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Dysfunctional response preparation and inhibition during a visual GoNogo task in children with two

Dysfunctional response preparation and inhibition during a visual GoNogo task in children with two
Dysfunctional response preparation and inhibition during a visual GoNogo task in children with two

Dysfunctional response preparation and inhibition during a visual Go/Nogo task in children with two subtypes of attention-deficit

hyperactivity disorder

Stuart J.Johnstone ?,Adam R.Clarke

School of Psychology,University of Wollongong,Northfields Avenue,Wollongong,NSW 2522,Australia

Received 16April 2007;received in revised form 13December 2007;accepted 2March 2008

Abstract

While a response inhibition problem is well-established in children with attention-deficit/hyperactivity disorder of the combined subtype (AD/HDcom),the predominantly inattentive subtype (AD/HDin)has not been investigated previously.This study examined control versus subtype differences in visually evoked response inhibition using task performance and event-related potential (ERP)measures.Children with AD/HDcom (n =15)and AD/HDin (n =15)and age-matched controls (n =15)performed a cued visual Go/Nogo task requiring either activation or inhibition (30%)of a button-press response to the S2(Go or Nogo stimulus)following the S1(warning stimulus),presented 1380ms earlier.Task performance and ERP indices of Warning,Go and Nogo stimulus processing,as well as preparation during the S1–S2interval,were examined for group differences.Behavioural results indicated a response inhibition deficit in children with AD/HDcom and AD/HDin,with additional response activation problems in AD/HDcom.Topographic ERP differences between controls and both clinical groups suggested atypical (a)preparation for S2as indexed by the late CNV ,(b)early sensory/attentional processing of both S1and S2,and (c)response inhibition as indexed by N2and P3.In addition to replicating previous AD/HDcom findings,these results indicate that children with AD/HDin differ from controls in response preparation and inhibition during a cued visual Go/Nogo task.?2008Elsevier Ireland Ltd.All rights reserved.

Keywords:Event-related potentials;Contingent negative variation;Child psychiatry;Attention;Impulsivity

1.Introduction

The DSM-IV (American Psychiatric Association,1994)outlines three subtypes of attention-deficit/hyperactivity disorder (AD/HD);the combined type (AD/HDcom),the predominantly inattentive type (AD/

HDin),and the predominantly hyperactive/impulsive type (AD/HDhyp).These subtypes are based on dif-ferent clusters of symptoms from within the two core symptom domains of Inattention and Hyperactivity/Impulsivity.Specifically,the diagnostic criteria for AD/HDcom require evidence of significant impairment across both domains,while AD/HDin and AD/HDhyp require evidence of significant impairment in only one domain,i.e.Inattention or Hyperactivity/Impulsivity,respectively.Diagnoses of AD/HDhyp are rare,with a prevalence rate of only 0.2%in Australia (Gomez et al.,

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Corresponding author.Tel.:+61242214495;fax:+61242214163.

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0165-1781/$-see front matter ?2008Elsevier Ireland Ltd.All rights reserved.doi:10.1016/j.psychres.2008.03.005

1999).This was confirmed in our setting,with no children fulfilling the diagnostic criteria for this subtype. Further,as questions have been raised about the validity of this subtype(Barkley,1997a;Power and DuPaul, 1996),it is not further addressed in this article.

The DSM-IV criteria indicate that hyperactive and impulsive symptoms differentiate AD/HDcom from AD/HDin.This distinction has apparent validity in the day-to-day life of the child,with a high prevalence of academic and behavioural problems in those with AD/ HDcom(73%and92%,respectively)and a high incidence of academic,but reduced behavioural,prob-lems associated with AD/HDin(75%and40%,respec-tively;Wolraich et al.,1996).Some of the hyperactive/ impulsive symptoms(e.g.fidgeting,excessive talking, interrupting others)can be viewed as related to response inhibition problems.While deficient inhibition has been put forward as being at the core of AD/HD(Barkley, 1997b;Quay,1988b,1997;Sergeant,2000),the rele-vance of these theoretical positions to subtypes is un-clear,as Sergeant and Quay do not make reference to subtypes of AD/HD,and Barkley specifically refers only to the AD/HDcom and AD/HDhyp types,with AD/ HDin considered a disorder of inattention.Diamond (2005)has proposed that AD/HDin is not a subtype of AD/HD,but rather a different disorder,with core prob-lems in motivation and working memory functioning but not response inhibition.Note also that the influence of intra-individual response variability,within the con-text of inhibition and other executive function tasks,is receiving increased research interest(e.g.Castellanos et al.,2006;Klein et al.,2006).

Previous behavioural research comparing the AD/ HD subtypes on inhibition tasks is limited and has produced mixed results.Some studies report problems of disinhibition in AD/HDcom but not AD/HDin(Nigg et al.,2002;Wang et al.,2003),while others show similar levels of poor inhibition performance in both subtypes(Lane,2004;Yonghui et al.,2005).This study will examine response inhibition during the Go/Nogo task in these subtypes,examining task performance and additionally using event-related potentials(ERPs)to investigate underlying neural activation related to res-ponse inhibition.

It has been consistently reported that children with AD/HDcom have problems with response inhibition, typically displaying higher levels of commission errors to Nogo/Stop stimuli(i.e.,those stimuli requiring the covert inhibition of a response)than control children (Iaboni et al.,1995;Nigg,1999;Rubia et al.,1999; Schachar et al.,1993).These behavioural findings are supported by brain imaging reports of atypical frontal activity during inhibitory processing in children with AD/HD(Rubia et al.,2000),and reports of atypical activation of inhibition-related ERP components such as the fronto-central N2(Broyd et al.,2005;Dimoska et al., 2003;Pliszka et al.,2000;Smith et al.,2004;Yong-Liang et al.,2000)and P3(Brandeis et al.,1998;Liotti et al.,2005;Overtoom et al.,2002).Group differences are not restricted to these endogenous components, however,with topographic differences and differential Nogo effects(i.e.,a larger component to Nogo than Go stimuli)reported in earlier exogenous(i.e.,obligatory/ sensory)components,such as the N1and P2(Broyd et al.,2005;Smith et al.,2004).

