Summaries: the best scientific articles for neurodevelopment and pediatric neuropsychology summarized

What is DNA methylation (DNAm)?

DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. DNAm refers to the addition of a methyl group primarily in the context of cytosine guanine (CpG) dinucleotides. CpG sites often cluster in CpG island which tend to be embedded in promoter regions of genes. When located in a gene promoter, DNA methylation typically acts to repress gene transcription, and hence can provide a mechanism that can trigger long-term alterations in phenotypes. Research suggests that DNAm can be sensitive to a range of environmental exposures and thus possibly can be influenced.

What can be the benefits of understanding the role of DNAm?

DNAm seems to be a potential mechanism through which the genome can capture the effects of environmental exposures and propagate their influence, and possibly explain altered biological processes that underlie the emergence of different forms of psychopathology. A better understanding of the role of DNAm can be used in the prevention, detection, and treatment of psychopathology (that is, if DNAm is identified as a causal link in the aetiology of a disease). If DNAm is simply a consequence of disease aetiology, it can still be used as an important biomarker of disease and have clinical utility.

What is an epigenome?

An epigenome consists of a record of the chemical changes to the DNA and histone proteins of an organism. Epigenetic mechanisms influence dynamic changes in transcription independent of the genomic DNA sequence. Epigenetic modifications are fundamental for the establishment and maintenance of cellular identity and also coordinate many biological processes, such as genomic imprinting, X chromosome inactivation, stress response, immune function, and neurodevelopment. Because epigenetic processes respond to both genetic and environmental factors, they represent a potential mechanism that can help explain the gene-environmental interplay and disease susceptibility. DNAm is an epigenetic mechanism.

How can DNAm be studied?

DNAm can be studies through different approaches:

• Global DNAm is used as a proxy for the overall degree of myelination in the genome. It can be derived through high-performance liquid chromatography or mass spectrophotometry.
• Candidate gene approaches focus on preselected genes based on a priori hypotheses, for example via pyrosequencing.
• Methods to assess DNAm across the genome include whole-genome bisulphate sequencing or array, bead-type hybridization.
• Experimental animal models enable the manipulation of environmental exposures, the investigation of time- and tissue-specific effects on DNAm, and the characterization of downstream consequences on gene expression and behavior.

What effects does nutrition have on DNAm?

DNAm is highly responsive to diet, because nutrients and bioactive compounds can alter the expression of genes at the transcriptional level and result in long-term phenotypic changes. The prenatal diet can be viewed on a spectrum that ranges from undernutrition to overnutrition. Undernutrition is linked to lower DNAm of the IGF2 gene, which is implicated in foetal development, as well as changes in prenatal growth, insulin signaling, birth weight, and low-density lipoprotein cholesterol levels. Overnutrition is linked to greater concentrations of glucose, fatty acids, and inflammatory markers to the developing foetus.

How does exposure to toxins influence DNAm?

Prenatal exposure to bioactive compounds have been shown to affect DNAm patterns in neonates. Children aged 5-7 who were prenatally exposed to maternal smoking showed lower levels of global and CpG-specific methylation in buccal cells. Research shows that some of the effects to the genes are reversible, whereas others show persistently perturbed patterns. Overall, prenatal exposure to teratogens can have long-term impact on the methylome.

How does early-life stress and adversity influence DNAm?

Prenatal and postnatal stress can cause long-term elevations in hypothalamic-pituitary axis reactivity and anxiety-like behaviors. This can partially be explained by altered glucocorticoid receptor gene expression. Research regarding prenatal maternal stress shows different results and more research is required. With regards to postnatal influences, research shows that early exposure to poverty and adversity is associated with altered DNAm. Childhood maltreatment is also associated with changes in DNAm in genes that are important for stress response, immune function, and neurodevelopment. Also, the maltreated children showed different methylation levels across CpG sites which contain markers of physical and psychiatric morbidity.

How do internalizing and externalizing difficulties relate to DNAm and psychopathology?

Research supports a link between higher NR3C1 methylation and internalizing difficulties. However, NR3C1 methylation does not seem to be a significant predictor of internalizing difficulties. This suggests that, if there is an association, it is probably of small effect size. With regards to externalizing difficulties, the research results show many discrepancies. These are due to wide methodological differences across the studies, including differences in sample characteristics, phenotype operationalisation, and analytical strategy.

Does DNAm mediate associations between risk exposures and psychopathology?

Studies show that DNAm can act as a mediator between risk exposure and child psychopathology. However, the results are associational and causality cannot be inferred. Some recommendations are made that may help to move the field forward:

• A more complete and precise understanding of environmental effects on DNAm needs to be reached. A lot of environmental factors are correlated, like poverty, smoking, low quality of diet, etc. Studies should look at the extent to which epigenetic patterns may differentiate between types of exposures, whether the effects of acute exposures differ from chronic ones, and whether environmental effects may be developmentally dependent.
• Improving understanding of the methylome. Three aspects of DNAm require further investigation: variability (DNAm is dynamic over time and varies across multiple factors), scale (the methylome as a whole is only one of multiple epigenetic mechanisms that work together and many epigenetic patterns are uninvestigated), and transmission (DNAm patterns may be passed on across generations).
• Establishing the functional significance of identified loci. It remains yet unclear to what extent statistical significance overlaps with functional significance. Some effects may be highly statistically significant, but only involve a small change in methylation with unknown biological consequences.
• Maximizing comparability across studies and opportunities for replication.
• Strengthening causal inference.

How does the human brain develop after birth?

The human brain changes dramatically in size and connectivity after birth. At age six, the brain will have reached about 90% of the adult volume. The growth of head circumference is largely driven by the growth of the underlying brain tissue.

What is occipitofrontal circumference?

Occipitofrontal circumference (OFC) refers to the largest circumference of the head (measure over the most prominent part on the back of the head and just above the eyebrows). OFC is a reliable predictor of brain volume in children younger than six. Clinicians can use OFC to detect brain growth abnormalities. Abnormal brain size in early postnatal years is often indicative of disorders of neurodevelopment.

What is microcephaly?

Microcephaly is a medical condition involving a shorter-than-normal head. Infants with primary microcephaly show small head circumference at birth and are often caused by genetic insults that disrupt neurogenesis. This is associated with intellectual disability at age seven. Infants with postnatal microcephaly show normal head circumference at birth, but then show subsequent attenuations in head circumference growth. This is often the result of defects in later-stage developmental mechanisms (for example with connectivity or gliogenesis). Postnatal microcephaly is associated with abnormal/absent language, social impairment, and epilepsy.

What is macrocephaly?

Macrocephaly is a condition in which head circumference is abnormally large. Postnatal macrocephaly refers to exaggerated head growth after birth, whereby infants are born with a normal head circumference, but then show abnormal head enlargement, often due to increased brain growth. This is associated with developmental delays of motor, language, and cognitive functions.

What are the potential biological mechanisms that cause postnatal brain growth?

Three biological mechanisms that underlie postnatal brain development are identified:

• Axonal and dendritic outgrowth increase during the second half of gestation. They form connections/synapses with other cells and give rise to early neural circuits. Dendrite elaboration accelerates during early childhood, followed by a gradual decline during late childhood and adolescence. Research indicates that altered axonal and dendrite formation are associated with intellectual and developmental disabilities.
• Synaptogenesis and experience-dependent synapse remodeling. Synapse formation begins prenatally, but the majority of synaptogenesis occurs in early childhood. It increases from birth until late childhood and is then followed by a gradual period of pruning that continues until early adulthood.
• Gliogenesis and myelination. The increase in number and size of glial cells are in large part responsible for early rapid and head growth. Myelination rapidly increases from six months to twenty-four months and gradually continues until late adolescence.

Which disorders are associated with abnormal postnatal brain growth?

Disorders may arise from an attenuation or an exaggeration of growth, and from monogenic of complex etiologies. Disorders with monogenic postnatal microcephalies are Angelman Syndrome, Rett Syndrome, and Christianson Syndrome. Disorders with monogenic postnatal macrocephalies are PTEN-related disorders, Tuberous Sclerosis Complex, and neurogenerative disorders.

What is the Angelman Syndrome?

The Angelman Syndrome is a postnatal microcephaly disorder that mainly affects the nervous system. Symptoms include a small head circumference, severe intellectual disability, developmental disability, speech problems, balance and movement problems, seizures, and sleep problems. Symptoms usually show after one year. The Angelman Syndrome arises from loss of expression of the maternally inherited allele of the imprinted ubiquitin protein ligase E3A gene.

What is the Rett Syndrome?

The Rett Syndrome is a progressive neurodevelopmental disorder characterized by impairments in language and coordination, repetitive movements, slower growth, difficulty walking, and a small head circumference. Other symptoms may be seizures, scoliosis, and sleeping problems. This disorder mainly affects females. Symptoms start to show after six to eighteen months. The majority of cases are the result from loss-of-function mutations in the X-linked gene MECP2. Loss of MECP2 leads to repression of several genes involved in brain development.

What is the Christianson Syndrome?

Christianson Syndrome is an X linked syndrome associated with intellectual disability, microcephaly, seizures, ataxia, and absent speech. There are also often common facial abnormalities, such as a long narrow face, large ears, open mouth, thick eyebrows, uncontrolled drooling, and abnormal eye movements. Christianson Syndrome is caused by a loss-of-function mutation in SLC9A&, which encodes for NHE6. NHE6 regulates endosomal lumen pH by allowing for electroneutral exchange of proton ions out of the endosome for monovalent cations into the endosome. Over-acidification of endosomal pH in absence of functional NHE6 may disrupt endosomal trafficking which is necessary for growth and neuronal development.

What are PTEN-related disorders?

Mutations in phosphatase and tensin homolog are implicated in various disorders with macrocephaly, including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Proteus syndrome. These disorders have a predisposition of tumors and are collectively referred to as PHTS (meaning PTEN Hamartoma Tumor Syndrome). The brain overgrowth is likely due to abnormalities in proliferation and connectivity. The loss of PTEN protein or function disrupts neurodevelopmental events that occur prenatally (for example neurogenesis) and postnatally (for example dendritic growth and myelination).

What is Tuberous Sclerosis Complex?

Tuberous Sclerosis Complex causes non-cancerous tumors to grow in the brain and on other vital organs. Other symptoms may include seizures, intellectual disability, behavioral problems, skin abnormalities, kidney disease, and lung disease. It is caused by mutations in either TSC1 or TSC2. Tumors develop because of a disruption to the functional allele or other TSC protein that leads to uncontrolled cell growth.

What are neurodegenerative disorders?

Neurodegeneration refers to the progressive loss of structure or function of neurons. Many neurodegenerative disorders are due to neurometabolic disease related to synthesis, metabolism, transport, or storage of biochemical compounds. Many patients show microcephaly as a result of brain atrophy and cerebral white matter reduction.

What are Autism Spectrum Disorders?

Autism Spectrum Disorders refer to genetically and clinically heterogeneous disorders of atypical neurodevelopment characterized by impaired communication and social interactions and stereotyped behaviors. Some of the Autism Spectrum Disorders are associated with larger head circumference and brain volume. There are associations with defects in postnatal pruning, hyperactivated mTOR, and impaired autophagy.

What is schizophrenia and how is it related to brain development?

Schizophrenia is characterized by continuous or relapsing episodes of psychosis. It may arise in part from abnormal brain growth that begins years before symptom onset. MRI studies show reduced brain and gray matter volume, increased extracerebral spinal fluid, exaggerated typical back-to-front gray matter loss (predominantly in the prefrontal and temporal cortices).

What is the developmental origins of disease or fetal programming model?

This model predicts that early exposures to adverse events and signals have life-long consequences for physical and psychological health. Programming refers to the effects of an environmental signal that acts during a sensitive developmental period to influence the construction of specific organ systems.

How can environmental cues experienced during fetal development influence health across the lifespan according to the fetal programming model?

A developing fetus is sensitive and responsive to maternal nutritional, immune, vascular, and endocrine signals. Those signals convey information about the quality of the external environment. In response to those signals, the fetus adjust its developmental trajectory to prepare for life after birth. These developmental alterations are not necessarily bad, if the postnatal environment matches the one predicted by the prenatal environment. But if there is a mismatch, the risk for disease may increase.

How is the hypothalamic-pituitary-adrenal axis related to prenatal experiences and later health outcomes?

The hypothalamic-pituitary-adrenal (HPA) axis is formed during fetal life and susceptible to prenatal influences. A mature HPA axis controls reactions to stress and regulates many body processes, such as digestion, the immune system, mood and emotion, and energy storage. Programming of the HPA axis during fetal life is proposed as a primary mechanism by which early experiences are linked to later health outcomes.

What is corticotropin-releasing hormone?

Corticotropin-releasing hormone (CRH) is a highly conserved peptide hormone comprising 41 amino acid residues. In the anterior pituitary it mediates the release of corticotrophin leading to the release of adrenocortical steroids. CRH is the primary regulator of the HPA axis. It is responsible for the release of many hormone events that mobilize the body´s physiological and psychological resources to cope with stress.

