Neurodevelopmental Trajectories Research Articles

Developmental Neuroimaging in Pediatric Obsessive-Compulsive Disorder.

This review examines emerging neuroimaging research in pediatric obsessive compulsive disorder (OCD) and explores the possibility that developmentally sensitive mechanisms may underlie OCD across the lifespan. Diffusion tensor imaging (DTI) studies of pediatric OCD reveal abnormal structural connectivity within frontal-striato-thalamic circuity (FSTC). Resting-state functional magnetic resonance imaging (fMRI) studies further support atypical FSTC connectivity in young patients, but also suggest altered connectivity within cortical networks for task-control. Task-based fMRI studies show that hyper- and hypo-activation of task control networks may depend on task difficulty in pediatric patients similar to recent findings in adults. This review suggests that atypical neurodevelopmental trajectories may underlie the emergence and early course of OCD. Abnormalities of structural and functional connectivity may vary with age, while functional engagement during task may vary with age and task complexity. Future research should combine DTI, resting-state fMRI and task-based fMRI methods and incorporate longitudinal designs to reveal developmentally sensitive targets for intervention.

Predictive role of early milestones-related psychomotor profiles and long-term neurodevelopmental pitfalls in preterm infants

BackgroundDevelopmental milestones are useful signposts developed to assess the pace and the trajectory of maturation occurring during specific time-windows called critical periods. The predictive role of their clinical assessment in premature infants is challenging, however, it actually represents an easy and reliable tool at follow-up. Aim and study designRelying on a milestone-based neurological examination, we aimed to detect the interdependence between time of achievement of each milestone with long-term neuropsychological and neurodevelopmental outcomes. The influence of pre-perinatal events was also considered. Patients & methodsTwo-hundred-eighty patients (53.2% M) were serially assessed by classic neurological examination during the first 18months and subsequently evaluated by Griffiths Developmental Mental Scale. Children were sorted by ranges of gestational age and compared according to their different profiles. ResultsThe Extremely PreTerms appeared to have a globally delayed development with subsequent attentional and behavioral troubles. Differently, the older peers, from Moderately to Full Term ones, although did not show significant differences in achievement of gross motor skills, had a stable delay of visual and social skills across the age ranges. This gap was not evidenced at the long-term evaluation, except for the Extremely PreTerm children. Pre-perinatal factors played a significant role on short and long term neurodevelopmental outcome. ConclusionsEarly assessed classic neurological examination might address neurodevelopmental trajectories in PreTerm children in which visual and social skills appear to be the mostly affected. It remains the easiest and most reliable tool of evaluation throughout the follow-up programs.

Aetiopathological mechanisms of negative symptoms in schizophrenia

Summary Background: Negative symptoms represent core features of schizophrenia and have an unfavorable impact on the disease outcome. Unfortunately, their aetiopathology has not been elucidated yet and the effectiveness of available treatments is not satisfactory. Aims: This review aims to provide a critical overview of research findings concerning negative symptom aetiopathology, highlighting limitations and future perspectives. Results: Enduring and transient negative symptoms, as well as motivation-related and expression-related domains of negative symptoms, have different risk factors and clinical correlates, and are associated to distinct brain abnormalities. Enduring negative symptoms seem to be related to subtle, pervasive deviations in neurodevelopmental trajectories. Expression deficit, as compared with avolition, shows a stronger association with neurological soft signs, cognitive impairment and diffuse disconnectivity. Avolition/apathy is a multifaceted construct probably related to deficits of reward and action valuation and instrumental learning, subtended by cortico-striatal dysfunctions. Conclusions: Research findings support the heterogeneity of negative symptoms and are likely to pave the way for the discovery of more effective treatments.

Cumulative trauma, adversity and grief symptoms associated with fronto-temporal regions in life-course persistent delinquent boys