While their functional significance is currently con-troversial(Nieuwenhuis et al.,2003;Smith et al.,2006), the N2and P3ERP components have shown reasonably consistent relationships with inhibition-related beha-viours(Falkenstein et al.,1999;Jodo and Kayama, 1992),and are generally considered to be electrophysio-logical markers of aspects of the inhibition processing sequence.The N2is maximal over frontal scalp regions (Kiefer et al.,1998)and is typically larger to Nogo than Go stimuli(Eimer,1993),an augmentation resulting from the inhibitory process and described as a“red flag”that the response to the stimulus is to be inhibited(Kok, 1986).The latency of N2is reduced in good compared with poor inhibitors(Falkenstein et al.,1999),providing further support for N2as related to the inhibition me-chanism.Nogo effects have been reported for N2in children(Broyd et al.,2005;Dimoska et al.,2003; Smith et al.,2004)and adults(Kiefer et al.,1998).The P3component typically exhibits a centro-parietal maxi-mum to Go stimuli,but is more anterior to Nogo stimuli (Bruin and Wijers,2002).Nogo P3latency is typically prolonged relative to Go stimuli(Eimer,1993),and in older compared to younger adults(Falkenstein et al., 2002).

We have previously investigated these subtypes using a task that primarily engages attention control (i.e.,a two-tone oddball),a process from the symptom domain common to both AD/HD subtype groups (Johnstone et al.,2001).There we reported that children with AD/HDin did not differ significantly from controls or AD/HDcom in task performance,but did show ERP differences from controls,several that were common to both subtypes and represent shared processing problems (e.g.increased P2amplitude),as well as unique dif-ferences(e.g.target N1,P2and P3topography).Further, each subtype showed differing patterns of abnormal age-based development for several ERP components, indicating qualitative differences in information proces-sing stage deficits in each of these AD/HD subtypes.

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The task used in the present study was a cued visual Go/Nogo,with a constant interval between Stimulus1, or S1(i.e.the Warning stimulus)and Stimulus2,or S2 (i.e.the imperative stimulus),allowing examination of responses to S1and S2and also the contingent negative variation(CNV),an electrophysiological index of response preparation,during the S1–S2interval.We have previously reported that children with AD/HDcom process cue stimuli differently than controls during a cued auditory Go/Nogo task,with increased commis-sion errors and concurrent differences in P1,N1and P2 components to these stimuli(Smith et al.,2004).Cue processing problems in AD/HD have also been reported in the visuospatial attention context(Huang-Pollock and Nigg,2003).

While early research reported reduced CNV in child-ren with concentration problems(Grunewald-Zuberbier et al.,1978),more recent investigations have yielded variable results.The early CNV,which is a frontally maximal component linked to orienting/expectancy (Loveless,1979),has been reported to be attenuated in AD/HDcom(Hennighausen et al.,2000;van Leeuwen et al.,1998).The fronto-central late CNV,an index of preparation for the target(Walter et al.,1964),has been reported to be reduced(Aydin et al.,1987;Banaschewski et al.,2003;Dumais-Huber and Rothenberger,1992; Perchet et al.,2001;van Leeuwen et al.,1998),increased (Hennighausen et al.,2000)and not different(Strand-burg et al.,1996;Yordanova et al.,1996)in children with AD/HD compared to controls.Given these varied re-sults,further investigation in this area is warranted,with this study extending previous research to include the AD/HDin subtype.

This study aimed to investigate response prepara-tion and response inhibition in children with AD/ HDcom and AD/HDin using the visual Go/Nogo task with the inclusion of electrophysiological information to provide an insight into the neural bases for task performance,especially in relation to the inhibition process.The CNV as well as N2and P3components(to S2)will be examined as indices of response preparation and inhibition,respectively.Other earlier components will also be evaluated,given the potential cascading nature of early processing issues as related to later endogenous aspects of processing.

2.Methods

2.1.Subjects

Participants comprised45children between8and14 years of age(M=11.7years,S.D.=1.9years)participated in the years),with15in each of the control(4female), AD/HDin(3female)and AD/HDcom(2female)groups. For inclusion in the study,each child had to obtain an estimated IQ of80or greater(M=110.7,S.D.=14.4), based on the Raven's Progressive Matrices(Raven,1989) and report no hearing or vision problems.Subjects were excluded if they had been known to suffer an epileptic seizure,serious head-injuries,periods of unconscious-ness,or serious psychiatric https://www.doczj.com/doc/2210632653.html,rmed written consent was obtained from the parent(s)after provision of an outline of the procedure,and verbal assent was ob-tained from the child after the testing procedure had been explained.The experimental protocol was approved by the University of Wollongong and Illawarra Area Health Service Human Research Ethics Committee.

Clinical subjects were diagnosed by a psychologist/ psychiatrist according to DSM-IV criteria,with con-firmation by an independent experienced psychologist. Subjects with a clinically significant comorbid disorder, based on consideration of questions related to autism, Asperger's syndrome,depression and anxiety during diagnostic interview,as well as behavior rating scales, were excluded from the sample.Those AD/HD subjects taking stimulant medication(73%of the AD/HDin group;87%of the AD/HDcom group)were required to refrain from taking it in the24h(5half-lives)prior to testing.

Control subjects were recruited from the local com-munity via newspaper advertising,and had no known health,mental or developmental problems,as reported by each child's parent(s).Control children were required to score in the non-clinical range on all scales of the Conners'Parent Rating Scale-Revised(CPRS-R;T b60) and Child Behaviour Checklist(CBCL;T b65).

2.2.Procedures

Parents completed the CPRS-R and CBCL to char-acterise their child’s typical behaviour,and an in-formation sheet used to screen for stimulant use, handedness and a brief history of health and physical concerns.Each child completed the South Australian Spelling Test(SAST)and Raven's Standard Progres-sive Matrices(Raven,1989),a test of general cognitive ability.

