Dysfunctional feedback processing in adolescent males with conduct disorder

    Dysfunctional feedback processing in adolescent males with conduct disorder Yidian Gao, Haiyan Chen, Huiqiao Jia, Qingsen Ming, Jinyao Yi, Shuqiao Yao PII: DOI: Reference:

S0167-8760(15)30050-7 doi: 10.1016/j.ijpsycho.2015.11.015 INTPSY 11058

To appear in:

International Journal of Psychophysiology

Received date: Revised date: Accepted date:

8 June 2015 23 November 2015 23 November 2015

Please cite this article as: Gao, Yidian, Chen, Haiyan, Jia, Huiqiao, Ming, Qingsen, Yi, Jinyao, Yao, Shuqiao, Dysfunctional feedback processing in adolescent males with conduct disorder, International Journal of Psychophysiology (2015), doi: 10.1016/j.ijpsycho.2015.11.015

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ACCEPTED MANUSCRIPT Dysfunctional feedback processing in adolescent males with conduct disorder

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Yidian Gao1, Haiyan Chen1, Huiqiao Jia1, Qingsen Ming1, Jinyao Yi1, Shuqiao Yao1, 2,

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3,*

Medical Psychological Institute, Second Xiangya Hospital, Central South University,

Changsha, Hunan 410011, China

National Province Technology Institute of Psychiatry, Central South University,

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Changsha, Hunan 410011, China

Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South

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Email addresses:

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University, Changsha, Hunan 410011, China

YG: [email protected]

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HC: [email protected] HJ: [email protected] QM: [email protected] JY: [email protected] SY: [email protected]

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Corresponding author. Psychological Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. Tel.: 86 731 85292126; fax: 86 731 85361328. E-mail address: [email protected] 1

ACCEPTED MANUSCRIPT Abstract Abnormalities in neural feedback-processing systems may play a role in the

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development of dysfunctional behavior in individuals diagnosed with conduct

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disorder (CD). The present study investigated the relation between CD adolescents and feedback processing by measuring event-related potentials (ERPs) in a single outcome gambling task, which included reward valence (loss and gain) and reward

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magnitude (10 and 50 cents) as outcomes. N2 and P3 components have been

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established as effective indicators in studies of behavioral disinhibition, reward processing, and decision making. Eighteen adolescent males (age: 13–17 years)

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diagnosed with CD and 19 healthy age-matched male controls were recruited.

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Compared to healthy controls, CD individuals exhibited reduced N2 amplitudes in

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response to loss condition. There was also a significant decreased P3 amplitude in all conditions. The amplitudes of P3 were negatively correlated with impulsivity scores

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across both groups, and the amplitudes of N2 were positively correlated with impulsivity scores across both groups. Our findings suggest that adolescents with CD may be impaired in neural sensitivity feedback and the processing of environmental cues compared to healthy controls. Moreover, N2 and P3 may be reliable indices to detect different sensitivity in reward and punishment feedback processing.

Keywords: conduct disorder; feedback processing; ERPs

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ACCEPTED MANUSCRIPT 1. Introduction

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Conduct disorder (CD) is a psychiatric disorder that emerges during childhood or

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adolescence. Affected individuals show repetitive and persistent patterns of violating

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the basic rights of others and difficulty in following major age-appropriate societal norms (APA, 2000). CD is accompanied by various behavioral problems, such as

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impulsivity, aggression, and risk-taking (Dougherty et al., 2000; Fairchild et al., 2009; Mathias et al., 2007), which represent latent externalizing traits. Previous studies have

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shown that individuals with CD lack empathy and compassion, and that they display

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impaired control over their emotions and impulses (Dougherty et al., 2000). Similar to

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patients with attention deficit hyperactivity disorder (ADHD), individuals with CD show deficits in tasks requiring sustained attention and cognitive function

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(Banaschewski et al., 2003). These characteristics are indicative of potential deficits in feedback-evaluation and self-monitoring systems (Sterzer et al., 2007).

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With the ability to predict and respond to feedback cues, we learn to survive in and adapt to the environment (Flores et al., 2015). The experiences that occur in anticipation and response to feedback appear to have important implications for our interpersonal adaption and intrapsychic regulation (Cole et al., 1994). A number of studies have addressed the influences of positive and negative feedback on cognition, motivation and behavior (Schultz, 2007). In particular, anticipation of positive feedback (reward or gain) facilitates approach behavior, whereas anticipation of negative feedback (punishment or loss) facilitates avoidance behavior (Young, 1959). The Reinforcement Sensitivity model developed by Gray et al. provides one of the 3

ACCEPTED MANUSCRIPT most cited theory for explaining reward and punishment processing (Bjork and Pardini, 2015; Byrd et al., 2014; Colder and O'Connor, 2004; Goodnight et al., 2006;

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Gray, 1991). Gray proposed two main systems: the behavioral inhibition system (BIS)

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and behavioral approach system (BAS). According to Gray, BIS serves to inhibit behavior in response to aversive stimuli or punishment, while BAS is thought to be sensitive to reward feedback or nonpunishment (Gray, 1991). Convergent findings

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from neurobiological studies imply that CD adolescents exhibit an aberrant difficulty

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in feedback-evaluation and adapting their behavior accordingly (Brazil et al., 2009; Brazil et al., 2013; Salim et al., 2015).