What is the role of cortisol in dysregulation of the HPA axis?

Cortisol binds to two types of receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Stress-induced elevations of cortisol lead to activation and regulation of cardiovascular and immune systems, utilization of energy stores, and inhibition of feeding, reproductive, and growth functions. High levels of cortisol inhibit HPA activity by binding to MRs and GRs. Prolonged or chronic stress may result in the dysregulation of the HPA axis.

How is HPA axis dysregulation related to adverse health outcomes?

The relation between HPA axis functioning and disease is complex and bidirectional. HPA axis functioning serves as a risk factor for as well as a consequence of disease. HPA axis dysregulation has been associated with different pathological conditions, such as metabolic and cardiovascular disease, obesity, hypertension, altered immune function, sleep disturbances, and affective disorders.

What is the role of the placenta in the link between maternal and fetal stress?

During the prenatal period there are big changes in both the maternal and developing fetal stress systems. The placenta is primarily responsible for these changes. The placenta produces its own hormones which bind to maternal hormone receptors and adjust maternal physiology to benefit both the mother and the fetus. One of the hormones produced by the placenta is CRH, which is the primary regulator of the stress response system. It both influences and is influenced by maternal and fetal stress signals. Though the placenta produces the main amount of CRH, the fetal stress system is immature and relies heavily upon maternal and placental inputs. The prenatal stress response system can be seen as an integrated maternal-placental-fetal steroidogenic unit.

How can prenatal psychological and biological stress influence the development of the fetal HPA axis?

Fetal exposure to maternal and placental stress hormones is seen as a primary biological pathway by which prenatal stress can influence the development of the fetal HPA axis. Maternal cortisol and placental CRH are important stress hormones which program the developing fetal HPA axis. The maternal-placental-fetal steroidogenic unit produces a lot of these hormones, which is normal. But extreme stress and rapidly increasing levels of stress hormones influence the development of the fetal HPA axis and may lead to preterm birth.

What does existing scientific research say about postnatal HPA axis functioning and maternal prenatal stress?

One limitation of the scientific research is the broad range of measures of prenatal stress and HPA axis functioning. Though, while variable in their methodologies and results, the studies provide strong support for the notion that prenatal stress programs the developing fetal HPA axis. The results can be organized in categories of neonates, infants, children, adolescents, and adults.

• Neonates exposed to elevated levels of maternal depressive symptoms exhibited higher levels of ACTH and higher levels of urinary cortisol. The studies suggest that prenatal stress predicts heightened HPA axis activity during the neonatal period.
• Stress-exposed infants show higher levels of cortisol responses and infants of mothers with prenatal depressive disorders show higher cortisol levels and greater response to stressors. After the first several months of life there is a developmental shift in HPA axis functioning and a period of hyporesponsiveness to stress. Infants that were exposed to higher levels of prenatal stress show greater HPA axis hypoactivity at this stage of development.
• Studies show a hyperactivity of the HPA axis in children exposed to higher levels of prenatal stress.
• Adolescents exposed to prenatal stress show hypoactivity in cortisol output and a flatter diurnal cortisol decline.
• With regards to adults, prenatal stress-exposed adults exhibited hypoactivity in several domains. They showed increased reactivity to stressors, with greater increases in cortisol in response to the stressor. There were no differences in diurnal cortisol output.

How does synthetic glucocorticoid exposure influence the HPA axis function?

Women at risk of premature delivery are often given synthetic glucocorticoids, because it reduces mortality and promotes lung maturity among infants born preterm. Because it is hard to determine if a woman will deliver preterm, many women receive synthetic glucocorticoids. However, evidence indicates that prenatal synthetic glucocorticoid exposures are related to dysregulated postnatal HPA axis function. This provides support for the programming effects of excess glucocorticoids on long-term HPA axis functioning.

What could we infer from the discrepancies in the results of studies looking at prenatal stress and HPA axis functioning?

It is possible that discrepancies found in the studies actually reflect developmental patterns. There are two possibilities:

• Both diurnal cortisol output and cortisol response to stress vary over the course of development. After the first few months of infancy there appears to be a period of hyporesponsiveness of the stress system, which coincides with the emergence of the diurnal rhythm of the HPA axis.
• Activity of the HPA axis may differ depending on whether stressors are acute or chronic. Exposure to prenatal stress may result in a more reactive HPA axis initially, but prolonged hyperactivity may eventually result in downregulation of the system, with a dampening of diurnal cortisol output and hyporeactivity to stress later in life.

How can the timing of prenatal stress be of importance for fetal HPA axis development?

Studies show that prenatal exposures during different gestational intervals exert differential effects, depending on the fetal developmental processes that are occurring at that time. Since maternal stress responsiveness is downregulated as gestation advances, stressful events that are experienced early in pregnancy may trigger greater maternal stress responses and may exert greater influence on the fetus than stressors that are experienced later in gestation.

How can fetal sex moderate the programming effects of prenatal stress on the fetal HPA axis?

Studies show that there are sex-specific trajectories of fetal development, related to the response of the placenta to stress. Females and males show contrasting growth strategies, whereby in response to stressors, females adjust their growth and males do not. The female placenta may be more sensitive and responsive to changes in cortisol concentrations during gestation as compared to the male placenta.

What should future research focus on with regards to investigating the effect of prenatal maternal stress on HPA axis functioning?

Future research should focus on placental CRH as an indicator of prenatal stress-induced alterations in HPA axis functioning, as placental CRH is a direct and integrative index of fetal exposure to a variety of stressors. Secondly they should further investigate the interactive influence of genes and environmental stressors on HPA axis development, especially looking at methylation in the promoter region of NR3C1, the gene encoding the glucocorticoid receptor. Finally, future research should examine how the pre and postnatal environments act independently or synergistically to shape development of the HPA axis.

How does the visual system work?

The purpose of the visual system is to transducer light reflected from surfaces in the environment into neural signals that are relayed to the brain for processing and action planning. Light goes through the cornea (the outer protective covering) and the lens (to provide focus of near and far objects), and then falls on the retina. The retina is a thin film of tissue covering the back of the eyeball and is comprised of layers of photoreceptors and a network of connections and nonsensory neurons that provide intial processing of visual information. There are different kinds of photoreceptors that are used for different tasks and there are specialized cells and circuits in the retina for color and contrast.

How does the visual system connect to the brain?

The visual system in the brain consists of a interconnected yet functionally segregated network of areas that are specialized in processing different aspects of visual scenes and visually guided behavior. Visual information is processed as follows:

• Information flows from the retina to the lateral geniculate nucleus and then to the primary cortical visual area. Reciprocal connections carry information to secondary visual areas.
• From these primary and secondary visual areas, visual information diverges to two segregated streams: ventral and dorsal.
• The ventral stream is connected to the temporal cortex and is specialized for object recognition, mostly in inferotemporal cortex. The inferotemporal cortex connects to the perirhinal cortex and other areas that are involved in categorization of visual stimuli and formation of visual memories.
• The dorsal stream codes for spatial information and connects primarily to parietal structures that are important for voluntary action planning and coordinating somatosensory, proprioceptive, and visual inputs.

How does the structure of the visual system develop?

The visual system takes shape early in prenatal development. The retina starts to form around forty days after conception. The growth and organization of cells and connections continues well past birth. The distinction between foveal and extrafoveal regions is present early. The topology and patterning of receptions and neurons continue to change throughout prenatal development and the first year after birth. The muscles used for eye movements develop before birth, as well as the subcortical systems to control these muscles. Later developments consist of the physical growth of neurons and the proliferation and pruning of synapses. As soon as neurons are formed and grow, they begin to connect to other neurons.

What does visual attention in newborns look like?

Infants are born with a functional visual system and they may react to visual stimulation with head and eye movements. The functional visual system of infants has the following characteristics:

• Vision is relatively poor, but acuity, contrast sensitivity, color sensitivity, and sensitivity to direction of motion all improve after birth.
• The field of view is relatively small.
• A lack of stereopsis.
• Certain visual preferences: patterned vs. unpatterned, curvature vs. rectilinear, three-dimensional vs. two-dimensional, moving vs. static.

How does gaze control work?

Gaze control in adults functions with a coordinated system comprised of both subcortical and cortical components. Six muscles are connected to the eyeball that are under control of the brainstem. Eye movements are initiated by the frontal eye field, the cortex, and the superior colliculus. These areas are connected to the brainstem from which the signals to drive eye movements originate.

How do infants develop gaze control?

During visual tracking, several types of eye movements that develop over the first six months are made:

• Reflexive eye movements are responses to sudden onset stimuli. They are supported by visual pathways that include the retina, lateral geniculate nucleus, superior colliculus, and potentially primary visual cortex.
• Voluntary eye movements are quick eye movements from location to location. They are planned attention-driven saccades that involve early cortical visual areas, parietal cortex, and frontal eye fields.
• Smooth pursuit eye movements are slower eye movements that track moving targets. They also require attention and are supported by visual pathways involving the medial temporal lobe, middle superior temporal lobe, and parietal cortex.

The pathways for reflexive eye movements are mature at birth, whereas voluntary eye movements mature rapidly during the first six months together with behavioral changes. Smooth pursuit eye movements continue to improve during the first two years.

What is foveation?

Foveation is the bringing of an image in the environment to the fovea, the center of the visual field and the location on the retina producing the highest acuity inputs to the brain. Foveation balances the need for detailed visual information from the world with the need to reduce the metabolic demands of the brain to process the information. The fovea has the highest concentration of photoreceptors. Acuity is best at the point of gaze and then drops off with increasing visual eccentricity into a low-resolution surround. The visual system compromises by shifting the point of gaze with saccadic eye movements and thus reorienting the specific location in the scene that is best represented and processed.

What are the primary eye movement systems?

There are four primary eye movement systems. Each is produced by a separate neural circuitry, channeled through the brainstem, which innervates the ocular musculature.

• Saccades are quick changes of fixation whose function is to place the retinal image of an object of interest on the fovea.
• Smooth pursuit eye movements maintain foveation on a moving item of interest.
• Optokinetic nystagmus is a semi-reflexive eye movement pattern driven by a large visual array that moves with respect to a stationary observer.
• Vestibo-ocular response is a semi-reflexive eye movement pattern driven by a stationary large visual array placed in front of, or surrounding, a moving observer.

What is scanning?

Scanning consists of sequencing of saccades and fixations. It is a form of observable visual attention.

• During a saccade, the point of gaze for both eyes sweeps rapidly across the scene. Its purpose is to direct attention to a different part of the scene for processing.
• During a fixation, the point of gaze is relatively stationary. During fixation information about the scene is acquired and analyzed.

How do infants develop scanning?

Newborns examine their surroundings with a series of fixations, indicating that some of the neural circuitry for saccade generation is already in place. But their fixations do not extend beyond areas of high contrast (such as edges). After three months infants appear to scan in a more exploratory way. As infants get older they also scan between individual stimuli more readily than younger infants. This development shows a shift from reflexive to more purposive scanning, which is consistent with the maturation of cortical pathways.

What is sticky fixation?

Sticky fixation refers to the phenomenon that one- and two-month-old infants exhibit longer looking times than either neonates or four-month-old infants. It is interpreted as a difficulty of disengaging attention and has been tied to tonic inhibition of the superior colliculus by the substantia nigra and basal ganglia, which is later controlled by cortical mechanisms subserving endogenous attentional control and peripheral expansion of the visual cortex. Attentional disengagement continues to improve throughout childhood.

Why are smooth pursuit eye movements limited in infants?

Very young infants may be incapable of engaging in predictive eye movement (so that the future location of a moving target cannot be computed) or they may be unable to track due to limitations in motion processing. Also, the immaturity of retinal photoreceptors may prohibit firm registration of the target on the fovea.

What is orienting?

Orienting can be described as the engagement of visual attention. Young infants seem to attend primarily to a single prominent feature, whereas older infants are more likely to scan between features and to direct saccades with greater accuracy. This may reflect a transition from reflexive to volitional scanning. Infants also become capable of covert orienting: an internal shift of attention that can facilitate saccades to particular spatial locations. Two related phenomena are inhibition of return and spatial negative priming. Inhibition of return is a delay in eye movement toward a previously cued location. Spatial negative priming is a delay in eye movements toward a separate location presented alongside the fixated one.

What is visual selective attention?

Visual selective attention is the ability to select relevant stimuli for processing and to ignore or inhibit competing alternatives. Efficiently allocating visual attention is important for learning in infancy. A child must attend to certain environmental features while at the same time ignore others to be able to organize the world. This requires selection of relevant stimuli for processing and inhibition of those that are irrelevant. Research into visual selective attention has been done by using visual search paradigms, mobile conjugate reinforcement techniques, and visual search tasks.

How does spatial perception develop?