After familiarisation with the testing equipment and procedure and subsequent equipment fitting,the child was taken to a sound-attenuated air-conditioned testing room where he/she completed three experimental tasks. After electrophysiological testing was completed,sub-jects were given a short break before moving to another quiet room where they completed the SAST and Raven's

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tasks.The entire session lasted for approximately2h. Independent of task performance,children received a certificate and a chocolate bar for their participation in the study,while their parent(s)received A$10to compensate for traveling expenses incurred,and a report on their child’s spelling and general cognitive ability test performance.

2.3.Tasks

All subjects completed a visual cued Go/Nogo task,as well as auditory and visual stop-signal tasks, with task presentation order rotated between subjects. Data from the stop-signal tasks are not presented here.

Stimuli in the visual Go/Nogo task consisted of the letters“W”(Warning),“G”(Go)and“S”(Stop,i.e., Nogo)presented centrally on a15-inch computer monitor1meter from the child at eye-level.The stimuli measured3×3cm on the screen.The sequence for each trial consisted of the presentation of the warning letter (S1)followed by a second letter(S2)which required either a button press response(Go)or the inhibition of a response(Nogo),depending on the letter presented.S2 required response execution on70%of trials,and the inhibition of a response on the remaining30%.The S1–S2interval was fixed at1380ms,while the S2–S1 interval varied randomly between1500and2500ms (mean2000ms).A central fixation cross was on screen at all times,except during discrete stimulus presenta-tions.A10-trial practice block was followed by two recording blocks,each consisting of100trials.If re-quired,children were given a2–3min break between blocks.Subjects responded with the index finger of their dominant hand(all but one subject in the con-trol group were right-handed)with a keyboard button press.Only presses to the Go tone with reaction time RT b1000ms were regarded as correct,although all button presses were recorded to allow omission and commission errors to be monitored.

It was explained to the children that the letter“W”represented a warning,instructing them to“get ready to press the button”,and that this would be followed by either the letter“G”which meant“Go,that is,press the button”,or the letter“S”which meant“Stop,that is,do not press the button”.Both speed and accuracy were encouraged.Subjects were asked to remain as still as possible,to watch the central fixation cross on the computer monitor,to respond as quickly and as ac-curately as possible to the presentation of Go stimuli, and to attempt to withhold that response if a Nogo stimulus occurred.2.4.Electrophysiological recording

The continuous scalp electroencephalogram(EEG) was recorded using an electrode cap with electrodes placed at19sites(Fp1,Fp2,F3,F4,F7,F8,Fz,C3,C4, Cz,P3,P4,Pz,T3,T4,T5,T6,O1,O2)of the Inter-national10–20system.The electro-oculogram(EOG) was measured vertically with two tin cup electrodes, 1cm above and below the left eye.All electrodes were referenced to linked ears.Impedance was kept below 5kΩfor EOG and reference electrodes,and3kΩfor cap electrodes.The subject was grounded by a cap electrode located between Fpz and Fz.EEG and EOG signals were amplified5000times,with a bandpass down3dB at0.01and100Hz(the high and low band-pass settings,respectively),via24channels of Grass amplifiers(Grass-Telefactor,USA),and sampled through a12-bit A/D card at512Hz.Prior to processing,the EEG data were digitally filtered using a low-pass filter3dB down at30Hz.

2.5.Data quantification

The ERP epoch was defined as100ms pre-stimulus to(a)1380ms post-stimulus for Warning trials,and (b)900ms post-stimulus for Go and Nogo trials. Epochs were excluded from analysis if they contained amplitudes outside the range of±100μV at any non-frontal site.EOG activity was subtracted from EEG epochs using a regression method in the time domain (Semlitsch et al.,1986).ERPs were calculated using correct responses only.To ensure comparability within subjects,the number of epochs available for averaging was determined for Nogo stimuli initially,with Go and Warning epochs restricted to the same number,being selected randomly from the total available.The mean number of epochs in each ERP for the control,AD/ HDin and AD/HDcom groups was50.4(S.D.2.8),47.9 (S.D.2.9)and47.6(S.D.9.1),respectively,with no dif-ferences between groups.

Grand average ERP waveforms for each trial type and task were displayed for the purpose of defining each component's latency range.Peak picking was carried out by an automatic peak-picking program,measured relative to the pre-stimulus baseline,with manual con-firmation by an experienced ERP researcher who was blind to any subject information.Peak latency at all sites was locked to the peak latency of the site of maximum amplitude.The peak search parameters for both Warn-ing and Go/Nogo stimuli were:N1(100–190ms;locked to Fz),P2(190–260ms;Cz),N2(260–360ms;Fz),P3 (360–750ms;Pz).CNV-E and CNV-L were quantified

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by determining the mean amplitude in the ranges 500–950ms and 950–1380ms after the Warning stimulus,respectively.

2.6.Statistical analyses

One-way Analyses of Variance (ANOVAs)were used to compare the groups on age,as well as psychometric,task performance and ERP latency variables.

For Go and Nogo stimuli,four-way repeated mea-sures ANOVAs were used to analyse ERP compo-nent amplitudes at 9sites with Lateral (Left [F3,C3,P3],Midline [Fz,Cz,Pz],Right [F4,C4,P4]),Sa-gittal (Frontal [F3,Fz,F4],Central [C3,Cz,C4],Parietal [P3,Pz,P4])and Stimulus (Go vs.Nogo)as within-subject factors,and Group (control,AD/HDin,AD/HDcom)as a between-subjects factor.Additional three-way repeated measures ANOV As examined com-ponents to Warning stimuli,including the CNV (Lateral ×Sagittal ×Group ).

Planned contrasts,which allow confirmation of ex-pected and characteristic variation in ERP components dependent on scalp location,were performed on the within-subjects factors Lateral (Left vs.Right electro-des,and Midline vs.the mean of the Left and Right electrodes)and Sagittal (Frontal vs.Parietal electrodes,and Central vs.the mean of the Frontal and Parietal electrodes).Within Group,two planned non-orthogonal contrasts compared each clinical group with the control group separately.As these contrasts were planned and there were no more of them than the degrees of freedom for effect,no Bonferroni-type adjustment to alpha was necessary (Tabachnick and Fidell,1989).Also,single

degree of freedom contrasts are not affected by violations of symmetry assumptions common in repeated measures analyses,and thus do not require Greenhouse –Geisser type corrections (Howell,1997).

