Brain Maturation Processes Research Articles

Network state transitions during cortical development.

Mammalian cortical networks are active before synaptogenesis begins in earnest, before neuronal migration is complete, and well before an animal opens its eyes and begins to actively explore its surroundings. This early activity undergoes several transformations during development. The most important of these is a transition from episodic synchronous network events, which are necessary for patterning the neocortex into functionally related modules, to desynchronized activity that is computationally more powerful and efficient. Network desynchronization is perhaps the most dramatic and abrupt developmental event in an otherwise slow and gradual process of brain maturation. In this Review, we summarize what is known about the phenomenology of developmental synchronous activity in the rodent neocortex and speculate on the mechanisms that drive its eventual desynchronization. We argue that desynchronization of network activity is a fundamental step through which the cortex transitions from passive, bottom-up detection of sensory stimuli to active sensory processing with top-down modulation.

The influence of anterior cingulateGABA+ and glutamateon emotion regulation and reactivity in adolescents and adults.

During adolescence, emotion regulation and reactivity are still developing and are in many ways qualitatively different from adulthood. However, the neurobiological processes underpinning these differences remain poorly understood, including the role of maturing neurotransmitter systems. We combined magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (dACC) and self-reported emotion regulation and reactivity in a sample of typically developed adolescents (n=37; 13-16 years) and adults (n=39; 30-40 years), and found that adolescents had higher levels of glutamate to total creatine (tCr) ratio in the dACC than adults. A glutamate Í age group interaction indicated a differential relation between dACC glutamate levels and emotion regulation in adolescents and adults, and within-group follow-up analyses showed that higher levels of glutamate/tCr were related to worse emotion regulation skills in adolescents. We found no age-group differences in gamma-aminobutyric acid+macromolecules (GABA+) levels; however, emotion reactivity was positively related to GABA+/tCr in the adult group, but not in the adolescent group. The results demonstrate that there are developmental changes in the concentration of glutamate, but not GABA+, within the dACC from adolescence to adulthood, in accordance with previous findings indicating earlier maturation of the GABA-ergic than the glutamatergic system. Functionally, glutamate and GABA+ are positively related to emotion regulation and reactivity, respectively, in the mature brain. In the adolescent brain, however, glutamate is negatively related to emotion regulation, and GABA+ is not related to emotion reactivity. The findings are consistent with synaptic pruning of glutamatergic synapses from adolescence to adulthood and highlight the importance of brain maturational processes underlying age-related differences in emotion processing.

Postoperative accurate pain assessment of children and artificial intelligence: A medical hypothesis and planned study.

Although the pediatric perioperative pain management has been improved in recent years, the valid and reliable pain assessment tool in perioperative period of children remains a challenging task. Pediatric perioperative pain management is intractable not only because children cannot express their emotions accurately and objectively due to their inability to describe physiological characteristics of feeling which are different from those of adults, but also because there is a lack of effective and specific assessment tool for children. In addition, exposure to repeated painful stimuli early in life is known to have short and long-term adverse sequelae. The short-term sequelae can induce a series of neurological, endocrine, cardiovascular system stress related to psychological trauma, while long-term sequelae may alter brain maturation process, which can lead to impair neurodevelopmental, behavioral, and cognitive function. Children's facial expressions largely reflect the degree of pain, which has led to the developing of a number of pain scoring tools that will help improve the quality of pain management in children if they are continually studied in depth. The artificial intelligence (AI) technology represented by machine learning has reached an unprecedented level in image processing of deep facial models through deep convolutional neural networks, which can effectively identify and systematically analyze various subtle features of children's facial expressions. Based on the construction of a large database of images of facial expressions in children with perioperative pain, this study proposes to develop and apply automatic facial pain expression recognition software using AI technology. The study aims to improve the postoperative pain management for pediatric population and the short-term and long-term quality of life for pediatric patients after operational event.

A Novel and Fast Online-SPE-LC-MS/MS Method to Quantify Thyroid Hormone Metabolites in Rat Plasma.

