Stimulants improve theory of mind in children with attention deficit/hyperactivity disorder

Abstract

Impairments in ‘theory of mind’ (ToM) were linked to social cognition and reciprocal relationships deficits in children with attention deficit/hyperactivity disorder (ADHD). Twenty-four children with ADHD (13 with inattentive type and 11 with combined type, mean age 10.2 years) completed the Interpersonal Reactivity Index (IRI), a self-reported empathy questionnaire. All children performed the ‘faux pas’ task and a computerized ToM task in two different sessions either with or without administration of methylphenidate (MPH). Administration of MPH was associated with an improvement in cognitive and affective ToM. Children with ADHD-combined type had significantly lower scores in total IRI and the fantasy scale compared to children with ADHD-inattentive type. We conclude that deficits in empathy and ToM may play an important role in the impairments in social cognition and peer relationship in children with ADHD, especially children a hyperactive component. Stimulants may improve ToM and empathic functions. Future studies including larger samples and additional cognitive tasks are warranted in order to generalize these results and to identify possible underlying mechanisms for improvement in ToM following the administration of MPH.

Keywords

Theory of mind attention deficit / hyperactive disorder stimulants

Introduction

Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children and youth, affecting approximately 5% of children worldwide (Polanczyk et al., 2007). ADHD is associated with a considerable negative impact on social functioning (Greene et al., 1996, 1997; Mash and Barkley, 2003), and children with ADHD suffer from peer rejection and impairments in reciprocal friendships (Hoza et al., 2005; Mrug et al., 2012; MTA Cooperative Group, 1999). Peer rejection may result from deficits in regulation of behavior and emotions, as well as from disengagement and passive and withdrawn behavior (Milich et al., 2001; Nijmeijer et al., 2008). Children with ADHD-combined type (ADHD-C) have been found to show poorer social problem-solving skills, impulsive responding, and more conduct problems compared to children with ADHD-inattentive type (ADHD-I) (Barkley, 2006). Studies also show that parents and teachers attribute poorer social skills and more social performance problems to children with ADHD-C compared to children with ADHD-I (Maedgen and Carlson, 2000; Semrud-Clikeman, 2010).

Despite the well documented social–behavioral and peer relationship problems of children with ADHD, the mechanisms underlying these difficulties remain poorly understood (Hoza et al., 2005; McQuade and Hoza, 2008). Impairments in ‘theory of mind’ (ToM) were linked in previous studies to poor interpersonal relationships in children with ADHD (Uekermann et al., 2010). For example, some studies showed deficits in recognition of facial emotions (Buhler et al., 2011; Corbett et al., 2009; Da Fonseca et al., 2009; Pelc et al., 2006; Singh et al., 1998). Other studies showed impairments in both first- and second-order ToM tasks (Buitelaar et al., 1999; Sodian et al., 2003). There is also some evidence that empathy, closely related to the affective component of ToM, is affected in ADHD and a few studies have demonstrated impaired empathy and lower levels of social perspective taking in children with ADHD (Braaten and Rosen, 2000; Dyck et al., 2001; Marton et al., 2009). However, the scarce data regarding ToM in children with ADHD is based almost exclusively on studies using facial recognition tasks. None of the studies differentiated between different types of ADHD. In addition, none of the studies differentiated between the cognitive and affective aspects of ToM (inference about other’s belief and intentions as compared to inference about other’s emotions and feelings), which involve separate prefrontal networks (Abu-Akel and Shamay-Tsoory, 2011; Shamay-Tsoory et al., 2009, 2010).

