Research ReportBrain activation to cues predicting inescapable delay in adolescent Attention Deficit/Hyperactivity Disorder: An fMRI pilot study
Highlights
► We tested a prediction of the delay aversion hypothesis in adolescents with ADHD. ► We confronted adolescents with and without ADHD with inescapable delay. ► We found more amygdala, insula, ventral striatum and orbito-frontal activation in ADHD. ► Our results provide evidence for the aversive nature of delay in ADHD.
Introduction
Attention Deficit/Hyperactivity Disorder (ADHD) is a common and debilitating condition marked by persistent and pervasive patterns of inattention, overactivity and impulsiveness that affect individuals across the lifespan (Taylor and Sonuga-Barke, 2008). There is a growing and fairly consistent body of evidence that maladaptive inter-temporal choices (i.e., preference for small earlier over larger later rewards), represent an important marker of ADHD-related impulsiveness (Scheres et al., 2010, Sonuga-Barke et al., 2008). A meta-analysis reported case–control difference of moderate effect size on simple choice delay tasks in 10 studies published up to 2007 (Willcutt et al., 2008). More recent studies have confirmed these effects (Gupta et al., 2011) across the life span: preschoolers (Wilson et al., 2011), adolescents (Marco et al., 2009) and adults (Marx et al., 2010).
A number of models have been proposed to explain impulsive choice in ADHD (Sagvolden et al., 2005, Sonuga-Barke et al., 2010, Tripp and Wickens, 2008). First, there are those accounts that focus on the way that the subjective value of rewards diminishes as they are moved through time into the future; so called temporal reinforcement discounting (Frederick et al., 2002). In normal individuals such discounting is thought to follow a quasi-hyperbolic function so that preference between two rewards reverses as one reward is moved into the future (Killeen, 2011). According to this model, impulsive choice occurs in ADHD because affected individuals discount the future at a higher rate so that choice performance is characterised by a steeper delay discounting function (Barkley et al., 2001, Scheres et al., 2010). At the neurobiological level steeper discounting in ADHD has been argued to result from attenuation of the dopamine signal to delayed rewards in the brain's reward centres (Sagvolden et al., 2005) or a failure of anticipatory dopamine cell firing (Tripp and Wickens, 2008). ADHD-related ventral striatal hyporesponsiveness during delayed rewards is consistent with this view (Plichta et al., 2009). A second class of accounts proposes that impulsive choice in ADHD is the result of a breakdown in higher order control whereby an affected individual is unable to suppress the drive to respond to the immediate option and so resist temptation (Barkley et al., 2001). According to this model impulsive choice is a specific expression of a general deficit in inhibitory-based executive dysfunction in ADHD which also affects functions such as working memory, planning and set shifting (Barkley and Murphy, 2011). Fronto-striatal circuits (e.g. dorso-lateral prefrontal and dorsal striatum and associated regions) which modulate executive functions and have been shown to be implicated in choices of large delayed rewards (McClure et al., 2004, McClure et al., 2007) are disrupted in ADHD (Durston et al., 2011).
The delay aversion model, offers a third and different perspective on impulsive choice in ADHD. It is based on the idea that, for ADHD patients delay is an aversive experience in and of itself, eliciting a negative affective state, which ADHD children work to escape or avoid (Sonuga-Barke, 1994, Sonuga-Barke et al., 2004). In this account choice of the small immediate reward is reinforcing because it allows the escape from delay associated with the large delayed outcomes and the subsequent avoidance of the negative affective state. The most recent account sees delay aversion acting in concert with processes such as steeper temporal discounting and an impulsive drive for immediate rewards to exacerbate impulsive choice (Marco et al., 2009, Sonuga-Barke et al., 2010) in ADHD. The delay aversion hypothesis makes predictions about the differential impact of delay on brain function that separates it from the other two accounts of impulsive choice. Most directly, if ADHD children find delay especially aversive they should show a relative hyper-activation of those brain regions implicated in processing of motivationally salient aversive events, when presented with a situation where one cannot escape delay (inescapable delay).
