Event-related potentials elicited during a visual Go-Nogo task in adults with phenylketonuria

Clinical Neurophysiology 117 (2006) 2154–2160 www.elsevier.com/locate/clinph

Event-related potentials elicited during a visual Go-Nogo task in adults with phenylketonuria J.J. Moyle

a,*

, A.M. Fox

a,*

, M. Bynevelt b, M. Arthur c, J.R. Burnett

d,e

a

d

School of Psychology, The University of Western Australia, Perth, Australia b Department of Radiology, Royal Perth Hospital, Perth, Australia c Department of Dietetics and Nutrition, Royal Perth Hospital, Perth, Australia Department of Core Clinical Pathology and Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital, Perth, Australia e School of Medicine and Pharmacology, The University of Western Australia, Perth, Australia Accepted 23 May 2006 Available online 21 August 2006

Abstract Objective: The aim of the present study was to examine the nature of previously reported deficits in sustained attention and response inhibition in adults with the developmental disorder, phenylketonuria (PKU). Methods: This study used event-related potentials (ERPs) to examine the performance of PKU adults (n = 9) and a matched control group (n = 9) on a visual Go-Nogo task. Results: Comparison of behavioural measures between the PKU and control groups failed to reach statistical significance, yet analysis of the ERPs showed statistically significant amplitude reductions in the P1 and N1 components elicited following presentation of stimuli, and a reduction in the amplitude of the N2 component elicited following presentation of Nogo stimuli. Conclusions: These results suggest that adults with PKU, despite being continuously treated from birth, manifest subtle impairments in distinct aspects of information processing including early sensory processing of visually presented information, as well as impairments in inhibitory functions. Significance: The results contribute to an understanding of the neurophysiological mechanisms that are implicated in PKU and highlight the sensitivity of ERP techniques for the identification of the loci of information processing deficits in clinical groups.  2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: PKU; Phenylketonuria; Event-related potential; ERP; Sensory processing; Response inhibition; Executive functions

1. Introduction Phenylketonuria (PKU; OMIM 261600) is an autosomal recessive disorder characterized by persistently increased levels of the essential amino acid phenylalanine (Phe) in the circulation; a condition known as hyperphenylalaninemia (HPA). HPA occurs due to deficient activity *

Corresponding authors. Present address: School of Psychology M304, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia. Tel.: +61 8 6488 3267; fax: +61 8 6488 1006. E-mail addresses: [email protected] (J.J. Moyle), afox@ psy.uwa.edu.au (A.M. Fox).

of the enzyme phenylalanine hydroxylase (PAH; EC 1.14.16.1). PAH is responsible for the metabolic conversion of Phe into tyrosine (Tyr), antecedent to dopamine (Scriver and Kaufman, 2001). Untreated, PKU causes severe structural brain damage. Treatment involves placing the individual on a diet, designed to reduce their intake of Phe, within one to two weeks of birth. Successful maintenance of the treatment diet during the first ten to 12 years of life prevents the more severe effects of this disorder, and current treatment guidelines in Australia, Europe and the United States advocate a lifetime adherence (National Institutes of Health Consensus Development Panel, 2001). Clients with PKU who remain on

1388-2457/$32.00  2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2006.05.027

