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Developmental Neuropsychology: Treatments and guidelines for phenylketonuria
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:
- 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.
- 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:
Executive functions
Social cognitive skills
Motor control
The questionnaires aimed to ascertain:
General demographic information
Executive functioning throughout daily life
Social functioning
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:
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.
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.
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Study guide with articlesummaries for Developmental Neuropsychology at the University of Groningen
Articlesummaries with Developmental Neuropsychology at the University of Groningen
Table of content
- Executive function and social cognition in the adolescent brain
- Cognitive control and motivational systems
- Mild spastic cerebral palsy
- Treatments and guidelines for phenylketonuria
- ADHD
- Autism
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Developmental Neuropsychology
Developmental Neuropsychology: Executive function and social cognition in the adolescent brain
Developmental Neuropsychology: Executive function and social cognition in the adolescent brain
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:
- Myelination (increasing the transmission speed of neural information)
- 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.
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Developmental Neuropsychology: Cognitive control and motivational systems
Developmental Neuropsychology: Cognitive control and motivational systems
Cognitive control and motivational systems in developmental neurobiology
Cognitive control is an executive process which can be vital to the maintenance and monitoring of long term goal oriented behavior. In the past, the development of cognitive control has been explained as a growth from infancy to adulthood. The role of context on cognitive control impacts one’s behavioral regulation abilities, for example in a stressful context one may experience diminished control. Recent studies suggest that cognitive control capacity is impacted by specific periods of development whereby one is more susceptible to incentive based modulation.
When examining studies on cognitive control performed in a controlled laboratory settings, we see a relatively stable improvement in cognitive control capacity from infants progressing to adults. However, outside of the laboratory setting, this is often not the case. This is particularly true for adolescence, who experience a reduced capacity for cognitive control when exposure to potentially risky behavior is at its peak. These fluctuations in behavior give evidence of dynamic maturation of the brain mechanisms responsible for motivation and cognitive processes. Two areas of the brain are highlighted for their importance in cognitive and motivational processes: the prefrontal cortex (essential for cognitive control) and the striatum (important for identifying interesting cues in an environment).
Examining the role of motivational modulation of cognitive control across development
Recently, research on the development of adolescences has focused on comparing cognitive capacity in neutral settings as opposed to motivational contexts. This research has implied that there exists a unique influence of motivation on cognition during the adolescent period, and that sensitivity to environmental cues (in particular incentive cues) changes at various points in development.
The behavior of adolescents has been shown to be differentially biased in motivational contexts. Studies have shown that motivational cues of potential reward are especially salient and potentially lead to the engagement in risky behavior and the further weakening of goal-orientated behavior.
Corticosubcortical control and its developmental neurobiology
This has led to the development of a neurobiological model of motivational and cognitive processes which aims to explain the behavior of adolescents outside of a laboratory context. Working with this model leads to the suggestion linear development of top down prefrontal regions relative to a n-shaped function for the development of bottom-up striatal regions involved in detecting particularly interesting cues in the environment.
The findings of Pasupathy and Miller
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Developmental Neuropsychology: Mild spastic cerebral palsy
Developmental Neuropsychology: Mild spastic cerebral palsy
Mild spastic cerebral palsy: An event-related brain potential study of error detection and response adjustment
The term cerebral palsy is used to define a number of disorders which affect posture and movement. Cerebral palsy is attributed to damage or abnormal development in the developing brain of fetus’s or infants. Though there are many contributing factors to cerebral palsy, one of particular note are infarcts (tissue death as a result of lack of oxygen) which lead to lesions in white and grey matter tracts. These lesions to white matter tracts are detrimental to executive functioning which has been proven when testing youths with cerebral palsy against a control group without.
The question posed by this study is whether youths with mild spastic cerebral palsy are aware of their errors when carrying out tasks requiring executive functioning.
It has often been the findings of neurocognitive research that poor motor preparation precedes error making. Error detection and the adjustments which follow are measured in this case using response-locked error-related negativity. The brain potential for incorrect responses is markedly higher than those following correct responses.
Method
Participants consisted of 11 patients, with a mean age of 14 years, diagnosed with mild cerebral palsy and a control group of 12 youths without cerebral palsy, with a mean age of 14, recruited from the same city. Though the intelligent quotient of some of the youths with mild cerebral palsy was within the range of learning disabilities, none were classified as being mentally retarded, as their daily lives were intact.
A computer based stimulus recognition task and electroencephalograms were used to record brain activity in the study. The task used was comparable to the Sternberg short-term memory paradigm. Participants were presented with 2 letters to be memorized, then were subsequently shown 4 letters, one or none of which were the letters which were memorized. Using two response buttons, participants would indicate either yes or no whether they identified there target letters in the new set. Reaction time was measured starting when the new set appeared until a button was pressed. Total time for the experiment was about 15 minutes.
Results
The results of the experiment find that the control group made more correct responses and less error responses than the experiment group. In addition, the patient group reacted slower on average than
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Developmental Neuropsychology: Treatments and guidelines for phenylketonuria
Developmental Neuropsychology: Treatments and guidelines for phenylketonuria
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:
- 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.
- Phe:Tyr and Phe variation may have predictive value
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Developmental Neuropsychology: ADHD
Developmental Neuropsychology: ADHD
- Examining a pilot study of methylphenidate, interstimulus interval, and reaction time performance of children with attention deficit/hyperactivity disorder
- State regulation and motivation in ADHD
- Investigating the dysfunctional modulation of default mode network activity in attention-deficit/hyperactivity disorder
Examining a pilot study of methylphenidate, interstimulus interval, and reaction time performance of children with attention deficit/hyperactivity disorder
Attention deficit/hyperactivity disorder (ADHD) is one of the most common found disorders in children. Characterized by inattention and hyperactivity, ADHD is primarily an inherited disorder. Treatment usually involves methylphenidate (MPH), which works by regulating the dopamine system. This often results in a decrease in impulsivity, hyperactivity, and inattention. Despite this, children on MPH still experience deficits in cognitive faculties. Other studies have shown that children with ADHD perform differently depending on the length of a stimulus they are exposed to. If the stimulus is a short interstimulus interval (ISI), the children experience a more positive performance in comparison to a long ISI. A short ISI has been shown to improve memory recognition, vigilance, motor timing, and more. It is thought that both MPH and a short ISI act upon the dopamine levels in the brain. It is proposed that having both of these working at the same time may over-activate the system and lead to detrimental effects. The goal of this study was to measure the isolated and combined effect of MPH and ISI on mean response times and errors of commission.
Procedure
For this study the sample consisted of 13 children (10 boys; 3 girls) diagnosed with ADHD. During the time of the study, MPH was gradually introduced for a two week period, either adjusting to a higher or lower dosage. After the children had been on MPH for 4 weeks, they were tested twice, once after the administration of MPH, and once after a placebo. The task which the participants engaged in was a computer based reaction time test known as Go/No-Go test. This involved pressing a button when the letter Q appeared onscreen and press nothing when the letter O appeared. If the participant responded to the letter O, this was recorded as an error of commission.
Looking at results
The results from the study indicate:
Children respond faster on MPH than not on MPH
Children respond faster in a condition with a short ISI rather than a long ISI
The interaction of ISI and MPH was not significant
Children on MPH made more errors of commission during the condition with a short ISI
Children on the placebo made fewer errors of commission during the condition with a short ISI
For discussion
This study set out to ascertain
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Developmental Neuropsychology: Autism
Developmental Neuropsychology: Autism
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:
In patients with autism, the frontal cortex is poor at interacting with other cortical regions
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
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