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Recent neuroimaging studies of individuals with CD have demonstrated structural

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abnormalities in various brain regions, including the bilateral temporal lobes, the

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orbitofrontal cortex, and the anterior cingulate cortex (ACC), which are brain structures associated with decision-making and reward processing (De Brito et al.,

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2009; Fairchild et al., 2011; Huebner et al., 2008; Jiang et al., 2015; Zhang et al., 2014). Generally, individuals benefit from these feedback-evaluations and feedback-monitoring systems to guide their decision making and to implement optimal behavior. Impaired processing or dysfunction in these brain areas may account for the lack of empathy and self-monitoring observed in CD individuals. People with CD may find it difficult to construct a socially adaptable behavior system (Gelhorn et al., 2007; Morcillo et al., 2012; Nock et al., 2006). Previous studies have examined electrophysiological correlates (e.g., ERPs) of feedback processing, including P2, N2 and P3 components (Franken et al., 2010;

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ACCEPTED MANUSCRIPT Holroyd and Coles, 2002; Pfabigan et al., 2011; Salim et al., 2015). These components are particularly sensitive to feedback valence (gain/loss), feedback magnitude

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(large/small), and behavioral outcome evaluations (positive/negative) (van Meel et al.,

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2005; Wu and Zhou, 2009). They have been proposed to encode different features of feedback evaluation and reflect motivational significance of feedback (Gentsch et al., 2013). For instance, P2 is implicated in attention selection and salience detection

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(Potts et al., 2006), and is related to reward system of brain (Riis et al., 2009; San

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Martin et al., 2010). Furthermore, the N2 and P3 components are used to examine cognitive processes that have been correlated with decision-making and

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feedback-evaluation processing (Baker and Holroyd, 2011; Kam et al., 2012;

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Kamarajan et al., 2010). Specifically, the P3 reflects a later, top-down controlled

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feedback evaluation process (Cui et al., 2013), whereas the N2 was thought to reflect the binary evaluation of resultant good versus bad outcomes (Holroyd et al., 2006;

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Kamarajan et al., 2009). These observations suggest that the two aspects underlying outcome evaluation are processed separately and rapidly in the brain (Wu and Zhou, 2009).

The N2 component of ERP has been used to study patients who exhibit traits consistent with behavioral disinhibition abnormalities. N2 is a fronto-central negative wave, occurring around 200 ms after stimulus onset, which indexes cognitive processes of stimulus evaluation, classification, decision-making and executive function, and these may be important for responding to environmental cues (Luck, 2005). Several researchers have focused on studying the behavioral disinhibitory

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ACCEPTED MANUSCRIPT processing in adolescents with externalizing problems using N2. The amplitude of N2 has been reported to be positively correlated with callous/unemotional temperament

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traits which may denote a more severe form of CD (Sumich et al., 2012). Compared

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to healthy controls, adolescents with comorbid ADHD+CD display significantly prolonged latency of both N2 and P3 (van Meel et al., 2005). Albrecht et al. found that the ADHD-only and oppositional defiant disorder (ODD)/CD-only groups

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displayed reduced Stop-N2 amplitude using a stop-task. Adolescents with comorbid

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ADHD+ODD/CD also showed similar or less disinhibition prominent deficits than other groups (Albrecht et al., 2005). Additionally, it has also been suggested that the

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N2 amplitude was reduced in the externalizing spectrum or juvenile non-psychopathic

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offenders compared with the control group (Anjana et al., 2010; Dikman and Allen,

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2000; Kroger et al., 2014; Vila-Ballo et al., 2014). P2, a medial frontal positive component at approximately 200 ms poststimulus is

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associated with the identification of task-relevant perceptual representations (Potts et al., 2006). The spatio-temporal distribution of P2 is similar with N2. P2 is elicited to error choices or responses resulting in monetary loss (Potts et al., 2006). It has been argued that amplitude of P2 is sensitive to feedback information which has a motivational value, and has been found to reflect sensitivity toward reward (Martin and Potts, 2009; Salim et al., 2015). Previous study reported that P2 amplitude in psychopathic individuals was enhanced for predicted rewards and reward omissions, but not for unpredicted feedback using a passive gambling task (Salim et al., 2015). When using an Emotional Stroop task, researchers found that individuals scoring high

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ACCEPTED MANUSCRIPT on psychopathic traits display reduced P2 amplitude to negative feedback compared to controls (Carolan et al., 2014). Larger P2 amplitude has also been reported in ADHD

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children, indicating deficiencies in early sensory processing in ADHD (Wiersema et

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al., 2006).

The P3 wave is a stimulus-evoked centro-parietal positivity that occurs approximately 300 to 400 ms after a stimulus. The P3 is most commonly associated

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with expectation violation. It has been linked to a broadly distributed neural network

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involving the locus-coeruleus norepinephrine system, and it is sensitive to motivationally important events (Ito and Bartholow, 2009; Wu and Zhou, 2009).