J.J. Moyle et al. / Clinical Neurophysiology 117 (2006) 2154–2160

the treatment diet throughout adolescence typically obtain higher Full-Scale IQ (FSIQ) than those who relax the controlled diet (Koch et al., 2002), although the most stable predictor of IQ and cognitive ability in adulthood is the strictness of dietary compliance up to the age of 12 years (Pietz et al., 1998). Despite early treatment, impairments of executive function have been reported in adolescents and adults with PKU (Channon et al., 2005), with reduced speed of information processing (Channon et al., 2004) and impaired response inhibition identified (Feldmann et al., 2005; Huijbregts et al., 2002; Pietz et al., 1995; Schmidt et al., 1994). Tasks commonly used in conjunction with neurophysiological measures, such as event-related potentials (ERPs), to assess response inhibition include the Go-Nogo task and the Stop-Signal task (Bokura et al., 2001; Falkenstein et al., 2001). The ERP component that has received the majority of research attention in relation to inhibitory processing is the Nogo N2. The Nogo N2 is a negative deflection in the waveform, maximal at fronto-central sites, occurring approximately 200–400 ms after the presentation of visual stimuli requiring the inhibition of a prepotent response. The functional significance of this component has been argued to reflect the processes of response inhibition (Falkenstein et al., 1999) or response conflict (Nieuwenhuis et al., 2003). An additional reported cognitive difficulty in PKU children, adolescents and adults is that of attention (Diamond et al., 1997; Huijbregts et al., 2002). The ERP components P1 and N1 are elicited over occipital sites during visual attention tasks, and the amplitude reflects modulation of sensory processing as a function of different mechanisms of visual–spatial attention (Eimer and Schro¨ger, 1995; Luck et al., 1990). The P1 component, peaking approximately 100 ms following presentation of visual stimuli, is generated in the lateral extrastriate cortex, and the amplitude of this component is typically enhanced for stimuli presented to attended spatial locations relative to the amplitude for stimuli presented to unattended locations (Hillyard and Anllo-Vento, 1998). The N1 component is a negative peak in the ERP occurring about 150 ms poststimulus, and is largest over the occipital cortex (Hopf et al., 2002). It represents further processing of attended stimuli, including the activation of a discriminative mechanism applied to the attended stimuli (Hopf et al., 2002; Vogel and Luck, 2000). This study examined the performance of on-diet PKU adults, continuously treated up to age 12, compared to matched controls on a Go-Nogo task. ERP recordings were obtained as a more sensitive measure, and to examine the stages of processing which may be affected in PKU. 2. Participants The data from nine early and continuously treated adult PKU patients (8 F, 1 M, median age = 26 years,

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inter-quartile range (IQR) = 25–30 years, median education level = 12 years, IQR = 10–12 years), and nine gender-, age-, education-matched control participants (8 F, 1 M, median age = 25 years, IQR = 23–28 years, median education level = 12 years, IQR = 10–12 years) were analysed. Participants in the PKU group had ceased dietary restriction in early adolescence. The mean average Phe levels over the individual’s first 12 years of life for the PKU group was 688 lmol/L (SE = 80.9) and the mean level recorded closest to the time of the recording was 1000 lmol/L (SE = 258.45). There was a significant difference between these two results (F (1,14) = 6.19; p = 0.03). 3. Apparatus The Go-Nogo task was performed on a Pentiumbased personal computer in the School of Psychology at the University of Western Australia. Continuous EEG recordings were obtained using an Electrocap (Surgicon Systems), with 30 channels referenced to the tip of the nose. The sites were based on a modification of the international 10–20 system, and comprised FP1, FP2, F3, F4, C3, C4, P3, P4, O1, O2, F7, F8, T3, T4, T5, T6, FPz, Fz, FCz, Cz, Pz, Oz, AF3, AF4, FC1, FC2, P5, P6, PO7, and PO8. Additional electrodes were placed on the outer canthus of each eye and above and below the right eye to identify artefacts. Artefact rejection was set as any deflection in the pre-stimulus baseline-adjusted EEG epoch that exceeded 100 lV. The EEG signals were subject to a 75,000 gain, with the band-pass filter for data acquisition ranging from 0.05 to 30 Hz ( 6 dB down), digitised at a sampling rate of 250 Hz. Artefact rejection and the generation of stimulus-locked ERPs were performed off-line. During the task, letters ‘O’ and ‘X’ appeared sequentially on the computer screen for 100 ms, with a presentation rate of one per second. Each subject was instructed to press the space bar with one hand when a specified letter appeared (Go letter) and not press the space bar when the other letter appeared (Nogo letter).