Data showing a Stimulus or Group main effect and an interaction with topography (https://www.doczj.com/doc/2210632653.html,teral or Sagittal factors)were normalised using the vector scaling procedure (McCarthy and Wood,1985).1This method removes the main effect amplitude difference between Stimuli/Groups —if the interaction remains significant after the procedure has been applied,it allows conclu-sions to be made about differing component generators between Stimuli/Groups.Accordingly,only interactions with topography that remained significant after this procedure are reported.3.Results

3.1.Demographic and psychometric

As can be seen in Table 1,the groups did not differ in mean age or IQ,but the AD/HDin group showed significantly reduced spelling performance,compared to controls.The AD/HDcom group showed average scores in the clinical range (i.e.,65+)for all CPRS subscales and the Attention Problem and Aggressive Behaviour subscales of the CBCL (clinical range =70+),with

Table 1

Mean scores of psychometric testing,Conners Parent Rating Scale (CPRS)and the Child Behaviour Checklist (CBCL)for each group.

Control

AD/HDin AD/HDcom Age 11.5(1.4)11.8(2.2)11.9(2.1)IQ

108.8(15.3)113.4(13.6)110.0(14.8)Spelling Age 13.4(2.1)10.8*(2.7)11.8(3.0)CPRS

ADHD Index

47.1(8.0)65.5***(6.2)77.5***(9.4)Cognitive Prob./Inattent.48.7(9.5)64.5***(6.9)74.7***(9.8)Hyperactivity 50.8(10.2)61.5*(13.2)81.6***(10.2)Oppositional

48.6(7.9)56.7(13.5)74.5***(17.3)CBCL

Anxious/Depressed 53.8(5.3)59.7*(9.4)60.6*(6.1)Withdrawn

55.4(6.6)59.0(8.4)59.3(6.5)Somatic Complaints 52.2(4.5)56.9*(5.3)58.9**(6.5)Social Problems 54.6(6.1)57.9(6.3)65.7***(8.7)Thought Problems 54.7(6.4)64.9**(8.8)69.3***(8.0)Attention Problems 53.0(5.8)64.9***(9.1)74.5***(10.1)Rule-breaking

51.6(3.7)59.5**(7.7)68.3***(9.8)Aggressive Behaviour

53.9

(6.0)

57.4

(9.0)

74.7***

(12.7)

Significant differences from controls for each AD/HD subtype are indicated by the asterisk (*P b 0.05,**P b 0.01,***P b 0.001).

1

Recent critical appraisals of the vector scaling method have resulted in an alternative method,which shows advantages especially when a linked-ear reference is used (Jing et al.,2006).When applied to the data from the current study,outcomes of the new method did not differ from those of the vector scaling method.

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Thought Problems and Rule-breaking subscales of the CBCL in the borderline range (i.e.,67–70).The AD/HDin group averaged a clinical level ADHD Index,as well as borderline clinical scores (i.e.,60–64)for the Cognitive Problems/Inattention and Hyperactivity sub-scales of the CPRS,with no borderline or clinical level scores for the CBCL.

In regard to group comparisons,the AD/HDcom group had higher scores than controls on all but one (i.e.,Withdrawn)subscale of the CPRS and CBCL.The AD/HDin group had higher scores than controls on all but the Oppositional subscale of the CPRS,and on the Thought Problems,Attention Problems and Rule Break-ing subscales of the CBCL.These results are consistent with previously reported subtype-specific symptom pro-files for children with AD/HD in Australia (Graetz et al.,2001).

3.2.Task performance

In relation to response activation,as shown in Table 2,both subtype groups had more errors of commission to warning stimuli than controls,with the AD/HDcom group showing reduced Go response accuracy compared with controls.This latter effect was not present in children

Table 2

Means (S.D.)for task performance measures for each group.

Control

AD/HDin

AD/HDcom

Warning Error %0.5(0.8) 1.2*(0.9) 1.5***(1.2)

Go Accuracy %96.2(4.6)94.8(4.0)92.6*(5.3)Go RT (ms)492.5(106.2)496.1(75.6)520.5(79.4)Inhibition probability %

95.2(3.9)89.3**(5.5)90.1**

(4.4)

Significant differences from controls for each AD/HD subtype are indicated by the asterisk (*P b .05,**P b .01,***P b

.001).

Fig.1.Grand mean ERP to Warning stimuli across the S1–S2interval at Cz (bottom panel)for the Control (solid line),AD/HDin (dotted line)and AD/HDcom (dashed line)groups.Note:Ticks on the x -axis=100ms;Stimulus onset is indicated by the y -axis (scale in μV).The top panels show topographic maps for each component labeled on the ERP plot,for each group.Darker shades equal larger positive amplitudes for each component.

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with AD/HDin.The RT to Go stimuli did not differ from

controls for either subtype.In relation to response inhi-

bition,the percentage of successfully inhibited responses

to Nogo stimuli was reduced in the AD/HDin and AD/

HDcom groups compared with controls.

3.3.ERPs

3.3.1.Warning stimuli

Fig.1shows the grand mean ERP to Warning stimuli

for each group at Cz and topographic maps of the quan-

tified components.N1peaked at141.9ms(with no Group

differences in latency)and was fronto-centrally maximal

in the sagittal dimension(Linear contrast F(1,42)=18.9,

P b0.001;Quadratic contrast F(1,42)=4.3,P b0.05)and

midline maximal in the lateral dimension(Quadratic

contrast F(1,42)=4.1,P b0.05).A near-significant

Group main effect and planned contrasts revealed that

N1tended to be larger in the AD/HDcom than control

group(?2.9vs.?1.3μV;P=0.07).A Frontal N Parietal

effect was larger in AD/HDin than the control group(F

(1,42)=6.3,P b0.05),highlighting a reduced parietal N1

in the AD/HDin group(see Figs.1and2A).

