Inhibitory control in children with phenylketonuria.
ABSTRACT Past studies have reported impairments in children with early-treated phenylketonuria (PKU) in executive abilities such as strategic processing and working memory. Findings have been inconsistent in terms of the integrity of inhibitory control, another executive ability. This study administered 4 inhibitory tasks (flanker, Stroop, go/no-go, antisaccade) to 26 children with PKU and 25 typically developing control children. Children with PKU performed more poorly than typically developing children on the 2 inhibitory tasks with the strongest experimental manipulations (go/no-go and antisaccade) between control and inhibitory conditions. Findings suggest that the inhibitory deficit associated with PKU is subtle and that inconsistent findings in past studies may be largely due to the insensitivity of experimental manipulations in some tasks.
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ABSTRACT: Sapropterin dihydrochloride effectively lowers plasma phenylalanine (Phe) for at least a third of phenylketonuria (PKU) patients, with potential for increased dietary Phe tolerance and decreased medical food requirement. To investigate long-term quality of life (QOL) in patients with phenylketonuria (PKU) who took sapropterin (BH4, Kuvan(R)) for up to one year. 37 PKU patients, ages 10-49 years, were asked to complete a PKU-specific self-report QOL questionnaire (QOLQ) at baseline, 1, 4, 8, and 12 months. Questions were scored on a 5-point Likert scale under 5 sub-sections measuring Impact, Worries, Satisfaction, Support, and General wellbeing in relation to PKU. Responders with a plasma Phe decrease >= 15% after 1 month on sapropterin remained on the drug; Nonresponders ceased sapropterin after the trial month. Responders able to relax medical diet and maintain plasma Phe control were classified as Definitive; Responders unable to relax medical diet were classified as Provisional. All patients were routinely monitored by a registered dietitian. Data was analyzed in SPSS 19.0 using regression techniques. Of 17 Responders, 11 could maintain adequate Phe control on a less restrictive diet. One year mean Impact sub-score trends improved significantly for all sapropterin response groups, with greatest improvement among Definitive Responders (p < 0.0001). Satisfaction sub-scores also improved for Definitive Responders (p = 0.001). Trends for Total QOL score improved significantly over time for both Definitive (p = 0.001) and Provisional Responders (p = 0.028). Improvements in Definitive Responder scores were associated with increased Phe tolerance (Impact: p < 0.0001, Satisfaction: p = 0.022, Total QOL: p = 0.005) and MF adjustment (Satisfaction: p = 0.014, Total QOL: p = 0.026). Other sub-section scores remained steady, unaffected by sapropterin response or diet modification. Increased Phe tolerance and reduced MF requirement in sapropterin Definitive Responders improves QOL perception across one year, specifically for life impact and satisfaction.Health and Quality of Life Outcomes 12/2013; 11(1):218. · 2.27 Impact Factor
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ABSTRACT: Phenylketonuria (PKU) is a well-defined metabolic disorder arising from a mutation that disrupts phenylalanine metabolism and so produces a variety of neural changes indirectly. Severe cognitive impairment can be prevented by dietary treatment; however, residual symptoms may be reported. These residual symptoms appear to overlap a more prevalent childhood disorder: Attention Deficit/Hyperactivity Disorder (ADHD). However, the aetiology of ADHD is a vast contrast to PKU: it seems to arise from a complex combination of genes; and it has a substantial environmental component. We ask whether these two disorders result from two vastly different genotypes that converge on a specific core phenotype that includes similar dysfunctions of Gray's (Gray, 1982) Behavioural Inhibition System (BIS), coupled with other disorder-specific dysfunctions. If so, we believe comparison of the commonalities will allow greater understanding of the neuropsychology of both disorders. We review in detail the aetiology, treatment, neural pathology, cognitive deficits and electrophysiological abnormalities of PKU; and compare this with selected directly matching aspects of ADHD. The biochemical and neural pathologies of PKU and ADHD are quite distinct in their causes and detail; but they result in the disorder in the brain of large amino acid levels, dopamine and white matter that are very similar and could explain the overlap of symptoms within and between the PKU and ADHD spectra. The common deficits affect visual function, motor function, attention, working memory, planning, and inhibition. For each of PKU and ADHD separately, a subset of deficits has been attributed to a primary dysfunction of behavioural inhibition. In the case of ADHD (excluding the inattentive subtype) this has been proposed to involve a specific failure of the BIS; and we suggest that this is also true of PKU. This accounts for a substantial proportion of the parallels in the superficial symptoms of both disorders and we see this as linked to prefrontal, rather than more general, dysfunction of the BIS.Brain research bulletin 10/2013; · 2.97 Impact Factor
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ABSTRACT: BACKGROUND: phenylketonuria is manifested by partial or total deficiency of the hepatic enzyme phenylalanine hydroxylase that, in excess, has a toxic effect on the central nervous system functions, reflecting in the individual's global development. PURPOSE: to submit the alterations in the development verified in scientific studies with individuals with phenylketonuria, and to contemplate the abilities related to language development. CONCLUSION: individuals with phenylketonuria are risky for alterations in the cognitive, linguistics, motor and social-behavior functions. Deficits in the executive functions and neuropsychological abilities are common and imply in discrepancies as for language abilities development. The findings justify the proposal forwarding to the Ministry of Health with views to contracting a Speech and Language Pathologist in the accredited Neonatal Screening Programs.Revista CEFAC 04/2010; 12(2):326-330.