Table 1 Medians and inter-quartile ranges for percentage of hits and percentage of false alarms; and median response times and inter-quartile ranges (ms) for hits and false alarms in Go and Nogo conditions for PKU and control groups PKU

Control

Median

IQR

Median

IQR

Go Percent hits RT hits

96.5 378

94–99 334–399

96.9 341

94–99 313–349

Nogo Percent false alarms RT false alarms

33.3 316

20–44 282–330

19.2 284

16–30 279–300

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N1

N1

P1 PO7

PO8

O1

O2

PO7

PO8

O1

O2

-10

Oz

500

mV

Oz

P1

PKU

Control

Fig. 1. Comparison of ERPs elicited by PKU group (left panel) and controls (right panel) at parieto-occipital sites, illustrating the P1 and N1 components ERPs elicited following presentation of Go stimuli are represented by the thin line in both panels, and following presentation of Nogo stimuli are represented by the thick line in both panels. Stimulus onset and offset occurred at time 0 and 100 ms, respectively.

4. Procedure The experimental procedure was described and participants provided written informed consent. Following application of the electrode cap, each participant performed a practice sequence of 20 trials, followed by 600 experimental trials, presented as two blocks of 300 trials. Of every 100 trials, 75 were Go letters and 25 were Nogo letters, presented randomly within the 100 trials. After completing one block of 300 trials there was a rest period of 30 s before the commencement of the second block. Presentation of the Go and Nogo letters was counterbalanced within each group, such that four PKU patients and matched controls had ‘O’ as their Go letter and five PKU patients and controls had ‘X’ as their Go letter. Accuracy and response times for each participant were recorded on-line, with off-line analysis determining the percentage of commissions (hits) and incorrect omissions (false alarms), and the median reaction time (RT, ms) for hits and false alarms. From the EEG recordings, epochs from 100 ms prior to stimulus onset to 1000 ms after stimulus onset were extracted. For the Go condition EEG epochs associated with correct responses were averaged to produce Go ERPs; while for the Nogo condition, epochs associated with correctly inhibited Nogo trials were averaged. This produced stimulus-locked ERPs for both conditions for each participant. The ERP components of interest were the P1 and N1, recorded from parieto-occipital sites as the most positive and negative peaks, respectively, between the time window of 50–200 ms after stimulus presentation; and the N2 and P3 recorded from fronto-central

sites as, respectively, the most negative peak occurring 170–350 ms after stimulus presentation, and the most positive peak occurring 300–500 ms after stimulus presentation. 5. Results 5.1. Behavioral results The behavioral results for both the PKU group and the control group are shown in Table 1, showing the median and IQR of the percentage of hits and false alarms, and the median individual median reaction times (ms) for hits and false alarms, for both groups. The percentage of false alarms is used a measure if inhibitory ability, while the reaction time to hits provides a suitable measure of the response speed. Examination of the respective distribution of these measures suggested they were robust enough to withstand parametric between-group analysis. Independent samples t-test did not reveal significant differences between the groups1 however, the mean level of performance by the PKU group was in the predicted direction, with a greater number of omissions and false alarms than the control group, and slower reaction times. It is acknowledged that measuring RT by recording the deflection of the space bar of a computer keyboard may not be as precise for the detection of movement onset as other response measures. 1

A further Mann–Whitney U-test, used to clarify issues related to skew of the RT to hits, produced the same result of no significant difference detected between the PKU and control groups.

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Table 2 Peak P1 and N1 amplitudes (lV) and latencies (ms) measured at parieto-occipital sites (O1, O2, Oz, PO7, and PO8) for PKU and control groups (Standard errors given in parentheses) Amplitude

Latency

PKU

Control

Go

Nogo

PKU

Go

P1 O1 O2 Oz PO7 PO8

0.78 0.70 0.88 1.57 3.00

(0.8) (0.8) (0.7) (0.8) (1.1)

1.19 0.70 0.11 1.69 3.13

(1.1) (1.0) (1.0) (1.1) (1.0)