Delinquent youth have substantial trauma exposure, with life-course persistent delinquents [LCPD] demonstrating notably elevated cross-diagnostic psychopathology and cognitive deficits. Because adolescents remain in the midst of brain and neurocognitive development, tailored interventions are key to improving functional outcomes. This structural magnetic resonance imaging study compared neuroanatomical profiles of 23 LCPD and 20 matched control adolescent boys. LCPD youth had smaller overall gray matter, and left hippocampal, volumes alongside less cortical surface area and folding within the left pars opercularis and supramarginal cortex. LCPD youth had more adversity-related exposures, and their higher Cumulative Trauma, Adversity and Grief [C-TAG] symptoms were associated with less surface area and folding in the pars opercularis and lingual gyrus. Neuroanatomical differences between LCPD and control youth overlap with data from both maltreatment and antisocial literatures. The affected left frontal regions also share connections to language- and executive-related functions, aligning well with LCPD youths' cognitive and behavioral difficulties. These data also dovetail with research suggesting the possibility of neurodevelopmental delays or disruptions related to cumulative adversity burden. Thus, concurrent treatment of LCPD youths' C-TAG symptoms and, cognitive deficits with overlapping neuroanatomical bases, may be most effective in improving outcomes and optimizing neurodevelopmental trajectories.

Trajectories of adolescent conduct problems in relation to cortical thickness development: a longitudinal MRI study

Multiple cross-sectional imaging studies have identified structural abnormalities in prefrontal, temporal and limbic regions related to conduct problems (CPs). However, the relationship between development of such neurobiological deficits and developmental pathways of CPs has remained unclear. The current study investigated distinct trajectories of CP and related trajectories of cortical thickness within a community-based sample of adolescents (n=239), age range 12–19, to address this gap. Three trajectory classes were revealed using latent class growth analyses (LCGAs), comprising a ‘desisting' CP group, an ‘intermediate' CP group and a ‘stable low' CP group. Structural magnetic resonance imaging (MRI) scans were collected with a subgroup of 171 adolescents at three waves throughout adolescence (ages 12, 16 and 19). Generalized estimating equation (GEE) analysis—comparing longitudinal changes in cortical thickness and subcortical volume between CP groups for several regions of interest (ROIs)—showed that these CP groups had differential trajectories of cortical thickness in the dorsolateral prefrontal cortex (dl-PFC), and the anterior cingulate cortex (ACC), and volume of the hippocampus. Adolescents in the desisting CP group showed an attenuation of the typical pattern of cortical thinning as present in the intermediate and stable low CP groups, in addition to an exaggeration of the typical pattern of hippocampal volume increase. These findings suggest that a deviant cortical thickness trajectory was related to a desisting CP pathway across adolescence. Such deviant neurodevelopmental growth trajectories may act as an underlying mechanism for developmental CP pathways, and possibly distinguish desisting antisocial adolescents.

Identification of neurodevelopmental trajectories in infancy and of risk factors affecting deviant development: a longitudinal birth cohort study.

We investigate patterns of neurodevelopmental trajectories in infants, using a representative population, and identify risk factors that predict delayed growth. Participating infants (n = 952; 82.8% of the total sample) were assessed by Mullen Scales of Early Learning at seven time points, from 1 month to 24 months of age. Mothers were recruited in early pregnancy and data on demographic characteristics were collected during pregnancy. Trajectory patterns were investigated using latent class growth analysis, and risk factors for the derived trajectory classes were investigated by multinomial logistic regression. Participants were found to be a fairly representative sample with respect to their demographic characteristics. Five classes of high normal (11.5%), normal (49.2%), low normal (21.2%), delayed (14.1%), and markedly delayed (4.0%) were identified. The markedly delayed class was characterized by overall delay from the early developmental stages; notably, such delay first became salient in motor domains and was then exceeded by language domains, especially receptive language. This class was predicted by male sex (odds ratio 4.0; 95% confidence interval 1.7-9.1), small for gestational age (2.8; 1.0-7.5), low placenta-to-birthweight ratio (2.8; 1.2-6.4) and low maternal education (4.7; 1.2-19.0). The delayed class was characterized by gradual downward deviation after the first birthday, and was predicted by male sex (2.5; 1.5-4.2), preterm birth (4.4; 1.6-12.6) and advanced paternal age (1.9; 1.0-3.5). Our results demonstrate that about 1 out of 5 infants exhibits delayed neurodevelopment. Infants with distinct patterns of delayed trajectories and varying risk factors are considered to have different pathophysiological mechanisms.

Annual Research Review: The role of the environment in the developmental psychopathology of autism spectrum condition.