P2peaked at195.4ms(with no Group differences in

latency)and was maximal in the parietal region(Linear

F(1,42)=52.7,P b0.001),with no variation across the

Lateral regions.There was a group difference in the

Lateral distribution of P2,as the control group had

a Left N Right effect(4.3vs.3.5μV)while the AD/

HDin group showed an opposite effect(3.0vs.4.5μV;

F(1,42)=5.8,P b0.05).

N2peaked at328.9ms and was fronto-centrally

maximal(Linear F(1,42)=39.0,P N0.001;Quadratic

F(1,42)=25.0,P b0.001),with no lateral variation.

As shown in Figs.1and2B,although a Left N Right effect

(?1.3vs.0.4μV)was observed for the AD/HDin group,

the opposite effect occurred for the controls(?0.4vs.?0.9μV;F(1,42)=4.3P b0.05).P3peaked at527.7ms and was midline(Quadratic F(1,42)=6.0,P b0.05)and

parietally(Linear F(1,42)=41.9,P b0.001)maximal.

There were no differences between the groups in either

amplitude or latency.

CNV-E(600–950ms)was smaller in the midline

than hemispheres(Quadratic F(1,42)=29.7,P b0.001).

There were no group differences for this component.

CNV-L(950–1380ms)was maximal in the central

region(Quadratic F(1,42)=8.8,P b0.01).This non-

fronto-central distribution is typical of children of this

age(Klein and Feige,2005).A tendency towards a group difference in the midline b hemispheres effect, which was very small in controls(0.1μV)and large in AD/HDin(0.9),highlighted the reduced midline CNV-L in the AD/HDin group(F(1,42)=3.6,P=0.07).Figs.1 and2C display the central N frontal/parietal effect,which was reduced in the AD/HDcom group compared with controls(central vs.frontal/parietal difference:

AD/HDcom Fig.2.Group differences in ERPs to Warning stimuli for(A)N1, (B)N2and(C)CNV-L component amplitude.

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0.1μV ,control 1.2μV;F (1,42)=4.4,P b 0.05),high-lighting reduced central CNV-L in AD/HDcom.3.3.2.Go/Nogo stimuli

Fig.3shows the grand mean ERP to Go and Nogo stimuli for each group at Cz and topographic maps of the quantified components.N1peaked at 149.0ms (with no differences in latency between Groups or Stimulus type)and was maximal in the midline (Linear F (1,42)=23.9,P b 0.001)and fronto-central (Linear F (1,42)=30.5,P b 0.001;Quadratic F (1,42)=16.3,P b 0.001)regions.As can be seen in Figs.3and 4,the N1of the control group showed a fronto-central distribution for the Go stimulus but was frontally maximal with a linear reduction to the parietal region for Nogo stimuli (Central vs.Frontal/Parietal difference:Go 1.4μV ,Nogo 0.1μV)—each clinical group differed significantly from this,with both stimuli found to be fronto-centrally maximal for the AD/HDin group (Go 1.6μV ,Nogo 2.4μV;F (1,42)=7.7,P b 0.01),while the ADHDcom group showed frontal and fronto-central distributions for the Go and Nogo stimuli,respectively (Go 1.1μV ,Nogo 0.6μV;F (1,42)=5.7,P b 0.05).

P2(mean latency 230.9ms)occurred later to Go than Nogo stimuli (242.6vs.219.2ms,F (1,42)=18.29,P b 0.001),with P2amplitude maximal in the midline (Quadratic F (1,42)=8.4,P b 0.01)and parietal (Linear F (1,42)=58.2,P b 0.001)regions.There were no Stimulus by topography interactions.Relative to controls (3.2μV),both the AD/HDin (5.3μV ,F (1,42)=5.0,P b 0.05)and AD/HDcom (5.4μV ,F (1,42)=4.4,P b 0.05)groups had globally increased P2amplitude.P2was larger in the right than left hemisphere for the AD/HDin group (5.7vs.4.3μV),differing significantly from controls (2.8vs.3.0μV;F (1,42)=6.1,P b 0.05)who had an opposite pat-tern (i.e.Left N Right)of reduced size (see Fig.5).The control group showed parieto-central and parietal dis-tributions for P2for Go and Nogo stimuli,respectively (Central vs.Frontal/Parietal difference:Go 1.7μV ,Nogo 0.1μV),with a significantly different distribution for the AD/HDin group where both stimuli were parietally dis-tributed (Go 0.7μV ,Nogo 0.7μV;F (1,42)=5.0,P b 0.05).N2(mean latency 310.7ms)occurred later in the AD/HDcom than control group (322.5vs.299.1ms;F (1,42)=5.0,P b 0.05).As shown in Figs.3and 5,N2latency was slightly longer to Go than Nogo stimuli for controls (300.8vs.297.4ms),but was substan-

tially shorter to Go than Nogo in the AD/HDin group (289.6vs.331.6ms;F (1,42)=8.4,P b 0.01).N2was maximal in the left hemisphere (Linear F (1,42)=7.2,P b 0.05)and fronto-central region (Linear F (1,42)=40.8,P b 0.001;Quadratic F (1,42)=3.9,P =0.056),and was larger to Nogo than Go stimuli (1.1vs.3.4μV ,F (1,42)=10.0,P b 0.01),a difference that was largest in the central-posterior region (Linear F (1,42)=3.7,P =0.06;Quadratic F (1,42)=5.4,P b 0.05).Across the scalp,N2was larger in controls (0.5μV)than both the AD/HDcom (2.9μV ,F (1,42)=4.1,P =0.05)and AD/HDin (3.3μV ,F (1,42)=5.6,P b 0.05)groups.