As our heads and bodies move around in space, the gaze moves frequently from place to place in the visual scene and the world is experienced as a stable place. Evidence suggests that visual stability emerges gradually across the first year:

• Young infants have difficulty discriminating optic flow patterns that simulate different directions of self-motion. Optic flow sensitivity may be improved by self-produced locomotion after six months of age or by maturation of the ventral visual stream.
• Young infants´ saccade patterns tend to be retinocentric, rather than body-centered. Retinocentric saccades are programmed without taking into account previous eye movements, whereas body-centered eye movements are programmed while updating the spatial frame of reference or coordinate system in which the behaviors occur. The visual-spatial coordinate system of the infant which is necessary to support perception of a stable visual world may be insensitive to extra-retinal information in planning eye movements. Also, as the child learns to walk, the field of view changes and they are presented with new kinds of visual experiences.
• There are limits in the ability of infants younger than two months to switch attention flexibly and volitionally to consistently maintain a stable gaze.

How does object perception develop?

Object perception follows a developmental pattern from kind of broken to coherent perception of the visual environment. It extends from birth through the first several months afterward, implying a big shift in the infant´s perceptual experience. One way by which infants come to perceive occlusion is by improvements of selective attention. Other advances in object perception come from coordinated visual attention and manual exploration to help infants understand objects as solid in three dimensional space.

What is scene perception?

Visual scenes are complex and characterized by a number of objects at different distances, often overlapping one another. Two scene characteristics are important: perceptual salience (low-level features such as edges, color, and contrast) and semantic relevance. In adults, the role of salience in scene perception is limited and eye movements are more driven by meaning.

How does scene perception develop?

Development of visual-spatial attention in infancy is seen as a shift from relying on exogenous features (perceptual salience) to more endogenous (knowledge), but recent research shows mixed results with regards to the role of salience. Detecting semantically relevant information is partly a function of emerging selective attention skills and age-related effects of perceptual salience on visual-spatial attention may actually be an increase in attention toward meaningful objects. All together the results suggest that development of scene perception is characterized by a growing tendency to look at semantically meaningful regions in scenes, and that this process is gated partially by the emergence of gaze control.

What scientific evidence and theories suggest that early childhood education (ECE) programs have meaningful and persistent effects over time?

• Neuroscience and biology show that the human brain and physiological systems are particularly malleable and open to environmental influences during prenatal and early childhood development. ECE programs can foster healthy brain development.
• Developmental science highlights the bidirectional nature of development and the active role that individuals play in this process.
• Economic science looking at human capital accumulation suggests that earlier skills beget later skills, and that human capital investments are more productive for individuals with higher levels of skill.

What is meant with fade-out and convergence?

The term fade-out refers to the commonly documented trend of declining or disappearing ECE program impacts over the long term. Generally it seems that ECE impacts on IQ and, to a lesser extent, achievement, diminish in magnitude over time. The extent to which ECE impacts fade for social-emotional skills and behavior is less clear. It is possible that the immediate impacts of ECE programs are reduced or eliminated over time because the average skills of program attendees and non-attendees become more similar. The term “convergence” is used to describe developmental patterns among ECE program attendees and non-attendees that contribute to declining program impacts over time.

What is the trifecta-skills hypothesis?

According to the trifecta-skills hypothesis, interventions are most likely to produce enduring effects when they target skills that are malleable, fundamental for success, and would not have developed without intervention.

What are the contributors to convergence?

• Program characteristics. It is possible that certain program characteristics are responsible for long term change among the attendees, whereas in the absence of those factors, change is less likely.
• Participant characteristics. ECE programs appear to have larger effects for higher-risk participants (low income, low education, single parent, low quality parenting, etc.).
• Preschool counterfactual context. By considering carefully the preschool experiences of comparison children who do not participant in ECE programs, ECE impacts can be placed in proper context.
• Subsequent schooling experiences. At this time, no study found clear evidence that alignment between ECE and subsequent experiences sustains ECE impacts.
• Ongoing intervention. It may be possible that intentionally coordinated, ongoing follow-through intervention across preschool and elementary school could sustain ECE impacts.

What are the mechanisms involved in long-term effects of ECE programs?

Five categories of mediators that are likely involved in the process of facilitating persistent intervention impacts over time are distinguished: cognitive improvements, motivational changes, social adjustment, family support, and school support. These five categories together account for large proportions of long-term ECE impacts. Cognitive skills appear to be important initiators of the intervention effect sequence and explain a large proportion of effects. They are followed by school support, family support, motivational adjustment, and finally social adjustment.

What can be recommended for future research into the long-term effects of ECE programs?

• Future research should conduct more long-term follow-up studies of ECE programs. Current research is limited by the few intervention models that have been examined, the methodological rigor of some of the studies, and the possibility that findings from previous trials do not generalize.
• Research should examine the impacts on social-emotional functioning over time. Interventions that improve social-emotional skills may capitalize on a developmental progression that results in better long-term outcomes.
• Future research should measure and test other potential mediators of persistent impacts. Many potential mechanisms remain unexamined, such as executive functioning, learning engagement, children´s stress response systems, and contextual processes.
• A research base on post-ECE contributors to skill convergence should be established. Future research should examine how specific proximal processes or unique combinations of processes contribute to convergence.
• Causal inference should be strengthened.
• The implications of potential ECE impact diffusion need to be considered. Children´s skills, which are in part a function of their prior ECE program participation, may influence their classmates´ experiences and skill development. As a result, the skills of ECE program attendees and non-attendees may converge when they come together in the classroom.

What is the mirror neuron system?

The mirror neuron system refers to a group of specialized neurons that mirror the actions and behaviors of others. Mirror neurons are found in the ventral premotor cortex and inferior parietal lobe and show a shared neural circuitry in the sensorimotor brain regions for both execution and observation of actions.

What is the EEG mu rhythm?

The mu rhythm consists of synchronized patterns of electrical activity involving large numbers of neurons in the part of the brain that control voluntary movement. The EEG mu rhythm provides one method of measuring activity of the mirror neuron system and measuring sensorimotor activity. The mu rhythm reflects oscillatory activity within the alpha band and exhibits changes in amplitude reflecting activation of the sensorimotor system. The amplitude of a signal decreases as compared to baseline activity, with peak suppression over sensorimotor areas. This suppression of activity is likely due to an increase in desynchronized neuronal activity associated with the processing of motoric information. 

What does the EEG mu rhythm of infants tell us about their action understanding?

The infant mu rhythm is sensitive to all coherent motion (not necessarily human actions or actions with which they have experience). Younger infants will attribute goals to both human and nonhuman agents, whereas older infants only do so for human and human-like agents, but not inanimate objects. This early pattern of non-discriminant mu rhythm desynchronization suggests that young infants are recruiting their motor system in trying to decipher the meaning or purpose behind all motion as they learn to discriminate that which is similar to their own developing motor repertoire and that which is not.

How could mirroring support action understanding?

There are several hypotheses to explain how the mechanism of how mirroring supports action understanding may work:

• Direct-matching hypothesis. This hypothesis suggests that internal representation of perceived actions is supported through activation of a one-to-one overlapping system with one´s own actions. Through a simulation process with resonant activation of the motor system, the visual description of an action is mapped on to the corresponding motor representation. Such motor activation indicates that an observed action is described into a motor format which belongs to the observer´s motor repertoire.
• Ideomotor theory. According to this theory, resonant motor activity during observation of actions supports goal interpretation through facilitating an expectation of the outcome. Repeated co-occurrence of an action and its effect creates a bi-directional link between the activation of one´s motor system and a representation of the effect. When watching another person perform the same or a similar action, the motor program for that action is engaged, which in turn activates the effect representation. The effect representation then facilitates anticipatory behaviors relevant to that effect.
• Associative learning. Contingency and contiguity of action-perception experiences create and shape the function of the motor system during action observation.

How can gestures be a link between action understanding and language?

Gestures support a transition from an earlier ability for interpreting concrete actions with visible consequences, to the more difficult process of interpreting spoken words which are completely abstract and arbitrary and have no visible consequence in the physical world. Action, gesture, and language may be overlapping cognitive systems. The ability to communicate through language builds from the ability to understand the intentions and goals driving one´s own and others´ actions.

How could gestures have served as an evolutionary step between action and language?

Our prehistoric ancestor learned that they could direct others´ attention through their physical movements. These physical movements became more refined and specific and used not only for directing attention but also to convey specific information. We would now refer to these actions as communicative gestures. As the use of gestures to communicate expanded, the gestures became paired with vocalizations which enlarged the number and specificity of ideas one could convey. Vocalizations then also became increasingly fine-tuned and eventually became representations and means for communication.

What is the gesture as intermediary hypothesis?

According to this hypothesis, infants extend their understanding of actions to communicative gestures, which in turn supports their understanding of spoken language. The same process for understanding the referential, intentional, and goal-directed nature of actions is applied to understanding gestures and word learning. Gestures support a transition from the earlier ability for interpreting concrete object-directed actions to the more difficult process of interpreting spoken words. Once an infant understands the goal-directedness of actions, it can extend that property to more abstract gestures, and in turn to words.

What is the mirror system hypothesis for the evolution of language?

The mirror system hypothesis for the evolution of language states that the mirror neuron system lays the foundation for the link between actions, action understanding, gestures, and language. Insofar as the ability to represent and interpret others´ actions supports the understanding of communicative gestures and spoken language, the mirror neuron system may serve as a means for that representation – it is a direct link between communicator and receiver.

What is emotion regulation?

Emotion regulation is defined as a set of processes that function at biological, behavioral, and social levels. These processes serve to modulate, maintain, inhibit, or enhance the intensity and valence of emotional experiences to accomplish an individual´s goals. Emotion regulation cannot be separated from the social context in which they occur and emotions can be regulated even as they are regulating an individual´s interactions with the environment. Previous research has found that:

• Emotion regulation becomes highly integrated into other biological, psychological, and social developmental processes over the course of childhood and adolescence. It is part of a larger system of self-regulation that emerges in development.
• There are multiple aspects of a child´s context that will affect the child in different way at different points in development. Key contextual moderators are parenting and parent functioning, and peers and school experiences.
• Development itself comes with different tasks at different ages, providing windows of opportunity as well as challenges.
• Emotion regulation may directly and indirectly influence physical health. The biological mechanisms that underlie emotion regulation also affect health-related processes in the short and long term.

How does emotion regulation develop in infancy and toddlerhood?

1. During the first few months of life, emotion regulation is controlled by innate and automatic physiological mechanisms, and almost entirely embedded in the infant-caregiver dyad.
2. There is a gradual transition from primary reliance on co-regulatory processes to increasing levels of independent self-regulation. Emotion regulation skills, strategies, and abilities that were given by the caregiver become integrated into the child´s own self-regulatory skill set.
3. As attentional neural networks mature and increased inhibitory control emerges, children begin to redirect attention to less emotionally relevant aspects of a situation. As inhibitory and attentional processes become increasingly integrated, children become more able to delay gratification and comply with adult demands.
4. Emotion regulation develops less rapidly and becomes more stable from early childhood onwards. Biological and behavioral aspects of emotion regulation continue to be refined into middle childhood and adolescence.
5. As children mature, they become better able to identify long-term consequences of their behavior, and they are better able to distinguish the effectiveness of long- and short-term regulatory strategies.

What causes individual differences in emotion regulation?

Certain constraints on the emergence of emotion regulation and its deployment cause individual variation in emotional regulation. These constraints are usually temperamental. Temperament is defined as relatively stable early differences in emotional, attentional, and behavioral reactivity that have a genetic and biological basis. Also causing individual differences in emotion regulation is the context in which children are trying to learn to regulate (e.g. variability in parental response).

How do biological systems support the development of emotion regulation?

The development of emotion regulation extends from the emergence of basic and automatic regulation of biological processes in infancy to the more self-conscious and intentional regulation of behavior and cognition. The maturation of different neural systems and processes that provide a functional mechanism for behavioral integration are fundamental to this developmental process. The development of emotion regulation skills is marked by continuous change across biological systems that support, among other processes, the behavioral control of emotion.

Which biological systems are involved in emotion regulation development?

Neural development (neural connectivity and functioning) is important to emotion regulation. Developing brain regions serve to coordinate, regulate, and process information from other neural networks and are involved in the control of cognition and emotion. Also the maturation of the autonomic nervous system (ANS) plays an important role.

What is the autonomic nervous system (ANS)?

The ANS is composed of a complex system of afferent and efferent feedback loops that are integrated with other neurophysiological and neuroanatomical processes, reciprocally linking cardiac activity with the functioning of the central nervous system. In this heart-brain connection, the parasympathetic and sympathetic branches of the ANS play a role.

How can the withdrawal of parasympathetic nervous system influence during emotional challenge be used as an indicator of emotion regulation?

The parasympathetic nervous system is concerned with the vagal control of the heart. In situations that do not elicit emotional arousal, the vagus nerve inhibits the sympathetic nervous system´s influence on cardiac activity through increased parasympathetic influence, producing a relaxed state. In situations that are emotionally taxing, the vagal influence is withdrawn or suppressed, resulting in increased sympathetic activity. This leads to an increase in heart rate, facilitating the focused attention that is necessary for generating emotional responses that are effective in modulating arousal.