Since the focus in regulatory toxicology has drifted toward the identification of endocrine disruptors, the improvement in determination of alterations in the thyroid hormone system has become more important. THs are involved in several molecular processes important for a proper pre- and postnatal development so that disturbances can inter alia lead to incorrect brain maturation and/or disturbed metabolic processes (thermogenesis or lipolysis). In this publication, a new automated online solid-phase extraction (SPE)-liquid chromatography (LC)-tandem mass spectrometry (MS/MS, xLC-MS/MS) is introduced which simultaneously analyzes total T4, T3, rT3, T2, and T1. Method validation parameters are presented, and the method was positively verified by analyzing control and PTU-treated rat plasma samples (time points day 7, 14, and 28) for their total TH content. The obtained results were compared to published results by using a radioimmunoassay method. The automated SPE system ensures a consistent unified sample preparation, and this method overall showed sufficient specificity and accuracy to detect the given analytes in rat plasma. For the preparation of 50 μL of rat plasma, the following LOQs were established: 0.020 nM for T1, 0.029 nM for T2, 0.023 nM for rT3 and T3, and 3.22 nM for T4. This method is suitable to assess the identification of mechanisms leading to adverse effects, such as disturbed TH metabolism and regulation.

2 Associations Between Motor Functioning and Intellectual Abilities in Pediatric Arterial Ischemic Stroke

Objective:Motor impairments are one of the most common adverse outcomes after pediatric arterial ischemic stroke (AIS), affecting approximately half of survivors. The development of motor and cognitive skills is closely interrelated, and they share common neural substrates. The objective of this study was to examine whether motor functioning after the acute phase of stroke is associated with school-age intellectual abilities. We also examined associations between concurrent motor functioning and intellectual abilities. Finally, we explored clinical features associated with motor impairments.Participants and Methods:Participants were 64 children, 34 childhood AIS (Meanage= 11.90[2.38]); 30 perinatal AIS (Meanage= 8.75[2.22]), from the Children’s Stroke Program at SickKids Hospital. Motor functioning was assessed with the Pediatric Stroke Outcome Measure sensorimotor subscale at two timepoints, Time 1 or early recovery (childhood group between 30 days post-stroke to 1 year; perinatal group between 2-5 years of age) and Time 2, closest to neuropsychological testing. Intellectual abilities were measured using the Wechsler Intelligence Scale for Children 4th or 5th edition. Associations between motor and intellectual functioning were examined separately in childhood and perinatal AIS groups. Clinical features associated with motor impairment were examined across the full sample.Results:Motor functioning during early recovery was significantly associated with processing speed (r= -.391, p= .036) in the perinatal group and with overall intellectual functioning (r= -.414, p= .018) verbal intellectual abilities (r= -.444, p= .011), working memory (r= .393, p= .026), and processing speed (r= -.351, p= .042) in the childhood group. There were no associations between concurrent motor and intellectual functioning in the perinatal group, and only with processing speed (r= -.525, p= .002) in the childhood group. When motor functioning was dichotomized as no/mild motor deficit and moderate/severe motor deficit at Time 1, children in the perinatal group with moderate/severe motor deficit had significantly lower perceptual reasoning scores (f[28]= 2.15, p= .040) and participants in the childhood group with moderate/severe motor deficit had significantly lower perceptual reasoning (f[32]= 2.35, p= .025) and processing speed (f[32]= 2.14, p= 0.41) scores. There were no differences between no/mild and moderate/severe motor deficit groups for either perinatal or childhood AIS at Time 2. Clinical features associated with moderate/severe motor deficit at Time 1 were cortical+subcortical infarcts, large lesions, presenting with hemiparesis and seizures at time of neuropsychological assessment, and accessing occupational therapy and physical therapy.Conclusions:Results suggest that motor functioning during early stroke recovery is associated with intellectual outcome, whereas motor functioning at time closest to neuropsychological assessment is not. This may be related neuroplastic changes post-injury, likely in frontal-subcortical connections, that result in observable motor deficits after stroke and affect subsequent hierarchal brain maturational processes thereby impacting later cognitive outcome. Different patterns of associations between motor functioning and specific intellectual abilities in perinatal and childhood groups suggest possible age-mediated effects on this relationship.

Clustering Schizophrenia Genes by Their Temporal Expression Patterns Aids Functional Interpretation.