P3latency averaged 534.1ms overall,being increased for Nogo compared to Go stimuli (562.3vs.505.9ms;F (1,42)=8.23,P b 0.01)and tended to be increased in AD/HDcom compared with controls (578.5vs.511.1ms;F (1,42)=3.79,P =0.058).P3was maximal in the midline-right (Linear F (1,42)=5.5,P b 0.05;Quadratic F (1,42)=53.1,P b 0.001)and central-parietal (Linear F (1,42)=109.1,P b 0.001;Quadratic F (1,42)=9.2,P b 0.01)regions,with no significant difference between Go and Nogo stimuli.A parietal N frontal effect was reduced in Nogo compared with Go stimuli (parietal vs.frontal difference:Nogo 6.8μV ,Go 11.8μV;F (1,42)=10.2,P b 0.01),reflecting the anteriorisation of P3to Nogo relative to Go stimuli.As shown in Figs.3and 4,this effect differed between groups,with a parietal maximum (linear reduction to frontal sites)for both stimuli for controls,along with a reduction in the parietal area for Nogo stimuli (central vs.fronto-parietal difference:Nogo 0.9μV ,Go 0.3μV),with a significantly different distribution for the clinical groups where both the AD/HDin (Nogo 1.3μV ,Go 3.5μV;F (1,42)=3.9,P =0.05)and AD/HDcom (Nogo 0.3,Go 2.9μV;F (1,42)=4.9,P b 0.05)groups showed increased central activity to Go stimuli.4.Discussion

The three groups did not differ in mean age or IQ.As expected,the clinical groups showed a reduced spelling age relative to controls,although it should be noted that while the AD/HDcom group lagged 1.6years behind controls,this difference was not significant.The CPRS-R and CBCL results indicate that unique groups with subtype-specific behavioural profiles were defined,confirming the initial diagnoses at the group level.Those diagnoses were based strictly on DSM-IV criteria,with

Fig.3.The middle panel shows the grand mean ERPs to Go (solid line)and Nogo (dashed line)stimuli at Cz for the Control (left side),AD/HDin (middle)and AD/HDcom (right side)groups.Note:Ticks on the x -axis=100ms;Stimulus onset is indicated by the y -axis on the middle plot;y -axis scale in μV .The top and bottom panels show topographic maps for each component labeled on the ERP plot,for Go (top panel)and Nogo (bottom panel)stimuli separately.Darker shades equal larger positive amplitudes for each component.

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independent confirmation by an experienced psychologist.The subtypes both showed higher levels of Inattention than controls,in the clinically significant range.In relation to Hyperactivity,the AD/HDin group scored higher than controls,but were not in the clinically significant range,while the AD/HDcom group showed a clinically sig-nificant group difference from controls.

In regard to task performance,the AD/HDcom group showed evidence of dysfunctional response inhibition,with increased commission errors to Nogo stimuli,in line with previous research (Iaboni et al.,1995;Nigg,1999;Nigg et al.,2002;Rubia et al.,1999;Schachar

et al.,1993;Wang et al.,2003).The AD/HDcom group also showed problems with performance related to Go stimuli,with reduced Go accuracy compared to controls,and although non-significant,the slowest Go RT (with the AD/HDin and control groups showing very similar RTs).

The AD/HDin group also showed dysfunctional res-ponse inhibition,in line with some previous behavioural research (Lane,2004;Yonghui et al.,2005),with in-creased commission errors to Nogo stimuli relative to controls,while their response activation variables did not differ from controls.Based on performance during the visual Go/Nogo task,it seems that both AD/HD subtypes showed evidence of dysfunctional response inhibition,with the addition of response activation problems in AD/HDcom.

4.1.ERPs to warning stimuli

The ERPs to Warning stimuli revealed group differ-ences in neural activation corresponding to processing this stimulus itself,and also in the subsequent prepara-tion for S2,as revealed by the CNV-L.The AD/HDcom group showed some evidence of atypical early proces-sing of the Warning stimuli,with a globally reduced N1indicating atypical activation of early sensory processing of,or attention to (Naatanen and Picton,1987)these stimuli.2The latter result is similar to our auditory mo-dality Go/Nogo findings (Smith et al.,2004)and reduc-tions reported during auditory attention tasks (Johnstone et al.,2001;Satterfield et al.,1994).This ERP effect is reported in the context of increased commission errors to Warning stimuli by this group.

Similarly,in conjunction with poorer task perfor-mance,the AD/HDin group showed several ERP dif-ferences,including reduced parietal N1,suggesting an early sensory/attentional deficiency,as well as differences in hemispheric maxima for P2and N2.These findings indicate that children with AD/HDin process these stimuli,which were essentially task-irrelevant and pro-vide only a cue to the upcoming S2,very differently from controls.

CNV-L was atypical in both AD/HD groups,being reduced across the midline (i.e.,Fz,Cz,Pz)for AD/HDin,and across the central region (i.e.,C3,Cz,C4)for

2

These N1effects should be considered with a degree of caution.Examination of the P100-N140complex present in occipital recordings during visual task would allow stronger conclusions to be drawn about the sensory/attention effects reported here as indexed here by N1.However,low quality occipital recordings for several subjects did not allow accurate quantification of these components at occipital locations in these

data.

Fig.5.Significant interactions for P2amplitude (Group×Lateral;top panel,y -axis scale in μV)and N2latency (Group×Stimulus;bottom panel,y -axis scale in ms)for ERPs to Go/Nogo stimuli.

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AD/HDcom.Although the CNV-L of each clinical group differed from controls in different ways,both showed indications of inadequate expectation of,or preparation for(Rohrbaugh and Gaillard,1983),the imperative Go or Nogo stimulus during the fixed S1–S2 interval.The present AD/HDcom finding supports previous research(Aydin et al.,1987;Banaschewski et al.,2003;Dumais-Huber and Rothenberger,1992; Perchet et al.,2001),with this study revealing the first evidence of this deficit in children with AD/HDin. 4.2.Go/Nogo ERPs

Across Groups,several characteristic Go vs.Nogo effects,such as larger N2to Nogo than Go stimuli and P3latency being longer in Nogo than Go stimuli,were found,supporting previous research in children(Broyd et al.,2005;Jonkman et al.,2003;Smith et al.,2004) and adults(Bokura et al.,2001;Falkenstein et al.,1999). N1topography differed between stimulus types(reduced frontally and increased parietally in Nogo compared to Go),suggesting differential activation of early sensory or attentional processes dependent on stimulus type,an effect reported previously in children(Johnstone et al., 2005).Other effects replicating previous research in children include increased P2latency to Go vs.Nogo stimuli(Broyd et al.,2005),and similar P3amplitude to Go and Nogo stimuli(Johnstone et al.,2005),both during auditory Go/Nogo tasks.