In addition to the lack of information concerning ToM and empathy in children with ADHD, the potential effects of the widespread treatment with stimulants on ToM has not been studied well enough. Although it is generally accepted that stimulants reduce negative peer interactions and improve social and behavioral functions in children with ADHD (Bagwell et al., 2001; Biederman and Spencer, 2008; Buhrmester et al., 1992; Hechtman et al., 1984; Molina et al., 2009; MTA Cooperative, 1999; Shaw et al., 2012), the direct influence of stimulants on social cognition, ToM and empathy is comparatively unknown (Uekermann et al., 2010). This is important because dopaminergic circuits, which are dysfunctional in children with ADHD and constitute the main target of stimulants action (Wu et al., 2012), also play a central role in ToM (Abu-Akel and Shamay-Tsoory, 2011; Lackner et al., 2010; Skuse and Gallagher, 2011). The only study to date, by Williams et al. (2008), showed that methylphenidate (MPH) normalized neural activity in regions found to be impaired and produced some improvement in emotion recognition. Clinically, the issue of the effect of pharmacological treatment on ToM and social function is of prime importance because social dysfunction, peer rejection and poor interpersonal relationships are central factors in the course of ADHD and its comorbidity (Buitelaar et al., 1999; Uekermann et al., 2010). For example, recent study in a large Swedish cohort of adults with ADHD has exemplified a significant reduction in criminal acts while being treated (Lichtenstein et al., 2012), which connects to the possible clinical applicability of studying the effect of stimulants on ToM and empathy.

The main purpose of this study is to broaden our understanding of ToM in children suffering from ADHD and the effect of the administration of stimulants on cognitive and affective components of ToM in children with ADHD. Based on the existing literature we hypothesized that the administration of MPH would be associated with an improvement in ToM performance in children with ADHD. A secondary hypothesis, based on several reports concerning differences in social skills between children with ADHD-C and ADHD-I (Barkley, 2006; Mikami et al., 2007; Semrud-Clikeman, 2010), was that children with ADHD-C would have lower baseline ToM performance compared to children with ADHD-I.

Methods

Participants

Participants in the study were 24 children with ADHD (16 boys and 8 girls). Participants were recruited from the ADHD clinic and the outpatient clinic of the Shalvata Mental Health Center, School of Medicine Tel Aviv University. Inclusion criteria were age between 6–12 years, normal IQ based on clinical assessment and data from school evaluations, and no current major depression, bipolar disorder, psychosis, substance abuse, disruptive behavior disorders or any medical or neurological condition or taking medications (e.g. psychotropic medications) that might affect the child’s participation in the study. All participants were examined and diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association, 2000) criteria for ADHD by a child neurologist or child psychiatrist and were prescribed to use methylphenidate (MPH, either long-acting Ritalin or osmotic-controlled release oral-delivery system (OROS). The study was approved by the institutional ethics committee and both parents of all participants signed a consent form.

Procedure

Apart from the initial clinical assessment at the clinic, all assessments were performed in the children’s houses. Each of the children participated in two sessions. In order to lessen a possible learning effect of the computerized task (see hereinafter), the session were performed at least two weeks apart. Each session lasted 45–60 min. Half of the patients performed the first session without medication (at least 24 h after the administration of the last pill) and the second session 1–5 h after administration of a long-acting MPH. The other half performed the sessions in the opposite order. Parents filled questionnaires regarding demographics and general information about the child’s academic and social functioning. In addition, all parents completed a Swanson, Nolan and Pelham Questionnaire-IV (SNAP-IV) (Swanson et al., 2001). This instrument contains subscales for inattention, hyperactive/impulsive behavior and oppositional behavior, and a Conners index which was developed by selecting the items which loaded highest on the multiple factors of the Conners rating scale. Self-reported empathy was measured using the Interpersonal Reactivity Index (IRI) (Davis, 1983), which showed high reliability in children over repeated administrations (Garton and Gringart, 2005; Litvack-Miller et al., 1997). The IRI is divided into four scales that can be organized in two components of empathy: cognitive and affective. The two scales that reflect the cognitive aspects of empathy are perspective taking and fantasy and the two scales that reflect the affective aspects of empathy are empathic concern and personal distress. Each of the four scales includes four or five items (a total of 18 items). Participants rate each item on a four Likert-type scale (from 0 – ‘does not describe me at all’ to 3 – ‘describes me very well’). The total score was then calculated. We used the modified version of IRI adapted for children (Garton and Gringart, 2005).