Although autism spectrum condition (ASC) is strongly genetic in origin, accumulating evidence points to the critical roles of various environmental influences on its emergence and subsequent developmental course. A developmental psychopathology framework was used to synthesise literature on environmental factors associated with the onset and course of ASC (based on a systematic search of the literature using PubMed, PsychInfo and Google Scholar databases). Particular emphasis was placed on gene-environment interplay, including gene-environment interaction (G × E) and gene-environment correlation (rGE). Before conception, advanced paternal and maternal ages may independently enhance offspring risk for ASC. Exogenous prenatal risks are evident (e.g. valproate and toxic chemicals) or possible (e.g. selective serotonin reuptake inhibitors), and processes endogenous to the materno-foeto-placental unit (e.g. maternal diabetes, enhanced steroidogenic activities and maternal immune activation) likely heighten offspring vulnerability to ASC. Folate intake is a prenatal protective factor, with a particular window of action around 4 weeks preconception and during the first trimester. These prenatal risks and protective mechanisms appear to involve G × E and potentially rGE. A variety of perinatal risks are related to offspring ASC risk, possibly reflecting rGE. Postnatal social factors (e.g. caregiver-infant interaction, severe early deprivation) during the first years of life may operate through rGE to influence the likelihood of manifesting a full ASC phenotype from a 'prodromal' phase (a proposal distinct to the discredited and harmful 'refrigerator mother hypothesis'); and later postnatal risks, after the full manifestation of ASC, shape life span development through transactions mediated by rGE. There is no evidence that vaccination is a postnatal risk for ASC. Future investigations should consider the specificity of risks for ASC versus other atypical neurodevelopmental trajectories, timing of risk and protective mechanisms, animal model systems to study mechanisms underlying gene-environment interplay, large-sample genome-envirome designs to address G × E and longitudinal studies to elucidate how rGE plays out over time. Clinical and public health implications are discussed.

Computational modeling of pathological layer formation in neurodevelopmental disorders

Event Abstract Back to Event Computational modeling of pathological layer formation in neurodevelopmental disorders Roman Bauer1* and Marcus Kaiser1 1 Newcastle University, United Kingdom The mammalian cortex is composed of six main cell layers with distinct form and function. This laminar structure is the result of a complex developmental process, which is implicitly specified in the genetic code, but contingent upon extracellular factors. Computational modeling provides a valuable approach for a better understanding of this dynamic process [1]. Here, we present a computer model to put in comparison the development of normal and pathological laminar organization. In particular, we investigated scenarios where the migration of certain cells does not take place properly, such as for example in the neurodevelopmental disease periventricular heterotopia (PH) [2]. In PH, certain neurons that have failed to migrate into the developing cerebral cortex remain as nodules or neurons that line the ventricular surface. To implement our model we used the software framework Cx3D [3], which is a software framework for simulations of neural development in 3D physical space. Based on this model, we simulate a gene regulatory network, which by differentiation, proliferation and migration of cells gives rise to a laminated structure. By introducing defects to our artificial genetic code, our simulations yield results that are in good accordance with experimental observations. Overall, our results constitute a comprehensive model for the laminar disorganization in PH, which can also be applied to better understand many other neurodevelopmental trajectories of brain disorders. Acknowledgements This work was supported by the Engineering and Physical Sciences Research Council of the United Kingdom (EP/K026992/1) as part of the Human Brain Development Project (http://www.greenbrainproject.org/) References [1] Zubler, F., Hauri, A., Pfister, S., Bauer, R., Anderson, J. C., Whatley, A. M., & Douglas, R. J. (2013). Simulating cortical development as a self constructing process: a novel multi-scale approach combining molecular and physical aspects. PLoS Comput Biol, 9(8), e1003173. [2] Fox, J. W., Lamperti, E. D., Ekşioğlu, Y. Z., Hong, S. E., Feng, Y., Graham, D. A., ... & Berkovic, S. F. (1998). Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron, 21(6), 1315-1325. [3] Zubler, F., & Douglas, R. (2009). A framework for modeling the growth and development of neurons and networks. Frontiers in computational neuroscience, 3, 25. Keywords: computational modeling, gene regulatory networks (GRN), layer formation, neurodevelopmental diseases, Subcortical heterotopia Conference: Neuroinformatics 2016, Reading, United Kingdom, 3 Sep - 4 Sep, 2016. Presentation Type: Poster Topic: Computational neuroscience Citation: Bauer R and Kaiser M (2016). Computational modeling of pathological layer formation in neurodevelopmental disorders. Front. Neuroinform. Conference Abstract: Neuroinformatics 2016. doi: 10.3389/conf.fninf.2016.20.00065 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Apr 2016; Published Online: 18 Jul 2016. * Correspondence: Dr. Roman Bauer, Newcastle University, Newcastle upon Tyne, United Kingdom, r.bauer@surrey.ac.uk Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Roman Bauer Marcus Kaiser Google Roman Bauer Marcus Kaiser Google Scholar Roman Bauer Marcus Kaiser PubMed Roman Bauer Marcus Kaiser Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Impact of Antenatal Glucocorticoid Therapy and Risk of Preterm Delivery on Intelligence in Term-Born Children.

