MultisegPipeline: Automatic tissue segmentation of brain MR images with subject-specific atlases

Automated segmentation and labeling of individual brain anatomical regions is challenging due to individual structural variability. Although, atlas-based segmentation has shown its potential for both tissue and structure segmentation, the inherent natural variability as well as disease-related changes in MR appearance is often inappropriately represented by a single atlas image. In order to have a more accurate representation, several atlases may be used for the segmentation task in a given neuroimaging study. In this paper, we present the MultisegPipeline, it uses multiple atlases that have been visually inspected and capture the expected variability in a neonatal population. The MultisegPipeline transfers the labeled regions from each atlas to the target image using deformable registration (ANTs or QuickSilver is available for this task). Additionally, the set of labels are merged using a label fusion technique that reduces the errors produced by the registration. The final output is a single label map that combines the results produced by all atlases into a consensus solution. In our study, the MultisegPipeline is used to segment brain MR images from 31 infants, a leave-one-out strategy was used to test our framework. The average dice score coefficient was 0.89

Intergenerational Effect of Maternal Exposure to Childhood Maltreatment on Newborn Brain Anatomy

Background Childhood maltreatment (CM) confers deleterious long-term consequences, and growing evidence suggests some of these effects may be transmitted across generations. We examined the intergenerational effect of maternal CM exposure on child brain structure and also addressed the hypothesis that this effect may start during the child's intrauterine period of life. Methods A prospective longitudinal study was conducted in a clinical convenience sample of 80 mother-child dyads. Maternal CM exposure was assessed using the Childhood Trauma Questionnaire. Structural magnetic resonance imaging was employed to characterize newborn global and regional brain (tissue) volumes near the time of birth. Results CM exposure was reported by 35% of the women. Maternal CM exposure was associated with lower child intracranial volume (F1,70 = 6.84, p =.011), which was primarily due to a global difference in cortical gray matter (F1,70 = 9.10, p =.004). The effect was independent of potential confounding variables, including maternal socioeconomic status, obstetric complications, obesity, recent interpersonal violence, pre- and early postpartum stress, gestational age at birth, infant sex, and postnatal age at magnetic resonance imaging scan. The observed group difference between offspring of CM-exposed mothers versus nonexposed mothers was 6%. Conclusions These findings represent the first report to date associating maternal CM exposure with variation in newborn brain structure. These observations support our hypothesis of intergenerational transmission of the effects of maternal CM exposure on child brain development and suggest this effect may originate during the child's intrauterine period of life, which may have downstream neurodevelopmental consequences

Neonatal brain volume as a marker of differential susceptibility to parenting quality and its association with neurodevelopment across early childhood

Parenting quality is associated with child cognitive and executive functions (EF), which are important predictors of social and academic development. However, children vary in their susceptibility to parenting behaviors, and the neurobiological underpinnings of this susceptibility are poorly understood. In a prospective longitudinal study, we examined whether neonatal total brain volume (TBV) and subregions of interest (i.e., hippocampus (HC) and anterior cingulate gyrus (ACG)) moderate the association between maternal sensitivity and cognitive/EF development across early childhood. Neonates underwent a brain magnetic resonance imaging scan. Their cognitive performance and EF was characterized at 2.0 ± 0.1 years (N = 53) and at 4.9 ± 0.8 years (N = 36) of age. Maternal sensitivity was coded based on observation of a standardized play situation at 6-mo postpartum. Neonatal TBV moderated the association between maternal sensitivity and 2-year working memory as well as all 5-year cognitive outcomes, suggesting that the positive association between maternal sensitivity and child cognition was observed only among children with large or average but not small TBV as neonates. Similar patterns were observed for TBV-corrected HC and ACG volumes. The findings suggest that larger neonatal TBV, HC and ACG may underlie susceptibility to the environment and affect the degree to which parenting quality shapes long-term cognitive development

Prospective association of maternal psychosocial stress in pregnancy with newborn hippocampal volume and implications for infant social-emotional development