On each of the sessions subjects performed two ToM tasks – the ‘faux pas’ and a ToM computerized task (TCT). The Faux Pas Recognition task (FPR), designed by Baron-Cohen et al., (1999), is designated to evaluate the ability of participants to recognize social ‘faux pas’ – social situations in which a speaker says something without understanding that there might be a difference between his state of knowledge and that of the listener (‘cognitive’ ToM), and thus should appreciate the emotional impact of a statement on the listener (‘affective’ ToM) (Shamay-Tsoory et al., 2003; Stone et al., 1998). At each session participants were given 10 short stories. Five stories contained faux pas situations to be identified. After hearing every story, the participants were asked ToM questions (see Appendix 1). The score consisted of the total number of all correct identification of a faux pas situation. The Hebrew version of the FPR was employed after validation by a group of normal subjects (Shamay-Tsoory et al., 2005).

The TCT is based on a task described previously by Baron-Cohen (1995). This task measures the ability to judge mental states based on verbal and eye gaze cues. The task is described in detail elsewhere (Shamay-Tsoory and Aharon-Peretz, 2007). In short, the task consists of 64 trials, each showing a cartoon outline of a face (named ‘Yoni’) and four colored pictures of objects belonging to a single category or faces, one in each corner of the computer screen. The subject’s task is to point to the correct answer (the image to which Yoni is referring), based on a sentence that appears at the top of the screen and available cues, such as Yoni’s eye gaze, facial expression or the eye gaze and facial expression of the face to which Yoni is referring (see Figure 1). The subjects are instructed to point to the correct picture using the computer mouse as fast as they can. There are two main conditions: ‘cognitive’ and ‘affective’. Another ‘physical’ condition was added to ensure that the participants understand the task and avoid responding automatically to eye gaze. The cognitive, affective and physical conditions require either a first-order (32 trials) or a second-order (32 trials) inference. In the cognitive conditions, both Yoni’s facial expression and the verbal cue are emotionally neutral, whereas in the affective conditions, both cues provide affective information (e.g., ‘Yoni is thinking of…’ or ‘Yoni loves’). Both positive and negative affective statements are used. In the second-order condition, the four stimuli consist of face images and the choice of the correct response requires understanding of the interaction between each of these figures and Yoni’s mental state (‘Yoni is thinking of/loves the toy that X wants’). Another control condition was added in 20 trials (in half of the physical conditions and half of the cognitive and affective second-order conditions), in which Yoni’s gaze was directed straight ahead. This was done following a pilot study which demonstrated that some individuals responded automatically to the stimuli to which Yoni’s gaze was directed and avoided reading the sentences. When Yoni’s gaze was directed straight ahead, the decision must be based on the verbal cue and the face’s gaze.

Statistical analysis

Demographic and clinical comparisons between groups (ADHD-I, ADHD-C) were performed using t test and Fisher’s exact test as appropriate. Spearman’s coefficient was used to assess correlations between SNAP and IRI scores. Multivariate analysis of variance was used to compare FTR scores among groups, controlling for the confounding effect of between-group sex differences. To examine the effect of MPH on FPR performance for the two types of ADHD, we used repeated measures analysis of variance (ANOVA) with drug (baseline, MPH) and story type (control, faux pas) as within-subjects factors and with ADHD type (ADHD-I, ADHD-C) as a between-subjects factor, followed by post-hoc matched paired t tests. For the TCT we created cognitive and affective indices for each patient by subtracting the cognitive/affective accuracy scores from the physical condition accuracy scores. Then, we performed repeated measures ANOVA with drug (baseline, MPH) and item type (cognitive index, affective index) as within-subjects factors and ADHD type (ADHD-I, ADHD-C) as a between-subjects factor, followed by post-hoc matched paired t tests. In light of previous evidence which points towards the role of baseline performance on the degree of improvement following administration of stimulants (de Wit et al., 2002; Farah et al., 2009; Kimberg et al., 1997; Mattay et al., 2003; Mehta et al., 2000), we performed a regression analysis for both tasks to determine the association between baseline performance and change in performance following the administration of MPH. The dependent measure was drug effect (the difference between baseline and post-administration performances) and the independent measures were baseline performance and session order. All tests were two-sided with a significance level set at 0.05.