Women at risk of preterm delivery are routinely treated with synthetic glucocorticoids (sGCs). Although this therapy substantially reduces neonatal morbidity, concerns remain whether sGC excess may disrupt neurodevelopmental trajectories underlying cognitive functioning. The present study is the first to disentangle direct effects of antenatal sGC treatment on possible long-term cognitive disadvantages from those of pregnancy complications and prematurity. This cross-sectional study included a mixed-sex cohort of 222 term-born children (aged 6-11 years) consisting of three groups: children of mothers admitted to hospital for threatening preterm delivery who had been treated (n = 97) or untreated (n = 36) with sGCs, and controls without pregnancy complications (n = 89). Antenatal sGC treatment consisted of single courses with dexamethasone or betamethasone. Psychometric intelligence was assessed using a German adaption of Cattell's Culture Fair Test. Children born to mothers at risk for preterm delivery scored, on average, 6-7 IQ points below children of mothers without pregnancy complications, irrespective of antenatal sGC treatment. Compared to females, boys were found to be more susceptible to cognitive disadvantages associated with maternal risk for preterm delivery. Our data indicate that conditions related to a threatening preterm delivery rather than antenatal sGC treatment per se are associated with long-term decreases in the child's intelligence. Although these findings imply that a single course of sGC therapy does not aggravate long-term cognitive deficits, they highlight the need for interventions to reduce the detrimental consequences of distress induced by a threatening preterm delivery.

Effects of paternal and peripubertal stress on aggression, anxiety, and metabolic alterations in the lateral septum

Early-life stress and biological predispositions are linked to mood and personality disorders related to aggressive behavior. We previously showed that exposure to peripubertal stress leads to increased anxiety-like behaviors and aggression against males and females, as well as increased aggression against females in their male offspring. Here, we investigated whether paternal (pS) and individual (iS) exposure to peripubertal stress may exert additive effects on the long-term programming of anxiety-like and aggressive behaviors in rats. Given the key role of the lateral septum (LS) in the regulation of anxiety and aggressive behaviors and the hypothesized alterations in balance between neural excitation and inhibition in aggression-related disorders, markers for these processes were examined in the LS. Peripubertal stress was applied both in naïve male rats and in the offspring of peripubertally stressed males, and anxiety-like and aggressive behaviors were assessed at adulthood. Proton magnetic resonance spectroscopy at 6-months, and post-mortem analysis of glutamic acid decarboxylase 67 (GAD67) at 12-months were conducted in LS. We confirmed that aggressive behavior was increased by pS and iS, while only iS increased anxiety-like behavior. Individual stress led to reduced GABA, confirmed by reduced GAD67 immunolabelling, and increased glutamate, N-acetyl-aspartate, phosphocholine and creatine; while pS specifically led to reduced phosphocreatine. pS and iS do not interact and exert a differential impact on the analyzed aspects of brain function and anxiety-like behaviors. These data support the view that early-life stress can affect the behavioral and neurodevelopmental trajectories of individuals and their offspring, which may involve different neurobiological mechanisms.