Why is emotion regulation often researched as a predictor of externalizing problem behavior?

Excessive emotional lability and reactivity, and a lack of behavioral and emotional regulation, are considered important symptoms for children with externalizing problem behaviors. Children who are less able to control their emotions are at higher risk for difficulties across different domains (e.g. negative peer interactions, poor social problem-solving behaviors, academic difficulties). Scientific research has focused a lot on the genetic and biological origins of temperamental anger, but the genes that may produce anger and dysregulation of anger have not yet been identified. A translational perspective may be able to identify the conditions under which emotional dysregulation develops.

What has research using a translational perspective uncovered about the relationship between emotion regulation and externalizing problem behavior?

Results showed that maternal behavior, specifically sensitivity and mother-child attachment, predicted emotionality and emotion regulation. Maternal behavior and frustration reactivity predicted increases in externalizing behavior across the preschool period. Also, lower vagal regulation was a characteristic of children with early externalizing problems. Poorer vagal regulation and a low-quality mother-child relationship accounted for worsening of behavior problems from age two to five.

What have longitudinal studies using a translational perspective uncovered about the patterns of growth and change in emotion regulation and externalizing problem behaviors?

Children with high and stable trajectories of externalizing behavior problems in toddlerhood and preschool were characterized by poor physiological regulation and low maternal control during toddlerhood. Also, early child and environmental factors affect the growth of emotion regulation skills over the preschool period. Maternal depression is predictive of less steep increases in emotion regulation trajectories, while greater physiological regulation is predictive of steeper increases.

How do we develop the ability to understand emotional states from facial configurations?

The term facial expression implies that certain configurations of facial muscles are manifestations of internal emotional states and that such facial configurations lead to the perception of the associated emotions. Being able to understand emotions from facial expressions requires facial processing (visual processing of the facial configurative features) and emotion-related processing (awareness and interpretation of the emotional state of the other person). This skill follows a protracted developmental pathway, beginning with a broad comprehension based on valence that progressively becomes more defined to allow distinguishing between specific emotional categories.

What is predictive processing?

Predictive processing captures the general idea that neural and cognitive systems process information by continuously generating predictions and comparing them to the actual inputs. The brain builds a prediction and compares it with the actual sensory input. If sensory input was successfully predicted, internal prediction does not have to be updated. If the prediction failed to account for the incoming sensory input, this produces a prediction error (PE). Prediction errors can be explained as information that remains to be explained in the input and serves to update subsequent predictions associated with the input. By updating predictions through the incorporation of PEs, the system will minimize PE in the future, creating a better predictive model of the input. 

What is the role of hierarchy in predictive processing loops?

Predictive processing occurs hierarchically. At the first level, predictions are about immediate sensory input. At the next level, predictions are about the predictions of the lower level. Prediction errors at each level of the hierarchy reflect the mismatch between the prediction from the higher level and activity from the lower level. Early in the predictive hierarchy there are predictions and prediction errors about fast occurring and local characteristics of stimuli. Further along the hierarchy there are predictions and prediction errors about the long-lasting features of the stimuli.

What is active inference?

Active inference refers to the modification of prediction errors by action rather than by updating the perceptual model. By acting on the environment, we may test how our actions affect our sensory input and verify whether those sensory inputs deviate from our internal predictions (for example by having a closer look at someone to see if they are really crying). Moving in and acting on the environment may produce changes to the sensory input that lead to a decrease in prediction error.

What are the three stages of belief building?

The three stages of belief building are:

1. A lack of commitment to a single interpretation and abudance of errors.
2. A convergence to a dominant general theme.
3. A progressive specification of representational details for both the percept and associated contextual features.

What is Johnson´s model of Interactive Specialization?

According to this model, the cortical and cognitive specialization that is observed during development results from interactions between the environment and the brain, and between different structures within the brain. One example of interactive specialization is the development of specialized neural circuits for face perception. Newborns have a visual bias towards faces that enhances and ensures a continued perception for facial stimuli. This continued exposure to facial stimuli drives the development of the regions of the visual cortex, turning it for face processing and resulting in perceptual expertise for face perception.

What are adaptation paradigms?

Adaptation protocols use different models with the same facial configurations or different intensities of the same emotion during the adaptation phase. Adaptation paradigms allow examination of whether the target stimulus is considered the same as the adaptor in some aspects, and allows one to determine whether there are order effects dependent on the adaptation.

What is the 'happiness advantage'?

The 'happiness advantage' refers to the facilitated processing of happy faces. It may be due to the higher prevalence of happy facial configurations experienced by young infants. Facial configurations of happiness are likely to be frequently present in the visual field of the child. Since perceptual priors are dependent on previous experiences of the world, the fact that configurations of happiness are regularly expected and confirmed makes this prior a more robust belief. In adaptation beliefs, the habituation to a facial recognition that is already a prior, increases the prior belief as well as the posterior belief.

What are Basic Emotion Models?

Basic Emotion Models considers that facial expressions are unique to each emotion and are signals that convey information of one´s internal state. That information is used to coordinate social interactions. The model assumes that emotions are unique events that occur as a result of special mechanisms, and that each emotion has its own respective neural network. The expression of each emotion has its own response, manifested in face, voice, and body .

What are Psychological Construction Models?

Psychological Construction Models consider emotion as a state that is composed of various ingredients and their associated manifestations. They consider valence and activation as fundamental dimensions of core affect. Basic psychological processes like affect, previous experiences, language, and executive functioning combine to form a discrete emotion experience. These models call into question the assumption that there are basic, discrete, universally recognized emotions. It believes instead that facial expressions can be better understood as symbols of emotion rather than signals.

What is autism spectrum disorder?

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by heterogeneous symptom profiles associated with varying levels of severity in social communication deficits and restricted and repetitive behaviors. The diagnostic symptoms emerge during the end of the first year of life. Differences in other developmental domains are detectable in the first year of life, including motor skills, response to name, visual reception, attention to faces and social scenes, and visual orienting. In the beginning of the second year there are also differences in language skills and disengagement of visual attention.

How is autism spectrum disorder related to brain development?

The above mentioned behaviors develop during a highly dynamic period of postnatal brain growth that is marked by cortical expansion, functional organization of neural circuitry, and fiber myelination and maturation. Atypical brain phenotypes emerge during infancy, with altered developmental trajectories that precede the consolidation of symptoms that begins in the second year of life. Presymptomatic magnetic resonance imaging (fMRI) in infants may be used to predict diagnostic outcomes in toddlerhood.

What is characteristic about brain growth in infants and children with ASD?

ASD is characterized by brain overgrowth. Brain overgrowth is not present at birth, but emerges at the end of the first year of life, and is present by two years of age in children with ASD. The rate of change in total brain volume during the second year of life is linked to the severity of ASD-related social deficits. Faster rates of cortical surface area growth from six to twelve months of age precedes brain overgrowth in the second year of life in infants who later developed ASD, supporting the hypothesis that cortical hyper-expansion drives brain overgrowth in ASD.

What have MRI studies revealed about cortical surface area, cortical thickness, and gyrification in children with ASD?

The results support the pathological hyper-expansion of cortical surface area in ASD:

• Increases in the surface area of the frontal, temporal, and parietal lobes in two year olds with ASD.
• Accelerated rates of total cortical surface area expansion.
• Regionalized expansion in areas in the occipital, temporal, and frontal lobes in infants who later developed ASD, with robust rates of expansion in the visual cortex.
• Results with regards to cortical thickness are mixed, but it seems that aberrant patterns of cortical thickness in ASD emerge sometime after age three and then follow a dynamic developmental pattern.
• Increased gyrification in older children and adults with ASD.

How does the development of the amygdala relate to the development of ASD?

There have been only few studies that investigated the development of the amygdala in relation to the development of ASD and the results vary slightly between them. They mostly indicate that an increased amygdala size is correlated with the severity of social and communication deficits. One research reported that amygdala enlargement was present and stable across the preschool period, but, contrasting previous research, that increased amygdala volume conferred better joint attention among children with ASD.

What other noteworthy results have been found by MRI studies investigating the brain and ASD development?

• Cerebellar structural abnormalities are frequently reported in older children and adults with ADS, but the direction of the effect varies. More research is necessary, and studies should carefully control for overall brain size to ensure that findings of volumetric enlargement are specific to the cerebellum.
• The development of the corpus callosum reflects a dynamic process. The size of the corpus callosum in individuals with ASD is increased in the first year of life, normalizes by age two, and becomes smaller in the third year of life.
• Extra-axial fluid is the cerebrospinal fluid that occupies the subarachnoid space surrounding the cortical surface of the brain. It is a robust brain biomarker of ASD in early life, as increased volumes of extra-axial fluid are present in the first year of life in infants who go on to develop ASD.
• Resting-state connectivity is an ASD biomarker. Two atypical circuits were found in young children with ASD: brain regions involved in social cognition exhibited under-connectivity, whereas sensory-motor and visual brain regions showed over-connectivity.

What is fractional anisotropy and how does it relate to ASD?

Fractional anisotropy (FA) reflects the degree of directed water diffusion in the brain, indicative of more mature white matter properties, including myelination, axonal density, and fiber packaging. ASD is characterized by increased FA in the first year of life. Then maturation slows down, which may ultimately result in reduced FA values observed in older children and adults. 

How do brain and behavioral phenotypes associated with ASD emerge during the prodromal period before the second birthday?

Aberrant white matter development (indicated by fractional anisotropy and corpus callosum size) and increased extra-axial cerebrospinal fluid volumes are detectable by six months of age. This coincides with motor delays, aberrant attention to social stimuli, and atypical visual orienting. Surface area hyper-expansion in the first year precedes brain overgrowth in the second year. Infants who develop ASD show altered response to name, beginning at nine months and continuing through twenty-four months. That coincides with differential trajectories in attention to eyes and the emergence of ASD symptoms.

What possible neurobiological mechanisms underlie the development of ASD?

ASD likely arises from multiple pre- and postnatal pathogenic mechanisms involving neural proliferation and migration, pruning, synaptogenesis, myelination, and axonal development and connectivity. Each of these processes contribute independently and interactively to brain development.

• Neural progenitor proliferation and neurogenesis may play a role in the development of ASD. Neural progenitor cells derived from individuals with ASD show excess proliferation, with the level of proliferation relating to the degree of brain overgrowth.
• Cortical hyper-expansion from six to twelve months, especially in the visual cortex, may underlie deficits in visual orienting behaviors. These in turn may alter experience-dependent neuronal development and result in inefficiently pruned circuits, brain overgrowth, and the emergence of ASD traits.
• Cerebrospinal fluid contains growth factors with age-dependent effects on neuronal proliferation. Increased volumes of extra-axial fluid suggest a disruption in the circulation of cerebrospinal fluid and an accumulation of brain metabolites that impact brain function.
• Alterations in corpus callosum morphology and in the development of white matter microstructure in early ASD implicates processes governing myelination, axon caliber, density, and axonal connectivity. White matter integrity and connectivity may also be altered through experience-dependent myelination (when oligodendrocytes selectively myelinate axons which receive more input from neurons).

How can MRI help predict ASD?

MRI has the potential to predict ASD diagnosis at twenty-four months using infant MRI scans that have been collected in the first year of life. Scientists have made a classification algorithm that relied primarily on measures of regional cortical surface area growth from six to twelve months of age to predict ASD diagnostic outcome at twenty-four months. Another study found that a support vector regression machine using whole-brain functional connectivity matrices could predict ASD diagnostic outcome.

How can support vector machines and deep learning in combination with MRI dataset assist in diagnosing ASD?

Support vector machines work by finding the optimal linear plane separating diagnostic groups using the original data or data mapped into a new feature space using pre-defined kernel functions where classes become linearly separable. Deep learning algorithms can automatically identify the optimal data representation in a data-driven manner, making the need for prior selection of appropriate non-linear mapping obsolete. Deep learning methods have a few advantages. Input features are learning from the data and not derived, and thus less prone to overfitting. It also allows for the detection of more subtle patterns in the data.

What is early life stress?

Early life stress (ELS) is the result of adversities that produce frequent or chronic activation of stress-responsive physiological systems. These adversities deprive infants and children of the social and physical care that they need, cause homeostasis, provoke fear and anxiety, and dysregulate the function of the stress system itself. The most common forms of ELS are characterized by an accumulation of adversity. For example, poverty is a chronic, multi-dimensional stressor, and maltreated children typically experience multiple types of abuse.

What is the effect of early life stress on emotion processing?

Research shows differences in emotion processing after experiencing early life stress. There are interesting results with regards to brain function. Increased amygdala activation to emotional contexts appears to be beneficial following early life stress. And activation in prefrontal and striatal regions differ based on the type of adversity experienced.

What is the effect of early life stress on reward processing?