Our AD/HDcom group showed further ERP evi-dence for both exogenous and endogenous inhibitory processing deficiencies,with corresponding poorer inhibitory task performance.The regional maximum of N1to Go and Nogo stimuli differed from controls (who showed a frontal maximum for Nogo,and fronto-central maximum for Go,stimuli)—similar to our recent auditory modality finding(Broyd et al.,2005). Parietal P2was globally increased in AD/HDcom com-pared to controls,replicating an auditory finding(Broyd et al.,2005),and in line with reports of localized group differences(Smith et al.,2004),as well as data from auditory attention tasks(Johnstone et al.,2001;Oades et al.,1996).The anteriorisation of P3to Nogo,relative to Go,stimuli differed between the control and both AD/ HD subtype groups.A larger Go N Nogo P3effect has been reported previously in AD/HDcom compared to controls(Yong-Liang et al.,2000).The frontal N2was globally reduced in amplitude in children with AD/ HDcom,an effect reported in the context of poorer inhibitory performance,replicating previous findings from visual(Yong-Liang et al.,2000)and auditory Go/ Nogo tasks(Broyd et al.,2005),as well as findings from the stop-signal task(Dimoska et al.,2003;Pliszka et al., 2000).Note that we have previously reported a larger N2 Nogo effect in children with AD/HDcom than controls, during a cued auditory Go/Nogo task with a random S1–S2interval,in the context of similar inhibitory perfor-mance for each group(Smith et al.,2004).N2peaked later in the AD/HDcom group compared to controls, similar to an effect that occurred when a visual Go/Nogo task was performed first,but not second,in a two para-digm protocol(Yong-Liang et al.,2000).This pattern of N2results across these studies gives some support to the proposal that AD/HDcom suffer from an inhibition re-gulation problem(Yong-Liang et al.,2000).

The AD/HDin group also differed from controls in the processing of Go/Nogo stimuli,in conjunction with poorer task performance.Some of these differences from controls were similar to those found in the AD/HDcom group,including globally decreased N2,globally in-creased P2,and the Nogo anteriorisation effect for P3. Further,similar to AD/HDcom,the distribution of N1to Go and Nogo stimuli(fronto-central for Go and Nogo stimuli)differed from controls.Unique group differences were also found,including P2distribution effects(L vs.R distribution,distributions of Go vs.Nogo),and N2latency being longer to Nogo than Go(opposite to controls)—these effects differentiate the neural responses of AD/ HDcom and AD/HDin groups to Go/Nogo stimuli.

https://www.doczj.com/doc/2210632653.html,mon differences

A number of important effects were present for both groups,warranting further consideration.Increased P2 amplitude has been reported previously in these AD/HD subtypes during the oddball task(to both target and standard stimuli),an effect that was present across an age-range of8to18years,suggesting that this com-ponent might serve as an age-and subtype-independent marker of AD/HD(Johnstone et al.,2001).Further,P2 features importantly amongst ERP variables that pro-vide maximum discrimination of children with AD/HD from controls,as well as AD/HDcom and AD/HDin groups from each other(Smith et al.,2003).The present data add weight to that position,with similar differences in the inhibitory context.Including P2measurements from the Go/Nogo task,along with oddball data,might enhance the utility of ERPs in differentiating children with AD/HD from controls.

There were no differences between any of the groups in the N2Nogo effect(confirmed by quantification and analysis of Nogo–Go difference waveforms)—instead, N2was globally reduced for both subtypes regardless of stimulus type.Thus,in regard to amplitude(seen as

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an indicator of the extent to which the process it represents was activated),a deficiency/atypicality in this stage of the processing sequence is evident for both AD/ HD subtypes relative to control children,and this differ-ence is not specific to Nogo stimuli.The timing of this inhibition-related component differed between groups, with the N2peaking later than controls regardless of stimulus type in AD/HDcom,suggesting a non-specific slowing of this process,while N2was slightly earlier to Go and much later to Nogo stimuli in AD/HDin com-pared to controls,suggesting a specific slowing of this process to Nogo stimuli.

The P3was larger to Go than Nogo stimuli for each group,consistent with previous findings in children (Johnstone et al.,2005;Jonkman et al.,2003),and interpreted as reflecting a relatively immature frontal inhibition system.Interestingly,each subtype had a dif-ferent P3anteriorisation effect than controls,with the subtypes showing evidence of a stronger effect(see Fig.4).While the effect is indeed larger in the subtypes, we consider that the results still indicate atypical processing in both AD/HD subtypes,given that healthy adults who perform the inhibition task with few errors typically show both the P3anteriorisation effect and a larger P3to Nogo than Go stimuli(Falkenstein et al., 2002;Johnstone et al.,2005;Kopp et al.,1996).

4.4.Conclusions

This study has provided further evidence of response inhibition problems in children with AD/HDcom,with several key ERP differences from controls replicated here in the context of poorer inhibition performance. Importantly,these Go/Nogo processing differences were subsequent to early sensory/attentional differences to Warning stimuli,as well as inefficient expectation of the imperative stimulus.

This was the first investigation of response inhibition in children with AD/HDin using concurrent ERP mea-sures.We report evidence of both behavioural and ERP indices of response disinhibition in children with AD/ HDin.More specifically,the results indicate(a)consi-derable differences in the processing of Warning stimuli compared to controls,including an early sensory/atten-tional deficiency,(b)inadequate expectation of the S2 as indicated by the CNV to S2,and(c)for Go/Nogo processing,similar problems to AD/HDcom,such as those with early visual detection(P2),and aspects of the inhibition process(N2and P3).Unique differences from controls were also found with aspects of the sensory/ exogenous responses(P2distribution)as well as with the timing of aspects of the inhibition process(N2latency).These findings are contrary to the notion that AD/HDin is primarily a disorder of Inattention,and that Hyper-activity/Impulsivity are the key differentiating features of AD/HDcom and AD/HDin.