PTPS-23A NOVEL ROLE FOR NEUROTROPHIN SIGNALING IN PEDIATRIC ATYPICAL TERATOID RHABDOID TUMORS

Malignant rhabdoid tumors (MRTs) are among the most aggressive and lethal tumors in pediatric oncology, yet little is known about their underlying biology, prohibiting successful treatment outcomes. Aside from a commonly observed alteration in the SMARC1B tumor suppressor, these tumors are characterized by a remarkably high degree of genomic stability, suggesting that posttranslational modification, alternative splicing, or interactions with other tumor suppressors and growth factors may be involved. Attempts at modeling MRTs have proven difficult due to embryonic lethality of SMARC1B loss. One novel candidate for exploring MRT biology may lie within the neurotrophin family. Utilizing a unique approach employing the RCAS/TVA system - which allows for somatic transfer of genes into specific cell types - we have found that neurotrophin signaling influences the normative neurodevelopmental trajectory in wild-type mice when altered in nestin-positive cells. In the context of tumor suppressor loss (Ink4a/ARF deletion, PTEN loss), perturbations in neurotrophin signaling generate tumors that recapitulate the rhabdoid phenotype of a specific type of MRT found in the central nervous system, known as atypical teratoid rhabdoid tumor (AT/RT). In vivo analysis of downstream effectors such PI3K/Akt pathway targets, RhoA signaling, and transcription factors, further elucidate mechanistic links between neurotrophin signaling and AT/RT biology, while in vitro experiments quantify basic cellular functions implicated in tumorigenesis such as migration, proliferation, and apoptosis. Together these data uncover a novel role for neurotrophin signaling in AT/RT biology and may offer insight into therapeutic responses for treatments such as radiation and chemotherapy.

Longitudinal in vivo maturational changes of metabolites in the prefrontal cortex of rats exposed to polyinosinic–polycytidylic acid in utero

Proton magnetic resonance spectroscopy (1H MRS) studies in schizophrenia patients generally report decreased levels of N-acetyl-aspartate (NAA), glutamate and glutathione, particularly in frontal cortex. However, these data are inconsistent in part due to confounds associated with clinical samples. The lack of validated diagnostic biomarkers also hampers analysis of the neurodevelopmental trajectory of neurochemical abnormalities. Rodent models are powerful tools to address these issues, particularly when combined with 1H MRS (clinically comparable technology). We investigated the trajectory of metabolic changes in the prefrontal cortex during brain maturation from adolescence to adulthood in vivo using 1H MRS in rats exposed prenatally to polyinosinic–polycytidylic acid (POL), a rodent model of maternal immune activation (MIA), an epidemiological risk factor for several psychiatric disorders with a neurodevelopmental origin. Longitudinal in vivo 1H MRS revealed a significant decrease in PFC levels of GSH and taurine in adult, but not adolescent rats. Significant age×MIA interactions for PFC levels of NAA were also observed. These data replicate some deficits observed in the PFC of patients with schizophrenia. There were no significant changes in the levels of glutamate or any other metabolite. These data suggest prenatal exposure to POL leads to subtle metabolic perturbations of the normal maturing PFC, which may be related to subsequent behavioural abnormalities. Further work is however required to examine any potential confound of shipping stress on the presumed imbalances in PFC metabolites in POL-exposed offspring. Testing the interactions between MIA with stress or genetic risk variants will also be an important advance.

Borderline intellectual functioning and neurodevelopmental disorders: prevalence, comorbidities and treatment approaches

Purpose– The purpose of this paper is to provide a synthesis of the literature on the topic of developmental framework and health comorbidities of children and adults with borderline intellectual functioning (BIF) and neurodevelopmental disorders.Design/methodology/approach– A rapid review of the literature and hand searching of relevant papers from 1999 to 2015 was carried out. Totally, 21 papers were identified covering a range of perspectives from neurodevelopmental trajectories to prevalence, treatment and service use.Findings– All papers were utilised and complemented a previous review which, however, had not covered the aspect of treatment approaches for this population. As a group they appear to have distinctly different profiles from people with mild intellectual disability and of peers with average intelligence.Practical implications– The evidence summary indicates an ongoing interest by the international scientific community in the topic of BIF. This group are often lost in the health system and may not receive appropriate care given their unique clinical profile. More should be done to increase clinicians’ awareness of their health needs.Originality/value– The paper adds substantially to a previous review of the topic. An international collaboration may help to increase the profile of this work and lead to further changes in the care these individuals receive across the diagnostic and treatment spectrum.

Neurodevelopmental Trajectories, Disconnection, and Schizophrenia Risk.

In the last century, the following 2 concepts have guided our thinking about schizophrenia: schizophrenia as a neurodevelopmental disorder and disconnection syndrome. Although past examinations of developmental trajectories as premorbid antecedents have focused on gray matter, altered properties of white matter and connectivity have been gaining more attention in the pathophysiology of schizophrenia. Several studies, including a JAMA Psychiatry article,1 are beginning to illuminate the nature, timing, and clinical consequences of alterations in such developmental trajectories. Thus, the 2 concepts are coming together.

A groundwork for allostatic neuro-education.