Results

There were 13 subjects with ADHD-I and 11 subjects with ADHD-C. As shown in Table 1, except for significantly more males in the ADHD-C group there were no other between-group demographic or academic differences. Children with ADHD-C had higher SNAP scores in Hyperactive/impulsive, Oppositional and Aggression subscales. In addition, their mean Conners index was significantly higher. Children with AHDH-C were evaluated by their teachers as having more behavioral problems. Children with ADHD-C had lower scores in all IRI scales (all p-values ≤0.05). However, after controlling for between-group sex differences, only the total IRI and fantasy scale scores remained significantly different (p-values ≤0.04). There was a significant negative correlation between scores in SNAP hyperactive subscale and IRI total, cognitive and affective scores (r≤ –0.43, all p-values≤0.05). There was no significant correlation between SNAP inattentive subscale and IRI scores.

Table 1.

Demographic and clinical characteristics of subjects according to ADHD type.

	Inattentive (n=13)	Combined (n=11)	Statistics	p value
Age, years	10.1 (1.3)	10.5 (1.5)	T=0.65	0.52
Sex (% male)	46%	91%	FET	0.03
Family income^a	3.46 (0.5)	3.36 (0.7)	T=0.39	0.69
Father’s age (years)	41.7 (4.4)	45.00 (9.6)	T=1.03	0.32
Father’s education (no. of years)	15.2 (2.0)	14.0 (1.8)	T=1.44	0.16
Mother’s age	41.9 (5.1)	40.9 (3.6)	T=0.52	0.61
Mother’s education (no. of years)	14.2 (1.7)	14.6 (2.2)	T=0.59	0.56
Number of siblings	2.1 (0.9)	2.5 (0.7)	T=1.19	0.25
Teachers evaluations Maths	81.2 (11.2)	78.2 (11.5)	T=0.64	0.53
Language	84.6 (8.8)	80.5 (7.9)	T=1.22	0.23
Behavior	92.7 (6.7)	82.7 (6.5)	T=3.71	<0.01
Reported no. of good friends	2.9 (1.0)	3.0 (0.9)	T=0.4	0.69
SNAP scores^b
Inattention	1.9 (0.4)	2.2 (0.5)	F=1.59	0.11
Hyperactive/Impulsive	0.6 (0.4)	2.2 (0.4)	F=48.03	<0.01
Oppositional	0.9 (0.3)	1.6 (0.6)	F=6.75	<0.01
Aggression	0.5 (0.3)	1.3 (0.5)	F=9.67	<0.01
Conners index	1.1 (0.3)	1.9 (0.3)	F=16.20	<0.01
IRI scores^b
Total	30.4 (7.1)	24.2 (6.9)	F=3.17	0.04
Cognitive	15.9 (4.4)	12.6 (3.9)	F=2.48	0.06
Fantasy	7.2 (2.8)	4.9 (2.1)	F=3.78	0.03
Perspective Taking	8.7 (2.7)	7.6 (2.1)	F=1.23	0.29
Affective	14.5 (4.3)	11.6 (4.8)	F=1.49	0.14
Empathic concern	8.5 (3.0)	6.8 (2.9)	F=1.69	0.18
Perspective distress	6.0 (1.9)	4.8 (2.4)	F=1.76	0.20

FET: Fisher’s Exact Test; IRI: Interpersonal Reactivity Index; SNAP-IV: Swanson, Nolan and Pelham Questionnaire-IV.

family income on scale of 1–5; ^bstatistics are controlled for sex differences. Values given are means (standard deviation (SD)) except for sex.