Differences in reward sensitivity have been observed following early life stress. There are differences between the type of ELS experienced and neural activation in the context of reward. In rewarding contexts neural activation is more consistent in maltreated and post-institutionalized individuals, while impoverished individuals show different patterns of activity. It is as of yet unclear whether altered reward sensitivity is protective and reduces the likelihood of risky behavior, or if it is a risk and leading individuals to seek larger rewards.

What is functional connectivity?

Functional connectivity refers to the connectivity between brain regions that share functional properties. In ELS literature, two main approaches have been used to investigate functional connectivity:

• Psychophysiological interaction (PPI) is used to understand the functional relationship between two regions in the context of a task. It examines the functional connectivity between two regions of interest whose activity has been convolved with task-related timing information.
• Seed-based resting-state functional connectivity (rsFC) looks at functional coherence between two regions of interest when the individual is not engaged in a task, the individual´s resting-state. In rsFC, a single region of interest is chosen as the “seed”. Then the time course of the seed´s functional activity is correlated with a set of regions or all other regions of the brain. Correlations with greater magnitude are interpreted as being more functionally connected.

What are the main findings from investigations of ELS and functional connectivity in the emotion processing system?

The main findings can be organized by ELS type:

• Poverty. Lower income-to-needs ratio is associated with diminished amygdala-prefrontal cortex connectivity. Individuals with lower family income during childhood show different patterns of frontolimbic connectivity when viewing aversive images or emotional faces, possibly causing altered emotion processing.
• Maltreatment. Maltreated individuals display lower amygdala- and hippocampus-prefrontal cortex connectivity, and lower amygdala-prefrontal cortex connectivity. These connectivity patterns are associated with poorer context memory and conflict regulation. Stronger amygdala-prefrontal cortex connectivity predicts more adaptive functioning regardless of maltreatment history. This means that high functioning individuals with a history of ELS may exhibit a compensatory neural phenotype that aids in adaptive functioning later in life, supporting the notion that adaptation may occur during the transition from adolescence into adulthood.
• Institutional care. Previously institutionalized children show more mature negative amygdala-mPFC coupling during emotion-matching, and they show significant amygdala- and hippocampus-PFC connectivity during aversive learning. The relationship between striatum-mPFC connectivity and social problems was moderated by age, in the way that functional connectivity was more likely to predict social problems in adolescents compared to children, highlighting the importance of investigating developmental trajectories after ELS.

Childhood is becoming more and more digitized. Though still not clear, there may be developmental and health risks with excessive screen-based media use. These risks include language delay, impaired executive function, poor sleep, impaired general cognition, decreased parent-child engagement, and possibly neurobiological risks. 

How can increased screen-based media use affect children’s development?

Childhood is becoming more and more digitized. Though still not clear, there may be developmental and health risks with excessive screen-based media use. These risks include language delay, impaired executive function, poor sleep, impaired general cognition, decreased parent-child engagement, and possibly neurobiological risks. 

What is diffusion tensor imaging?

Diffusion tensor imaging (DTI) is a technology to quantify white matter integrity in the brain and its various factors. Parameters of DTI include fractional anisotropy (FA) and radial diffusivity (RD), scalar values associated with microstructural organization, and myelination of white matter tracts. 

What are the structural neurobiological correlates of screen-based media use in preschool-aged children?

A cross-sectional study revealed the following results:

• Fractional anisotropy is associated with organization of white matter in parallel bundles, whereas radial diffusivity is inversely associated with degree of myelination of such bundles, as well as axonal packing and other microstructural processes. 
• Increased screen time was associated with lower fractional anisotropy and higher radial diffusivity of the arcuate fasciculus, and also with lower EVT-2 and CTOPP-2 scores. 

What can be concluded based upon these correlations?

Increased use of screen-based media was associated with lower microstructual integrity of brain white matter tracts that support language, executive functions, and emergent literacy skills. Screen use was also associated with lower scores on corresponding behavioral measures.

What general principles are essential for understanding the developmental dynamics of fetal and baby brain?

• Developmental events occur in specific architectonic compartments, such as embryonic and fetal zones. 
• The compartments are transient, but can be visualized in historical sections and MR images.
• To be able to understand the development of functional connectivity, the nature and timing of development of basic connectivity elements and their molecular properties need to be analyzed. 

What are important events in brain development in the early fetal period (eight to fifteen postconceptional weeks)?

• There are processes of proliferation, migration, and cell aggregation. 
• All embryonic brain divisions and their major subdivisions are clearly visible on coronal sections at the end of the embryonic period.
• The formation of the cortical plate is an important cytoarchitectonic event. After its formation, the cerebral wall of the lateral neocortex consists of the marginal zone, the cortical plate, the presubplate, the intermediate zone, the subventricular zone, and the ventricular zone. 
• According to the radial unit hypothesis, the cortical neurons are generated in proliferative units of the ventricular zone, migrate along radial glial guides and settle in vertical ontogenetic columns within the cortical plate. 
• With regards to the growth of early afferents to the human cerebral cortex, thalamocortical fibers pass through the cerebral stalk, cross the diencephalo-telencephalic and subpallio-pallial border and fan out within the intermediate zone on their way to the cortical anlage. Basal forebrain fibers reach the neocortical cerebral wall through the external capsule. Corticospinal and corticopontine pathways are located medial to thalamic radiation and are partily intermingled with it. 
• The first synapses in the neocortical anlage appear. 
• There is a trilaminar pattern of organization consisting of the cortical plate, the intermediate zone, and periventricular proliferative zone. 
• Changes in cell aggregation (cytoarchitectonics), proliferation and migration, neuronal and dendritic differentiation, and axonal growth.

What are important events in brain development in the midfetal period (fifteen to twenty three postconceptional weeks)?

• Four histogenetic-neurogenetic events are most important during this period: neuronal aggregation and cytoarchitectural development, axonal outgrowth and ingrowth, dendritic differentiation, and molecular specification.
• The formation of synapses continues in the subplate and marginal zone. 
• Molecular specification of cerebral cortex can be divided in two processes, namely the areal specification and the specification of subsets of cortical neurons. 
• Major protection and commissural pathways are still growing (think of corticostriatal, corticospinal, thalamocortical, corticopontine, and corpus callosum).
• Associative pathways are not well developed, except for associative fibers connecting frontal cortex with cingulate neocortical portion of the limbic lobe.
• The presence of synapses in the subplate and the dense distribution of synapses in the marginal zone indicate circuitry development.

What are important events in brain development in the late fetal period (twenty four to thirty four postconceptional weeks)?

• Three histogenic and neurogenetic processes are most important during the beginning of the late fetal period: ingrowth of axons, synaptogenesis, and dendritic differentiation of pyramidal neurons.
• Rapid development of primary sulci and gyri. The central, precentral, and postcentral sulcus delineate the developing precentral and postcentral gyrus. Superior and inferior temporal sulcus appear in the temporal lobe. Superior and inferior frontal sulci mark the position of future superior, medial, and inferior frontal gyrus in the frontal lobe.
• On the medial hemispheric surface, there is deepening of the parieto-occipital and calcarine fissure and the appearance of the cingulate sulcus.
• Gradual decrease in the intensity of neuronal proliferation in ventricular and subventricular zone.
• At the end of the late fetal period secondary sulci develop rapidly, there is an increase in the volume of the cerebral wall, and there is a decline in proliferative zones.
• During the end of the late fetal period, the most intensive histogenetic events are neuronal aggregation, cytoarchitectonic changes in laminar pattern, axonal ingrowth and outgrowth, dendritic differentiation, and synaptogenesis in the cortical plate.

What are important events in brain development in the neonatal period?

• The main event is the formation of tertiary gyri.
• There are advances in neuronal aggregation and cytoarchitecture, with parallel establishment of tangential and radial patterns. There is gradual resolution of layer IV in the premotor cortex and the disappearance of this layer in the motor cortex, resolution of the voluminous subplate and its transformation into a characteristic thin band at the interface between layer VI and the gyral white matter, and an increase in size of pyramidal cell bodies.
• There is growth of short corticocortical fibers.
• Dendritic differentiation.
• Synaptogenesis.
• Myelination and increase in compactness of axonal pathways.
• Cell death and axonal pruning.
• The proliferation and migration of neurons have ceased, while the proliferation of astrocytes and oligodendrocytes is continuing.

What are important events in brain development in early infancy?

There is a rapid and massive increase in the total brain volume during the first year. The elaboration of cortical gyrification continues. Some histogenetic processes rapidly increase in intensity (such as synaptogenesis and dendritic differentiation), while others follow a steady pace (such as cytoarchitectonig development, neurochemical maturation, and myelination). There is a decline in the growth of axonal pathways.

What are important events in brain development in late infancy?

The cerebral hemispheres continue to grow. The most intense histogenetic and neurogenetic events during this period are morphological differentiation of neurons and dendrites, synaptogenesis, myelination, and changes in cortical cytoarchitectonics.

What are the effects of excessive screen media use on young children´s health?

Scientific research has identified positive as well as negative effects on young children´s health. Negative effects include obesity, short sleep duration, language delay, and children´s injury. Positive effects include increasing letter knowledge, training learning abilities, and reducing the attention problem. Many factors have been identified that are related to screen use among children, such as parental media use, family income, parental age, and parental education background.

What results were found in the meta-analyses by Li et al. (2020)?

More screen media use was found to be related to higher adiposity (obesity), more sleep problems and aggressive behaviors, more risk of musculoskeletal pain and bullying, poorer health dietary behavior, worse executive function and motor development, less physical activities, and worse behavioral and emotional outcomes.

What is the 24h theory?

According to this theory, the more screen media time a child has in a day, the less time they have left for physical activity. Screen media use, along with snacks and fast food, increases the risk of overweight in children. Additionally, most advertisements on television are about sugar, sweet drinks, and other energy-dense and nutrient-poor food, leading to unhealthy dietary behavior for children.

What is the relationship of social economic status, screen media use, and obesity in children?

Research indicates that family factors such as social economic status are related to children´s obesity. More television time possibly mediates the relationship between children´s obesity and social economic status. Social economic status of a family can be seen as the foundation of consumption of unhealthy food that children watch on television. Children with low social economic status appear more likely to buy unhealthy food when they have more screen time with sugar advertisements.

How does screen media use cause sleeping problems?

Several mechanisms have been put forward that may explain how screen media use causes sleeping problems in children:

• Blue light from screen media devices suppress melatonin levels of children, changing their circadian rhythm.
• Screen media use takes up potential sleep time.
• Screen media use increases physical and psychological arousal.
• Media exposure improves levels of night alertness and reduces duration of rapid eye movement sleep.

What is the mirror neuron system?

The mirror neuron system (MNS) is an integrative network that communicates information across multiple regions of the brain. It involves a group of specialized neurons that integrate visual, auditory, and motor stimuli to generate social cognitive processes. They are involved in motor action observation and execution, verbal and non-verbal communication, transitive and intransitive gestures, behavioral, motor, and social communication and interpretation, intention understanding, emotional understanding, and intersubjectivity.

Where are the mirror neurons?

The mirror neurons extend through the dorsal premotor cortex, posterior temporal cortex, somatosensory system, inferior frontal gyrus, ventral premotor cortex, inferior parietal lobe, left medial frontal gyrus, bilateral cerebellum, right temporal lobe, and thalamus. Two kinds of mirror neurons are distinguished:

• Action mirror neurons fire during action observation.
• Inaction mirror neurons demonstrate predictive discharge.

They communicate through a series of network pathways that appear to be damaged in autism and autism spectrum disorder.

What do neuroimaging techniques show when examining the MNS in people with autism?

EEG and fMRI studies show a lack of activity in the mirror neuron system and instances of disrupted connectivity (either under-connectivity and/or over-connectivity in cortical networks) in people with autism. This results in the brain functioning as a less cohesive unit.

How can learning about MNS development help shed light on the development of autism spectrum disorders?

Research shows that MNS activity is present in infants as young as six months old. Even more so, imitative behaviors have been observed in neonates in the first days of their lives. This indicates that they immediately begin responding to their social environment. Knowing when the MNS begins to develop can help in fully understanding how and when disruptions in neural circuitry occur, and how it influences neurodevelopmental disorders.

What are brain mapping and sensory-to-motor mapping?

Brain mapping refers to a set of neuroscience techniques predicated on the mapping of (biological) quantities or properties onto spatial representations of the brain resulting in maps. Sensory-to-motor mapping is a process in which the one observing an action creates a simulation in their mind. These mapping procedures are pairing stimuli with an appropriate response, creating automatic response capability. If an action has not been previously mapped, automatic response and motor resonance are suppressed.

What is the role of brain mapping in autism spectrum disorders?

The mapping system allows people to build a repertoire of social meaning to communicate through motor, verbal, behavioral, and symbolic actions. It also serves to interpret the person´s own internal stimuli and integrate these stimulus-response behaviors with social meaning. If the development of these maps is disrupted, it could lead to impairments in neurotypical function, seen in the stages when children are developmentally expected to begin performing the motor, social, and language skills they had previously observed.

What is the difference between mirror neurons and canonical neurons?