The two brain regions that have been most consistently shown to be activated by the prospect of contingent aversive events in human imaging studies are the amygdala and insula. The amygdala is a core limbic system structure with extensive and reciprocal connections to higher pre-frontal cortex and lower ventral striatum brain centres (Cardinal et al., 2002). In particular the basolateral amygdala is involved in the processing and representation of cue salience and valence that underpin conditioning (Kim et al., 2011). Most studies have focused on its role in processing negative stimuli (Carretie et al., 2009): including cues signalling aversive events (Iidaka et al., 2010), responses to physical and social threats (Staugaard, 2010), fear-generating stimuli (Sehlmeyer et al., 2009) and punishment (Hahn et al., 2010). Amygdala dysfunction is implicated in accounts of mood disorders where inappropriate perception and response to aversive and threatening stimuli seem core (Elliott et al., 2011). However, the amygdala has also been implicated in the regulation of responses to positive or rewarding stimuli (Bermudez and Schultz, 2010) suggesting a broader role in motivational control (Tye et al., 2008). With regard to ADHD, recent studies have reported smaller amygdala volumes in children (Frodl et al., 2010, Sasayama et al., 2010). There are also reports of altered amygdala functioning during perception of emotional faces (Brotman et al., 2010) and the suggestion that these may be linked to emotional dysregulation (Herrmann et al., 2010). Crucially, for the present study, Plichta et al. (2009) found significant hyper-activation of the amygdala in ADHD individuals when confronted with choices with delayed outcomes. The insula is a cortical structure folded within the lateral sulcus lying between the temporal and the frontal lobe. It plays a key role in the subjective appreciation of physical pain, especially located in the posterior portion of the insula (Isnard et al., 2011) and empathy for pain in others, modulated by the anterior portion (Gu et al., 2010). The anterior insula plays a key role in visceral representation and emotional awareness (Nieuwenhuys, 2012). The insula has also been identified as having a role in punishment learning (Hester et al., 2010, Wachter et al., 2009) and the regulation of attention to aversive emotional cues (Straube and Miltner, 2011), especially disgust (Deen et al., 2011). Altered insula activation is seen in individuals with anxiety disorders (Shah et al., 2009) and phobias (Rosso et al., 2010). Insula dysfunction has been implicated in ADHD across a number of domains including error processing (Spinelli et al., 2011), loss avoidance (Stoy et al., 2011) and sensori-motor timing (Valera et al., 2010).
The first aim of this study was to employ a region of interest (ROI) approach to test the strong prediction that ADHD children will activate the insula and amygdala more than controls when faced with the prospect of inescapable, as opposed to escapable, delay. The second aim of the paper was to explore activations to cues of inescapable delay in two other brain regions heavily implicated in the regulation of response to motivationally salient events. The ventral striatum is known to be involved in reward processing and is activated by cues of impending rewards (Knutson et al., 2001). Its role in the anticipation of aversive stimuli remains unresolved with mixed results from imaging studies (Jensen et al., 2003, Knutson and Greer, 2008). The orbito-frontal cortex is involved in coding reinforcer value and guiding decision making between different outcomes (Kennerley and Walton, 2011). A specific role for OFC in relation to aversive events remains uncertain (Ursu and Carter, 2009).
Section snippets
Results
The ADHD and control groups did not differ on hit rate while performing the task. For the escape condition the average success rate was 62% and for the no-escape condition 63% (F(1,18) = 0.216, p = 0.647). No significant difference between RT escape hits versus RT no-escape hits (F(1,18) = 1.41, p = 0.251) or interaction effect (escape versus group) was found (F(1,18) = 0.852, p = 0.368).
ROI analysis was performed for the amygdala, insula, ventral striatum and orbito-frontal cortex. In Table 2, the
Discussion
Impulsive choice is a core characteristic of ADHD (Marco et al., 2009). The delay aversion model proposes that the choice of immediate over delay rewards characteristic of ADHD inter-temporal choice is driven in part by the desire to escape delay in order to avoid the negative affective states which it elicits (Sonuga-Barke et al., 2010). Our goal in the current study was to begin to test a number of predictions about the neuro-biological mediators of this aversion to delay in ADHD using fMRI.
Participants
Twelve adolescents with combined type ADHD who met DSM-IV diagnostic criteria and 12 age matched controls took part in the study. Patients were recruited from the outpatient clinic of the university hospital. The control group comprised 12 children that were recruited from several regular primary and secondary schools. None of the control children had a history of prematurity (PML < 36 weeks), head trauma or any neurological and/or psychiatric disorder. All subjects presented a Full Scale
Acknowledgments
This study was supported by FWO (Scientific Research Fund Belgium) grant G.0821.11 and a clinical research fund from UZLeuven, Belgium.
The authors thank all participants, parents and their schools for their willing collaboration. We thank Sofie Cromheeke and Sylvia Kovacs for assistance with programming the computer task and Sofie Cromheeke for assistance with data collection.
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