Faux pas

The ANOVA revealed a significant main effects for drug (F(1, 22)=9.39, p<0.01], story type (F(1,22)=8.094, p<0.01), and ADHD type (F(1, 22)=10.595, p=0.04). There was no significant interaction between drug, story type, and ADHD type. There was, however, a significant drug by story type interaction effect (F(1,22)=9.13, p<0.01). Post-hoc analysis indicated that the mean score in the faux pas stories was significantly higher following the administration of MPH compared to baseline (4.75 compared to 4.21, p<0.01), whereas the difference in the control stories was not significant (Table 2). To examine the effect of drug along with those of sessions order we repeated the same analysis but with the use of order as the between-subjects factor and obtained the same pattern of results (data available upon request). The regression analysis showed greater improvement in mean faux pas scores following the administration of MPH for children with lower baseline performance compared to children with higher baseline performance (r = −0.76, p<0.01).

Table 2.

Changes in performances in Faux Pas Recognition test and computerized theory of mind (ToM) tasks at baseline and after administration of methylphenidate (MPH).

	Baseline	With MPH	Post-hoc t tests	p-value
Faux Pas Recognition accuracy
Overall score, mean (SD)	8.87 (1.15)	9.54 (0.83)	n/a
Control stories	4.66 (0.48)	4.79 (0.41)	–1.00	0.32
Faux pas stories	4.21 (0.78)	4.75 (0.53)	–3.41	<0.01
ToM computerized task
Overall score, mean (SD)	–0.0996 (0.57)	0.1900 (0.52)	–2.64	0.02
Cognitive index	–0.0079 (0.30)	0.1279 (0.29)	n/a
Affective index	–0.0917 (0.29)	0.0621 (0.25)	n/a

n/a: not applicable; SD: standard deviation.

TCT

The ANOVA revealed a significant main effects for drug (F(1, 22)=6.903, p<0.05) and item type (F(1, 22)=8.312, p<0.01). There was no statistically significant main effect for ADHD type. There were also no significant interaction effects between drug and item type, drug and ADHD type, or between drug, item type and ADHD type. Post-hoc analysis indicated that the mean TCT scores were significantly higher following the administration of MPH compared to baseline (–0.0996 and 0.1900, p=0.015). To examine the effect of drug along with those of session order we repeated the same analysis but with the use of order as the between-subjects factor and obtained the same pattern of results (data available upon request). As with the FPR, post-hoc regression analysis showed that baseline performance predicted the magnitude of the improvement following the administration of MPH in both the cognitive and affective indices (r= −0.527 and r= −0.661 respectively, p-values≤0.01), such that lower-performing individuals had greater improvement (Figure 2).

Discussion

The current study sought to investigate the effect of MPH on ToM abilities among children with ADHD. In our clinical experience, parents often fear that the cognitive improvement induced by MPH will be accompanied by emotional and social blunting. Some studies in animal models support a decline in social playfulness, and thus in a way substantiate these concerns (Vanderschuren et al., 2008). However, these concerns are seemingly not supported by current literature in children with ADHD (Graham and Coghill, 2008). In our study, the administration of MPH was associated with a significant improvement in ToM performance as measured by FPR and TCT. These findings correspond with previous clinical studies showing that the administration of stimulants improves social functions in children with ADHD (Biederman and Spencer, 2008; MTA Cooperative, 1999; Swanson et al., 2011). Nevertheless, the exact effect of MPH on social cognition and ToM is not well understood. One prior study, by Williams et al., (2008) showed only minor improvement in emotion recognition following the administration of MPH. However, emotion recognition tasks mostly involve occipitotemporal brain systems, while cognitive and affective ToM tasks as described in our study primarily engage the dorsomedial prefrontal cortex, as well as other interacting brain regions (e.g. dorsal anterior cingulate cortex, dorsal striatum, ventromedial and orbitofrontal cortices) (Abu-Akel and Shamay-Tsoory, 2011; Kalbe et al., 2010; Shamay-Tsoory et al., 2009). Improvement in ToM performance as measured by FPR and TCT might be derived from a direct action of MPH in brain regions associated with reasoning about mental states of others. ToM is dependent, amongst others, on the integrity of the dopaminergic system (Abu-Akel and Shamay-Tsoory, 2011; Lackner et al., 2010). Since stimulants target their action mainly on catecholaminergic systems in the prefrontal cortex and the striatum (Abu-Akel and Shamay-Tsoory, 2011; Stahl, 2010), it is possible that they have a direct enhancing effect on ToM. In such a case, the action of stimulants is not selective to specific regions and therefore improvement is expected in both cognitive and affective components of ToM, which engage different brain regions (Abu-Akel and Shamay-Tsoory 2011; Kalbe et al. 2010; Shamay-Tsoory et al. 2009). On the other hand, improvement in ToM as measured in this study might be secondary to enhancement of other cognitive functions required in these tasks like the participants’ ability to stay concentrated during a continuous task, better attention to specific details, or a decrease in impulse responding. More comprehensive studies to evaluate the effect of stimulants on ToM with respect to changes in other cognitive functions (e.g. executive functions such as working memory and inhibition) are warranted to address this issue.