To be able to study the pathophysiology of autism, a distinction needs to be made between mirror neurons and canonical neurons. A mirror neuron refers to a neuron that must be activated when observing an action as well as while executing an action. Canonical neurons are the neurons that respond just by observing a graspable object without performing any action.

Which brain areas are involved in autism and ASD?

• The cerebellum is affected in autism and ASD, showing a reduction in size and differences in cerebellar circuitry. There is a possibility that mirror neurons exist in the cerebellum as some fMRI studies showed separate clusters in brain regions with mirror properties.
• The hippocampus and amygdala have a smaller volume in autistic individuals, and neurons are smaller and showing higher cell density.
• The size of the cerebral lobes is increased in autism. There appear to be mirror neurons located in the parietal and frontal cortex.
• Brain ventricles are increased in size in autism and ASD, but the presence of mirror neurons has not yet been proven.
• The basal ganglia, putamen, and caudate nucleus show a decreased volume in autism. ASD patients may also show gray matter augmentation, mostly in the frontal and temporal lobes, medial frontal gyrus, Broca´s area, posterior temporal cortex, and parietal and occipital subcortical regions.

What is the role of self-regulation in classroom behavior and learning?

Self-regulation has important implications for classroom behavior. Students with good self-regulation show fewer behavioral problems and positive teacher-student relationships (which propels learning). Self-regulation directly influences learning as it allows students to attend to important information, stay on task, remember instructions, and process necessary information.

Which neurocognitive processes are involved in self-regulation?

• Response inhibition: the suppression of actions that are inappropriate in a given context and interfere with goal-driven behavior.
• Voluntary attention: attention that is deliberately applied and controlled by the individual.
• Working memory: a cognitive system with a limited capacity that can hold information temporarily.

What is the role of response inhibition in self-regulation?

Response inhibition creates a delay period during which one can prepare a better response to the environmental demands. Deficits in inhibition are expressed in difficulty waiting, making careless mistakes, interrupting others, and impulsivity. Early inhibition problems fail to support, or even stand in the way of, children´s abilities to develop more skills over time. In school response inhibition is an important skill, for example, children should not run in the hallway, lower their voice, control impulsive behavior, and stop an incorrect response.

What is the role of attention in self-regulation?

Attentional control is very important for learning and the regulation of emotions and behavior. Selectivity is an important feature of attention, as attention does not only allow for selecting important information, but also for ignoring irrelevant information. Children with attention problems are easily distracted, appear disengaged and forgetful, require repeated directions, and make careless errors. They also tend to have less positive relationships with peers, and in combination with negative emotions are at higher risk for behavioral problems.

Which attentional networks can be identified?

Several attentional networks are identified that have differential effects on learning and behavior:

• Alerting network provides a necessary level of arousal and prepares students to learn.
• Orienting network directs attention to a stimulus. Involuntary orienting underlies distractibility and happens when there are strong cues from the environment. Voluntary orienting involves intentional focusing attention on an object or event which is relevant to one´s goals.
• Executive attention allows resolving the conflict between competing stimuli or actions by suppressing activity in areas of the brain which process a competing response.

What is the role of working memory in self-regulation?

Self-regulation is guided by internal representations including goals, rules, and plans. These internal representations are held in working memory. In school, working memory is necessary for following rules and directions, self-monitoring, and error correction. Working memory difficulties are expressed in difficulty following instructions and keeping conversations, forgetting details or procedures, reluctance to respond, and mind wandering.

How can interventions support self-regulation?

Self-regulation skills are responsive to intervention and can be improved. In the classroom, promoting self-regulation can help to increase learning time (by decreasing time spent on student´s problem behaviors) and promote full participation in learning (by students being less dependent on the environment). Self-regulation training should be given throughout the day and progress from less cognitively demanding tasks to tasks that require greater executive control. Interventions that can support self-regulation in early childhood education classroom are organization of the classroom environment, behavioral interventions, and instructional strategies.

How can organization of the classroom environment support self-regulation?

Effective classroom management, together with teacher´s emotional and instructional support, are associated with better self-regulation and academic engagement and less off-task behavior. Consistently enforced rules and routines allows for progression from regulation provided by teachers to self-regulation. Also, environmental distractions, such as noise and visual stimuli, should be managed to prevent interference that can reduce cognitive resources allocated for learning.

Which instructional strategies can promote self-regulation?

Different strategies can be used to promote self-regulation and these strategies can focus on different aspects of self-regulation:

• Strategies to build and actively maintain mental representations. The success of self-regulation depends on the quality of mental representations that guide task performance and behavior, their active maintenance in working memory, and their fidelity. Orienting basis of an action is an externally represented schema that guides students in the execution of their actions. Teachers should also have the goals and rules readily available, repeat them, and minimize irrelevant images and words.
• Strategies to support voluntary attention. Verbal attention coaching includes securing students´ attention before introducing a task and directing children´s attention to important information. Another strategy is On-Task in a Box, an intervention that combines self-monitoring with video modeling.
• Strategies to improve inhibition control. Intentionally inserting a delay can strengthen students´ ability to stop their incorrect behavioral responses. This can be done by using signals or verbal prompts to slow down, or using response cards instead of hand raising. Another strategy is having students reflect on task performance.

Which behavioral self-regulation interventions can promote self-regulation?

Different behavioral self-regulation interventions can be used to foster self-regulation skills in the classroom:

• Movement activities are associated with better motor inhibition, fewer behavioral problems, better behavioral regulation, more mature private speech, improved attention, and improved ability to stay on task.
• Game-based interventions. Movement-based games and cognitive games can improve motor inhibition, academic skills, knowledge of rules of conduct, verbal interference control, and delayed gratification, inhibition control, and working memory.
• Mindfulness requires sustained attention on a target object or activity and disengaging from distracters. It increases connectivity between attentional networks, resulting in more efficient and flexible allocation of attentional resources in the earlier stages of stimulus processing. It can be applied in different ways, such as mindfulness practice, mindful movement, and mindful meditation.

What is child maltreatment?

Child maltreatment is defined as any interaction or lack of interaction reasonably within the control of a parent or person in a position of caregiving responsibility, that does (potential) harm to the health of the child or physical, mental, moral, spiritual, or social development in the context of the society in which the child grows up. There are different types of maltreatment, including child sexual abuse, emotional abuse, physical abuse, neglect including physical neglect, emotional neglect, educational neglect, and witnessing family violence. There exists a high degree of comorbidity, co-occurrence, and poly-victimization in child maltreatment.

What are risk factors of child maltreatment?

• From an evolutionary perspective it can be argued that humans have an innate bias to promote one´s inclusive fitness which might be accompanied by abuse and infanticide of infants that compete with procreation of one´s own offspring. Also, the distribution of scarce resources to the infant with the best chances to survive may result in neglect of less fit and passive infants.
• Intergenerational transmission of maltreatment. Parents who have been the victims of child maltreatment are at heightened risk of maltreating their offspring.
• The spillover hypothesis states that marital quality is related to parent-child relationship quality. Interpersonal or intimate partner violence is predictive of child abuse.
• Psychological and neurodevelopmental factors. Parental characteristics and psychopathology may interfere with normative caretaking of young children. Think of low inhibitory control, a low threshold for aggression, major depressive disorder, or borderline personality disorder.
• New research indicates that children with certain neurodevelopmental features such as the presence of a learning disorder and/or an autism spectrum disorder may be at increased risk of maltreatment.
• Dysregulation of the neurophysiology of perpetrating parents would make them more liable to become abusive. If the balance between the sympathetic and parasympathetic systems is dysregulated, over- or underreactivity to stressful stimuli may result in neglect or harsh parenting.
• Single parenthood.
• Lack of social support.
• Low socioeconomic status.

What are protective factors of child maltreatment?

Protective factors may act as moderators of the association between risk factors and maltreatment. They may decrease the chances of child maltreatment even when risk factors are present. The following protective factors are identified:

• A social support network.
• Intervention.
• The presence of stable, safe, and nurturing relationships with intimate partners.
• High levels of maternal warmth.

What is the umbrella synthesis approach?

An umbrella synthesis involves the systematic collection and assessment of multiple meta-analyses published on a specific topic. The results from the meta-analyses are integrated and reviewed following a uniform approach to allow their comparison. This approach leads to comparable estimates of combined meta-analytic effect sizes, a systematic stratification of the evidence, an evaluation of the heterogeneity and potential biases, and sensitivity analyses to identify potential reporting biases.

Based on the umbrella synthesis, which antecedents of child maltreatment were identified?

Five categories of antecedents of child maltreatment were identified, namely parental experience of childhood maltreatment, parental personality characteristics, parental experience of intimate partner violence, parental baseline physiology and physiological reactivity, and socioeconomic status.

Which interventions can prevent or reduce child maltreatment risks?

Effective interventions appeared to be parenting programs involving parent training, such as Multisystemic Therapy for Child Abuse and Neglect, and parent-child interaction therapy. Nurse home visitations did not reduce reports of child maltreatment, but did lead to improvements in other domains such as health and cognitive developments. The umbrella synthesis revealed that certain interventions did not manage to affect the risk of child maltreatment, including interventions providing only support to the families, promoting healthy behaviors during pregnancy and early parenthood, establishing social support networks, and screening for developmental delay.

Why should more knowledge be gathered with regards to the antecedents of child maltreatment?

From the antecedents that have been shown to relate to child maltreatment, the underlying mechanisms are still unclear. Additionally, the antecedents that have been identified only account for a small percentage of the variance in child maltreatment. Finally, there is an absence of replicable evidence on potentially divergent precursors of different types of maltreatment.

Why should future research gather more information about the neurobiological antecedents of child maltreatment?

There exists no meta-analytic evidence on parental neural or genetic antecedents of child maltreatment. Also, intergenerational transmission of maltreatment may occur due to heritable characteristics of parent and child. If parents were maltreated themselves, prevention efforts can be helpful, independently of the genetics behind transmission.

What is recommended with regards to current and future interventions aimed at reducing and preventing child maltreatment?

More effective interventions need to be developed to protect more children and support more families. Currently, interventions are barely capable of preventing or decreasing child abuse and neglect in the next generation. Research into the effects of changing the socioeconomic conditions of families in low-resource environments is necessary. Limited social and material resources for families are one of the strongest correlated of elevated maltreatment risks. Universal health care, affordable education, paid parental leave, and more and better paid jobs may lead to less stress and better parental coping with challenging child behavior, which may lead to lower basal physiological levels and lower risks of maltreatment.

How can the vicious cycle of maltreatment and the failure to develop effective interventions be broken?

Two ways are recommended. Firstly, parents should be empowered to cope more sensitively with challenging child behavior and to set gentle but consistent limits to oppositional and coercive interactions. Secondly, attention should be paid to differential susceptibility. Differential susceptibility refers to the idea that some individuals are more open to environmental influences than others. The efficacy of intervention effects on child maltreatment may be hidden in susceptible subgroups of participants, which goes unnoticed now due to the evaluation of average effects across all parents involved.

According to differential susceptibility theory, what differentiates the more susceptible from the less susceptible individuals?

Differential susceptibility theory proposes three markers on the levels of genetic, stress regulatory, and temperamental makeup.

• Genetic markers have been found in genes involved in the dopaminergic and serotonergic system. The carriers of the dopamine receptor D4 7-repeat alleles seem to be open to the environment and this genotype may be embedded in larger dopamine-related genetic pathways or polygenetic susceptibility scores.
• Individuals may have a biological sensitivity to context, involving heightened stress and immune reactivity to negative stimuli in a chaotic and stressful environment.
• Individuals may differ in temperamental difficultness. Difficultness is broadly defined as encompassing negative emotionality, surgency, and effortful control. It predicts higher levels of internalizing and externalizing behavioral problems, as well as a heightened openness to the influence of change in the environment for the better.

How does differential susceptibility theory explain why there is not always intergenerational transmission of child maltreatment?

According to this theory, resilient individuals are characterized by a lower degree of susceptibility to the environment. Less susceptible individuals can rely on their constitutional resilience which is rooted in a less reactive temperament and neurobiological makeup. More susceptible individuals on the other hand must rely more on a supportive environment as a buffer against adversities. These individuals may do very well if they grow up in a warm and sensitive caregiving scaffold, highlighting the role of social context in resilience.

In graph theoretical modeling, a network is composed of a certain number of nodes that are connected by weighted or un-weighted edges. A graph can be classified as a director or undirected type, depending on the existence or absence of directional information associated with the edges. In human brain development studies, the macro-scale network is often used. It is a model that can record the inter-regional connections in the whole brain in vivo through neuroimaging data. Network modes in this model are usually defined by brain partitions that are previously assigned, and the edges are determined by the structural or functional interactions between the separate brain regions.

What is the graph theoretical modeling framework?

