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.

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.