Schizophrenia is a highly heritable brain disorder with a typical symptom onset in early adulthood. The 2-hit hypothesis posits that schizophrenia results from differential early neurodevelopment, predisposing an individual, followed by a disruption of later brain maturational processes that trigger the onset of symptoms. We applied hierarchical clustering to transcription levels of 345 genes previously linked to schizophrenia, derived from cortical tissue samples from 56 donors across the lifespan. We subsequently calculated clustered-specific polygenic risk scores for 743 individuals with schizophrenia and 743 sex- and age-matched healthy controls. Clustering revealed a set of 183 genes that was significantly upregulated prenatally and downregulated postnatally and 162 genes that showed the opposite pattern. The prenatally upregulated set of genes was functionally annotated to fundamental cell cycle processes, while the postnatally upregulated set was associated with the immune system and neuronal communication. We found an interaction between the 2 scores; higher prenatal polygenic risk showed a stronger association with schizophrenia diagnosis at higher levels of postnatal polygenic risk. Importantly, this finding was replicated in an independent clinical cohort of 3233 individuals. We provide genetics-based evidence that schizophrenia is shaped by disruptions of separable biological processes acting at distinct phases of neurodevelopment. The modeling of genetic risk factors that moderate each other's effect, informed by the timing of their expression, will aid in a better understanding of the development of schizophrenia.

The hierarchy of coupled sleep oscillations reverses with aging in humans.

A well-orchestrated coupling hierarchy of slow waves and spindles during slow wave sleep supports memory consolidation. In old age, duration of slow wave sleep and number of coupling events decreases. The coupling hierarchy deteriorates, predicting memory loss and brain atrophy. Here, we investigate the dynamics of this physiological change in slow wave-spindle coupling in a frontocentral electroencephalography position in a large sample (N=340, 237 female, 103 male) spanning most of the human lifespan (ages 15-83). We find that, instead of changing abruptly, spindles gradually shift from being driven by-, to driving slow waves with age, reversing the coupling hierarchy typically seen in younger brains. Reversal was stronger the lower the slow wave frequency, and starts around midlife (∼age 40-48), with an established reversed hierarchy at age 56-83. Notably, coupling strength remains unaffected by age. In older adults, deteriorating slow wave-spindle coupling, measured using phase slope index (PSI) and number of coupling events, is associated with blood plasma glial fibrillary acidic protein (GFAP) levels, a marker for astrocyte activation. Data-driven models suggest decreased sleep time and higher age lead to fewer coupling events, paralleled by increased astrocyte activation. Counterintuitively, astrocyte activation is associated with a back-shift of the coupling hierarchy (PSI) towards a "younger" status along with increased coupling occurrence and strength, potentially suggesting compensatory processes. As the changes in coupling hierarchy occur gradually starting at midlife, we suggest there exists a sizable window of opportunity for early interventions to counteract undesirable trajectories associated with neurodegeneration.Significance StatementEvidence accumulates that sleep disturbances and cognitive decline are bi-directionally and causally linked forming a vicious cycle. Improving sleep quality could break this cycle. One marker for sleep quality is a clear hierarchical structure of sleep oscillations. Previous studies showed that sleep oscillations decouple in old age. Here, we show that, rather, the hierarchical structure gradually shifts across the human lifespan and reverses in old age, while coupling strength remains unchanged. This shift is associated with markers for astrocyte activation in old age. The shifting hierarchy resembles brain maturation, plateau, and wear processes. This study furthers our comprehension of this important neurophysiological process and its dynamic evolution across the human lifespan.

Impact of electronic devices used at an early age on language

The acquisition of language in infants is largely the result of the process of brain maturation, as well as environmental stimulation. Currently, society is in an era of technology and use of electronic devices from an early age. The aim of this study was to demonstrate if the amount of time of use of electronic devices in children under 5 years of age affects language development. An observational, comparative, survey-type study was carried out in 269 infants of both sexes, with an age range of 6 to <60 months. The language development section of the Child Development Scale (EDI) was used. A logistic regression was performed to determine the strength of association between the factors to be studied. 269 participants were included, of which 224 (83.2%) presented their level of neurological maturation, 44 infants (16.4%) presented laged development and one (0.4%) was classified as having developmental delay. It was found that the number of daily hours that an electronic device is used behaved as a risk factor by increasing the risk of delayed language development by 1.37 times for each hour of exposure (OR: 1.37, CI95%: 1.15-1.62). It was shown that a greater number of hours of use of electronic devices is a risk factor for delayed language development in children under 5 years of age. Therefore, it is vital to limit its use in this population.

