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Progress in Neuro-Psychopharmacology & Bio

Potential effects of zinc on information processing in boys withattention deficit hyperactivity disorder

Ozgur Yorbik a, M. Fatih Ozdag b, Abdullah Olgun c, M. Guney Senol b,⁎,Semai Bek d, Serif Akman e

a Department of Child Psychiatry, Gulhane School of Medicine, Ankara, Turkeyb Department of Neurology, Gulhane School of Medicine, Haydarpasa Education Hospital, Istanbul, Turkeyc Rehabilitation Center Biochemistry Laboratory of Gulhane School of Medicine, Bilkent Ankara, Turkey

d Department of Neurology, Gulhane School of Medicine, Ankara, Turkeye Department of Biochemistry, Gulhane School of Medicine, Ankara, Turkey

Received 30 July 2007; received in revised form 6 November 2007; accepted 9 November 2007Available online 17 November 2007

Abstract

Purpose: The aims of the present study were to investigate the relationship between plasma zinc levels and amplitudes and latencies of P1, N2,and P3 in parietal and frontal areas in children with ADHD, and to compare these zinc levels and event-related potentials (ERPs) indices withcontrols.Methods: 28 boys with ADHDwere divided into two groups according to plasma zinc levels: low zinc group (N=13, zinc level b80 μg/dL) and zincnon-deficient group (N=15, zinc level≥80 μg/dL). ERP indices from parietal and frontal brain regions were recorded in children with ADHD and in24 normal boys by using an auditory oddball paradigm. Plasma zinc levels were measured by an atomic absorption spectrophotometer.Results: The plasma zinc levels were significantly lower in both ADHD groups (means are 65.8 μg/dL in low zinc group and 89.5 μg/dL in zincnon-deficient group) than controls (mean: 107.8 μg/dL; both p values b0.017). In ADHD compared to controls, the amplitudes of P3 in frontaland parietal regions were significantly lower, and the latency of P3 in parietal region was significantly longer (all p values b0.017). In low zincADHD group compared to zinc non-deficient ADHD group, the latencies of N2 in frontal and parietal region were significantly shorter (all pvalues b0.017). In addition, there was a medium but significant positive correlation between plasma zinc levels and amplitude and latency offrontal N2 wave in ADHD.Conclusions: These results can suggest that plasma zinc levels might have an effect on information processing in ADHD children, and lower zinclevels seem to affect N2 wave. Since N2 wave changes may reflect a different inhibition process, further studies are warranted to investigate theeffect of zinc on inhibitory process in children with ADHD, and in low zinc and non-deficient ADHD groups.© 2007 Elsevier Inc. All rights reserved.

Keywords: Attention deficit hyperactivity disorder; Event-related potentials; N2; P1; P3; Zinc

Abbreviations: ADHD, Attention deficit hyperactivity disorder; CNS, centralnervous system; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders,Forth Edition; EDTA, ethylene diamine tetra-acetic acid; EEG, Electroencephalo-graphy; EMG-EP, Electromyography-Evoked Potentials; ERP, event-relatedpotentials; FN2A, frontal N2 amplitude; FN2L, frontal N2 latency; FP1L, frontalP1 latency; FP3A, frontal P3 amplitude; FP3L, frontal P3 latency; GABA, gammaamino butyric acid; PN2L, parietal N2 latency; IO, infraorbital; PP1L, Parietal P1latency; PP3A; Parietal P3 amplitude; PP3L, Parietal P3 latency.⁎ Corresponding author. GATA Haydarpasa Egitim Hastanesi, Noroloji

Servisi, Kadikoy, 34668, Istanbul, Turkey. Tel.: +90 216 542 2020; fax: +90216 348 7880.

E-mail address: mgsenol@yahoo.com (M.G. Senol).