Despite the multifaceted nature of the processing problems in these subtypes of AD/HD,both would benefit from operant training of response preparation and inhibition abilities.In relation to AD/HDin specifically, our results indicate that management and treatment approaches should additionally consider the response inhibition problem,not previously thought to be a pro-minent feature for this subtype.

While strict criteria were used to accurately identify the subtype of AD/HD participants,there is undoubtedly a margin for error when relying of subjective informa-tion provided mostly by parents–thus it must be con-sidered possible that the AD/HDin group were not a pure subtype group,but rather a subthreshold AD/ HDcom group–a group which would also suffer from inhibition problems,albeit at a reduced level.Accord-ingly,replication of these results is required.Future investigations in this area would benefit from reliable objective measures of subtype group membership(such as cognitive or neuropsychological tests)so that diag-nostic accuracy is increased,as well as a sample large enough to allow the consideration of age.Additionally, examining other types of inhibition,including response inhibition tasks such as the stop-signal,and those accessing interference control,such as the flanker task, would allow further clarification of the nature of the inhibition problem in AD/HD subtypes. Acknowledgements

We thank the children who participated and their parents, as well as Aneta Dimoska,Janette Smith and Rodney Croft for helpful comments on earlier drafts of this article.This study was supported by the Australian Research Council Discovery funding scheme(DP0559048).

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英文回复信范例ResponseLetter

Dear Editors and Reviewers, Thank you for your letter and comments on our manuscript titled “Temporal variability in soil moisture after thinning in semi-arid Picea crassifolia plantations in northwestern China” (FORECO_2017_459). These comments helped us improve our manuscript, and provided important guidance for future research. We have addressed the editor’s and the reviewers’comments to the best of our abilities, and revised text to meet the Forest Ecology and Management style requirements. We hope this meets your requirements for a publication. We marked the revised portions in red and highlighted them yellow in the manuscript. The main comments and our specific responses are detailed below: Editor: Please explain how the results in this paper are significantly different from those in Zhu, X., He, Z.B., Du, J., Yang, J.J., Chen, L.F., 2015. Effects of thinning on the soil moisture of the Picea crassifolia plantation in Qilian Mountains. Forest Research. 28, 55–60.)

雅思口语素材

雅思口语素材 Document serial number【LGGKGB-LGG98YT-LGGT8CB-LGUT-

Useful Expressions: Words and phrases Friends and communication: solidify/ strengthen/ enhance/ promote communication / connection with mutual understanding relationship network/circle of f r i e n d s cultivate/develop friendship with s b . keep steady relationship with sb. establish interpersonal networksac build up the social circle spur message transmission Knowledge and experience widen one’s outlook broaden one’s vision/horizon acquire knowledge and skills comprehensive/overall quality

expand/enlarge one’s scope of knowledge knowledge reserve/base/storage theoretical knowledge practical skills social experience broaden one’s knowledge base promote one’s overall/ comprehensive competence accumulate experiences learn lessons from past experiences Work and experience the scarcity of employment o p p o r t u n i t i lay the foundations for career p r o s p e r i t y

投稿coverletter写法

Case 1 Dear Editor, We would like to submit the enclosed manuscript entitled "GDNF Acutely Modulates Neuronal Excitability and A-type Potassium Channels in Midbrain Dopaminergic Neurons", which we wish to be considered for publication in Nature Neuroscience. GDNF has long been thought to be a potent neurotrophic factor for the survival of midbrain dopaminergic neurons, which are degenerated in Parkinson’s disease. In this paper, we report an unexpected, acute effect of GDNF on A-type potassium channels, leading to a potentiation of neuronal excitability, in the dopaminergic neurons in culture as well as in adult brain slices. Further, we show that GDNF regulates the K+ channels through a mechanism that involves activation of MAP kinase. Thus, this study has revealed, for the first time, an acute modulation of ion channels by GDNF. Our findings challenge the classic view of GDNF as a long-term survival factor for midbrain dopaminergic neurons, and suggest that the normal function of GDNF is to regulate neuronal excitability, and consequently dopamine release. These results may also have implications in the treatment of Parkinson’s disease. Due to a direct competition and conflict of interest, we request that Drs. XXX of Harvard Univ., and YY of Yale Univ. not be considered as reviewers. With thanks for your consideration, I am Sincerely yours, case2 Dear Editor, We would like to submit the enclosed manuscript entitled "Ca2+-binding protein frequenin mediates GDNF-induced potentiation of Ca2+ channels and transmitter release", which we wish to be considered for publication in Neuron. We believe that two aspects of this manuscript will make it interesting to general readers of Neuron. First, we report that GDNF has a long-term regulatory effect on neurotransmitter release at the neuromuscular synapses. This provides the first physiological evidence for a role of this new family of neurotrophic factors in functional synaptic transmission. Second, we show that the GDNF effect is mediated by enhancing the expression of the Ca2+-binding protein frequenin. Further, GDNF and frequenin facilitate synaptic transmission by enhancing Ca2+ channel activity, leading to an enhancement of Ca2+ influx. Thus, this study has identified, for the first time, a molecular target that mediates the long-term, synaptic action of a neurotrophic factor. Our findings may also have general implications in the cell biology of neurotransmitter release. 某杂志给出的标准Sample Cover Letter Case 3 Sample Cover Letter Dear Editor of the : Enclosed is a paper, entitled "Mobile Agents for Network Management." Please accept it as a candidate for publication in the . Below are our responses to your submission requirements. 1. Title and the central theme of the article. Paper title: "Mobile Agents for Network Management." This study reviews the concepts of mobile agents and distributed network management system. It proposes a mobile agent-based implementation framework and creates a prototype system to demonstrate the superior performance of a mobile agent-based network over the conventional client-server architecture in a large network environment.

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