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Reduced P3 amplitude has been consistently linked to a spectrum of externalizing

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disorders, such as CD (Cappadocia et al., 2009; Iacono et al., 2002), illicit substance

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abuse (Iacono et al., 2002), antisocial behavior (Bauer and Hesselbrock, 2001, 2003; Costa et al., 2000) and ADHD (Iacono et al., 2002). In a comprehensive study, Iacono

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et al. found that reduced P3 amplitude was associated with several behavior disinhibition disorders, including ADHD, ODD, CD, antisocial personality disorder, alcoholism, as well as illicit drug abuse and dependence (Morcillo et al., 2012). In sum, these previous studies have shown that P2, N2 and P3 components are all linked to patients with impaired feedback processing which is found underlying the behavioral adaptation deficits. However, the majority of neuropsychologic studies related to CD adolescents have rarely considered the confounding effects of comorbid psychiatric conditions (e.g. ADHD). Few studies have directly examined the feedback evaluation in adolescents

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ACCEPTED MANUSCRIPT with CD. It also remains unknown as to whether the symptoms of CD are associated with reward-processing abnormalities. Therefore, the present study aimed to examine

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whether CD adolescents have abnormalities in the evaluation of monetary reward and

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punishment while performing a simple outcome gambling task. This study also investigate whether the early N1, P2, later N2 and P3 components correlate with externalizing factors, such as impulsivity. Since there were distinct gender differences

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observed in the ERP indices of affective stimuli, the participants in present study were

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designed to be male adolescents only (Criado and Ehlers, 2007). Therefore, our first hypothesis is that adolescents with CD will show decreased amplitude in both N2 and

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P3 components. Second, we posited that adolescents with CD will exhibit increased

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amplitude in P2 component. Third, we think that adolescents with CD will

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demonstrate higher impulsivity scores on the behavioral measures. And lastly, the decreased N2 and P3 amplitude will be correlated with increased impulsivity scores.

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2. Methods

2.1 Participants 40 participants were recruited, 3 participants were excluded due to excessive artifacts in the EEG recording. Finally, CD group consisted of 18 male adolescents (age range: 13–17 years, mean: 15.4 years, standard deviation [SD]: 1.3 years), who were recruited from the outpatient clinics affiliated with the Second Xiangya Hospital of Central South University in Changsha, Hunan, China. Controls included 19 healthy age-matched male adolescents (mean age: 15.5 years, SD: 1.3 years), recruited from a

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ACCEPTED MANUSCRIPT school in the same city. The study was approved by the Ethics Committee of the Second Xiangya Hospital of Central South University. Written informed consent was

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obtained from all participants and their parents. All participants received monetary

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compensation upon completion of the study.

CD was diagnosed independently by two psychiatrists, according to the Structured Clinical Interview for the DSM-IV-TR Axis I Disorders-Patient Edition (SCID-I/P)

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(First, 2002), which has been translated into Chinese and adapted for use in both

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patients and healthy individuals (Cassidy et al., 2011; Shi et al., 2005). Additionally, one parent of each subject was interviewed to obtain detailed information. The

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psychiatrists made the final decision in the case that information obtained from the

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patients and parents was inconsistent.

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For the recruitment of healthy control individuals, students, selected randomly from class rosters, were matched with CD subjects by age and gender. Participants who

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agreed to be interviewed by the psychiatrists were subjected to the SCID-I/P and Wechsler Intelligence Scale for Children-Chinese revision (C-WISC) examinations (Gong, 1993). Information provided by the students was verified by their parents on an as-needed basis. None of the healthy control participants met the criteria for CD. Subjects were excluded from both groups if they reported a history of any of the following: ADHD or any other psychiatric or emotional disorder; diagnosis of any pervasive developmental or chronic neurological disorder, Tourette syndrome, posttraumatic stress disorder, or obsessive compulsive disorder; persistent headaches; head trauma; alcohol or substance abuse in the past year; or an IQ of ≤ 80 on the

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ACCEPTED MANUSCRIPT C-WISC. All subjects were right-handed according to the Edinburgh Handedness Inventory (Oldfield, 1971). All subjects had normal or normal corrected vision. We

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also used the Chinese version of the Center for Epidemiologic Studies Depress Scale

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(CES-D) and the Multidimensional Anxiety Scale for Children (MASC) to rate the depression and anxiety severity respectively (Radloff, 1991; Yao et al., 2007a). To assess the impulsivity trait, participants were required to complete the Chinese version

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of the Barratt Impulsiveness Scale-11 (BIS-11) (Yao et al., 2007b), which is a reliable

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and valid assessment tool to measure impulsivity in Chinese adolescents. The BIS-11 is a widely used self-reporting questionnaire that contains 30 items and includes three

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subscales: attentional impulsiveness (making decisions quickly), motor impulsiveness

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(acting without thinking), and unplanned impulsiveness (lack of prior planning or

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future orientation). The sum of scores for all items provides an overall impulsiveness score, with higher scores indicating greater impulsiveness.