0278-5846/$ - see front matter © 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.pnpbp.2007.11.009

1. Introduction

Attention deficit hyperactivity disorder (ADHD) is acommon juvenile psychiatric disorder characterized by inatten-tion, hyperactivity, and impulsivity. One of the essential theoriesregarding ADHD proposes that deficient inhibitory control incentral nervous system (CNS) impairs the ability of childrenwith ADHD to engage executive processing and adaptive motorcontrol (Barkley, 1997). Inattention may be due to a failureto inhibit interfering activities; distractibility may reflect an

663O. Yorbik et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 662–667

inability to inhibit attention to irrelevant information, with im-pulsivity being a manifestation of general cognitive disinhibi-tion (Barry et al., 2003). Having high temporal sensitivity andcorrelations with underlying sensory and cognitive processes,event-related potentials (ERPs) could be a useful tool exploringdifferent processing states in ADHD.

P3 is a positive wave form deflection occurring approxi-mately 300 ms after stimulus onset that indexes stimulus eval-uation (Pritchard, 1981). P3 is most pronounced when stimulusis unpredictable, or task relevant, or related to response selection(Winsberg et al., 1997). Extensive research on the children withattention deficit disorder has shown that the ‘novel-P3’ resultsmight be related to the allocation of attention capacity andfurther, that capacity-allocation deficits play an important role intheir attention problems (Jonkman et al., 2000). P3 latency istaken as a reflection of the speed of information processing(Johnson, 1986). Most of the ERP studies on ADHD reportedthat P3 latency was significantly longer and P3 amplitudesmaller in children with ADHD compared to normals (Franket al., 1994; Holcomb et al., 1986; Winsberg et al., 1993).

The N2 component reflects focused attention to stimulusfeatures (Breton et al., 1988). This component likely indexes theprocess of stimulus classification in the present task (i.e. whetherthe stimuli match and hence whether to respond) (Sunoharaet al., 1999). N2 component has been reported to show age-related changes that were highly correlated with behavioralindications of improvements in task performance, i.e. decreasingreaction time and errors of commission (Johnstone et al., 2001,1996). Some studies on ADHD showed a decrease in amplitudeof N2 waves only in younger subjects (Barry et al., 2003;Satterfield et al., 1984). An earlier N2 latency in ADHD subjectsto oddball task targets has been reported in the some previousstudies (Hermens et al., 2005; Sunohara et al., 1999), not others(Lazzaro et al., 2001; Ozdag et al., 2004).

P1 potential may be generated within the ascending reticularactivating system, and its generator system must be functionallyrelated to states of arousal (Erwin and Buchwald, 1986a,b). Inthe auditory modality, smaller P1 amplitudes at Cz to all stimuliwere reported in children with ADHD (Kemner et al., 1996).

Zinc plays significant roles in the metabolism of proteins,carbohydrates, and lipids (Vallee, 1988). It is incorporated intothe active sites of many metalloenzymes (Vallee and Falchuk,1993), and is probably used in the central neural system (CNS)as a neurotransmitter or neuromodulator (Frederickson, 1989).Human zinc deficiency syndrome has been associated withimpairment in concentration and cognitive development(Aggett and Harries, 1979; Black, 1998). Some studies havereported that zinc levels in the children with ADHD were foundto be significantly lower than normals (Arnold et al., 2005;Bekaroglu et al., 1996; Yorbik et al., 2004a). Interestingly, adouble-blinded placebo-controlled study demonstrated that zincis effective in patients with ADHD (Bilici et al., 2004). To ourknowledge, there is no study investigating the relationshipbetween zinc and ERP indices in children with ADHD.

The aims of the present study were to investigate the rela-tionship between plasma zinc levels and amplitudes and laten-cies of P1, N2, and P3 in parietal and frontal areas in children

with ADHD, and to compare these zinc levels and ERP indiceswith normals.