Running Head: INHIBITORY CONTROL IN PHENYLKETONURIA
Inhibitory Control in Children with Phenylketonuria
Shawn E. Christ1, Ph.D., Robert D. Steiner2, M.D., Dorothy K. Grange3, M.D.,
Richard A. Abrams1, Ph.D., & Desirée A. White1, Ph.D.
1. Department of Psychology
St. Louis, Missouri
2. Departments of Pediatrics and Molecular & Medical Genetics
Child Development and Rehabilitation Center
Doernbecher Children’s Hospital
Oregon Health & Science University
3. Department of Pediatrics
Washington University Medical School
St. Louis, Missouri
Address correspondence to:
Shawn E. Christ
Department of Psychology
Campus Box 1125
St. Louis, MO 63130-4899
Telephone: (314) 935-8892
Fax: (314) 935-7588
Past studies have documented impairments in children with early-treated phenylketonuria (PKU)
in executive abilities such as strategic processing and working memory. Findings have been
inconsistent in terms of the integrity of inhibitory control, another executive ability. In this study,
we administered four inhibitory tasks (flanker, Stroop, go/no-go, antisaccade) to 26 children with
PKU and 25 typically developing control children. Children with PKU performed more poorly
than typically developing children on the two inhibitory tasks with the strongest experimental
manipulations (go/no-go and antisaccade) between control and inhibitory conditions. Our
findings suggest that the inhibitory deficit associated with PKU is subtle, and that inconsistent
findings in past studies may be due largely to the insensitivity of experimental manipulations in
Key words: Inhibitory control, executive function, frontal cortex, children, phenylketonuria
Inhibitory Control in Children with Phenylketonuria
Inhibitory control is the ability to suppress the activation, processing, or expression of
information that would otherwise interfere with the efficient attainment of a cognitive or
behavioral goal. Findings from recent neuroimaging studies of children (for a review, Casey,
Trainor et al., 1997; Durston et al., 2002) indicate that inhibitory control is associated with
activity in the prefrontal cortex of the brain. In the current study, we examined the hypothesis
that children with prefrontal dysfunction related to phenylketonuria (PKU) exhibit deficits in
Experimental tasks commonly used to examine inhibitory control include go/no-go,
Stroop, flanker, and antisaccade. In go/no-go tasks (e.g., Casey, Castellanos et al., 1997),
participants respond to designated target stimuli (e.g., letters) and withhold responses to
designated nontarget stimuli (e.g., the letter “F”). In contrast, in Stroop, flanker, and antisaccade
tasks, alternative responding is the goal. During traditional Stroop tasks (for a review, MacLeod,
1991), participants are shown color names (e.g., “Red,” Blue,” “Green”) displayed in
incongruent colors (e.g., “Red” displayed in blue). The goal is to inhibit the prepotent reading
response and instead identify the color in which the color name is displayed. The performance of
individuals in this inhibitory condition is typically compared with a control condition in which
participants are shown non-color names in various colors (e.g., “Dog” in blue). In a classic
flanker task (Eriksen & Eriksen, 1974), participants respond to the identity of a centrally
presented target (e.g., press the left button for “S” and the right button for “H”) that is flanked
closely by distracter stimuli. Distracters may be compatible (mapped to the target response; e.g.,
“SSS”), neutral (mapped to no response; e.g., “XSX”), or incompatible (mapped to a different
response; e.g., “HSH”). Finally, in antisaccade tasks (for a review, Everling & Fischer, 1998;
Hallet, 1978), reflexive eye movements toward a peripheral stimulus (prosaccades) are inhibited
and eye movements are instead made away from the stimulus (antisaccades).
Neuroimaging studies have shown that the prefrontal cortex and related brain regions
(e.g., anterior cingulate) are activated during go/no-go (Casey, Trainor et al., 1997; Durston et
al., 2002), Stroop (Bench et al., 1993; Pardo, Pardo, Janer, & Raichle, 1990), flanker (Botvinick,
Nystrom, Fissell, Carter, & Cohen, 1999; Casey et al., 2000; Hazeltine, Poldrack, & Gabrieli,
2000), and antisaccade (Everling & Fischer, 1998) tasks. Lending further support to the notion
that prefrontal brain regions play a major role in inhibitory control, findings from developmental
studies using these same tasks have related improvements in inhibitory control to prefrontal
maturation (go/no-go: Casey, Trainor et al., 1997; flanker: Enns & Akhtar, 1989; antisaccade:
Fischer, Biscaldi, & Gezeck, 1997; Stroop: Schiller, 1966).
The importance of prefrontal brain regions in the development of inhibitory control is
underscored by the fact that inhibitory deficits are observed across a range of childhood
disorders, including attention deficit disorder (Casey, Castellanos et al., 1997), Tourette
syndrome (Leckman et al., 1987), obsessive-compulsive disorder (Insel, 1988), and childhood-
onset schizophrenia (Asarnow, Brown, & Strandburg, 1995). Although the specific etiology of
each disorder remains to be defined precisely, in each instance it is believed that prefrontal
development is disrupted (Bradshaw, 2001). In addition, in each instance prefrontal
abnormalities have been identified (attention deficit disorder: Casey, Castellanos et al., 1997;
Tourette syndrome: Pennington, 1997; childhood-onset schizophrenia: Rapoport et al., 1999;
obsessive-compulsive disorder: Saxena, Brody, Schwartz, & Baxter, 1998).
