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Neurological soft signs in children with attention deficit hyperactivity disorder: Their relationship to executive function and parental neurological soft signs Jingbo Gong, Jingtao Xie, Gui Chen, Yajie Zhang, Suhong Wang

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S0165-1781(15)00208-5 http://dx.doi.org/10.1016/j.psychres.2015.04.017 PSY8854

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Psychiatry Research

Received date: 11 September 2014 Revised date: 29 March 2015 Accepted date: 15 April 2015 Cite this article as: Jingbo Gong, Jingtao Xie, Gui Chen, Yajie Zhang, Suhong Wang, Neurological soft signs in children with attention deficit hyperactivity disorder: Their relationship to executive function and parental neurological soft signs, Psychiatry Research, http://dx.doi.org/10.1016/j.psychres.2015.04.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Neurological soft signs in children with attention deficit hyperactivity disorder: their relationship to executive function and parental neurological soft signs Jingbo Gonga, Jingtao Xiea, Gui Chenb, Yajie Zhanga, Suhong Wangc


Department of Applied Psychology, Traditional Chinese Medicine University of Hunan, Changsha, Hunan 410208, PR China 

Department of Social Medicine and Health Management, School of Public Health,

Central South University, Changsha, Hunan, China c

Department of Neuroscience, the Third Affiliated Hospital of Soochow University,

China *Corresponding author at: Department of Neuroscience, the Third Affiliated Hospital of Soochow University, Juqian Road No. 185, Changzhou 213003, China. Tel: +86 519 6887 0976, Fax: +86 519 8662 1235. E-mail address: [email protected] (S. Wang) Neurological soft signs in children with attention deficit hyperactivity disorder: their relationship to executive function and parental neurological soft signs

Abstract The correlations between neurological soft signs (NSS) in children with attention deficit hyperactivity disorder (ADHD) and their executive function, symptoms of inattention, and hyperactivity-impulsivity and the NSS of their parents remain unclear. This study aimed to examine: (1) the prevalence of NSS in children with ADHD and their parents; (2) the correlation between the NSS of children with ADHD and the NSS of their parents; (3) the correlation between the NSS of children with ADHD and their executive function and symptoms. NSS were assessed with the Cambridge Neurological Inventory (CNI) in 57 children with ADHD (and 80 parents) and 60

healthy children (and 75 parents). Executive function was measured with the Behavioral Rating Inventory of Executive Function (BRIEF). Children with ADHD and their parents had significantly higher NSS than normal children and their parents, respectively, and the NSS of children with ADHD were correlated more strongly with the NSS of their fathers than their mothers. No correlation was found between NSS and BRIEF executive function, but Disinhibition in children with ADHD was significantly correlated with hyperactivity-impulsivity symptoms. Paternal and maternal NSS provided different predictions for child NSS. It may be that NSS are more likely to be genetically transmitted by fathers. Key Words: ADHD; NSS; CNI; BRIEF Running Title: NSS and EF in Children with ADHD and Their Parents 1. Introduction Attention deficit hyperactivity disorder (ADHD) is a prevalent, heterogeneous, and debilitating neurodevelopmental disorder with an early onset, affecting around 5.2% of the school-age population globally (Sadock et al., 2009). ADHD is characterized by the principal symptoms of inattention, hyperactivity and impulsivity, with an estimated prevalence of 2.2% for males and 0.7% for females (Erskine et al., 2013). It has been suggested that ADHD results from structural defects in the brain networks that influence cognitive, affective and motor behaviors (Makris et al., 2008). Children with ADHD have been found to have difficulties in negotiating their physical environment, exerting fine motor control (e.g., writing and tying shoe laces), participating in social play and developing interpersonal relationships (Denckla and Rudel, 1978; Piek et al., 1999; Mostofsky et al., 2003). In addition to the main symptoms of inattention, impulsiveness and hyperactivity, a significant excess of soft

signs are often associated with ADHD, which may aid the clinical evaluation of ADHD (Ferrin and Vance, 2012). NSS were originally defined as non-localizing neurological abnormalities that could not be related to a specific brain region or a well-defined neurological syndrome (Kennard, 1960). NSS include different types of impairments in fine motor coordination, right-left orientation, laterality and sensory-perceptual performance. The growing interest in NSS has led to the development of multiple, structured instruments to assess neurological impairment: e.g., the Woods scale, the Cambridge Neurological Inventory (CNI), the Condensed Neurological Examination (CNE), the modified Quantified Neurological Scale, the Neurological Evaluation Scale (NES), and the Heidelberger Scale. Malla et al. (1997) divided NSS into four categories of neurological problems: motor coordination, motor integration, sensory integration, and continuous coordination activities. Chen et al. (1995) divided NSS into three categories of neurological problems: motor coordination, sensory integration, and inhibition. In the present study, CNI was used to assess the NSS of children with ADHD and their parents. NSS have been shown to be increased in a variety of mental disorders, including schizophrenia (Buchanan and Heinrichs, 1995; Bombin et al., 2005; Mayoral et al., 2008; Ruiz-Veguilla et al., 2008; Aksoy-Poyraz et al., 2011), ADHD (Uslu et al., 2007; Udal et al., 2009; Chan et al., 2010; Ferrin and Vance, 2012), post-traumatic stress disorder (Gurvits et al., 2002), obsessive-compulsive disorder (Peng et al., 2012), early onset bipolar disorder (Dickstein et al., 2005), and pervasive developmental disorders (Jones and Prior, 1985; Halayem et al., 2010; Mayoral et al., 2010). These studies have indicated that NSS are significantly associated with the illness and were found to show a graded pattern of severity: patients have the most, healthy controls have the least, and first-degree relatives have