2. Methods

2.1. Subjects

28 drug-free boys, aged 7–12, who were admitted to GülhaneMilitary Medical Academy, Child and Adolescent PsychiatricDepartment and diagnosed as ADHD according to the DSM-IVcriteria (American Psychiatric Association, 1994) were includedin this study. Patients were assessed using parent completed theTurgay Diagnostic and Statistical Manual of Mental Disorders,4th edition (DSM-IV)-Based Child and Adolescent BehaviorDisorders Screening and Rating Scale (T-DSM-IV-S) (Ercanet al., 2001). All of the ADHD children were outpatients. ADHDgroup was divided into two groups according to a median split ofthe plasma zinc levels: low zinc group (N=13, zinc levelb80 μg/dL) and zinc non-deficient group (N=15, zinc level≥80 μg/dL). 24 mentally and physically healthy boys that hadsimilar socio-demographic characteristics were included in thestudy as a normal control group. All subjects in the study wereCaucasians (white). As inclusion criteria, subjects were asked tohave written informed consent from their parents, not haveseizure disorders, mental retardation, autistic disorder, severehead injury, organic brain damage, psychotic disorder, conductdisorder, and any other acute or chronic physical illnesses. Therewere no psychotic disorders in the first-degree relatives of allsubjects. Boys with a history of any drug use during the lastmonth were excluded from the study. Gulhane Military MedicalFaculty Local Ethic Committee approved this study.

2.2. Procedures and measures

The subjects were tested in sitting position with eyes closed ina silent room. ESAOTEBIOMEDICA 4-Channel (Italy) EMG-EP device was used for all tests. The skin of the scalp wascleaned. We recorded the bioelectrical signal by surface elec-trodes (plate shaped electrode, 11 mm diameter, DANTECElectronic A/S, Denmark) placing along the midline Pz, Fz andFpz according to the 10–20 International System of EEG elec-trode placements. The subject was grounded by a surface groundelectrode located midway between Fpz and Fz. Referenceelectrode was placed on the mastoids and an electrode wasplaced infraorbitally (IO) to monitor the eye movements.The impedance was less than 5 kΩ and the filter band passwas 0.5–50 Hz. The analysis time was 1000 ms. Tone intensitywas manually raised until a reliable count was obtained. Afurther minute counting aloud served as a practice and to ensurethat the task was understood. Intensity was typically at 60 dB butwas subject-dependent.

Auditory event-related potentials were elicited with anauditory discriminated task paradigm. Non-target (frequency3000 Hz) and target (rare 2000 Hz) stimuli were presentedbinaurally over headphones with 60 dB hearing level and 5.3 msrise/fall times. The tones were presented at a rate of 0.7 Hz. Thesubjects were asked to count the target tones (2000 Hz), which

Table 1Plasma zinc levels in ADHD, low zinc, zinc non-deficient, and control groups

Plasma zinclevels (μg/dL)

SD Cohen's d(comparedwith normals)

p values(comparedwith normals)

ADHD group 78.5 15.7 2.3 0.00Low zinc ADHD group 65.8 9.5 4.5 0.00Zinc non-deficientADHD group

89.5 10.9 1.8 0.00

Normal control group 107.8 9.0

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occurred among the non-target tones (3000 Hz) randomly. Thefrequency of target tones was 20% and of non-target tones was80%. A total of 40 target stimuli artifact free trials were acquiredand the test was repeated twice. The data of the P1, N2 and P3from the Pz and Fpz obtained from the target stimuli arepresented in this article. In the analysis of potentials, theamplitudes were measured for P3 from peak of N2 to peak ofthe P3; for N2 from the peak of P1 to peak of N2 and for P1from the first positive deflection to peak of P1 recorded at Pzand Fpz. We measured the latencies of the potentials from themidline of each potential.

2.3. Blood analysis

Blood was withdrawn into EDTA containing evacuatedblood collection tubes from overnight fasting patients in themorning (between 9 and 10 am). In maximum 3 h, the bloodsamples were centrifuged at 4000 rpm for 15 min at 4 °C;plasma was separated and stored at −70 °C until the day ofanalysis. Plasma zinc levels were measured by an atomicabsorption spectrophotometer (Varian, 30/40, Australia).