PKU is another childhood disorder associated with early prefrontal dysfunction (for an
overview, Scriver & Kaufman, 2001). PKU is a genetic disorder occurring in approximately 1 in
15,000 newborns in the United States (National Institutes of Health Consensus Developmental
Panel, 2001) and is characterized by the disrupted metabolism of phenylalanine (an amino acid)
due to a deficiency in phenylalanine hydroxylase (an enzyme) (Scriver & Kaufman, 2001). As a
result, a neurochemical cascade (phenylalanine → tyrosine → dopamine) of crucial importance
to prefrontal function is disrupted. Excess phenylalanine also competes with tyrosine in crossing
the blood-brain barrier (Diamond, Ciaramitaro, Donner, Djali, & Robinson, 1994; Thompson,
1995), further limiting the availability of the essential dopamine precursor.
In addition to dopamine disregulation, white matter abnormalities have been identified in
postmortem (Alvord, Stevenson, Vogel, & Engle, 1950; Poser & van Bogaert, 1959) and
neuroimaging (Bick et al., 1993; Cleary et al., 1994; Hasselbach et al., 1996; Huttenlocher, 2000;
Pietz et al., 1996; Thompson et al., 1993) studies of individuals with PKU. Of particular
relevance to prefrontal function, Hasselbalch et al. (1996) found white matter abnormalities in
the frontal lobes of adults using magnetic resonance imaging and noted a 36% reduction in
glucose metabolism (i.e., the amount of glucose converted to energy) in anterior periventricular
brain regions using positron emission tomography. Most recently, abnormalities in white matter
integrity have been identified using diffusion weighted imaging (Dezortova, Hajek, Tintera,
Hejcmanova, & Sykova, 2001; Phillips, McGraw, Lowe, & Hainline, 2001). It has been
postulated that such white matter abnormalities may underlie the psychomotor slowing that has
been observed in individuals with PKU (e.g., Gourovitch, Craft, Dowton, Ambrose, & Sparta,
1994). Although speculative at present, given that the prefrontal cortex is so highly
interconnected with other brain regions, it is likely that white matter abnormalities may further
compromise prefrontal function in individuals with PKU.
The crucial role of prefrontal brain regions in subserving executive abilities has led some
researchers to conceptualize PKU as a model of the cognitive effects associated with early
prefrontal dysfunction (Welsh, 1996). Deficits in specific aspects of executive ability such as
problem solving (Brunner, Jordan, & Berry, 1983; Pennington, van Doorninck, McCabe, &
McCabe, 1985; Seashore, Friedman, & Norelly, 1979), planning (Koff, Boyle, & Peuschel, 1977;
Welsh, Pennington, Ozonoff, Rouse, & McCabe, 1990), cognitive flexibility (Anderson,
Anderson, Northam, Jacobs, & Mikiewicz, 2002; Diamond, 1998; Huijbregts, de Sonneville,
Licht, Sergeant, & van Spronsen, 2002; Pennington et al., 1985; Ris, Williams, Hunt, Berry, &
Leslie, 1994), strategic processing (White, Nortz, Mandernach, Huntington, & Steiner, 2001),
and working memory (Channon, German, Cassina, & Lee, 2004; White, Nortz, Mandernach,
Huntington, & Steiner, 2002) have been identified.
Inhibitory control is another aspect of executive ability that has been examined in
children with PKU, but findings have been inconsistent across studies. For example, using a
Stroop paradigm, Weglage, Pietsch, Funders, Koch, and Ullrich (1996) found that children with
PKU performed more poorly in the inhibitory condition than age-matched controls. Later studies
(Feldman, Denecke, Pietsch, Grenzebach, & Weglage, 2002; White et al., 2002), however, failed
to replicate this finding.
Additional studies of inhibitory control in children with PKU have been conducted by
Huijbregts and colleagues. In each of their three studies, a different inhibitory measure was
administered: a flanker-like task (Huijbregts, de Sonneville, van Spronsen, Licht, & Sergeant,
2002), a stimulus-response reversal task (Huijbregts, de Sonneville, Licht, Sergeant et al., 2002),
and a continuous performance task (Huijbregts, de Sonneville, Licht, van Spronsen et al., 2002).
The results of these studies were mixed. Although PKU-related impairments in performance
were evident on the stimulus-response reversal and continuous performance tasks, children with
PKU performed comparably to controls on the flanker task.
Work by Diamond (1998) and others provides additional support for the supposition that
inhibitory control may be impaired in individuals with PKU. Using a version of Piaget’s A not-
B task, Diamond found that infants with PKU made more perseverative errors than controls.
Similarly, increased perseverative errors on the Wisconsin Card Sorting Test have been
documented in studies of older children and adults with early-treated PKU (Pennington et al.,
1985; Ris et al., 1994).
A difficulty in interpreting results from studies of inhibitory control in individuals with
PKU is that it is not always possible to determine if the primary impairment is related to
inhibitory control or to another area of cognition. PKU-related impairments on the A not-B task
(Diamond, 1998) and the Wisconsin Card Sorting Test (Pennington et al., 1985; Ris et al., 1994)
may be due to difficulties with working memory and strategic processing, respectively, rather
than inhibitory control. Similarly, in the absence of a separate measure of processing speed,
slower response times for individuals with PKU on a speeded inhibitory task could be related to
impaired inhibitory control, psychomotor slowing, or both.