An additional finding in our study was the significant correlation between poorer baseline ToM performance and greater improvement following the administration of MPH. This is actually not surprising since studies regarding other aspects of stimulants’ action (e.g. executive functions, behavior) also show the same pattern of results (Biederman and Spencer, 2008; Kimberg et al., 1997; Mehta et al., 2000).

Several studies have reported that children with ADHD-C suffer from more severe deficits in peer relationships compared to children with ADHD-I (Barkley, 2006; Maedgen and Carlson, 2000; Semrud-Clikeman, 2010). In our study, children with ADHD-C had lower scores compared to children with ADHD-I in total IRI and fantasy scale (which taps the subject’s tendencies to transpose themselves imaginarily into fictional situations). These findings, along with the negative correlation found between the SNAP hyperactivity subscale and IRI scores suggest that children with ADHD-C might be more impaired in their empathetic functions compared to children with ADHD-I. Lower IRI scores in children with ADHD-C may also be related to the fact that the ADHD-I group had significantly more females (Banerjee et al., 2011; Schulte-Ruther et al., 2008). However, the results remained significant after controlling for sex differences between groups. In addition, comparing only males in both groups did not change the results. We could not find a significant difference in baseline performances in FPR or TCT between children with ADHD-I and ADHD-C, meaning that these tasks might not capture the whole cognitive mechanism that leads to the apparent difference in empathic functions as reflected by the IRI. Nonetheless, the significant main effect found for ADHD type in the FPR implies that children with ADHD-C might also be more impaired in their faux pas. The clinical relevance is supported by previous studies showing that children with ADHD-C are more disliked and suffer from more peer rejection compared to children with ADHD-I (Bagwell et al., 2001; Milich et al., 2001). Studies with larger samples and more comprehensive instruments are needed in order to clarify the potential differences in ToM abilities between children with ADHD-I and ADHD-C.

Several limitations of the study need to be addressed. First, our findings are limited by the small sample size. Nevertheless, the data presented here provides a first justification for further investigation of ToM and empathic functions and the effect of pharmacological treatment in children with ADHD. Second, we did not have a healthy control group as well as a control group administrating placebo in a double blinded manner. Third, the evaluation of the children in their own houses could have created a bias since the participants were not examined at the exact same conditions. Fourth, the mean time of discontinuation of MPH prior to the session without MPH was 28.1 h and there is a possibility that some of the results are influenced by rebound effect of long-acting MPH. Finally, given its preliminary nature, this study does not explain the findings of improvement in ToM in a broader context of change other cognitive processes (such as improvement in sustained attention or working memory).

In conclusion, ToM deficits may play an important role in the impaired social cognition and peer relationship in children with ADHD, especially children with the hyperactive component. Stimulants, known to endorse a significant improvement in cognitive functions, may also improve ToM and empathic functions, and even more so in children with poorer baseline ToM performance. Given the significant social and interpersonal impairments that often accompany ADHD, the decision whether to treat a child with ADHD and how, should take into account this potential benefit. Future studies including larger samples and additional cognitive tasks are necessary in order to generalize our results and to identify possible underlying mechanisms for improvement in ToM following the administration of MPH.

Footnotes

Appendix 1 Conflict of interest

The authors declare that there are no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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