2.4. Statistical analysis

Measures of ERP indices (amplitudes and latencies) andplasma zinc levels in the children with ADHD and control

Table 2The ERP indices in ADHD, control, low zinc ADHD, and zinc non-deficient ADHD

ADHD group Normalcontrol group

d p

Mean SD Mean SD

PP3L (ms) 370.1 56.2 324.3 32.0 1.0 0PP3A (μV) 8.7 6.7 13.9 6.2 0.8 0PP1L (ms) 140.6 31.8 168.5 38.9 0.9 0PP1A (μV) 5.1 4.7 5.0 4.4 0.0 0PN2L (ms) 222.6 40.3 236.1 29.5 0.4 0PN2A (μV) 9.6 6.9 10.0 5.1 0.1 0FP1L (ms) 146.9 27.5 160.8 41.0 0.4 0FP1A (μV) 4.9 3.2 6.3 5.9 0.3 0FN2L (ms) 214.8 31.0 226.1 37.8 0.3 0FN2A(μV) 7.2 4.9 10.6 6.6 0.6 0FP3L (ms) 360.5 61.0 323.0 30.8 0.8 0FP3A (μV) 8.5 6.5 13.8 7.5 0.8 0

d: Cohen's d; PP3L: parietal P3 latency; PP3A: parietal P3 amplitude; PP1L: parietparietal N2 amplitude; FP1L: frontal P1 latency; FP1A: frontal P1 amplitude; FN2L: ffrontal P3 amplitude.

subjects were compared by using Kruskal Wallis test. The levelof significance evaluating Kruskal Wallis test results was setat 0.05. Statistically significant results were analyzed againby using Mann Whitney U test (Dawson and Trapp, 2001).Bonferonni correction for multiple comparisons was usedto reduce Type I error. Because there were three groups, thep value (0.05) divided by 3 was 0.017. After Bonferonni cor-rection, the level of significance was 0.017. To examine therelationship between ERP indices (amplitudes and latencies) ofchildren with ADHD and plasma zinc levels, Pearson correla-tion was used.

3. Results

The age range of the ADHDgroupwas between 7 and 12 years(9.5±1.9 years), and that of the normal control group wasbetween 7 and 12 years (8.5±1.7 years). There was no signifi-cant difference for the ages of the children between the two groups(Z=−0.177; pN0.05). No significant difference was found inthe age between low zinc and non-deficient group (Z=−1.485;pN0.05).

The plasma zinc level was significantly lower in low zincADHD group (65.8±9.5 μg/dL), in non-deficient ADHD group(89.5±10.9 μg/dL), and in children with ADHD (78.5±15.7 μg/dL) than in that of healthy controls (107.8±9.0 μg/dL) (Z=−4.965; Z=−4.276; Z=−5.582 respectively; and all p valuesb0.017; Table 1). In addition, the plasma zinc level was sig-nificantly lower in low zinc ADHD group compared to non-deficient group (Z=−4.496; pb0.017).

Parietal P3 latency (PP3L) was significantly longer, andparietal P3 amplitude (PP3A), and frontal P3 amplitude (FP3A)were smaller in children with ADHD compared to normals (Z=−3.021; Z=−3.043, Z=−2.657 respectively; and all p valuesb0.017; Table 2). No significant difference was found in otherERP parameters between two groups (all p values N0.017;Table 2). Fig. 1 shows ERPs recorded from healthy controls,low zinc and non-deficient ADHD groups.

groups

Low zincADHD group

Zinc non-deficientADHD group

d p

Mean SD Mean SD

.00 357.6 51.5 381.8 59.6 0.4 0.25

.00 8.6 6.3 8.9 7.4 0.0 0.96

.04 140.3 26.4 140.8 36.8 0.0 0.68

.74 4.4 3.3 5.7 5.6 0.3 0.50

.28 209.2 51.5 234.2 23.4 0.6 0.01

.45 8.5 5.2 10.6 8.3 0.3 0.80

.32 135.7 28.5 156.5 23.4 0.8 0.04

.76 4.2 3.0 5.5 4.0 0.4 0.44

.45 198.8 35.2 228.5 18.7 1.1 0.01

.04 6.0 3.2 8.2 6.0 0.5 0.40

.03 343.2 50.8 376.6 66.8 0.7 0.26

.01 7.5 5.7 9.4 7.2 0.1 0.54

al P1 latency; PP1A: parietal P1 amplitude; PN2L: parietal N2 latency; PN2A:rontal N2 latency; FN2A: frontal N2 amplitude; FP3L: frontal P3 latency; FP3A:

Fig. 1. ERPs recorded from IO (infraorbital electrode), Cz, Pz and Fpz. A) ERPsfrom a healthy boy. B) ERPs from an ADHD boy with low zinc level. C) ERPsfrom an ADHD boy with normal plasma zinc level. Note the shortening of PN2Land FN2L in the ADHD boy with low zinc level compared to non-deficientpatient.