AbstractMaternal psychosocial stress during pregnancy can impact the developing fetal brain and influence offspring mental health. In this context, animal studies have identified the hippocampus and amygdala as key brain regions of interest, however, evidence in humans is sparse. We, therefore, examined the associations between maternal prenatal psychosocial stress, newborn hippocampal and amygdala volumes, and child social-emotional development.In a sample of 86 mother-child dyads, maternal perceived stress was assessed serially in early, mid and late pregnancy. Following birth, newborn (aged 5–64 postnatal days, mean: 25.8 ± 12.9) hippocampal and amygdala volume was assessed using structural magnetic resonance imaging. Infant social-emotional developmental milestones were assessed at 6- and 12-months age using the Bayley-III.After adjusting for covariates, maternal perceived stress during pregnancy was inversely associated with newborn left hippocampal volume (β = −0.26, p = .019), but not with right hippocampal (β = −0.170, p = .121) or bilateral amygdala volumes (ps > .5). Furthermore, newborn left hippocampal volume was positively associated with infant social-emotional development across the first year of postnatal life (B = 0.01, p = .011). Maternal perceived stress was indirectly associated with infant social-emotional development via newborn left hippocampal volume (B = −0.34, 95% CIBC [-0.97, −0.01]), suggesting mediation.This study provides prospective evidence in humans linking maternal psychosocial stress in pregnancy with newborn hippocampal volume and subsequent infant social-emotional development across the first year of life. These findings highlight the importance of maternal psychosocial state during pregnancy as a target amenable to interventions to prevent or attenuate its potentially unfavorable neural and behavioral consequences in the offspring.</p

Cerebellar Volumes in School Age Boys with Autism Spectrum Disorder and Fragile X Syndrome

ASD is a neurodevelopmental disorder characterized by social deficits, stereotyped and repetitive behaviors, and communication deficits while FXS is an X-linked genetic disorder that results from expansions of a CGG repeat near the promoter region of FMR1. The current study includes school age males with ASD, FXS, and typical development. Measures of motor control, communication, repetitive behaviors, and cognitive ability were examined. Anatomical 3 Tesla MRI scans were obtained. Gray matter volumes in cerebellar anterior and posterior lobes were calculated with the Diedrichsen SUIT toolbox, which uses a probabilistic atlas and semi-automated pipeline to produce the segmentations. No significant differences between groups were found for adjusted mean anterior gray matter volumes (p=0.46) or posterior lobe gray matter volumes (p=0.74). Anterior lobe gray matter volumes were not significantly associated with motor skills standard scores in ASD, FXS, or TYP groups (p=0.93). The interaction term of ASD diagnosis by posterior lobe gray matter volumes was trending toward a significant association with communication standard scores (p=0.097). Posterior lobe gray matter volumes were not significantly associated with repetitive behaviors in ASD, FXS, or TYP groups (p=1.00). These findings indicate that more research should be performed to explore cerebellar lobe gray matter volumes associations with the behaviors characteristics of ASD and FXS.Bachelor of Scienc

Einfluss mütterlicher DHA-Plasmakonzentrationen während der Schwangerschaft auf das Gehirnvolumen des Kindes bei der Geburt