an intermediate degree of these anomalies (Rossi et al., 1990). In addition, some studies have reported a general or selective correlation between the presence of NSS and the degree of cognitive dysfunction (Kolakowska et al., 1985; Liddle, 1987; Mohr et al., 1996; Flashman et al., 1996). Empirical findings have also demonstrated that NSS are predictive of neuropsychological performance in patients with schizophrenia (Flashman et al., 1996; Arango et al., 1999; Mohr et al., 2003; Chan et al., 2009). However, the relationship between NSS and the clinical symptoms of schizophrenia has been questioned in a number of studies, with some studies suggesting that negative/positive dimensions of the illness are not related to the frequency of NSS (Chen et al., 1996; Flyckt et al., 1999; Chen et al., 2000). Others however suggest that negative symptoms are strongly correlated with the prevalence of neurological impairments (Merriam et al., 1990; Wong et al., 1997). Recently, a meta-analysis of respected longitudinal studies suggested NSS may be used to identify individuals at risk to develop schizophrenia and to monitor disease progression (Bachmann et al., 2014). To date, only one study has examined the relationship between NSS and key cognitive processes (e.g., working memory) in children with ADHD (Ferrin and Vance, 2012). Numerous previous studies have reported a higher prevalence rate of NSS in children and adolescents suffering from ADHD. Chan et al. (2010b) found a higher incidence of NSS in children with ADHD and a significant association between motor coordination and Stroop interference. Logistic regression has supported the utility of soft-sign scales to discriminate between children with ADHD and controls, and significant abnormality of NSS in children with ADHD may be a useful marker of developmental disruption. In a follow-up study of ADHD children with developmental coordination disorder, Rasmussen et al. (2000) found that NSS can be

a very effective screening tool for ADHD diagnosis and pathology. Studies have reported increased overflow movements (Mostofsky et al., 2003), impaired timing of motor responses (Rubia et al., 1999), deficits in motor coordination (Rasmussen et al., 1983; Piek et al., 1999; Watemberg et al., 2007), and repetitive motor impairment (Epstein et al., 2003; Dickstein et al., 2005) in cases of ADHD. Meyer et al. (2006) found that children with ADHD performed significantly poorer on the Grooved Pegboard and Motor Coordination Task, compared to Finger Tapping Test, and that the impairment was most severe for children with ADHD-C subtypes. Interestingly, the origin of NSS appears to be genetic, at least in part. Studies of relatives of patients with schizophrenia (Ismail et al., 1998; Flyckt et al., 1999; Chen et al., 2000; Lawrie et al., 2001; Egan et al., 2001; Compton et al., 2007; Mechri et al., 2009) and obsessive-compulsive disorder (Peng et al., 2012) also indicated that NSS are, to some extent, heritable. A meta-analysis by Chan et al. (2010a)established that the prevalence of NSS in unaffected first-degree relatives of patients with schizophrenia are between those of their psychotic probands and those of healthy controls. Several twin studies have also demonstrated similar findings in twins with schizophrenia relative to their unaffected co-twin (Hyde, 1994; Niethammer et al., 2000), while Kelly et al. (2004) found no significant difference in NSS scores between patients with schizophrenia and their non-psychotic co-twin. To date, no study has specially examined the prevalence of NSS in unaffected first-degree relatives of individuals with ADHD to understand the role of NSS in the etiopathogenesis of ADHD. This is the first study to examine whether the NSS of children with ADHD have a significant correlation with the NSS of their parents. The main goals of the present study were to measure the prevalence rate of NSS in children with ADHD and their parents, and to examine whether the parents of

children with ADHD would demonstrate a higher prevalence rate of NSS than the parents of normal controls. Moreover, since it is known that NSS are heritable in some ways, the correlation between the NSS of children with ADHD and NSS of their parents was examined. The final goal of this study was to examine the power of NSS to