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Table 1 summarizes the demographic and background characteristics of the two groups. All CD individuals were treatment-naive and met the criteria for adolescent-onset CD, demonstrating at least one sign of CD after 10 years of age (APA, 2000).

2.2 Simple Outcome Gambling task The simple outcome gambling task used in this study is illustrated in Fig 1. It is a modified version of the classical gamble task initially developed by Gehring and Willough (Gehring and Willoughby, 2002; Kamarajan et al., 2009). Using the

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ACCEPTED MANUSCRIPT gambling task, we may be able to examine emotional responses to monetary reward and punishment in adolescents with CD, and to study the processing of feedback

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(Cappadocia et al., 2009). In each trial, the participant was presented with a choice

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stimulus of two numbers (corresponding to an equivalent monetary value in Chinese cents) on a computer screen. A box on the left-hand side of the screen contained the number 10 (10 cents, with which one can buy a ballpoint pen refill), and a box on the

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right-hand side displayed the number 50 (50 cents, with which one can buy a ballpoint

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pen). These two numbers were shown for 800 ms, followed by a random interval of 700 to 1700 ms. The participant pressed the right or left button to choose the number

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on the same side of the screen during a period of 200 to 1000 ms.

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If the participants did not react during the response period, then the program would

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proceed to the next trial without feedback (reward or punishment) (Kamarajan et al., 2009). If the participants did react during the response period, then the feedback

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stimulus appeared at the center of the screen. The feedback stimulus lasted 800 ms and was followed by an interval of 700 to 1700 ms. The feedback stimulus of “+10” or “+50” indicated “gain”, whereas the feedback stimulus of “-10” or “-50”, indicated “loss”. Thus, there were four possible feedback stimuli, depending on the participant's preceding choice: small loss (-10) and small gain (+10) if "10" was chosen, large loss (-50) and large gain (+50) if "50" was chosen. Participants started with 10 Yuan (with which one can buy a story book) and were told to try to win as much money as possible. Unbeknownst to the participants, no matter which option (10/50) was chosen, the probabilities of loss or gain feedback in

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ACCEPTED MANUSCRIPT each block were equal (50%). The order of loss or gain feedback was also pseudo-randomized. A total of 344 trials were presented, which were divided into four

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equal blocks of 86 trials each. Participants took a break of approximately 5 min

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between each block. To increase motivation, participants were told they would be paid the amount of money that they won during the experiment. Participants performed the gambling task with the STIM-2 software package (Neuroscan, Inc.) (Yi et al., 2012).

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The reaction time for the task conditions and responses was calculated (Table 1).

2.3 Event-related potential recordings

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EEG readings were obtained with 63 Ag/AgCl ring electrodes, in accordance with

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the Extended International System, using 10-20 electrode caps. Two electrodes were

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placed on the left and right mastoids, and a ground electrode was secured on the forehead. Electrodes were subsequently re-referenced to the average of the right and

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left mastoids. Vertical electrooculography (EOG) data were recorded from electrodes placed above and below the left eye. Horizontal EOG data were recorded from the outer canthi of each eye. All electrode impedances were maintained below 5 kΩ. EEG data were recorded continuously with a bandpass filter of 0.05 to 100 Hz and digitized at 250 Hz.

2.4 Electroencephalography data analysis All ERP analyses were done offline with the Neuroscan 4.3 Edit software package. Ocular artifacts were corrected with an eye-movement correction algorithm

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ACCEPTED MANUSCRIPT (Semlitsch et al., 1986). Before further analysis, the ERP data were digitally filtered with a low-pass filter at 30 Hz (24 dB/ octave). Continuous EEG output was

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segmented into intervals of 200 ms before the feedback stimulus and 800 ms after

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feedback onset. Epochs were baseline-corrected by subtracting the average activity of that channel during the baseline period from each sample. After baseline correction, sweeps in which amplitudes exceeded ±100 μV were rejected automatically as

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artifacts.

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ERPs were obtained by averaging the EEG signals according to feedback type (gain vs. loss) and reward condition (10 vs. 50) for each channel. We measured the N1, P2

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in the time windows of 100-150 ms and 150-220 ms, respectively (Salim et al., 2015).

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The N2 amplitude was scored as the averaged amplitude of a 100 ms interval ranging

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from 200-300 ms (Groen et al., 2013; van Meel et al., 2011). Analyses of N1, P2 and N2 amplitudes were limited to the anterior frontal midline electrode (Fz), the

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frontal-central midline electrode (FCz), and the central midline electrode (Cz) in all conditions. The P3 amplitude was measured as the averaged amplitude within 300-450 ms after feedback onset at the Pz electrode (Schulreich et al., 2013; Yeung and Sanfey, 2004). These time-windows were determined according to the largest differences based on visual inspection of grand average waveforms and previous studies. The average number of trials under the four feedback conditions did not significantly differ between the CD and the control groups [F =0.04, p = 0.84]. The averaged numbers of trials were 66.61 for the CD group and 65.58 for the control

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ACCEPTED MANUSCRIPT group. The average numbers of trials in the four conditions are shown in Table 1. 2.5 Statistical analysis

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All statistical analyses were carried out in SPSS 19.0 (SPSS Inc., Chicago, IL).