Hintergrund: Das Forschungsfeld der fötalen Programmierung befasst sich mit mütterlichen Einflussfaktoren, die während der Embryonalzeit die Gesundheit des Kindes langfristig verändern. In diesem Forschungsfeld haben Nährstoffe, wie die Omega-3-Fettsäure DHA (Docosaheaxaensäure), aufgrund ihres Einflusses auf die neuronale Entwicklung immer weiter an Aufmerksamkeit gewonnen. In klinischen Studien konnte gezeigt werden, dass Kinder von Müttern mit einer DHA-reichen Ernährung während der Schwangerschaft eine bessere motorische und kognitive Entwicklung aufweisen. Omega-3-Fettäsuren wird eine tragende Funktion im Aufbau von neuronalen Membranen und Synapsen, sowie eine anti- apoptotische Wirkung zugeschrieben. Zudem sind Omega-3-Fettsäuren essentiell, das heißt, sie müssen über die Nahrung aufgenommen werden. Demnach ist der Fötus in seiner DHA- Aufnahme vollständig vom DHA-Gehalt der Mutter abhängig. In der Ernährung der heutigen westlichen Welt hat sich das Verhältnis von Omega-3- zu Omega-6-Fettsäuren stark zu Gunsten der Omega-6-Fettsäuren verschoben. Die Vermutung liegt nahe, dass eine an DHA mangelnde Ernährung der Mutter während der Schwangerschaft möglicherweise einen negativen Einfluss auf die neuronale Entwicklung des Kindes haben kann. Diese Arbeit untersucht, ob die mütterliche DHA-Plasmakonzentration während der Schwangerschaft mit dem Gehirnvolumen der grauen Substanz und des Hippocampus des Kindes bei der Geburt korrelieren. Methode: Es wurde eine prospektive Studie mit einer Studienpopulation von 63 Müttern und deren Neugeborenen durchgeführt. In jedem Schwangerschaftstrimester erfolgte eine Blutentnahme bei den Müttern und die DHA-Konzentrationen (LPC 22:6 und NEFA 22:6) im Blutplasma der Mütter wurden anhand eines speziellen Massenspektrometrie-Verfahrens bestimmt. Möglichst früh nach der Geburt wurde ein cMRT des neugeborenen Kindes durchgeführt. Es erfolgte die Segmentierung der MRT-Bilder in die graue Substanz und in das rechte sowie linke hippocampale Volumen. Ergebnis: Es zeigte sich keine Assoziation zwischen den mütterlichen DHA-Konzentrationen während der Schwangerschaft und dem Volumen der grauen Substanz (NEFA 22:6 T=-0,668, ß=-0,3, p=0,504; LPC 22:6 T=-0,070, ß=0,004, p=0,945) oder des rechten (NEFA 22:6 T=-0,116, ß=-0,009, p=0,908; LPC 22:6 T=0,354, ß=0,035, p=0,724) bzw. linken Hippocampus ihres Neugeborenen (NEFA 22:6 T=-0,609, ß=-0,06 , p=0,542; LPC 22:6 T=-0,443, ß=-0,038, p=0,658). Zusammenfassung: Der heutigen Kenntnis nach, ist dies die erste MRT-Studie, die den Zusammenhang zwischen mütterlicher DHA-Plasmakonzentration während der Schwangerschaft und dem Gehirnvolumen des neugeborenen Kindes untersucht. Im Gegensatz zu den meisten bisherigen Ergebnissen, konnte in dieser Studie keine Assoziation zwischen DHA-Plasmakonzentrationen der Mutter während der Schwangerschaft und dem Gehirnvolumen des Kindes gefunden werden. Die geringe Probandenzahl (N=63) und die Komplexität des Fettsäure-Stoffwechsels schränken jedoch die Aussagekraft der Studie ein.Background: The current theory of Fetal Programming emphazises the importance of early factors that can influence health and disease in a lifelong perspective. In this field of research, maternal nutrients such as omega-3 fatty acids, especially docosahexanoic acid (DHA), and their impact on fetal neurodevelopment gained unprecedented attention. Clinical studies indicate that children from mothers who had a DHA enriched diet during pregnancy show improved motor and cognitive performance in early life. Animal research and in vitro trials demonstrate that omega-3 fatty acids enhance synaptic structure and function, neuronal membrane morphology, and anti-apoptotic pathways of neuronal cells. Omega-3 fatty acids are essential nutrients which means that humans are unable to synthesize them de novo and that fetuses completely depend on the omega-3 intake of their mother. However, western diet is deficient in omega-3 fatty acids with an omega-3/omega-6 ratio that has been rapidly changing in favor to omega-6-fatty acids. It is possible that DHA deficiency during pregnancy has an adverse effect on fetal neurodevelopment. The aim of this study is to show whether there is an association between maternal DHA plasma concentrations during pregnancy and grey matter as well as left and right hippocampal volume of the child early after birth. Methods: A prospective, clinical study was conducted in a sample of 63 mother-child-dyads. A special mass spectrometry technique was used to analyze the mother‘s DHA concentrations (LPC 22:6 and NEFA 22:6) during each pregnancy trimester. Structural magnetic resonance imaging was employed to characterize newborn grey matter, left hippocampal and right hippocampal brain volume. Results: No associations were found between maternal DHA concentrations during pregnancy and grey matter volume (NEFA 22:6 T=-0,668, ß=-0,3, p=0,504; LPC 22:6 T=- 0,070, ß=0,004, p=0,945), right hippocampal volume (NEFA 22:6 T=-0,116, ß=-0,009, p=0,908; LPC 22:6 T=0,354, ß=0,035, p=0,724) and left hippocampal volume of the newborn child (NEFA 22:6 T=-0,609, ß=-0,06 , p=0,542; LPC 22:6 T=-0,443, ß=-0,038, p=0,658). We found no sex specific associations between the DHA concentrations and the child's brain volume. Conclusion: To the best of our knowledge, this is the first clinical MRI-study to analyze the association between maternal DHA concentrations during pregnancy and the child’s brain volume soon after birth. In contrast to previous studies, no association was found between maternal DHA-concentrations and the brain volume of her child. However, conclusions from this study are limited because of the weak numer of participants (N=63) and the complexitiy of DHA metabolism in the body

A CAD system for early diagnosis of autism using different imaging modalities.