The goal of the present investigation was to shed additional light on the integrity of
inhibitory control in children with PKU. Four widely-used inhibitory tasks were administered to
children with early-treated PKU and demographically-matched control children. The inclusion
of a neutral/baseline condition for each inhibitory task allowed us to control for individual
differences in other cognitive abilities (e.g., processing speed, memory, etc.) that may influence
performance. To anticipate our results, we found that children with PKU demonstrated impaired
performance on only two of the four inhibitory tasks, a finding that is generally consistent with
the pattern of sparing and impairment in inhibitory control observed in past studies of PKU. We
also explored possible age-related differences in the degree of inhibitory impairment experienced
by children with PKU and the possible relationship between inhibitory ability and phenylalanine
The sample included 26 children (13 female, 13 male) with early treated PKU and 25
typically developing control children (14 female, 11 male). Children in the PKU group ranged
from 6 to 18 years of age (M = 11.2; SD = 3.1) and were recruited through the Division of
Medical Genetics/Department of Pediatrics at St. Louis Children’s Hospital in St. Louis,
Missouri and through the Metabolic Clinic at the Child Development and Rehabilitation Center
at Doernbecher Children's Hospital in Portland, Oregon. Children in the control group ranged
from 7 to 18 years of age (M = 11.3; SD = 3.4), were recruited from the St. Louis and Portland
communities and had comparable socio-economic backgrounds to the children with PKU (i.e.,
the groups did not differ significantly in terms of household income, p > .05). Children with
histories of mental retardation, learning disorders, or major medical disorders unrelated to PKU
For all children with PKU, diagnosis was made and treatment was implemented shortly
after birth as indicated by medical records and/or parental report. At the time of participation, all
children were prescribed restricted phenylalanine intake diets. Recent blood phenylalanine
levels were obtained through review of medical records. Blood phenylalanine levels obtained
closest to time of study (M = 3.3 days, SD = 3.7 days) ranged from 0.2 to 20.2 mg/dL (M = 7.0
mg/dL; SD = 5.6 mg/dL). Levels within 30 days of time of study were unavailable for five
children. Phenylalanine levels obtained closest to time of study were highly correlated (r = 0.82,
p < .001) with mean levels during the year preceding our study. As such, the phenylalanine
levels obtained closest to time of study appear to accurately describe those generally experienced
by children in our study.
The Vocabulary and Matrix Reasoning subtests from the Wechsler Abbreviated Scale of
Intelligence (Psychological Corporation, 1999) were administered to estimate general intellectual
ability. For children with PKU, standard scores ranged from 74 to 119, with a mean (SD) of
102.2 (9.9). For children in the control group, standard scores ranged from 83 to 129, with a
mean (SD) of 107.7 (10.6). The scores of the control group were significantly higher than those
of the PKU group, t(49) = 1.92, p < .05.
The order in which tasks were administered was counterbalanced across children.
Reaction time (RT) and error rate were recorded for each condition of each task. Children used
both hands to respond during the flanker task (i.e., left hand to the left button; right hand to the
right button). For the Stroop, go/no-go, and baseline RT tasks, participants used their dominant
hand to respond.
As evidenced by the relatively low error rates observed, none of the children exhibited
difficulties in understanding task instructions or feedback for any of the tasks. In addition, to
further insure that the children had time to become comfortable with the tasks, each task included
a block of practice trials that was administered prior to data collection.
Go/no-go task. Children were seated in front of a computer monitor and a large response
button. Two experimental conditions were administered: go and no-go. On each trial, one of four
stimuli (i.e., ◊, ?, ∆, Ο) subtending approximately 6º vertically and horizontally was centrally
displayed. Prior to beginning the task, one of the stimuli was designated as the non-target.
Children were asked to press the response button as quickly as possible when any stimulus
appeared except the non-target (go trials). Children were instructed to make no response when
the non-target appeared (no-go trials). After an intertrial interval of 2000 ms, a new trial was
If a child responded in less than 100 ms after the presentation of a target (an anticipatory
error), a brief tone followed by the visual message “Early response” was presented. If a child
failed to respond within 1500 ms (an inattentive error), a tone and “Too slow” were presented. If
a child responded on a no-go trial (a false alarm error), a tone and “No response needed” were
Following 20 practice trials, children completed 200 experimental trials. Presentation was
balanced such that each stimulus was equally likely to occur; non-targets were presented on a
minority (25%) of trials. The trial types were mixed randomly. The stimulus designated as the
non-target was counterbalanced across children. At intervals of 40 trials, children were offered a
Neutral RT task. Because the go/no-go task does not include a processing speed control
condition, a neutral RT task was administered. Children were seated in front of a computer
monitor and a large response button. On each trial, children were presented with a large cross
subtending 6º vertically and horizontally. Children were instructed to press the response button
as quickly as possible when the stimulus appeared. To discourage anticipatory responding, the
intertrial interval varied randomly from 700 and 2500 ms. If a child responded in less than 100
ms (an anticipatory error), a brief tone followed by the visual message “Early response” was
presented. If a child failed to respond within 1500 ms (an inattentive error), a tone and “Too
slow” were presented. Following 10 practice trials, children completed 80 experimental trials.