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Independent sample t-tests were used to examine differences in age, IQ, BIS-11 scores, and reaction time. The ERP data were analyzed with repeated-measures analysis of variance (ANOVA). The amplitude of the N1, P2, N2 and P3 were evaluated

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statistically with reward valence (gain vs. loss), reward magnitude (10 vs. 50), and

with

group

(CD

vs.

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electrodes (topographic factor; only not for P3) as repeated-measurement factors, and healthy control)

as

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between-group

factor.

The

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Greenhouse-Geisser correction for non-sphericity was applied, when appropriate, for

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repeated measures (Holroyd and Coles, 2002). Subsequently, Pearson’s correlations

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were calculated between BIS scores and N1/P2/N2/P3 amplitudes. P-values < 0.05

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were considered statistically significant.

3. Results

3.1 Demographic and behavioral results There were no significant differences in age, IQ, or reaction time in response to the guess prompt between CD individuals and healthy controls (Table 1). There same results were also found in CES-D or MASC scores. Compared to the healthy control group, the CD group exhibit higher scores for attention impulsiveness [t (35) = 3.4, p = 0.002], motor impulsiveness [t (35) = 2.8, p = 0.008], and unplanned impulsiveness

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ACCEPTED MANUSCRIPT [t (35) = 2.4, p = 0.025], as well as for the BIS total score [t (35) = 3.5, p = 0.001].

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3.2 Event-related potential results

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Figure 2. shows the grand-average ERP waveforms elicited by four outcome stimuli (-10, +10, -50 and +50) at electrode sites Fz, Cz and Pz. Topographic scalp maps depicted in Figure 2. show differences between the two groups in four feedback

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conditions at the indicated time windows. Figure 3. plots the values of the mean

results are compiled in Table 2.

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3.2.1 N1 brainwave responses

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amplitudes of N1, P2, N2 and P3 at each electrode site. Repeated-measures ANOVA

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Repeated-measures ANOVAs found a significant differences in N1 amplitudes

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between CD group and healthy control group [F (1, 35) = 5.6, p = 0.023], showing a reduced N1 amplitude in CD adolescents compared to healthy controls. The site of

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electrode placement demonstrate a significant effect [F (2, 70) = 5.8, p = 0.008], with a larger N1 response at the FCz than at the Fz or Cz electrode site. No other significant effects or interactions were observed.

3.2.2 P2 brainwave responses We found a main effect of magnitude [F (1, 35) = 14.3, p = 0.001]. P2 amplitude was larger in response to large magnitude compared to small magnitude feedback. Furthermore, we found a main effect of electrode [F (2, 70) = 15.9, p < 0.001]. The amplitude of P2 component at the Cz was larger than at the Fz or FCz electrode site.

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ACCEPTED MANUSCRIPT Repeated-measures ANOVA of P2 showed a significant group effect [F (1, 35) = 4.4, p = 0.043], as well as significant interactions between group and feedback valence [F

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(1, 35) = 4.4, p = 0.044]. Follow-up analyses revealed that in the gain condition, P2

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amplitudes did not differ between two groups (p >0.05), whereas P2 amplitude in the CD group was larger than healthy control group in loss condition (p = 0.019).

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3.2.3 N2 brainwave responses

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Repeated-measures ANOVAs found a significant differences in N2 amplitudes between CD patients and healthy controls [F (1, 35) = 6.6, p = 0.015], showing a

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reduced N2 amplitude in CD group compared to healthy controls. N2 amplitudes were

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also significantly affected by reward valence [F (1, 35) = 8.0, p = 0.008 ], but this

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effect was qualified by the Group×Valence interaction [F (1, 35) = 5.2, p = 0.029]. Pairwise comparisons demonstrated that healthy controls displayed larger N2

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amplitudes in response to loss feedback compared to gain feedback (p = 0.001). In contrast, N2 amplitudes did not differ between loss and gain conditions in the CD group (p >0.05). The site of electrode placement had a significant effect [F (2, 70) = 48.2, p < 0.001], with a larger N2 response at the Fz than at the Cz or FCz electrode site. The interaction of Group × Electrode was found significant [F (2, 70) = 7.0, p = 0.007]. Pairwise comparisons demonstrated that the differences of N2 amplitudes between two groups were the largest at the Fz electrode (p = 0.001). The interaction of Magnitude × Electrode was also significant [F (2, 70) = 4.0, p = 0.030], demonstrating the differences of N2 amplitudes between electrodes were larger in

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ACCEPTED MANUSCRIPT large magnitude (50) than in small magnitude (10) (p < 0.001) (Table 2).

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3.2.4 P3 brainwave responses

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There was a significant difference in P3 amplitude between two groups [F (1, 35) = 5.0, p = 0.032], indicating more positive-going ERP responses in the healthy control group than in the CD group. We found a main effect of valence [F (1, 35) = 17.7, p <

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0.001]. P3 amplitude was more pronounced following gain as compared to loss

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feedback. Reward magnitude also had significant effects on the P3 amplitude [F (1, 35) = 14.6, p = 0.001], indicating more positive P3 responses to large magnitude than

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to small magnitude. Repeated-measures ANOVAs revealed no significant interactions

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(Table 2).