We propose to enliven educational practice by marrying a conception of education as guided human development, to an advanced scientific understanding of the brain known as allostasis (stability through change). The result is a groundwork for allostatic neuro-education (GANE). Education as development encompasses practices including the organic (homeschooling and related traditions), cognitive acquisition (emphasis on standards and testing), and the constructivist (aimed to support adaptive creativity for both learner and society). Allostasis views change to be the norm in biology, defines success in contexts of complex natural environments rather than controlled settings, and identifies the brain as the organ of central command. Allostatic neuro-education contrasts with education focused dominantly on testing, or neuroscience based on homeostasis (stability through constancy). The GANE perspective is to view learners in terms of their neurodevelopmental trajectories; its objective is to support authentic freedom, mediated by competent, integrated, and expansive executive functionality (concordant with the philosophy of freedom of Rudolf Steiner); and its strategy is to be attuned to rhythms in various forms (including those of autonomic arousal described in polyvagal theory) so as to enable experiential excitement for learning. The GANE presents a variety of testable hypotheses, and studies that explore prevention or mitigation of the effects of early life adversity or toxic stress on learning and development may be of particular importance. Case studies are presented illustrating use of allostatic neurotechnology by an adolescent male carrying diagnoses of Asperger’s syndrome and attention-deficit hyperactivity disorder, and a grade school girl with reading difficulties. The GANE is intended as a re-visioning of education that may serve both learners and society to be better prepared for the accelerating changes of the 21st century.

Structural and functional connectivity in the default mode network in 22q11.2 deletion syndrome.

BackgroundThe neural endophenotype associated with 22q11.2 deletion syndrome (22q11DS) includes deviant cortical development and alterations in brain connectivity. Resting-state functional magnetic resonance imaging (fMRI) findings also reported disconnectivity within the default mode network (DMN). In this study, we explored the relationship between functional and structural DMN connectivity and their changes with age in patients with 22q11DS in comparison to control participants. Given previous evidence of an association between DMN disconnectivity and the manifestation of psychotic symptoms, we further investigated this relationship in our group of patients with 22q11DS.MethodsT1-weighted, diffusion, and resting-state fMRI scans were acquired from 41 patients with 22q11DS and 43 control participants aged 6 to 28 years. A data-driven approach based on independent component analysis (ICA) was used to identify the DMN and to define regions of interest for the structural and functional connectivity analysis. Prodromal psychotic symptoms were assessed in adolescents and adults using the positive symptom scores of the Structured Interview of Prodromal Syndromes (SIPS). Connectivity measures were compared between groups and correlated with age. Repeating the between-group analysis in three different age bins further assessed the presence of age-related alterations in DMN connectivity. Structural and functional connectivity measures were then correlated with the SIPS scores.ResultsA simultaneous reduction of functional and structural connectivity between core medial nodes of the DMN was observed. Furthermore, structural connectivity measures significantly increased with age in the control group but not in patients with 22q11DS, suggesting the presence of an age-related alteration of the DMN structural connections. No correlations were found between the DMN disconnectivity and expression of prodromal symptoms in 22q11DS.ConclusionsThese findings indicate the presence of functional and structural DMN disconnectivity in 22q11DS and that patients with 22q11DS fail to develop normal structural connections between medial DMN nodes. This suggests the presence of altered neurodevelopmental trajectories in 22q11DS.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-015-9120-y) contains supplementary material, which is available to authorized users.

Symptom presentation and functioning in neurodevelopmental disorders: Intellectual disability and exposure to trauma

Summary The neurodevelopmental hypothesis posits that altered, pathological, or delayed maturation of the developing brain shifts the neurodevelopmental trajectory, later followed by the onset of neuropsychiatric illness. The United States Supreme Court has clearly established the constitutional obligation that attorneys bear to thoroughly investigate and present evidence of the multigenerational bio-psychosocial history. In this context, this paper recommends that the best clinical, forensic and ethical assessment is to more thoroughly document and present the neurodevelopmental trajectory, the symptoms and functioning associated with the specific manifestation in the patient, and to recognize the limitations of diagnostic categorization. We consider two conditions, which have been considered to have different mechanisms and developmental trajectories, and generally, to be unrelated: exposure to trauma (trauma) and intellectual disability (ID). Our focus is on the circumstances under which it is ethically necessary and clinically useful to differentiate between the overlapping symptoms of trauma and ID, when it is more appropriate to diagnose them as comorbid, and the times at which the behavioral and functional outcome of these conditions are more important than the labeling. Our approach emphasizes understanding the scientific basis for functioning and behavior, where and when people can or cannot accomplish a goal or task, and how the symptoms affect daily life and lived experience. This approach is descriptive, but it is also more than that: it is the process of describing the observed and its causes, in the context of seeking to accurately understand and elucidate functional ability. We believe that this is the best ethical, clinical and forensic approach and, in the long run, what this population deserves.