N1 O1 O2 Oz PO7 PO8

4.94 4.83 4.57 6.92 5.69

(1.3) (1.0) (0.9) (1.7) (1.7)

9.01 8.43 9.51 11.86 8.55

(1.8) (1.8) (1.7) (2.7) (2.3)

Nogo

3.03 (0.9) 2.20 (0.8) 1.76 (0.6) 4.9 (1.0) 5.23 (1.3) 9.51 9.01 9.09 11.32 12.16

(1.6) (1.7) (1.6) (1.7) (2.3)

Control

Go

Nogo

Go

Nogo

3.52 2.70 2.58 6.14 7.00

(0.9) (1.1) (1.0) (1.4) (1.7)

122 109 117 126 139

(10) (12) (16) (7) (12)

118 111 96 107 127

(12) (9) (12) (9) (13)

126 123 122 126 115

(10) (10) (11) (10) (4)

109 121 107 116 112

(7) (10) (6) (3) (4)

13.32 12.06 12.94 16.59 16.00

(2.1) (1.9) (1.7) (2.0) (2.5)

139 164 153 151 139

(16) (5) (12) (14) (17)

153 152 155 158 148

(13) (13) (12) (12) (13)

164 161 165 166 162

(3) (3) (4) (3) (4)

167 162 167 170 163

(3) (3) (2) (3) (3)

5.2. ERP results All ERP results were analysed using a repeated measures Condition (Go or Nogo) · Site (O1, O2, Oz, PO7, PO8; or Fz, FCz, Cz) design. Probability levels associated with the Greenhouse–Geisser adjustment to degrees of freedom are reported when the assumptions of sphericity were violated. Parieto-occipital ERPs for the PKU group and control group are shown in Fig. 1. Table 2 contains the mean amplitudes and latencies of the parieto-occipital ERP components.

P1 was minimal at Oz and maximal at PO8, main effect of site F (1.55,24.77) = 10.01, p < 0.01, partial g2 = 0.39. The amplitude of the component was greater in the control group than the PKU group, (F (1,16) = 5.35; p = 0.03; partial g2 = 0.25), and had a longer latency in the Go condition than the Nogo condition (F (1,16) = 10.68; p < 0.01; partial g2 = 0.40). N1 was maximal at PO7 (Site: F (2.43,38.85) = 5.89; p < 0.01; partial g2 = 0.27), had a greater amplitude in the Nogo condition (Condition: F (1,16) = 18.29; p < 0.01; partial g2 = 0.53), and was greater in the control group than the PKU group (Group:

Fz

Fz

FCz

FCz N2

Cz

P3

Cz

mV

-10

Go

600

Nogo

Fig. 2. Comparison of ERPs elicited by PKU group (heavy line) and controls (light line) at fronto-central sites, illustrating the Nogo N2 and Nogo P3 components. ERPs elicited following presentation of Go stimuli are displayed in the left hand panel and following presentation of Nogo stimuli are displayed in the right hand panel. Stimulus onset and offset occurred at time 0 and 100 ms, respectively.

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Fz

Fz

FCz

FCz N2

N2

P3

P3 Cz

Cz

-10 mV

600

PKU

Control

Fig. 3. Comparison of ERPs elicited by PKU group (left panel) and controls (right panel) at fronto-central sites, illustrating the Nogo N2 and Nogo P3 components. ERPs elicited following presentation of Go stimuli are represented by the thin line in both panels, and following presentation of Nogo stimuli are represented by the thick line in both panels. Stimulus onset and offset occurred at time 0 and 100 ms, respectively.