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The only difference between low zinc and non-deficient groupin ADHD subjects was that parietal N2 latency (PN2L) andfrontal N2 latency (FN2L) were significantly shorter in low zincgroup compared with non-deficient group (Z=−2.470; Z=−2.468; respectively; and both p values b0.017; Table 2).PN2L was significantly shorter; PP3A and FP3Awere smaller inlow zinc ADHD group compared with normals (Z=−2.419; Z=

−2.438; Z=−2.598 respectively; and all p values b0.017). PP3Land FP3L were longer, and PP3A smaller, in zinc non-deficientADHD group than normals (Z=−2.983; Z=−2.529; Z=−2.561respectively; and all p values b0.017). There was no significantdifference in other ERP parameters between groups (all p valuesN0.017). In addition, there was a medium but significant positivecorrelation between plasma zinc levels of children with ADHDand FN2L, and FN2A (Pearson correlation=0.407 and 0.409;p=0.032 and p=0.016 respectively), but not other ERPparameters (pN0.05).

4. Discussion

Zinc is stored within vesicles in presynaptic boutons(Frederickson et al., 1983), released together with glutamate bymembrane depolarization in a Ca2+ dependent manner (Assaf andChung, 1984), and modulates the activity of glutamate andgamma amino butyric acid (GABA) receptors (Vallee andFalchuk, 1993). In addition, zinc is an important trace elementfor biogenic amine metabolism which is thought to have a role inADHD (Dakshinamurti et al., 1990; Hsu et al., 1988; Nakano andMcCormick, 1991). Plasma zinc levels were significantly lowerin children with ADHD compared with normals in the presentstudy. This result is consistent with previous reports (Arnold et al.,2005; Bekaroglu et al., 1996; Yorbik et al., 2004a). Arnold et al.reported that serum zinc was found to be correlated at r=−0.45(p=0.004) with parent–teacher-rated in attention, even aftercontrolling for gender, age, income, and diagnostic subtype(Arnold et al., 2005). A double-blind placebo-controlled studyshowed that zinc monotherapy was significantly superior toplacebo in reducing symptoms of hyperactivity, impulsivity, andimpaired socialization in children with ADHD (Bilici et al.,2004). However biochemical, clinical, and electrophysiologicaleffects of lower zinc levels is unknown in ADHD.

Because both frontal and parietal areas have a role in attentionfunctions (Cohen et al., 2005; Paus, 2000; Rauschecker, 1998;Shomstein and Yantis, 2006; Wu et al., 2007), present studyexamined the possible effect of plasma zinc levels on auditorylate information processing in the parietal and frontal regions inADHD boys. ADHD group was divided as low zinc group(plasma zinc level b80 μg/dL) and zinc non-deficient group(plasma zinc level≥80 μg/dL). N2 latency in the parietal regionwas shorter in low zinc ADHD group than normals; whereasthere was no difference in N2 wave between zinc non-deficientgroup and normals. Low zinc group had significantly shorter N2latencies in the frontal and parietal regions compared to zincnon-deficient group. Ponton et al. reported that the N2 amplitudeincreases from age 4 to 10 and thereafter decreases to reach adultvalues by age 17 (Ponton et al., 2000). No significant differencewas found in age between groups in the present study. There wasa medium but significant positive correlation between plasmazinc levels of children with ADHD and the amplitude andlatencies of N2 in the frontal region. These results suggestedthat lower plasma zinc levels affect information processing inADHD children, particularly N2 wave. Previous studies re-ported smaller N2 wave in ADHD children (Broyd et al., 2005;Johnstone et al., 1996; Satterfield et al., 1984). Interestingly,

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Satterfield et al. reported that N2 was smaller in the youngerpatients, but larger than normals in the older ones (Satterfieldand Braley, 1977; Satterfield et al., 1984). This finding may beattributed to developmental delays in ADHD. The earlier N2latency in ADHD subjects to oddball task targets was reported insome previous studies (Hermens et al., 2005; Sunohara et al.,1999), but not others (Lazzaro et al., 2001; Ozdag et al., 2004).The latency of N2 component in the parietal region was shorterin only low zinc ADHD group than normals in this study. Sinceinhibition is important in ADHD due to the role it plays inattention systems, and since N2 wave changes may reflectatypical inhibition process (Barry et al., 2003), further studiesare warranted to investigate the effect of zinc on inhibitoryprocess in children with ADHD, and in low zinc and non-deficient ADHD groups.