3.3 Correlation analyses

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Pearson’s correlation analyses revealed that N2 responses evoked by various conditions were positively correlated to the BIS attentional impulsiveness except for a small-magnitude gain (+10). N2 amplitudes after loss conditions (-10/-50) were positively correlated to the BIS total scores (Table 3). Additionally, the P3 amplitudes after some conditions were negatively correlated with the scores of attentional impulsiveness except for a small-magnitude loss (-10) (Table 3).

4. Discussion Conduct disorder has been widely associated with deficits in cognitive control,

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ACCEPTED MANUSCRIPT feedback evaluation and behavioral inhibition. The present report is aimed at studying the electrophysiological correlates of feedback processing using a gambling task in

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adolescent males with CD. Specifically, we examined whether CD individuals show

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altered ERP responses to signals of gain and loss when compared to controls. The key findings of several analyses are that CD and healthy adolescents differ in their feedback processing under conditions of gain and loss.

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Gain and loss feedback processing has been conceptualized in terms of behavioral

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activation system (BAS) and behavioral inhibition system (BIS) (Byrd et al., 2014; Gray, 1991). Our data suggest that CD adolescents showed aberrant P2 and N2

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amplitudes in response to loss feedback, and a decreased P3 amplitude in all

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conditions compared to controls. Our results are partially consistent with past findings,

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lending further empirical evidence to the idea that individuals with disinhibition syndrome have a less sensitive BIS system (Gray, 1991). The group differences found

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in our study suggest that adolescents with CD exhibited less concern and monitoring towards the feedback during trials on which they were punished in contrast to reward. A decreased response to punishment feedback indicates a lower level of activation in the BIS system, which in turn suggests hyposensitivity to punishment or negative feedback, leading to increased aggression or antisocial tendency. The abnormalities of self-monitoring ongoing behaviors, while ignoring negative outcomes, increase the likelihood of engaging in harmful behaviors. The P3 wave component has been reported to play an important role in enabling individuals to differentiate good from bad outcomes during decision making and

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ACCEPTED MANUSCRIPT allowing them to optimize their actions (Nieuwenhuis et al., 2005). Reduction of the P3 amplitude is seen in some mental and neurological disorders, such as

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schizophrenia (Jeon and Polich, 2003) and disinhibition disorders (Polich et al., 1994).

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Our findings are in line with previous reports about the ERP abnormalities of the P3 in CD adolescents. Previous reports have likewise described reduced P3 amplitudes in individuals with CD compared to their healthy peers (Cappadocia et al., 2009). In CD

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patients, observed reduction of the P3 amplitude to both reward and punishment

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conditions implies a low physiological arousal which may be caused by an overactive reward system (BAS) , requiring them to seek external stimulation in order to increase

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their internal arousal (Byrd et al., 2014; Cappadocia et al., 2009).

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To some extent, individuals with CD appear to be less aware of the importance of

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negative feedback compared to healthy controls. The observed features in self-monitoring capabilities in CD individuals may reflect diminished neural activity

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in key brain regions necessary to evaluate external feedback responses compared to their healthy peers (Yi et al., 2012). Consistent with Gray’s theory, the reduced amplitudes of N2 and P3 in adolescents with CD may reflect abnormalities in environmental cues processing and sensation seeking (Gray, 1991). The impaired monetary reward and punishment processing in CD adolescents may result from diminished

neural

activity

in

reward-evaluation

pathways

or

deficits

in

decision-making systems, thereby increasing the tendency of repeating a previously rewarded behavior even when such behaviors is no longer producing reward but punishment instead (Patterson and Newman, 1993).

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ACCEPTED MANUSCRIPT In addition, we found that there was an early difference in the N1 component between the two groups. The anterior N1 was reduced in the CD group. Previous

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studies suggested that the high impulsive individuals differ on early sensory and

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attention-related components, with reduced N1 amplitudes, indicating reduced inhibiting and enhanced orienting (Houston and Stanford, 2001). It is reported that larger amplitudes of N1 in high impulsive individuals indicate enhanced attention

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orienting (Houston and Stanford, 2001). The difference in N1 amplitude in the current

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study may suggest that individuals with conduct disorder are less engaged by stimulus information about the consequences of their decisions and lack of inhibition.

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Despite the differences exhibited in adolescents with CD compared to healthy

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controls, several aspects of the neural mechanisms of feedback processing were

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similar in both groups. Our correlation analyses showed that the amplitudes of N2 and P3 were significantly associated with BIS-11 attentional scores, which is a measure of

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concentration capacity. Specifically, N2 amplitude was positively associated with BIS-11 total scores. The relations between N2, P3 amplitudes and BIS-11 scores speak to participants’ concentration during the tasks (Dikman and Allen, 2000). The decreased amplitudes of N2 and P3 support the aforementioned idea that CD individuals may be less concerned about the consequences of having punishment. Furthermore, the N2 and P3 amplitudes vary with reward valence and their magnitude may due to the different motivational or affective significance of reward and punishment, reflecting a meaningful change in neural processing. There are several potential limitations that should be mentioned. First, it's important

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ACCEPTED MANUSCRIPT to note, there may be inter-individual variation among healthy controls, and as well as disinhibited individuals will probably show these effects (Dikman and Allen, 2000).