Default mode network maturation and psychopathology in children and adolescents.

The human default mode (DMN) is involved in a wide array of mental disorders. Current knowledge suggests that mental health disorders may reflect deviant trajectories of brain maturation. We studied 654 children using functional magnetic resonance imaging (fMRI) scans under a resting-state protocol. A machine-learning method was used to obtain age predictions of children based on the average coefficient of fractional amplitude of low frequency fluctuations (fALFFs) of the DMN, a measure of spontaneous local activity. The chronological ages of the children and fALFF measures from regions of this network, the response and predictor variables were considered respectively in a Gaussian Process Regression. Subsequently, we computed a network maturation status index for each subject (actual age minus predicted). We then evaluated the association between this maturation index and psychopathology scores on the Child Behavior Checklist (CBCL). Our hypothesis was that the maturation status of the DMN would be negatively associated with psychopathology. Consistent with previous studies, fALFF significantly predicted the age of participants (p<.001). Furthermore, as expected, we found an association between the DMN maturation status (precocious vs. delayed) and general psychopathology scores (p=.011). Our findings suggest that child psychopathology seems to be associated with delayed maturation of the DMN. This delay in the neurodevelopmental trajectory may offer interesting insights into the pathophysiology of mental health disorders.

Prefrontal gyrification in psychotic bipolar I disorder vs. schizophrenia

Bipolar disorder and schizophrenia share phenotypic and genotypic features, but might differ in aspects of abnormal neurodevelopmental trajectories. We studied gyrification, a marker of early developmental pathology, in high-resolution MRI scans of 34 patients with schizophrenia, 17 euthymic bipolar I disorder patients with previous psychotic symptoms, and 34 matched healthy controls in order to test the hypothesis of overlapping and diverging prefrontal gyrification abnormalities. We applied a novel, validated method for measuring local gyrification in each vertex point of the reconstructed cortical surface. Psychotic bipolar I patients had higher gyrification in dorsal anterior and infragenual cingulate cortex compared to either schizophrenia or healthy controls, while schizophrenia patients had higher gyrification than controls in anterior medial (BA 10) and orbitofrontal areas, altogether indicating disease-specific alterations in the prefrontal cortex. Our findings indicate gyrification changes in a specific subgroup of bipolar I disorder to affect an area relevant to emotion regulation, and distinct from changes seen in schizophrenia.

Development and validation of a brain maturation index using longitudinal neuroanatomical scans

BackgroundMajor psychiatric disorders are increasingly being conceptualized as ‘neurodevelopmental’, because they are associated with aberrant brain maturation. Several studies have hypothesized that a brain maturation index integrating patterns of neuroanatomical measurements may reliably identify individual subjects deviating from a normative neurodevelopmental trajectory. However, while recent studies have shown great promise in developing accurate brain maturation indices using neuroimaging data and multivariate machine learning techniques, this approach has not been validated using a large sample of longitudinal data from children and adolescents. MethodsT1-weighted scans from 303 healthy subjects aged 4.88 to 18.35years were acquired from the National Institute of Health (NIH) pediatric repository (http://www.pediatricmri.nih.gov). Out of the 303 subjects, 115 subjects were re-scanned after 2years. The least absolute shrinkage and selection operator algorithm (LASSO) was ‘trained’ to integrate neuroanatomical changes across chronological age and predict each individual's brain maturity. The resulting brain maturation index was developed using first-visit scans only, and was validated using second-visit scans. ResultsWe report a high correlation between the first-visit chronological age and brain maturation index (r=0.82, mean absolute error or MAE=1.69years), and a high correlation between the second-visit chronological age and brain maturation index (r=0.83, MAE=1.71years). The brain maturation index captured neuroanatomical volume changes between the first and second visits with an MAE of 0.27years. ConclusionsThe brain maturation index developed in this study accurately predicted individual subjects' brain maturation longitudinally. Due to its strong clinical potentials in identifying individuals with an abnormal brain maturation trajectory, the brain maturation index may allow timely clinical interventions for individuals at risk for psychiatric disorders.