In graph theoretical modeling, a network is composed of a certain number of nodes that are connected by weighted or un-weighted edges. A graph can be classified as a director or undirected type, depending on the existence or absence of directional information associated with the edges. In human brain development studies, the macro-scale network is often used. It is a model that can record the inter-regional connections in the whole brain in vivo through neuroimaging data. Network modes in this model are usually defined by brain partitions that are previously assigned, and the edges are determined by the structural or functional interactions between the separate brain regions.

How are network nodes defined?

Acquiring network nodes relies on neuroimaging. In EEG, fNIRS, and MEG studies, nodes are determined by using their derived cortical locations of electrodes, detectors, or sensors. In MRI studies, a parcellation scheme or atlas is needed to divide the brain into different regions of interest which are defined based on anatomical or functional information or on a random algorithm. Different parcellations capture different patterns of structural or functional pathways. The number of nodes significantly influences the absolute value of topological attributes.

How are network edges defined?

Brain regions are structurally connected through a large number of fiber bundles that provide biological pathways for information transfer. Through dMRI-based tractography, these fiber tracts can be reconstructed and then used to define edges of the structural connectivity network. The number of reconstructed streamlines or averaged informative diffusion indexes of the connection can be used as the edge weight.

What is network thresholding?

Before obtaining the brain network, a thresholding step is usually performed to define the edges to be used in the subsequent graph theoretical analysis, though some studies use the raw weighted network without thresholding. There are different ways of doing this:

• Setting an absolute cut-off value to select edges with greater weights in an individual network. Excluding weak edges may reduce the effects of weak covariance or spurious connections that could be caused by imaging noise, cumulative tractography errors, or head motions.
• In proportional thresholding a fixed number of the strongest connections are retained in each subject. It equals the network density across individuals to minimize its influence on network topological properties, though it may ignore potentially valuable connections.

What are global and nodal aspects?

The topology of a brain network can be characterized in terms of its global and nodal aspects. The global attributes measure the architecture of the whole network graph. The nodal attributes measure topological features of a single node.

What is meant with the segregation of a network?

The segregation of a network refers to the ability of local information processing that is responsible for specialized functions. The clustering coefficient and modularity are two attributes that provide a quantitative measurement of the segregation capacity of brain network.

What is the clustering coefficient of a node and of a network?

The clustering coefficient of a node refers to the tendency to which the neighboring nodes of a node are interconnected. It reflects the density of local clusters. The clustering coefficient of a network refers to the average nodal clustering coefficients across all nodes in the network.

What is meant with the integration of a network?

Network integration refers to the ability of parallel communication with distributed nodes which can be quantitatively measured by the characteristic path length or global efficiency. The characteristic path length of a network can be calculated by averaging the shortest path lengths between each pair of nodes in the network. A path represents a route of edges that connect one node with others. Its length is defined as the sum of the number or weights of the edges. The global efficiency of a network is the inverse of the average values of the shortest path length between any two nodes. A high degree of network integration is seen in a network that has high global efficiency and the low shortest path length has high global information transfer efficiency.

What is a small-world network?

A small-world network possesses a shorter characteristic path length than a regular network and a higher clustering coefficient than a random network, to guarantee high capacity for local and global information transfer networks. It is an optimized topology that balanced between a regular and a random network. A regular network has a high clustering coefficient and long characteristic path length. A random network has a low clustering coefficient and a short characteristic path length.

What is nodal degree?

Nodal degree is the most direct nodal metric, referring to the number of edges linking to a node. High degree nodes function as hubs in information transmission. The degree distribution of a network indicated the proportion of nodes that have a certain degree, which can be an indication of the resilience of the network. Rich-club organization refers to highly connected hubs, indicating that the hub nodes tend to be more densely interconnected with each other than by random chance would be expected.

Which types of network edges are distinguished?

The network edges can be classified into three types:

• Rich-club connections which link between rich-club nodes.
• Feeder connections which link between peripheral and core nodes.
• Local connections which link between non-rich-club nodes.

How does the prenatal brain network develop?

The prenatal structural network already shows broadly adult-like topological structures. The network is already highly efficient at local and global information transfers, possessing the specialized local communities for segregation and the high-cost backbones for integration. Increased normalized clustering coefficient, stable normalized shortest path length, and increasing small-worldness with development indicate that the shaping of the network seems to lean toward segregation enforcement during the prenatal stage. Short-range connections develop fast, hub regions expand into the inferior frontal cortex and insula regions and develop fast on their nodal connectivity and nodal betweenness centrality.

How does the postnatal brain network develop?

Structural segregation appears to be decreasing while structural integration is increasing, as can be seen by decreased modularity and characteristic path length and increased number of inter-module connectors and global efficiency. During early postnatal life there is dynamic regional reshaping in the structural network, as expressed by upgrades in network robustness and the left anterior cingulate gyrus and left superior occipital gyrus which become hubs. Neonatal functional brain networks maintain highly efficient small-world and modularity structure. The dorsal attention network and default mode network mature at one year of life, whereas the salience network and bilateral frontoparietal network are still developing at that time.

What is the topological development of the baby brain network?

With regards to the structural network, the hypothesis is that the structural network is well-established at the time of birth, with many local connections within modules and several major distant connections between modules. With development, the network becomes more segregated with enhancement of local clusters during prenatal development. Then it becomes more integrated with increasing inter-module connections during postnatal development. With regards to the functional network, the hypothesis is that it is still immature and incomplete at birth. With development, the network shows enhanced segregation during prenatal development. Then the emergence and increase of long connections intensify the integrated ability of networks.

How does preterm growth affect the development of the brain network?

Preterm growth is the most common type of early atypical growth. It involves the sudden interruption of typical development processes as a result of complex genetic and environmental processes. The abnormal brain topology is characterized by disruptions in cortical-subcortical connectivity and short-distance cortico-cortical connections, as well as reduced edge strengths in widespread tracts, increased clustering coefficient, and increased nodal clustering coefficients located at the lateral parietal, ventral, and lateral frontal cortices. The changes in brain network caused by preterm birth continue into later life.

Investigating the role of the frontal cortex in autism

Little is known about the underlying neural developmental defects which result in the emergence of autistic behavior during the early years of life. The frontal lobe has been identified as the most likely region to be involved, and yet little is known about it. The frontal lobe plays a key role in higher order language, cognitive, emotional, and social faculties, each one affected by autism. This has provided support for the frontal lobe hypothesis of autism. Through the collection of data from MRI and postmortem anatomical, and also already existing neurofunctional, postmortem, and MRI results from more mature autistic patients, the authors find two suggestions:

1. In patients with autism, the frontal cortex is poor at interacting with other cortical regions

2. During early development, the frontal cortex appears to be irregularly over-connected with itself

Examining macroscopic evidence of early frontal maldevelopment

Brain growth of patients with autism is normal at birth, ranging from average to slightly smaller than average. However this is followed by a period of excessive growth which results in an enlarged brain volume at the toddler age. Investigations into which brain regions cause this growth indicate the frontal lobes to be at the site of peak growth. Grey and white matter in the frontal lobes are both disparately deviant in regards to other cortical regions. While several studies have shown that primary sensory cortices in autism function normally, the same cannot be said for the frontal lobes. The deficient functionality found in the frontal lobe is hypothesized as being a factor which disrupts the frontal lobes interaction with other areas of the brain. It is unknown whether autism is to be classified as disorder of overconnectivity, underconnectivity, or a combination of the two.

Examining microscopic evidence of frontal maldevelopment

There remains a lack of knowledge on the microstructural abnormalities that disrupt frontal neural circuit development, facilitate the macroscopic overgrowth of frontal white and grey matter, and facilitate abnormal frontal mediated behavior. Where the link exists between abnormal neuroinflammatory response and initial brain overgrowth in autism is a mystery. It has been suggested that activated glia could be a reflection of a fetal state or development. When it comes to cerebral cortical information processing, a cortical minicolumn is an essential component. Studies have shown that minicolumns and their surrounding neuropil space are unusually small in children with autism throughout the frontal cortex, but not the occipital cortex. One older study found an increased neuron density and reduced neuron size within the frontal cingulate cortex in a number of autistic cases. It is suggested that these glial and neuronal abnormalities are in some way connected.

Drawing a conclusion

This is the first time that studies have shown early developmental abnormalities at the microscopic level and the macroscopic level and the presence of the frontal lobes as the peak of cerebral pathology. The work of abnormal processes (neuroinflammation, migration defects, excess cerebral neurogenesis) cause deformity, which leads to the malfunction of frontal minicolumn micro-circuitry. This in turn leads to reduced connectivity effectiveness between brain regions.

The role of response inhibition and immediate arousal in children with high functioning autism

It has long been the goal of many researchers to investigate the number of impairments that underlie the symptoms which characterize Autism Spectrum Disorder (ASD). Through the use of the executive functioning criteria, studies on ASD have highlighted planning, cognitive flexibility, and working memory to be areas which are weak in individuals with the disorder. The area of response inhibition is what the authors chose to focus on. More specifically, the study aimed to use an immediate arousal task to examine inhibition of responses in children with high functioning autism (HFA), and to look for an association with impulsivity, hyperactivity, or inattention.

Procedure

Participants for the study consisted of 39 children with HFA and a control group of 29 average functioning children. Once written permission was obtained from the parents, questionnaires were sent to the children to ascertain their suitability and possible comorbid disorders. The task consisted of a computer based reaction test. Participants were instructed in condition A to press a response button as quickly as they could upon the appearance of a white cross onscreen. In condition B they were instructed to wait for an acoustic signal before reacting as fast as they could to a white cross onscreen. The speed of the presentation rate was varied. An A-B-B-A style of sequencing of conditions was used.

Results and discussion

The aim of the study was to examine whether or not there existed a response inhibition deficit in children with HFA. The presentation of an auditory signal and a visual stimulus produced an arousal effect which resulted in an increase in error rate and a decrease in reaction time. It was hypothesized that this effect would be strongest in children with HFA. Inhibition errors did increase with the addition of the auditory signal, however this was not unique to the HFA group. The results of this study suggest that children with HFA don’t have a deficit in the inhibition system. This result is in dispute of some studies.

The role of cognitive flexibility in adults with functioning autism

Researchers are agreed that both social inadequacy and a deficit in executive functioning are both large factors which encompass autism. The main aim of this study focuses on investigating cognitive flexibility, more specifically response inhibition, set shifting, and motor presetting in regards to autism. Additionally a priori analysis was conducted by investigating the effects of the stimulus probability on performance. The authors mention the failure of previous studies in this area. Earlier studies failed to mention the patient’s medication status and thus failed to control for it. Additionally, these earlier studies often used experiment groups with varying age ranges. The authors generate four questions:

1. Is HPA associated with problems presetting the motor system in favor of the most common response type

2. Is HPA associated with weak set shifting

3. Is HPA associated with weak response inhibition

4. Is HPA associated with sensitivity for the given stimulus probability

Procedure

The sample consisted of 23 adults with HFA, and a control group of 32 typically functional individuals. The task consisted of a computer based variant of the Sternberg reaction time paradigm. The task presented participants with a set of letters to be memorized and then another set was displayed. If the participant recognized an item from the memory set in the display set, they gave a ‘yes’ response, otherwise they gave a ‘no’ response. The baseline condition consisted of 50% of the trials requiring a ‘no’ response; the response bias condition consisted of 75% of trials requiring a ‘no’ response. Each condition consisted of 64 trials.

Results and discussion

The aim of this study was to examine elements of cognitive flexibility, mainly set shifting, response inhibition, presetting, and a priori planning in individuals with HFA. Results show that participants with HFA experienced no deficit in response inhibition and the ability to change the response set. Despite this, there was a slow speed of performance found in participants with HFA, in particular those on medication. This slowness in speed may have been a contributing factor to cognitive flexibility deficit found in earlier studies which did not control for it. The study identifies a possible ceiling effect caused by an overall slowness of responses.

Executive function and social cognition in the adolescent brain 

Adolescence is a period of development characterized by intense fluctuations in both physical and hormonal change. Research has been sparse in this area, empirical research on neural and cognitive development is still lacking. For such a period that reflects the growth of cognitive flexibility, self-consciousness and changes in identity, the need for further research is apparent.

Beginning to experiment on adolescent brains

Through studies on animals, we have seen that specific sensory regions of the brain go through sensitive periods starting after birth, in which environmental stimulation seems to be crucial fro the normal development of the brain and perceptual capabilities. Experiments suggest that while this is true for animals, it may also be true for humans. During the 1970’s and 1970’s, it was demonstrated that certain brain areas, especially the prefrontal cortex develop far beyond early childhood. Further studies in the decades that followed showed that during the period of puberty and adolescence, the structure of the prefrontal cortex goes through substantial changes. Two important changes highlighted are:

1. Myelination (increasing the transmission speed of neural information)
2. Synaptogenesis (regularly used connections are strengthened and seldom used connections are removed)

Synaptogenesis was first found in 1975 within experiments using cats and was further researched using rhesus monkeys. Synaptic pruning (a period of synaptic destruction) and synaptogenesis in the brain area the prefrontal cortex exist on a differential time line. Proliferation of synapses occurs in the prefrontal cortex during childhood and once again during puberty, however this is followed by a stagnant period and elimination and reorganization of prefrontal synaptic connections following puberty.