Semi-Automatic GUI Platform to Characterize Brain Development in Preterm Children Using Ultrasound Images.

The third trimester of pregnancy is the most critical period for human brain development, during which significant changes occur in the morphology of the brain. The development of sulci and gyri allows for a considerable increase in the brain surface. In preterm newborns, these changes occur in an extrauterine environment that may cause a disruption of the normal brain maturation process. We hypothesize that a normalized atlas of brain maturation with cerebral ultrasound images from birth to term equivalent age will help clinicians assess these changes. This work proposes a semi-automatic Graphical User Interface (GUI) platform for segmenting the main cerebral sulci in the clinical setting from ultrasound images. This platform has been obtained from images of a cerebral ultrasound neonatal database images provided by two clinical researchers from the Hospital Sant Joan de Déu in Barcelona, Spain. The primary objective is to provide a user-friendly design platform for clinicians for running and visualizing an atlas of images validated by medical experts. This GUI offers different segmentation approaches and pre-processing tools and is user-friendly and designed for running, visualizing images, and segmenting the principal sulci. The presented results are discussed in detail in this paper, providing an exhaustive analysis of the proposed approach's effectiveness.

Effects of emerging alcohol use on developmental trajectories of functional sleep measures in adolescents.

Adolescence is characterized by significant brain development, accompanied by changes in sleep timing and architecture. It also is a period of profound psychosocial changes, including the initiation of alcohol use; however, it is unknown how alcohol use affects sleep architecture in the context of adolescent development. We tracked developmental changes in polysomnographic (PSG) and electroencephalographic (EEG) sleep measures and their relationship with emergent alcohol use in adolescents considering confounding effects (e.g. cannabis use). Adolescents (n = 94, 43% female, age: 12-21 years) in the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study had annual laboratory PSG recordings across 4-years. Participants were no/low drinkers at baseline. Linear mixed effect models showed developmental changes in sleep macrostructure and EEG, including a decrease in slow wave sleep and slow wave (delta) EEG activity with advancing age. Emergent moderate/heavy alcohol use across three follow-up years was associated with a decline in percentage rapid eye movement (REM) sleep over time, a longer sleep onset latency (SOL) and shorter total sleep time (TST) in older adolescents, and lower non-REM delta and theta power in males. These longitudinal data show substantial developmental changes in sleep architecture. Emergent alcohol use during this period was associated with altered sleep continuity, architecture, and EEG measures, with some effects dependent on age and sex. These effects, in part, could be attributed to the effects of alcohol on underlying brain maturation processes involved in sleep-wake regulation.

Association between sleep slow-wave activity and in-vivo estimates of myelin in healthy young men

Sleep has been suggested to contribute to myelinogenesis and associated structural changes in the brain. As a principal hallmark of sleep, slow-wave activity (SWA) is homeostatically regulated but also differs between individuals. Besides its homeostatic function, SWA topography is suggested to reflect processes of brain maturation. Here, we assessed whether interindividual differences in sleep SWA and its homeostatic response to sleep manipulations are associated with in-vivo myelin estimates in a sample of healthy young men. Two hundred twenty-six participants (18–31 y.) underwent an in-lab protocol in which SWA was assessed at baseline (BAS), after sleep deprivation (high homeostatic sleep pressure, HSP) and after sleep saturation (low homeostatic sleep pressure, LSP). Early-night frontal SWA, the frontal-occipital SWA ratio, as well as the overnight exponential SWA decay were computed over sleep conditions. Semi-quantitative magnetization transfer saturation maps (MTsat), providing markers for myelin content, were acquired during a separate laboratory visit. Early-night frontal SWA was negatively associated with regional myelin estimates in the temporal portion of the inferior longitudinal fasciculus. By contrast, neither the responsiveness of SWA to sleep saturation or deprivation, its overnight dynamics, nor the frontal/occipital SWA ratio were associated with brain structural indices. Our results indicate that frontal SWA generation tracks inter-individual differences in continued structural brain re-organization during early adulthood. This stage of life is not only characterized by ongoing region-specific changes in myelin content, but also by a sharp decrease and a shift towards frontal predominance in SWA generation.