The term “autism spectrum disorder” (ASD) refers to a collection of neuro-developmental disorders that affect linguistic, behavioral, and social skills. Autism has many symptoms, most prominently, social impairment and repetitive behaviors. It is crucial to diagnose autism at an early stage for better assessment and investigation of this complex syndrome. There have been a lot of efforts to diagnose ASD using different techniques, such as imaging modalities, genetic techniques, and behavior reports. Imaging modalities have been extensively exploited for ASD diagnosis, and one of the most successful ones is Magnetic resonance imaging(MRI),where it has shown promise for the early diagnosis of the ASD related abnormalities in particular. Magnetic resonance imaging (MRI) modalities have emerged as powerful means that facilitate non-invasive clinical diagnostics of various diseases and abnormalities since their inception in the 1980s. After the advent in the nineteen eighties, MRI soon became one of the most promising non- invasive modalities for visualization and diagnostics of ASD-related abnormalities. Along with its main advantage of no exposure to radiation, high contrast, and spatial resolution, the recent advances to MRI modalities have notably increased diagnostic certainty. Multiple MRI modalities, such as different types of structural MRI (sMRI) that examines anatomical changes, and functional MRI (fMRI) that examines brain activity by monitoring blood flow changes,have been employed to investigate facets of ASD in order to better understand this complex syndrome. This work aims at developing a new computer-aided diagnostic (CAD) system for autism diagnosis using different imaging modalities. It mainly relies on making use of structural magnetic resonance images for extracting notable shape features from parts of the brainthat proved to correlate with ASD from previous neuropathological studies. Shape features from both the cerebral cortex (Cx) and cerebral white matter(CWM)are extracted. Fusion of features from these two structures is conducted based on the recent findings suggesting that Cx changes in autism are related to CWM abnormalities. Also, when fusing features from more than one structure, this would increase the robustness of the CAD system. Moreover, fMRI experiments are done and analyzed to find areas of activation in the brains of autistic and typically developing individuals that are related to a specific task. All sMRI findings are fused with those of fMRI to better understand ASD in terms of both anatomy and functionality,and thus better classify the two groups. This is one aspect of the novelty of this CAD system, where sMRI and fMRI studies are both applied on subjects from different ages to diagnose ASD. In order to build such a CAD system, three main blocks are required. First, 3D brain segmentation is applied using a novel hybrid model that combines shape, intensity, and spatial information. Second, shape features from both Cx and CWM are extracted and anf MRI reward experiment is conducted from which areas of activation that are related to the task of this experiment are identified. Those features were extracted from local areas of the brain to provide an accurate analysis of ASD and correlate it with certain anatomical areas. Third and last, fusion of all the extracted features is done using a deep-fusion classification network to perform classification and obtain the diagnosis report. Fusing features from all modalities achieved a classification accuracy of 94.7%, which emphasizes the significance of combining structures/modalities for ASD diagnosis. To conclude, this work could pave the pathway for better understanding of the autism spectrum by finding local areas that correlate to the disease. The idea of personalized medicine is emphasized in this work, where the proposed CAD system holds the promise to resolve autism endophenotypes and help clinicians deliver personalized treatment to individuals affected with this complex syndrome

Infant Gut Microbiome Associated with Cognition, Fear Behavior, and Brain Structure

The gut microbiome has emerged as an important contributor to human health and development. Experimental manipulation of gut microbes in animal models alters cognitive performance, fear behavior, and neurodevelopment. In humans, the first years of life are a dynamic time in gut colonization and brain development, but little is known about the relationship between these two processes. This represents a critical gap in knowledge, given that changing the gut microbiome could represent a novel therapeutic approach for cognitive delay or fear-related psychopathology if similar observations were found in humans. The work described in this dissertation addresses this gap by examining how the composition of the human infant gut microbiome relates to cognition, fear behavior, and brain development. We also investigated the role of metabolites as potential microbiome-gut-brain axis mediators. Our results revealed that infants in a cluster defined by greater relative abundance of Bacteroides at 1 year of age scored significantly higher on overall cognitive ability, expressive language, and receptive language at 2 years of age. Higher alpha diversity at 1 year was associated with lower scores on overall cognitive ability, visual reception, and expressive language at 2 years of age. In a separate cohort, we found that 1-year gut microbiome composition (Weighted Unifrac; decreased Bacteroides, increased Veillonella, Dialister, and Clostridiales) was significantly associated with increased facial fear, bodily fear, vocal distress, and escape behavior during a non-social fear paradigm as well as larger amygdala volumes at 1 year. Infants with a less diverse microbiome at 1 month displayed increased non-social fear at 1 year. Analysis of salivary metabolites did not reveal any metabolic pathways mediating microbiome and fear behavior associations. However, exploratory analysis suggested that future research should investigate tyrosine metabolism and its role in fear behavior as well as sphingolipids and glycerophospholipids in relation to the microbiome and myelination. Overall, our findings are the first to demonstrate associations of the human infant gut microbiome with cognition, fear behavior, and brain structure. As such, these results fill an important translational gap and represent an important step in understanding the role of the gut microbiome in human neurodevelopment and behavior.Doctor of Philosoph