F (1,16) = 4.64; p < 0.05; partial g2 = 0.23). There were no significant interactions. Fronto-central ERPs for the PKU group and control group, in both Go and Nogo conditions, are shown in Figs. 2, 3. Table 3 contains the Nogo N2 and P3 peak amplitudes and latencies for both the PKU and control groups. A larger N2 was elicited following Nogo stimuli than following Go stimuli in the control group than the PKU group (condition · group interaction; F (1,16) = 7.18; Table 3 Peak Nogo N2 and Nogo P3 amplitudes (lV) and latencies (ms) measured at fronto-central sites (Fz, FCz, and Cz) for PKU and control groups (standard errors given in parentheses) Amplitude PKU Nogo N2 Fz FCz Cz

1.15 (1.5) 1.6 (2.1) 2.08 (2.1)

Nogo P3 Fz FCz Cz

21.40 (3.2) 23.75 (3.7) 23.16 (3.6)

Latency Control 7.15 (1.9) 9.18 (2.1) 8.39 (1.6) 22.6 (2.4) 27.2 (3.1) 26.0 (2.5)

PKU

Control

254 (19) 258 (17) 252 (17)

271 (6) 268 (5) 266 (5)

414 (9) 419 (9) 416 (10)

384 (8) 388 (9) 396 (10)

p < 0.05; partial g2 = 0.31). The difference in the amplitude of the Go-N2 and Nogo-N2 failed to reach statistical significance in the PKU group (F (1,8) = 3.53; p = 0.10; partial g2 = .31; control group: F (1,8) = 60.9; p < 0.001; partial g2 = .88). The Nogo N2 latency was longer in the Go than the Nogo condition (F (1,16) = 12.78; p < 0.01; partial g2 = 0.44), and was shorter at Cz than the other two sites (F (1.21,19.30) = 7.20; p < 0.05; partial g2 = 0.31). The condition · group interaction was significant (F (1,16) = 4.37; p = 0.05; partial g2 = 0.21), with the PKU group having a longer latency in the Go condition than the control group (238 ms versus 204 ms, respectively). Examination of the mean P3 peak amplitudes did not reveal any significant differences between the two groups. P3 was maximal at FCz (main effect of site: F (1.26, 20.11) = 13.34; p < 0.01; partial g2 = 0.45), and smaller in the Go condition than the Nogo condition (main effect of condition: F (1,16) = 44.89; p < 0.01; partial g2 = 0.74). There was no significant group difference in P3 peak latency. 6. Discussion This study used ERPs to examine the neurophysiological differences between adults with PKU and age-, gender-, education-matched controls. Specifically, ERP

J.J. Moyle et al. / Clinical Neurophysiology 117 (2006) 2154–2160

components associated with the inhibition of responses in a visual Go-Nogo task were examined. The behavioral results did not produce any significant group differences. Parieto-occipital ERPs revealed a significantly reduced P1 and N1 following presentation of all stimuli, and frontocentral ERPs revealed a significantly reduced Nogo N2 in the PKU group. Executive functioning has been regularly reported in the literature as being the primary deficit in PKU (Diamond et al., 1997), with impairments of attention and response inhibition identified (Feldmann et al., 2005; Schmidt et al., 1994). In the present study, there was a significant group difference in the Nogo N2 peak amplitude at all fronto-central sites, with the PKU group producing a reduced Nogo N2 peak amplitude compared to the control group. The Nogo N2 component has been associated with either (1) a mechanism of inhibiting a prepotent response (Falkenstein et al., 1999; Jodo and Kayama, 1992) or (2) response conflict (Fallgatter et al., 2002; Nieuwenhuis et al., 2003). The present results suggest a weakness in the functioning of the mechanism measured by this component in the PKU group. The P3 peak amplitude was larger for both groups in the Nogo condition than the Go condition, consistent with previous studies, however there was no between-group difference. The dissociation between the group differences of the N2 and P3 components suggests that the N2 and P3 are modulated by different, functionally independent, underlying cognitive processes; furthermore, those processes measured by the P3 are operating at the same capacity in both the PKU and control groups, yet those processes measured by the N2 are not operating in a like manner between the groups. Attentional mechanisms can be measured through the P1 and N1 components of an ERP on a visual–spatial attention task (Luck, 1995), with N1 representing enhanced processing of a stimulus at an attended location, particularly when stimulus discrimination is required (Eimer, 1994; Hopf et al., 2002; Vogel and Luck, 2000), and the P1 representing the modulation of visual information processing through either the enhancement of attended information of the suppression of unattended information (Eimer, 1999; Handy and Khoe, 2005; Luck, 1995). There was a significant difference in the amplitude of the P1 component between the PKU and control groups, with the control group having a greater peak P1 than the PKU group, however there was no effect of condition. As a hypothesis, if P1 reflects the modulation of a noise-suppression mechanism then these results suggest that PKU patients have a reduced functioning of this mechanism. The results from the present study suggest that early visual processing mechanisms may be affected in adults with PKU, although the precise nature of this deficit is not clear from the present study. This finding warrants further experimental research to determine whether the PKU patients are unable to modulate visual information processing due to an inability to selectively attend to relevant material or to suppress irrelevant additional distracting information present in a task.