P3, the most commonly studied component, is thought toreflect updating working memory and post decisional processes(Picton, 1992). Agreed with most of the previous studies (Franket al., 1994; Holcomb et al., 1986; Ozdag et al., 2004; Winsberget al., 1993; Yorbik et al., 2004b), we found that children withADHD had significantly smaller P3 amplitudes in frontal andparietal regions compared to normals. These results suggest thatchildren with ADHD may have ineffective working memoryupdating and a problem with post decisional processes. However,other studies did not found differences in P3 amplitude betweennormal and ADHD subjects (Johnstone and Barry, 1996Johnstone et al., 2001; Lazzaro et al., 1997, 2001). The latencyof the P3 component is believed to reflect the timing of stimulusevaluation process. In zinc non-deficient ADHD group comparedto control, the latencies of P3 in the frontal and parietal regionswere longer. Longer latency of P3 in children with ADHDcompared with controls in this study is consistent with previousfindings (Ozdag et al., 2004; Winsberg et al., 1993; Yorbik et al.,2004b), but not others (Holcomb et al., 1986; Johnstone et al.,1996, 2001; Lazzaro et al., 1997). Longer P3 latencies in ADHDchildren may reflect their inattention since it takes longer toupdate memory and prepare for the next stimulus for them(Sunohara et al., 1999).

It has been proposed that P1 and N1 components representpresynaptic incoming impulse (Dafny et al., 1975), and theearliest potentials in the brainstem (latency b10 ms) and the‘midlatency’ potentials (b100 ms) represent the synaptic stagesfor the passage of sensory information to cortex (Oades et al.,1996). No difference was found in the P1 wave in accordancewith previous studies (Ozdag et al., 2004; Yorbik et al., 2004b),except the study of Oades et al. reporting a shorter P1 latency(Oades et al., 1996). In addition, there was no difference in P1wave between the groups that have different zinc levels inpresent study. This result can suggest that zinc levels do notlikely affect presynaptic incoming impulse.

These results can suggest that plasma zinc levels might havean effect on information processing in ADHD children.Especially, lower zinc levels seem to affect N2 wave whichhas been suggested to be in relation with inhibitory processing(Barry et al., 2003). However results of the present study shouldbe interpreted carefully. Because the comorbid disorders wereexcluded only clinically, not by a structured tools, and the

sample size was small, and plasma zinc levels and ERP indiceswere analyzed at once, and the fact of that all subjects beingCaucasian impedes generalization of the results to all races. Inaddition, the positive correlation between plasma Zn levelsof children with ADHD and FN2L, and FN2A was medium(Pearson correlation=0.407 and 0.409, respectively). There-fore, the differences in ERP parameters measured might beascribed to other causes which are not necessarily linked plasmaZn levels.

5. Conclusion

Results of present study suggested that the differences in N2latencies in frontal and parietal regions may reflect the effects ofzinc deficiency on information processing in ADHD, whereasthe differences in parietal P3 amplitude and latency, and frontalP3 amplitude between normals and ADHDmay reflect the effectof ADHD. The contradictory results of published studiesinvestigating ERP indices in ADHD may be attributed tomethodological differences and heterogeneity of the samples. Itis also plausible to suggest that diverse subgroups of ADHD(i.e., low zinc vs non-deficient ADHD) with a problem in dif-ferent processing stages may have similar symptom profiles inthe clinical presentation. Further studies investigating differentprocessing stages in diverse subgroups of ADHD and effect ofzinc treatment and comorbidity on ERP indices may provideboth a better understanding of the electrophysiological data andinsight into ADHD.

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