Defined, Simplified, Scalable, and Clinically Compatible Hydrogel-Based Production of Human Brain Organoids

Human brain organoids present a new paradigm for modeling human brain organogenesis, providing unprecedented insight to the molecular and cellular processes of brain development and maturation. Other potential applications include in vitro models of disease and tissue trauma, as well as three-dimensional (3D) clinically relevant tissues for pharmaceuticals development and cell or tissue replacement. A key requirement for this emerging technology in both research and medicine is the simple, scalable, and reproducible generation of organoids using reliable, economical, and high-throughput culture platforms. Here we describe such a platform using a defined, clinically compliant, and readily available hydrogel generated from gelatin methacrylate (GelMA). We demonstrate the efficient production of organoids on GelMA from human induced pluripotent stem cells (iPSCs), with scalable production attained using 3D printed GelMA-based multiwell arrays. The differentiation of iPSCs was systematic, rapid, and direct to enable iPSCs to form organoids in their original position following seeding on GelMA, thereby avoiding further cell and organoid disruption. Early neural precursors formed by day 5, neural rosettes and early-stage neurons by day 14, and organoids with cellular and regional heterogeneity, including mature and electrophysiologically active neurons, by day 28. The optimised method provides a simplified and well-defined platform for both research and translation of iPSCs and derivative brain organoids, enabling reliable 3D in vitro modelling and experimentation, as well as the provision of clinically relevant cells and tissues for future therapeutics.

Neurological soft signs in adolescents are associated with brain structure.

Neurological soft signs (NSS) are minor deviations in motor performance. During childhood and adolescence, NSS are examined for functional motor phenotyping to describe development, to screen for comorbidities, and to identify developmental vulnerabilities. Here, we investigate underlying brain structure alterations in association with NSS in physically trained adolescents. Male adolescent athletes (n = 136, 13-16 years) underwent a standardized neurological examination including 28 tests grouped into 6 functional clusters. Non-optimal performance in at least 1 cluster was rated as NSS (NSS+ group). Participants underwent T1- and diffusion-weighted magnetic resonance imaging. Cortical volume, thickness, and local gyrification were calculated using Freesurfer. Measures of white matter microstructure (Free-water (FW), FW-corrected fractional anisotropy (FAt), axial and radial diffusivity (ADt, RDt)) were calculated using tract-based spatial statistics. General linear models with age and handedness as covariates were applied to assess differences between NSS+ and NSS- group. We found higher gyrification in a large cluster spanning the left superior frontal and parietal areas, and widespread lower FAt and higher RDt compared with the NSS- group. This study shows that NSS in adolescents are associated with brain structure alterations. Underlying mechanisms may include alterations in synaptic pruning and axon myelination, which are hallmark processes of brain maturation.