The experimental trials were grouped into two blocks of 40 trials each, allowing children to take
a break in between blocks.
Antisaccade task. The apparatus and procedure were identical to those used previously
(Christ, White, Brunstrom, & Abrams, 2003). Children were seated in front of a computer
monitor with their heads steadied by a chin rest. Two conditions were administered: prosaccade
(a neutral condition) and antisaccade. The sequence of events in both conditions was identical;
the conditions differed only in response instructions. Each trial began with a display comprising
a central fixation dot flanked 8º to the left and right by 1º peripheral boxes. After 300 ms, the
fixation dot was replaced by a plus sign, and a warning tone (400 Hz for 50 ms) sounded.
Following a delay of 850 ms, one of the boxes brightened. In the prosaccade condition, children
were asked to look at the brightened box as quickly as possible. In the antisaccade (i.e,
inhibitory) condition, children were asked to look at the unbrightened box. The display remained
for 1500 ms, and during this period eye position was recorded. After an intertrial interval of 1000
ms, a new trial was presented.
Eye movements were recorded using an ISCAN RK426PC eye movement monitor
(Iscan, Inc., Cambridge, MA). To determine the onset of saccades, eye movement samples were
filtered and differentiated to obtain a smooth record of velocity. A saccade was deemed to have
occurred if the velocity exceeded 10º/s for a period of 34 ms or longer.
Anticipatory errors were recorded when children initiated eye movements within 100 ms
of target onset. Inattentive errors were recorded when children failed to initiate eye movements
within 1500 ms of target onset. When eye movements were made in the incorrect direction (e.g.,
looking toward the brightened box in the antisaccade condition), accuracy errors were recorded.
Following trials on which no error was detected, a brief tone and the message “good eye
movement” were presented.
Half of the children received the prosaccade condition first; the remaining children
received the antisaccade condition first. Each condition comprised 15 practice trials followed by
60 experimental trials. The experimental trials were grouped in blocks of 30 trials each, allowing
children to take breaks.
Flanker task. Children were seated in front of a computer monitor and two large response
buttons. Three experimental conditions were administered: compatible, incompatible, and
neutral. The stimuli employed were a subset of those used previously (Enns & Akhtar, 1989).
Each trial began with the presentation of a central fixation dot. After 300 ms, the dot brightened
for 500 ms then disappeared. Following a delay of 300 ms, one of four target stimuli (?, Ο, +, Χ)
subtending 1° was displayed centrally. Children were asked to respond as quickly as possible to
target identity. Half of the children pressed the left button when the target was a ? or Ο and
pressed the right button when the target was a + or Χ. The stimulus-response mapping was
reversed for the remaining children.
On compatible trials, the target was closely flanked (< 0.5°) to the left and right by a
stimulus mapped to the same response button (e.g., ?Ο?). On incompatible (i.e., inhibitory)
trials, the target was flanked by a stimulus mapped to the alternative response button (e.g., +Ο+).
On neutral trials, the flankers were one of two stimuli (∆ or ∗), neither of which mapped to a
response button. For each trial, stimuli remained until a response was made or until more than
3000 ms elapsed. After an intertrial interval of 2000 ms, a new trial was presented.
If a child responded in less than 100 ms after presentation of the target (an anticipatory
error), a brief tone followed by the message “Early response” was presented. If a child failed to
respond within 3000 ms (an inattentive error), a tone and “Too slow” were presented. If a child
responded by pressing the incorrect button (an accuracy error), a tone and “Wrong response”
Children completed two practice blocks of 20 trials. In the first block, target stimuli were
presented without flankers. In the second block, practice trials were identical to experimental
trials. After practice, children completed 96 experimental trials, with 32 trials in each of the three
conditions. Presentation was balanced such that all possible stimulus-flanker pairings were
equally likely to occur. The conditions were mixed randomly. At intervals of 24 trials, children
were offered a break.
Stroop task. Children were seated in front of a computer monitor and a panel of three
large response buttons. One of the buttons was red, another blue, and another green. Three
experimental conditions were administered: congruent, incongruent, and neutral. The stimuli
employed in each condition were a subset of those used previously (Carter, Robertson, &
Nordahl, 1992). On congruent trials, one of three stimulus words (i.e., RED, BLUE, or GREEN)
was presented in its associated color (e.g., the word RED presented in red) at the center of the
monitor. On incongruent (i.e., inhibitory) trials, one of the three color words was presented in an
incongruent color (e.g., the word BLUE presented in red). On neutral trials, one of three stimulus
words (i.e., DOG, BEAR, or TIGER) was presented in blue, red, or green.
The stimuli subtended approximately 2° vertically and 5° to 7° horizontally. Children
were asked to press the response button indicating the color in which each stimulus was
presented. For each trial, the stimulus remained on the display until a response was made or until
more than 3000 ms elapsed. After an intertrial interval of 2000 ms, a new trial was presented.
Three types of errors were possible. If a child responded in less than 100 ms after the
presentation of a stimulus (an anticipatory error), a brief tone followed by the visual message
“Early response” was presented. If a child failed to respond within 3000 ms (an inattentive
error), a tone and “Too slow” were presented. If a child responded by pressing the incorrect
button (an accuracy error), a tone and “Wrong response” were presented.