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The parieto-occipital N1 was greater overall in the control group than the PKU group. The Go-Nogo task requires the participant to discriminate between two stimuli, such that each stimulus needs to be classified as a Go or Nogo stimulus. That the PKU group produces, on average, smaller peak N1 amplitudes than the control group may suggest a reduced activation in their discriminatory process. However, the earlier processing impairment manifest in the P1 amplitude reduction may have been influential in this regard. The above discussion outlines a process which may be occurring in PKU patients, whereby impaired early stage attentional processes could contribute to subsequent inhibitory deficits. We have presented evidence of neurophysiological differences between early treated PKU patients and non-PKU control participants, despite the absence of behavioral differences between the groups. Furthermore, we have outlined a possible deficit in PKU patients in perceptual processes occurring very early after stimulus presentation. The results highlight the advantages of investigating the time course of information processing using ERPs in tasks where overt behavioural measures may not provide sufficiently detailed information regarding the nature of the underlying neural deficits. References Bokura H, Yamaguchi S, Kobayashi S. Electrophysiological correlates for response inhibition in a Go/NoGo task. Clin Neurophysiol 2001;112:2224–32. Channon S, German E, Cassina C, Lee P. Executive functioning, memory, and learning in phenylketonuria. Neuropsychology 2004;18:613–20. Channon S, Mockler C, Lee P. Executive functioning and speed of processing in phenylketonuria. Neuropsychology 2005;19:679–86. Diamond A, Prevor MB, Callender G, Druin DP. Prefrontal cortex cognitive deficits in children treated early and continuously for PKU. Monogr Soc Res Child Dev 1997;62:1–208. Eimer M. An ERP study on visual spatial priming with peripheral onsets. Psychophysiology 1994;31:154–63. Eimer M, Schro¨ger E. The location of preceding stimuli affects selective processing in a sustained attention situation. Electroenceph Clin Neurophysiol 1995;94:115–28. Eimer M. Attending to quadrants and ring-shaped regions: ERP effects of visual attention in different spatial selection tasks. Psychophysiology 1999;36:491–503. Falkenstein M, Hielscher H, Dziobek I, Schwarzenau P, Hoormann J, Sundermann B, et al.. Action monitoring, error detection, and the basal ganglia: An ERP study. Neuroreport 2001;12:157–61. Falkenstein M, Hoormann J, Hohnsbein J. ERP components in Go/Nogo tasks and their relation to inhibition. Acta Psychol 1999;101:267–91. Fallgatter AJ, Bartsch AJ, Herrmann MJ. Electrophysiological measurements of anterior cingulate function. J Neural Transm 2002;109:977–88. Feldmann R, Denecke J, Grenzebach M, Weglage J. Frontal lobedependent functions in treated phenylketonuria: blood phenylalanine concentrations and long-term deficits in adolescents and young adults. J Inherit Metab Dis 2005;28:445–55. Handy TC, Khoe W. Attention and sensory gain control: a peripheral visual process? J Cogn Neurosci 2005;17:1936–49. Hillyard SA, Anllo-Vento L. Event-related brain potentials in the study of visual selective attention. Proc Natl Acad Sci USA 1998;95:781–7.

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