtain the 30-day mortality outcome. The 30-day mortality in those with MDR community-acquired bacteraemia, healthcare-associated bacteraemia, and hospital-acquired bacteraemia were 35% (549/1555), 49% (247/500), and 53% (640/1198), respectively. We estimate that 19,122 of 45,209 (43%) deaths in patients with hospital-acquired infection due to MDR bacteria in Thailand in 2010 represented excess mortality caused by MDR. We demonstrate that national statistics on the epidemiology and burden of MDR in LMICs could be improved by integrating information from readily available databases. The prevalence and mortality attributable to MDR in Thailand are high. This is likely to reflect the situation in other LMICs.

The axolotl can regenerate multiple organs, including the brain. It remains, however, unclear whether neuronal diversity, intricate tissue architecture, and axonal connectivity can be regenerated; yet, this is critical for recovery of function and a central aim of cell replacement strategies in the mammalian central nervous system. Here, we demonstrate that, upon mechanical injury to the adult pallium, axolotls can regenerate several of the populations of neurons present before injury. Notably, regenerated neurons acquire functional electrophysiological traits and respond appropriately to afferent inputs. Despite the ability to regenerate specific, molecularly-defined neuronal subtypes, we also uncovered previously unappreciated limitations by showing that newborn neurons organize within altered tissue architecture and fail to re-establish the long-distance axonal tracts and circuit physiology present before injury. The data provide a direct demonstration that diverse, electrophysiologically functional neurons can be regenerated in axolotls, but challenge prior assumptions of functional brain repair in regenerative species.