Following 20 practice trials, children completed 108 experimental trials, with 36 trials in
each of the three conditions. Presentation was balanced such that all possible stimulus-color
pairings (e.g., RED presented in blue, RED presented in green, etc.) were equally likely to occur.
The conditions were mixed randomly. At intervals of 27 trials, children were offered a break.
Before conducting analyses to examine inhibitory control in children with PKU, it was
necessary to determine which, if any, of the variables identified as potential confounds (i.e.,
general intellectual ability, age, general processing speed, and general error rate) should be given
further consideration. First, any significant differences between the PKU and control groups on
these variables were identified. Second, the relationship between potential confounding
variables and performance in the inhibitory condition of each of the four inhibitory tasks was
examined using correlations.
The PKU and control groups differed in terms of general intellectual ability; however,
there was no significant correlation between general intellectual ability and performance in the
inhibitory condition of any task (p > .05 in all instances). As a result, this variable was not
included in the analyses described below. A number of previous studies have also failed to find a
relationship between general intellect and performance on inhibitory tasks (e.g., Christ et al.,
2003; Kindlon, Mezzacappa, & Earls, 1995; Oosterlaan & Sergeant, 1996; Rubia et al., 1999;
Schachar, Tannock, Marriot, & Logan, 1995), including a previous study of PKU and inhibitory
control (i.e., Huijbregts, de Sonneville, Licht, van Spronsen et al., 2002).
In terms of age, the PKU and control groups did not differ significantly. In contrast with
general intellectual ability, however, age correlated significantly with performance in the
inhibitory condition of the inhibitory tasks in several instances; therefore, age was included as a
variable in the analyses.
To evaluate and, if need be, control for individual differences in general processing speed
and general error rate, each task in our study included a neutral condition. The performance of
the PKU group in the neutral condition of each task was compared with that of the control group.
Although several past studies have documented slower RTs in individuals with PKU (Feldman et
al., 2002; Huijbregts, de Sonneville, Licht, van Spronsen et al., 2002; Weglage et al., 1996;
White et al., 2001), there was no evidence in the present study of a difference between the PKU
and control groups in general processing speed (p > .05 in all instances). Similarly, no
significant between-group differences were found in general error rate (p > .05 in all instances).
Mean RTs and error rates in the neutral condition of each task are shown in Table 1. As was the
case for age, performance in the neutral conditions correlated significantly with performance in
the inhibitory conditions in most instances. As a result, RTs and error rates from the neutral
conditions were included in analyses.
[Insert Table 1]
Hierarchical regression was used to control for individual differences in age and neutral
condition performance. This method of analysis was preferred over alternatives (e.g., z score
transformation: Faust, Balota, Spieler, & Ferraro, 1999) because of its inherent flexibility,
readily allowing one to control for several factors at once. RT in the inhibitory condition served
as the dependent variable. Age and neutral condition RT (i.e., a measure of processing speed)
were included in the first step of the statistical model. Group (PKU and control) was then
entered into the second step of the model. By utilizing this approach, we were able to partial out
variability in inhibitory performance related to age and processing speed. The portion of
remaining variance attributable solely to group membership was then identified (i.e., partial
correlation; pr2). Analysis of error rates was conducted in a similar fashion, with age and error
rate in the neutral condition (i.e., a measure of general error rate) entered in the first step of the
model. Median RTs and accuracy error rates for each condition of each task are listed in Table
1. The results of the regression analyses are summarized in Table 2. For the findings reported
below, one-tailed independent samples t-tests were used, and non-significant results reflect p >
[Insert Table 2]
Go/no-go task. Children with PKU performed comparably to controls on go trials. This
was true for both RT and inattentive error rate (PKU error rate: M = 3.1%; Control error rate: M
= 2.8%). Anticipatory error rates were very low (M = 0.6% for both groups) and were not
analyzed. Of greater interest, on no-go trials children with PKU made significantly more false
alarm errors than controls, t(49) = 1.79, p < .05. Group membership accounted for 6.3% of the
variance in false alarm error rate after removing the contributions of age and error rate on go
Antisaccade task. To insure accurate eye movement tracking, it was necessary for
children to maintain head position with the aid of a chin rest. One 7 year old child in the control
group had difficulty adhering to this constraint and data are not available for this child. Data for
another control child were not available due to technical difficulties. Children with PKU
responded significantly slower in the inhibitory condition than controls, t(47) = 2.05, p < .05.
Group membership accounted for 6.9% of the variance in inhibitory RT after removing the
contributions of age and RT in the prosaccade condition. The groups did not differ significantly
in accuracy errors or anticipatory errors (PKU anticipatory error rate: 4.8%; Control anticipatory
error rate: 5.4%). Inattentive error rates were very low (M < 0.5% for both groups) and were not
Flanker task. The RT and accuracy error rate of children with PKU in the inhibitory
condition did not differ significantly from that of control children. Anticipatory and inattentive
errors were almost nonexistent (M < 0.3% and M < 0.6%, respectively) and were not analyzed.
Stroop task. Analyses were confined to data from children 7 years of age or older,
resulting in the exclusion of one child in the PKU group. Past research suggests that by 7 years
of age children have developed reading abilities sufficient to generate substantial Stroop effects
(Comalli, Wapner, & Werner, 1962; Schiller, 1966). Neither the RT nor the accuracy error rate
of children with PKU in the inhibitory condition differed significantly from that of control
children. Anticipatory and inattentive errors were almost nonexistent (M < 0.2% for both) and
were not analyzed.