An overall decrease in synaptic density as a result of synaptic pruning in the frontal lobes ensues during adolescence. This process is thought to be essential for refining the effectiveness of neural networks. This is especially true when given the sensitive case of sound recognition development.

The adolescent brain seen through MRI

Through the implementation of modern technology, it has become possible to view the brain of living specimens. With the introduction of magnetic resonance imaging, we can non-invasively view the human brain in a detailed three-dimensional visual. This has been instrumental in the furthering of research on the maturation of the frontal cortex of adolescence and onwards into adulthood.

Linear increases in white matter during adolescence

Over the past years, researchers have found one consistent outcome across MRI studies: during adolescence and childhood there is a steady increase in white matter located in certain brain regions. One study found a significant between the white and grey matter levels between two age groups. This increase in white matter has been suggested to be the result of developmental changes by some studies. One study found an increase in white matter in the right internal capsule and left arcuate fasciculus. Both regions are associated with speech so it was hypothesized that the increase in white matter was due to speech development.

Non-linear decreases in grey matter during adolescence

Grey matter, in contrast to white matter, does not seem to follow a linear pattern. Rather it seems to follow a region specific, non-linear pattern. Research has shown that grey matter follows an inverted-U shape in certain brain regions. Studies suggest that grey matter volume in the frontal lobe reaches its peak during puberty, which is then followed by a stagnation period and a steady decline until though adolescence until early adulthood. MRI research on the decline of grey matter throughout adolescence has two explanations:

1. Axonal myelination both facilitates an increase in white matter and a decrease in grey matter
2. The decrease in grey matter is a reflection of the reorganization which occurs during puberty

Examining the role of gender differences in the development of brain structure

Research has shown that there exists a significant difference in the amount of grey and white matter found in males and females. This was particularly true in the area known as the inferior frontal gyrus (IFG). Researchers corrected for the possible confound of total cerebral volume but still they found that males had a significantly higher amount of grey matter. Some researchers believe this difference is a result of differential steroid levels, others believe it may be due to greater hemispheric specialization found in males. As of current research, more study is needed to examine variability in frontal cortex anatomy.

The continuing brain changes after adolescence

Recent research using MRI suggests that the period at which the brain reaches maturity could be later than the end of adolescence. This change is seen especially in the frontal and parietal cortices following post-mortem cellular examinations of human brains which support an extended period of development. The adolescent brain appears to develop in a dynamic nature when looking at the growth of white and grey matter.

Examining the development of executive function

Executive functioning refers to a set of cognitive mechanisms which govern how well we control and coordinate our behavior and cognition. Lesion studies have shown that many of the skills involved in executive functioning are dependent on the frontal lobes. Given that changes occur in the frontal cortex during adolescence, executive functioning might be expected to improve during this period. Behavioral studies have shown that inhibitory control, processing speed, working memory, and decision making continue to develop throughout adolescence.

Examining the development of social cognition

Evidence suggests that the prefrontal cortex is associated with many high level cognitive functions, such as self-awareness and theory of the mind. In tandem with this neural development, puberty marks a great period of change for hormonal development. These two factors combined mark a significant change in social cognition. Research concerning the effects of puberty on social cognition capacitates has been limited.

Looking at perspective taking

The act of perspective taking refers to putting oneself in another’s shoes and it is an essential component for effective social communication. This act of estimating what another individual is thinking is  related to the first-order theory of mind. It is an area of much theoretical debate. One view surmises that we understand others by simulating their actions and cognitions. In support of this, research has shown that similar brain areas are activated when we perform an action and when we see another perform the same action. This is in line with the function of mirror neurons.  

The adolescent brain in action seen through fMRI

With the introduction of fMRI, we have a safe and effective way to examine brain regions.  As an example, through the use of fMRI we were able to examine how response inhibition has developed in addition to examining the structure supporting its development. During studies involving inhibition of a normal response, it was shown that activation of certain brain regions was for the most part the same across age groups.  An exception was a significantly larger volume of activation in the prefrontal of children. In contrast to this, adults showed higher activation in the ventral region of the prefrontal cortex. One suggested reason for this is that children have a heftier dependence on this area than adults.

The confounds on task performance

An issue which has been found when conducting fMRI is that of confounding effect of task performance. If there is a difference in the performance between two groups i.e. one outperforms the other, the results are often difficult to interpret.

Examining the development of social cognition within the brain

In terms of brain regions, the amygdala is an area which has repeatedly been shown to have a high functioning role in facial recognition and emotional processing. Though research in this area has been investigated with adolescents, still little is known about the continued development of facial recognition. Studies have shown that children may identify neutral faces as being more ambiguous than fearful faces, resulting in an increase in activation in the amygdala.

Effect on teenagers

puberty marks a period of synaptic reorganization, and as a result can be more susceptible to experiential input, in particular regarding social cognition and executive functioning. Further studies are needed to examine the further development of brain maturation beyond childhood and the implications this has on cognition. The authors specify questions into which skills undergo perturbation, sensitive periods for improvement and how does the environmental quality impact the changes which occur in the brain.

Revision of treatments and guidelines for phenylketonuria: evidence from neurocognition

An inborn, inherited, error of metabolism, phenylketonuria (PKU) is a rare, highly treatable disease. In contrast to its relatively treatable nature, when left untreated, PKU can result in seizures, intellectual disability, and further medical issues. The most common method for prevention is the early introduction of a strict diet highlighting the restriction of phenylalanine (Phe). Despite its treatability, patients with PKU show an average 8-10 points lower than normal in addition to underperforming in neuropsychological tests.

Cognitive impairments have been associated with concurrent blood Phe levels, and even more so with lifetime blood Phe levels. The question being raised by the authors concerns whether or not the recommend Phe level for patients with PKU is too high. Currently, from the age of 0-10, this level varies between 240 and 360 micromolars/L. The drawback is that this range is not the result of studies comparing outcomes at Phe levels <240 micromolar/L, between 240 and 360 micromolar/L, and >360 micromolar/L.

Current treatment advises an absolute upper target level for Phe levels, not taking into account possible fluctuations of Phe values and the phenylalanine:tyrosine ratio (Phe:Tyr). This feeds into the second area of question the authors pose: what are the effects of lifetime Phe, concurrent Phe, variation in lifetime Phe levels, and lifetime and concurrent Phe:Tyr in predicting cognitive outcome in early and continuously treated children and adolescents with PKU

Methods

Participants consisted of 67 patients with PKU with a mean age of 10.8, and a control group of 73 participants with a mean age of 10.9 recruited from friends and families of patients and also local newspaper advertisements. Of the patients with PKU, 27 had pretreatment Phe levels of > 1200, 18 had pretreatment Phe levels between 600-1200, and 18 had pretreatment Phe levels <600, and 12 patients had pretreatment Phe levels <360. To test for concurrent Phe and Tyr levels, a blood sample was taken in the morning following an overnight fast. This was also used to test for lifetime Phe level. Through a series of computer based neuropsychological tests, executive functions inhibitory control and motor control were measured.

Results and discussion

Patients with Phe levels >360 differed in 2 of 3 inhibition tasks, motor control, and cognitive flexibility. Controls performed notably more accurately than patients with Phe levels between 240-360. A key finding was that patients with Phe levels <240 performed no different to the control group. Additionally, patients with Phe levels <240 outperformed those with Phe levels between 240-360.

It was found that Phe variation, lifetime and concurrent Phe, and lifetime and concurrent Phe:Tyr were significantly related to speed and accuracy on numerous cognitive tests and also to each other.

The two major findings of this study are:

1. Youths from the age of 6-15 with mean Phe levels of <240 since birth outperformed their peers with Phe levels between 240-360 on cognitive tests measuring motor control, inhibition, and cognitive flexibility.
2. Phe:Tyr and Phe variation may have predictive value in regards to motor control ad executive functioning.

The PKU-COBESO study

As mentioned in previous studies examined, phenylketonuria (PKU) is an inherited metabolic disorder. In the case of someone with the disease, there is a deficiency in the phenylalanine hydroxylase enzyme and as a result, phenylalanine (Phe) cannot be converted into tyrosine (Tyr). This excess of Phe, in combination with a lack of Tyr can lead to shortages of important neurotransmitters such as serotonin and dopamine. Serotonin is linked to cognitive functioning and a lack of it can result in decreased cognitive functioning. Dopamine is associated with the executive functioning primarily in the prefrontal cortex. There is a considerate lack of studies concerning behavioral problems and social skills for those with PKU. The aim of the study presented here is to explain a new Dutch multicenter study, namely the PKU-COBESO study. The primary goal of the PKU-COBESO study is to examine the behavioral problems, social functioning, cognitive functioning, and executive functioning in both continuous and early treatment patients principally in regards to their metabolic control.

Looking at the procedure for the PKU-COBESO study

The experiment sample for the study consisted of young adult patients with PKU who had beforehand participated in a neuropsychological study 10-15 years previous, and another group of patients who did not participate in the previous neuropsychological study. In the control group, participants were recruited from either the families and friends of the patients, or from non-family participants.

The study itself consisted of a neuropsychological assessment, questionnaires, and an analysis of the PKU patients’ metabolic control. The neurological assessment comprised of a combination of either the WISCIII or WAISCIII (depending on the participants age) and the ANT (Amsterdam Neuropsychological Tasks), and numerous paper and pencil tasks. The aim of the neuropsychological component was to measure:

1. Executive functions

2. Social cognitive skills

3. Motor control

The questionnaires aimed to ascertain:

1. General demographic information

2. Executive functioning throughout daily life

3. Social functioning

4. Mental health/behavioral problems

Blood samples were taken from the PKU patients in order to determine concurrent Phe and Tyr levels, and the levels of other metabolic features.

Examining the findings in the preliminary results

In the preliminary analysis, results showed that adult PKU patients differed on ‘internalizing problems’, reported more ‘avoidant personality problems’, scored worse on ‘relationships’ and also ‘self care’. Additionally, the concurrent Phe levels of adults with PKU were not significantly related to social skills and behavioral problems. Childhood Phe levels were shown to be significantly related to ‘thinking problems’ and ‘somatic problems’.

For discussion

The PKU-COBESO study has two main questions it seeks to answer:

1. How does leniency of diet in early stages of PKU go on to influence cognitive and behavioral functioning, and the potential for an adult to thrive in life.

2. To what extent do Phe influenced cognitive problems manifest in the daily living of PKU patients.

The results of the study should be considered preliminary. Having said that, the results are complimentary to the expected findings and provide evidence for the importance of further study focusing on the mental health and social functioning in early treated PKU.

Investigating the usefulness of BRIEF in day to day care of patients with phenylketonuria

The origins, effects, and treatment of PKU have been discussed previously. The following article focuses on the effects PKU has on executive functioning specifically. To ascertain these effects the implementation of the Behavior Rating Inventory of Executive Functioning (BRIEF) is proposed. This is an easily applied standardized questionnaire which can also be employed by non-psychologists. However, the accuracy of the BRIEF has been called in to question. To address this, the authors also use the Amsterdam Neuropsychological Tasks (ANT) measure, which has been used several times in the past to ascertain the neurocognitive functioning of PKU patients of various ages and early and continued treatment. Using the two tests, the authors attempt to investigate whether the BRIEF-A (adult version) is a useful instrument in the screening of patients with PKU during their daily living.

Procedure

The sample for this study consisted of 55 Dutch adult patients with PKU. Additionally, this study was a part of the PKU-COBESO mentioned in the previous article. The BRIEF-A test consisted of 75 questions 9 subdomains related to executive functioning, 4 subdomains which determine the Behavioral Regulation Index (BRI). The overall executive functioning in daily life score is denoted as the Global Executive Composite (GEC).

For the ANT, three tests were used to measure executive functioning: Shifting Attentional Set Visual (SSV), Sustained Attention Dots (SAD), and Feature Identification (FI).

Looking at results

Of the 55 patients, 23 scored within the borderline/clinical range of the BRIEF-A. Patients showed problems in the domains of cognitive flexibility and inhibitory control when compared to the healthy population. Subsequently, two groups were formed on the basis of BRIEF-A GEC scores using a cutoff T-score of >= 60 (>1 SD above the mean). No significant differences were found between the groups on the basis of gender, age, and IQ. Additionally, no significant differences were found between the two groups on concurrent and historical Phe concentration levels. There was found to be some agreement between the BRIEF and the ANT indicating that the null hypothesis could not be rejected.

For discussion

The fact that patients with PKU still face problems in attention and learning was the driving factor for this investigation into the efficacy of the BRIEF as a tool for monitoring patients. The results show that 42% of patients scored in the borderline/clinical range. Despite this, only 11% of patients showed scores greater than 1 SD. From the results of the ANT, we see that PKU patients had problems with inhibitory control and cognitive flexibility. The BRIEF-A appears to identify executive dysfunction across studies.