0192 Effects of emerging alcohol use on developmental trajectories of functional sleep measures in adolescents

Abstract Introduction Adolescence is characterized by developmental changes in sleep timing and architecture as well as alcohol use initiation. While the effects of acute and chronic alcohol use on sleep in adults are well-documented, much less is known in adolescents. We used longitudinal data from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) to examine how emerging alcohol use affected sleep architecture in adolescents. Methods Overnight polysomnographic recordings were made each year, for 4 years, in 94 adolescents (12–21 years at baseline, 43% female) from the NCANDA cohort. All participants were no or low (youth adjusted Cahalan score of zero) alcohol users at baseline. These data were used to examine developmental trajectories of sleep macro-architecture and sleep electroencephalographic (EEG) measures using linear mixed effect models (LMMs), considering age, sex, family history of alcohol use, body mass index, ethnicity, and alcohol use class (i.e., no-to-low, moderate or heavy) at each annual assessment. Results There were strong developmental changes in sleep macro-structure and EEG, most notably, a decrease in slow wave sleep percentage and slow wave (delta) EEG activity with advancing age (p=0.02)​. Compared to those who remained no-to-low drinkers, participants who became moderate/heavy drinkers during the follow-up period, had different sleep trajectories, especially those older at baseline at baseline, including higher slow wave activity (p = 0.04), higher REM sleep percentage (p = 0.03), poorer sleep efficiency​ (p=0.003), and longer latency to sustained sleep (p = 0.03). The effects of alcohol use depended on sex, with male heavy drinkers having more REM sleep than female heavy drinkers (p = 0.04). Overall, a positive family history of alcohol use was associated with less NREM sleep and shorter sleep duration. Conclusion Our results present novel findings showing that emerging alcohol use during adolescence exerts complex effects on sleep macro- and micro-structure, over and above normal developmental changes in sleep. These effects could, in part, be alcohol effects on brain maturation processes underlying sleep regulation. Support (If Any) AA021696, AA021690

BRAIN INJURY IN PRETERM INFANTS - PATIENTS OF THE DEPARTMENT OF INTENSIVE THERAPY OF NEWBORN

Introduction. Advances in reproductive and perinatal technologies have led not only to an increase in the number of premature babies and an increase in survival rates, but also to an increase in the incidence of complications. Nervous system diseases play a leading role in the structure of pathologies of premature infants. Early onset of extrauterine life contributes to the disruption of physiological processes of brain maturation, increasing the risk of neurological complications.Objective. To establish the frequency and structure of brain damage in premature infants-patients of the intensive care unit. Materials and methods. The mortality and morbidity rates of premature infants-patients of the intensive care unit who were born in 2019-2020 and the first 3 quarters of 2021 were estimated. The frequency of lesions of the nervous system in premature infants, namely the presence of intraventricular hemorrhages of varying severity, hypoxic-ischemic encephalopathy, periventricular leukomalacia, hydrocephalus. Statistical processing of the obtained results was performed using the software system Microsoft Excel 2010 (14.0.6024.1000) SP 1 MSO (14.0.6023.1000).Results. In 2021, the number of premature babies weighing &lt;1,500 g increased compared to 2019. The decrease in mortality rates of premature infants-patients of the intensive care unit was revealed. The most common pathologies of premature infants are respiratory distress syndrome and lesions of the nervous system. Analysis of the obtained data showed that the structure of neurological pathology in premature infants is dominated by hypoxic-ischemic encephalopathy and intraventricular hemorrhage.Conclusions. Against the background of declining mortality rates, the number and severity of HSV in premature infants are increasing.

White Matter Tracts and Diffuse Lower-Grade Gliomas: The Pivotal Role of Myelin Plasticity in the Tumor Pathogenesis, Infiltration Patterns, Functional Consequences and Therapeutic Management.

For many decades, interactions between diffuse lower-grade glioma (LGG) and brain connectome were neglected. However, the neoplasm progression is intimately linked to its environment, especially the white matter (WM) tracts and their myelin status. First, while the etiopathogenesis of LGG is unclear, this tumor seems to appear during the adolescence, and it is mostly located within anterior and associative cerebral areas. Because these structures correspond to those which were myelinated later in the brain maturation process, WM myelination could play a role in the development of LGG. Second, WM fibers and the myelin characteristics also participate in LGG diffusion, since glioma cells migrate along the subcortical pathways, especially when exhibiting a demyelinated phenotype, which may result in a large invasion of the parenchyma. Third, such a migratory pattern can induce functional (neurological, cognitive and behavioral) disturbances, because myelinated WM tracts represent the main limitation of neuroplastic potential. These parameters are critical for tailoring an individualized therapeutic strategy, both (i) regarding the timing of active treatment(s) which must be proposed earlier, before a too wide glioma infiltration along the WM bundles, (ii) and regarding the anatomic extent of surgical resection and irradiation, which should take account of the subcortical connectivity. Therefore, the new science of connectomics must be integrated in LGG management, based upon an improved understanding of the interplay across glioma dissemination within WM and reactional neural networks reconfiguration, in order to optimize long-term oncological and functional outcomes. To this end, mechanisms of activity-dependent myelin plasticity should be better investigated.