Age-related effects on inhibitory control. Additional regression analyses were conducted
to determine if the impairments in inhibitory control observed using false alarm errors from the
go/no-go task and RT from the inhibitory condition of the antisaccade task were different for
older children with PKU compared with younger children with PKU. An interaction between
group and age was not present for either task (t < 1 in both instances).
Inhibitory performance and phenylalanine levels. In the present study, blood
phenylalanine levels obtained closest to the time of study accounted for 24.6% of the variance in
accuracy error rate for children with PKU in the inhibitory condition of the antisaccade task after
removing the contributions of age and error rate in the prosaccade condition, t(21) = 2.62, p <
.05. Phenylalanine levels did not account for a significant portion of variance in inhibitory
performance on any of the other tasks (t < 1 in all instances).
The present study was undertaken to provide additional information regarding the
integrity of inhibitory control in children with early-treated PKU. We administered four
inhibitory tasks to children with PKU and to a control group of uncompromised children. On two
of the tasks, flanker and Stroop, RT and error rates were comparable for the PKU and control
groups. On the other two tasks, however, there was clear evidence of impaired inhibitory control
for children with PKU. Specifically, children with PKU were slower to respond in the inhibitory
condition of the antisaccade task, and they made more false alarm errors in the no-go condition
of the go/no-go task than their control counterparts. Poorer performance on these two tasks was
evident even after controlling for individual differences in age and non-inhibitory task variables
(e.g., general processing speed).
Our findings map onto those of previous studies quite well. Our antisaccade task is
similar to the stimulus-response reversal task used by Huijbregts, de Sonneville, Licht, Sergeant
et al. (2002) to identify impaired inhibitory control in children with PKU. Although the
antisaccade and stimulus-response reversal tasks differ in response modality (i.e., eye
movements versus manual responses), in both tasks children are required to inhibit the prepotent
tendency to make an ipsilateral response to a lateralized stimulus and instead generate a
contralateral response. For flanker tasks, our finding of comparable performance for PKU and
control groups is consistent with that of Huijbregts de Sonneville, van Spronsen, et al. (2002).
We are unaware of past studies in which go/no-go tasks have been administered to children with
PKU; thus, it is not possible to compare the present findings with those of past studies.
Turning to Stroop tasks, our finding of comparable performance for children with PKU
and control children is consistent with the results of White et al. (2002) but not those of Weglage
et al. (1996). White et al. attributed the discrepancy between studies to the fact that some
children in the Weglage et al. study were not on a phenylalanine-restricted diet at the time of
testing and that the range of phenylalanine levels was broader in the Weglage et al. study. It is
possible that the inhibitory impairment may have been less subtle for children in the Weglage et
al. study because their dietary control was poorer and their phenylalanine levels were higher than
is typical in more recent studies. In the present study and in White et al. (2002), all children with
PKU were on phenylalanine-restricted diets and blood phenylalanine levels obtained closest to
time of testing had a mean of approximately 8 mg/dL. Taken together, these results indicate that
as dietary control improves more sensitive measures provide better opportunities to detect the
subtle impairments in cognition that are related to PKU.
The PKU and control groups also performed comparably across the neutral/baseline
conditions of all four of our tasks. Although a number of past studies of PKU found that
individuals with PKU were slower on simple/neutral RT measures than individuals without PKU
(e.g., Feldman et al., 2002; Huijbregts, de Sonneville, Licht, van Spronsen et al., 2002; Weglage
et al., 1996; White et al., 2001), other studies have failed to find such a difference (e.g., Brunner
& Berry, 1987; Brunner et al., 1983; Huijbregts, de Sonneville, Licht, Sergeant et al., 2002;
Huijbregts, de Sonneville, van Spronsen et al., 2002). The reason for past discrepant findings
remains unclear, but we postulate that the lack of group differences in baseline RT in our study
may be due to the subtlety of the impairments experienced by our sample of children due to their
relatively low phenylalanine levels. In support of this notion, a number of studies have found a
relationship between phenylalanine levels and RT (e.g., Clarke, Gates, Hogan, Barrett, &
MacDonald, 1987; Feldman, Denecke, Grenzebach, & Weglage, 2005; Krause et al., 1985).
Our results are clearly consistent with those of previous research, but a significant
question remains. Why were PKU-related impairments in inhibitory control evident using
go/no-go and antisaccade-like tasks but not using Stroop and flanker tasks? Given that the
cognitive impairments associated with PKU are relatively subtle (Welsh, 1996; White et al.,
2001, 2002), we propose that the PKU-related impairments in inhibitory control may be evident
only when relative demands on inhibitory control are especially high. In other words, the pattern
of sparing and impairment observed across different inhibitory tasks is related to the strength of
the response tendency to be inhibited.