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Earlier studies have demonstrated that the P3 amplitude was related to the severity of

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the “rules violation” subtype, but not related to aggression, deceitfulness, or theft (Bauer and Hesselbrock, 2003). The current study did not differentiate each subtype of CD due to limited sample size. Future studies are needed to further improve the

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homogeneity of subjects and explore the individual differences within controls and

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subtypes of CD. The second is that the study included no females, so future studies should validate our findings in CD individuals of different subtypes and genders.

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Third, our study is cross-sectional which is common in neuroimaging studies of

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psychiatric disorders. Therefore, our findings are limited in making any causal claims

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about the etiology of the problem behaviors in CD individuals. In addition, the participants recruited in the present study are CD-only. In order to gain more insight

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on potential confounding effects in feedback processing, future studies should include the comparison between CD and/or ADHD adolescents. In conclusion, the present study provides insights into the electrophysiological processing of differential responses to reward and punishment between adolescent with CD and healthy controls. This study demonstrates a decreased N2 amplitude following a loss as well as an overall decreased P3 responses in CD individuals. These findings suggest an underlying deficit in feedback processing, which may increase the propensity for behavioral disinhibition in CD individuals.

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ACCEPTED MANUSCRIPT Competing interests

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All authors declare that they have no competing interests.

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Authors’ contribution

Author SY and JY designed the study and wrote the protocol. YG, HC and HJ carried out the studies and participated in the data collecting. YG and HC managed statistical

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analysis and drafted the manuscript. QM and JY helped to draft the manuscript. All

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authors read and approved the final manuscript.

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Acknowledgments

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This study was supported by the grants from the National Nature Science Foundation

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of China (grant no. 81471384), National Key Technologies R&D Program in China’s 11th 5-year plan (grant no. 2009BAI77B02), Specialized Research Fund for the

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Doctoral Program of Higher Education (SRFDP, no. 20130162110043) and the construct program of the key discipline in Hunan Province.

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Adolesc Psychiatry 53, 466-475 e461.

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ACCEPTED MANUSCRIPT Figures

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Figure 1. Schematic illustration of the single outcome gambling task

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One of the two numbers (10 or 50) in the choice stimulus (800 ms) is displayed to be selected by the participants. The selected number results in feedback stimulus, which could indicate a “gain” (+10 or +50) or “loss” (-10 or -50). (A) Typical trial showing a

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loss of 10 in the box (-10). (B) Trial showing a gain of 50 in the box (+50). (C) Time

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window for task events: the selection window (1000 ms) wherein the subject selects either of the numbers, and the analysis window (200 ms prestimulus + 800 ms

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poststimulus) that was used for the ERP analyses.

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Figure 2. Average ERP waveforms and Topographic scalp maps for both groups

ERP waveforms showing comparisons for each condition across groups on electrode sites of Fz, Cz and Pz, respectively. Gain condition-evoked potentials are depicted on

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the left side, and loss condition-evoked potentials on the right side. Solid and dashed blue lines represent the average ERP waveforms for the healthy controls group. Solid and dashed red lines represent the average waveforms for the CD group. Topographies delineate the differences between groups and all conditions in the indicated time windows.

Figure 3. Schematic illustration of the mean voltage and standard error (SE) of the N1, P2, N2 and P3 in both groups

(A) Comparison of mean voltage and SE of the N1 at FCz electrode site. (B) 28

ACCEPTED MANUSCRIPT Comparison of mean voltage and SE of the P2 at Cz electrode site. (C) Comparison of mean voltage and SE of the N2 at Fz electrode site. (D) Comparison of mean voltage

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and SE of the P3 at Pz electrode site. Comparisons between CD individuals (black

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bars) with healthy controls (grey bars) were elicited by negative (-10, -50) and

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positive (+10, +50) feedback. *p < 0.05, **p < 0.01.

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ACCEPTED MANUSCRIPT Tables

t

p

-0.19

0.85

-1.30

0.20

30.74 ± 11.1

-0.42

0.68

38.95 ± 15.2

-0.03

0.98

HC (n = 19)

15.44 ± 1.3

15.53 ± 1.3

IQ

101.20 ± 11.2

104.80 ± 9.3

CES-D

28.89 ± 15.6

MASC

38.78 ± 16.9

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Age

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CD (n = 18)

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Table 1- Demographic and behavioral characteristics of study groups

Chinese version of the Barratt Impulsiveness Scale-11 (BIS-11) Attentional

19.00 ± 2.5

Motor

25.56 ± 5.1

Non-planned Total

3.42

0.002**

20.95 ± 4.8

2.83

0.008**

28.50 ± 3.9

25.21 ± 4.6

2.35

0.025*

73.06 ± 9.2

63.79 ± 8.9

3.46

0.001**

58.20 ± 22.9

59.00 ± 15.6

-0.12

0.90

72.60 ± 22.4

68.56 ± 17.3

0.62

0.54

59.75 ± 22.6

61.83 ±18.2

-0.31

0.76

Gain 50

75.90 ± 23.7

72.94 ±18.1

0.17

0.67

Reaction time

321.08 ± 55.3

297.14 ± 37.6

1.54

0.13

Loss 10 Loss 50

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Gain 10

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Usable trials

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D

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16.11 ± 2.6

CD: conduct disorder group; HC: healthy control group; CES-D, Center for Epidemiologic Studies Depress Scale; MASC, Multidimensional Anxiety Scale for Children. Difference are statistically significant at *p < 0.05, **p < 0.01.