Actively supporting youth participation and autonomous decision-making in health matters

The adolescent's process of brain maturation has important consequences for their ability to reason in decision-making processes. The notion of evolving capacity, for which age is not a sufficient indicator, implies a progressive vision of the nature and degree of participation according to the level of maturity. Health professionals are at the forefront of actively promoting young people's participation, supporting their decision-making about their own health, and seeing them as true partners and agents of change. The active participation of young people in all decisions that concern them is essential to make real progress in the field of adolescent health. This step implies a paradigm shift from "thinking for them" to "thinking with them".

Brain MRI in Autism Spectrum Disorder: Narrative Review and Recent Advances

AbstractAutism spectrum disorder (ASD) is neuropsychiatric continuum of disorders characterized by persistent deficits in social communication and restricted repetitive patterns of behavior which impede optimal functioning. Early detection and intervention in ASD children can mitigate the deficits in social interaction and result in a better outcome. Various non‐invasive imaging methods and molecular techniques have been developed for the early identification of ASD characteristics. There is no general consensus on specific neuroimaging features of autism; however, quantitative magnetic resonance techniques have provided valuable structural and functional information in understanding the neuropathophysiology of ASD and how the autistic brain changes during childhood, adolescence, and adulthood. In this review of decades of ASD neuroimaging research, we identify the structural, functional, and molecular imaging clues that most accurately point to the diagnosis of ASD vs. typically developing children. These studies highlight the 1) exaggerated synaptic pruning, 2) anomalous gyrification, 3) interhemispheric under‐ and overconnectivity, and 4) excitatory glutamate and inhibitory GABA imbalance theories of ASD. The application of these various theories to the analysis of a patient with ASD is mitigated often by superimposed comorbid neuropsychological disorders, evolving brain maturation processes, and pharmacologic and behavioral interventions that may affect the structure and function of the brain.Level of Evidence4Technical EfficacyStage 3

Recovery of memory from infantile amnesia is developmentally constrained.

Episodic memories formed during infancy are rapidly forgotten, a phenomenon associated with infantile amnesia, the inability of adults to recall early-life memories. In both rats and mice, infantile memories, although not expressed, are actually stored long term in a latent form. These latent memories can be reinstated later in life by certain behavioral reminders or by artificial reactivations of neuronal ensembles activated at training. Whether the recovery of infantile memories is limited by developmental age, maternal presence, or contingency of stimuli presentation remains to be determined. Here, we show that the return of inhibitory avoidance memory in rats following a behavioral reactivation consisting of an exposure to the context (conditioned stimuli [CS]) and footshock (unconditioned stimuli [US]) given in a temporally unpaired fashion, is evident immediately after US and is limited by the developmental age at which the reactivations are presented; however, it is not influenced by maternal presence or the time interval between training and reactivation. We conclude that one limiting factor for infantile memory reinstatement is developmental age, suggesting that a brain maturation process is necessary to allow the recovery of a “lost” infantile memory.

Neuroepigenetic consequences of adolescent ethanol exposure.

Adolescence is a critical developmental period characterized by ongoing brain maturation processes including myelination and synaptic pruning. Adolescents experience heightened reward sensitivity, sensation seeking, impulsivity, and diminished inhibitory self-control, which contribute to increased participation in risky behaviors, including the initiation of alcohol use. Ethanol exposure in adolescence alters memory and cognition, anxiety-like behavior, and ethanol sensitivity as well as brain myelination and dendritic spine morphology, with effects lasting into adulthood. Emerging evidence suggests that epigenetic modifications may explain these lasting effects. Focusing on the amygdala, prefrontal cortex and hippocampus, we review studies investigating the epigenetic consequences of adolescent ethanol exposure. Ethanol metabolism globally increases donor substrates for histone acetylation and histone and DNA methylation, and this chapter discusses how this can further impact epigenetic programming of the adolescent brain. Elucidation of the mechanisms through which ethanol can alter the epigenetic code at specific transcripts may provide therapeutic targets for intervention.