predict

executive

function

and

symptoms

of

inattention

and

hyperactivity-impulsivity. 2. Methods 2.1 Participants The participants were 57 medication-free children with ADHD (42 males and 15 females) (paired with 40 mothers and 40 fathers), aged 6-14 years, who were outpatients at the Clinic of Child Psychiatry of the Third Affiliated Hospital of Soochow University. Diagnoses were established by board psychiatrists, meeting the Diagnostic and Statistical Manual of Mental Disorder-fourth edition (DSM-IV) (APA, 1994) criteria for ADHD and the Kiddie-Sads-Present and Lifetime Version (K-SADS-PL); ADHD symptoms were assessed using the Swanson, Nolan, and Pelham Scale-version IV. Children with serous head injury, epilepsy, drug abuse, or psychiatric disorders (e.g., schizophrenia, pervasive developmental disorder, mental retardation, or mood disorder) were excluded from the study. Sixty healthy children, who were selected from local primary schools, served as controls (40 males and 20 females) (paired with 38 mothers and 37 fathers). The K-SADS-PL was used to exclude controls who displayed symptoms of ADHD. The full-scale IQ of all participants was above 80, based on the Wechsler Intelligence Scale for Children-Revised in China (C-WISC). The NSS of all participants and their parents were assessed using the Cambridge Neurological Inventory.

2.2 Measures 2.2.1 Neurological soft signs The Cambridge Neurological Inventory (CNI) was used to assess neurological soft signs (Chen et al., 1995), by a standardized clinical examination with three categories of soft signs: Motor Coordination, Sensory Integration, and Disinhibition. Each item is scored as “present” (which covered the abnormal or grossly abnormal scale scores) or “absent” (which covered the normal or equivocal scale scores) (Chan and Chen, 2007). The total score is 25, including Motor Coordination, Sensory Integration, and Disinhibition, which are 9, 8, and 8, respectively. The CNI has been found to be sensitive to neurodevelopmental disorder and sub-clinical samples in Chinese settings (Chan and Chen, 2007; Chan et al., 2009; Chan et al., 2010b; Chan et al., 2010c). The inter-observer reliability was found to be 0.83. 2.2.2 Clinical symptoms ADHD symptoms (inattention, hyperactivity/impulsivity, and combined) were assessed with the Swanson, Nolan and Pelham Scale-version IV (SNAP-IV) (Bussing et al., 2008), which is a widely used standardized measure of ADHD. The SNAP-IV is a 26-term questionnaire, using a 4-point point Likert scale, that evaluates ADHD symptoms and severity, including 18 items that measure ADHD symptoms (9 for Inattentive, and 9 for Hyperactive/Impulsive), and 8 items that measure Oppositional Defiant Disorder symptoms. Each item is rated on a 0-3 score scale (0 = not at all, 1 = just a little, 2 = quite a bit, and 3 = very much). The scale was completed by parents of each children. The cutoff scores for sums of ADHD-Inattention items and ADHD- Hyperactive/Impulsive items are 16 and 13, respectively. According to the DSM-IV criteria, individuals with six or more

symptoms of inattention, but fewer than six symptoms of hyper-impulsive were identified as Inattentive type ADHD; participants with six or more hyper-impulsive symptoms and fewer than six symptoms of inattention were categorized as Hyper-Impulsive type ADHD; and individuals with six or more symptoms on both dimensions were identified as Combined type ADHD. 2.2.3 Executive function The Behavioral Rating Inventory of Executive Function (BRIEF), as completed by the parents in this study, is an 86-item standardized rating scale that provides information about the nature and extent of executive function deficits displayed by children and adolescents between 5-18 years of age (Gioia et al., 2002). The BRIEF yields a composite score–the Global Executive Composite and two indices: Behavioral Regulation (3 subscales: Inhibition, Shifting, and Emotional Control) and Metacognition (5 subscales:Initiate, Working memory, Plan/Organizing, Organization of Materials, and Monitoring). The total scores are converted to standardized scores, in which scores above 60 reflect EF impairments. The test-retest reliability has been reported to be r = 0.86 for the Global Executive Composite, 0.88 for the Behavioral Regulation, and 0.84 for Metacognition (Gioia et al., 2000). 2.3 Statistical analysis The data analyses were performed using SPSS software (SPSS, version 17 for Windows. Inc., Chicago, IL, USA). Values are expressed as means and SDs. We compared NSS scores in children with ADHD and controls, parents of children with ADHD and parents of controls, respectively, using analysis of covariance (ANCOVA), controlling for age and IQ, as these factors have been consistently associated with NSS performance. Pearson’s correlation coefficients were used to examine the

correlations between the NSS of children with ADHD and parental NSS, BRIEF executive function scores, and symptoms of inattention and hyperactivity-impulsivity, respectively. A stepwise multiple regression analysis was used to examine the predictive power of NSS on executive function and symptoms of inattention and hyperactivity-impulsivity. The variables in the statistical analysis are normally distributed. Statistical significance was set at p