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N1 amplitude

P2 amplitude

N2 amplitude

P3 amplitude

F

p

F

p

F

F

p

Group

4.51

0.041*

4.41

0.043*

6.56

0.015*

T

4.99

0.032*

Valence

3.46

0.07

0.48

0.50

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Table 2- Mixed-model ANOVA results

7.98

0.008**

17.71

< .001***

Magnitude

0.20

0.66

14.34

0.001**

12.75

0.001**

14.57

0.001**

Electrode

5.57

0.006**

15.91

< .001***

48.24

< .001***

—

—

Group ×valence

0.09

0.76

4.35

0.044*

5.17

0.029*

0.81

0.38

Group ×magnitude

1.10

0.30

0.60

0.45

0.27

0.61

1.10

0.30

Group ×electrode

0.34

0.67

2.82

0.07

6.95

0.007**

—

—

Valence ×magnitude

1.65

0.21

0.80

0.38

2.19

0.15

0.37

0.55

Group ×valence ×magnitude

0.88

0.36

1.81

0.19

0.43

0.52

0.80

0.38

Valence ×electrode

3.48

0.06

2.39

0.12

1.79

0.18

—

—

Group ×valence ×electrode

0.26

0.66

0.50

0.55

1.03

0.35

—

—

0.46

0.57

1.56

0.22

4.04

0.030*

—

—

0.93

0.37

0.95

0.38

0.39

0.64

—

—

0.85

0.39

2.21

0.14

0.24

0.68

—

—

0.34

0.62

0.23

0.69

0.40

0.58

—

—

Variable or interaction

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Group ×magnitude ×electrode

Valence ×magnitude ×electrode

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D

TE

Magnitude ×electrode

p

×electrode

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Group ×valence ×magnitude

Difference is statistically significant at *p < 0.05, **p < 0.01.

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Table 3 - Correlation analysis results

BIS

BIS

BIS

Attentional

Motor

Non-planned

Total

p

IP

r

p

SC R

0.87

0.14

0.42

-0.04

0.83

0.11

0.53

0.08

0.64

0.22

0.21

0.10

0.59

0.19

0.26

0.61

0.06

0.72

0.14

0.40

0.97

0.04

0.83

0.06

0.71

0.76

0.05

0.77

0.12

0.46

0.76

0.02

0.91

0.02

0.92

D

T

BIS

0.06

0.28

0.09

0.38

0.018*

0.16

0.34

0.21

0.21

0.24

0.14

0.30

0.07

0.32

0.05

0.40*

0.013*

0.048*

0.15

0.36

0.25

0.13

0.26

0.12

0.05

- 0.13

0.45

-.0.02

0.92

- 0.14

0.42

0.004**

- 0.23

0.19

- 0.01

0.99

- 0.24

0.17

- 0.39

0.021*

- 0.21

0.22

- 0.01

0.99

- 0.18

0.29

- 0.43

0.009**

- 0.21

0.22

- 0.10

0.57

- 0.25

0.15

p

r

p

r

N1 -10

0.34

0.047*

0.11

0.52

-0.03

N1 +10

0.28

0.09

0.06

0.74

N1 -50

0.27

0.11

0.20

0.26

N1 +50

0.30

0.09

0.17

0.34

P2 -10

0.21

0.22

0.09

P2 +10

0.11

0.52

0.01

P2 -50

0.23

0.17

0.05

P2 +50

0.14

0.40

-0.05

N2 -10

0.37

0.021*

N2 +10

0.26

0.11

N2 -50

0.45

0.005**

N2 +50

0.32

P3 -10

- 0.33

P3 +10

- 0.48

P3 -50 P3 +50

MA

TE

0.30

CE P

AC

NU

r

Correlation coefficient is statistically significant at *p < 0.05, **p < 0.01 (all p-values were uncorrected).

32

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

AC

CE P

TE

D

Fig. 1

33

AC

Fig. 2

CE P

TE

D

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

34

AC

Fig. 3

CE P

TE

D

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

35

IP

T

ACCEPTED MANUSCRIPT

Highlights

SC R

We examined ERP correlates of reward processing in conduct disorder individuals. Participants chose between small- and large-amount options in a gambling task.

NU

Conduct disorder group shows decreased N2 following loss feedback. Conduct disorder group shows overall decreased P3 amplitudes. Feedback-related ERPs were modulated by effects of feedback valence and

AC

CE P

TE

D

MA

magnitude.

36