To explore this issue further, the effect size comparing the neutral and inhibitory
conditions of each of our four tasks was calculated separately. In each case, we focused on the
primary variable of interest (i.e., for the go/no-go task: error rate; for the antisaccade, Stroop, and
flanker tasks: response time), the analysis was confined to children in the control group, and we
collapsed across age. The resulting effect sizes were clearly greater for the go/no-go and
antisaccade tasks (ηP2 = 0.76, ηP2 = 0.64, respectively) than for the Stroop and flanker tasks (ηP2
= 0.26, ηP2 = 0.26, respectively), suggesting that the experimental manipulation distinguishing
the inhibitory condition from the neutral condition was stronger for the antisaccade and go/no-go
tasks. Thus, consistent with our assertion, the relative inhibitory demands appear to have been
greater in the go/no-go and antisaccade tasks, the two tasks on which inhibitory impairments in
children with PKU were apparent. Similar evaluation of findings from other studies has not been
possible because there are few other studies in which more than one inhibitory task has been
administered; and in studies using more than one task, the strengths of the experimental
manipulations have not been reported.
A separate but related issue for consideration is the possibility that our relatively small
sample size (i.e., 26 children with PKU) did not afford sufficient statistical power to detect
significant group differences on the Stroop and flanker tasks. Examination of our data, however,
suggests that it is unlikely that the addition of more participants would have altered findings of
comparable performance for children with PKU and control children on these tasks. As shown in
Table 1, the added time needed to perform in the inhibitory condition relative to the neutral
condition (Inhibitory RT minus Neutral RT) on the Stroop task was quite similar for children
with PKU and controls (PKU = 64 ms; Control = 63 ms). For the flanker task, the difference
was actually less for children with PKU than controls (PKU = 11 ms; Control = 29 ms).
To borrow the analogy of an automobile, engine problems may be so subtle that they are
not apparent when driving on a side street. The problems become more evident, however, when
driving on a freeway. Regardless of how many times the car is driven on the side street, the
problems will not be detected. Returning to children with PKU, we believe that their inhibitory
impairments are subtle and may be evident only when inhibitory demands are greatest. In other
words, impairments are not evident when using less demanding inhibitory tasks, regardless of the
number of individuals sampled.
As evidenced by the lack of significant correlation between performance on our
inhibitory tasks and performance on a measure of overall intellectual ability, the inhibitory
impairment observed for the children with PKU appears to be fairly independent of any general
difficulties that they may also experience. Given that the present study focused primarily on
inhibitory control, however, it remains unclear whether potential impairments in other abilities
(e.g., working memory, cognitive flexibility) also may become more apparent with increased
A possible alternate explanation for our pattern of results is that our tasks each measured
different aspects of inhibitory control. Thus, children with PKU exhibit impairments in certain
subtypes of inhibitory control but not others. Along these lines, Casey and colleagues (Casey,
Durston, & Fossella, 2001; Casey, Tottenham, & Fossella, 2002) proposed that inhibitory control
can be divided into subtypes and that each subtype is mediated by one of five frontostriatal
pathways previously outlined by Alexander, DeLong, and Strick (1986). Due to the lack of
detail regarding the neuroanatomical and neurophysiological sequelae of PKU, however,
attributing differential patterns of performance across inhibitory tasks to disruptions in specific
prefrontal circuits at this time would be highly speculative.
An additional issue in examining inhibitory control in children with PKU is the possible
relationship with blood phenylalanine levels. Some studies have reported a relationship between
performance on cognitive tests and blood phenylalanine levels taken at the time of study (e.g.,
Brunner et al., 1983; Weglage et al., 1996; Welsh et al., 1990), whereas others have failed to find
such a relationship (e.g., Channon et al., 2004; Griffiths, Campbell, & Robinson, 1998; White et
al., 2002). In the present study, blood phenylalanine levels obtained closest to the time of study
were related to the accuracy error rate for children with PKU in the inhibitory condition of the
antisaccade task. Interestingly, this relationship was present even though children with PKU did
not differ significantly from controls in terms of antisaccade accuracy error rate. The reason that
this relationship is present for accuracy error rate on the antisaccade task but not for other
measures of inhibitory ability is unclear, but it is possible that the requirement for ocular rather
than manual responses (and the neural systems subserving these responses) makes this task more
sensitive to variations in phenylalanine levels.
To fully understand cognitive compromise in children with PKU, it is also necessary to
discern whether the degree of inhibitory impairment is relatively static during childhood or
changes in an age-related fashion. Previous work suggests that impairments in some executive
abilities (i.e., strategic memory processing and working memory) are more pronounced in older
than younger children with PKU (White et al., 2001, 2002). It appears, however, that difficulties
in inhibitory control are equivalent at various ages in children with PKU (Huijbregts, de
Sonneville, Licht, Sergeant et al., 2002). The degree of inhibitory impairment observed in our
study is comparable for older and younger children with PKU. This result is not surprising given
that inhibitory control may develop quite early. In a study across the life-span, Christ, White,
Mandernach, and Keys (2001) showed that by 6 years of age the performance of typically
developing children has reached adult levels on a stimulus-response reversal task. Given that
inhibitory control may develop earlier than other executive abilities, it stands to reason that
impairments in inhibitory control would be evident earlier as well. We have a longitudinal study
with a larger sample of children with PKU underway to investigate this issue more thoroughly.
In conclusion, findings from our study point to the importance of obtaining converging
and diverging evidence when assessing cognition, particularly in children with relatively subtle
impairments. This is best accomplished through the administration of multiple measures of the
same broad constructs. In addition, in reconciling conflicts within the literature, it is important to
examine differences between study samples and between experimental measures carefully. In
this manner, we will achieve a more thorough understanding of the cognitive strengths and
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