The first hypothesis of this study was largely confirmed. In the cue phase of the task, a between group comparison for the red minus green contrast indicated that adolescents with ASDs showed less frontal (BA 10), parietal (BA 7, and BA 40), and occipital (BA 18) activation than typically developing participants. The red minus green trial contrast was further explored by examining activation following green and red cues separately. Individuals with ASDs and typical development showed a similar level of activation to green cues. However, individuals with ASDs exhibited less activation on red trials across most of the same regions found during the between group analysis. This suggests that the ASD group’s failure to increase activation following cues indicating the need to engage cognitive control processes is driving the results of the red minus green subtraction, and that group differences are not due solely to an absence of activation across both trial types in the ASD group, but were the result of performance on the more difficult red trials.
In support of the second hypothesis, both the time series and the beta series correlation methods illustrated reduced functional connectivity between frontal and parietal regions in the ASD group. For red trials, the time series correlation method showed reduced connectivity between anterior frontal and visual areas. During green trials, there were also reductions in connectivity between DLPFC and anterior PFC and premotor, parietal, cingulate and occipital regions. A factor analysis illustrated that, for the typically developing group during red trials, all brain regions activated on a similar time course. The ASD group, however, exhibited less regional integration during red cue trials with visual and superior parietal regions acting independently of the frontal, cingulate, and inferior parietal regions. The beta series method provided additional evidence of an impairment in fronto-parietal connectivity, as individuals with ASD exhibited reduced connectivity between the left anterior PFC and parietal, and visual areas. This analysis also revealed deficits between prefrontal, striatal, and medial temporal areas.
Task performance (red error rates) in typically developing individuals was related to fronto-parietal connectivity. In individuals with ASD, there were modest positive relationships between functional connectivity between prefrontal and visual areas and speeded responding, however these correlations did not survive correction for multiple comparisons. It bears mention that there now have been several findings of speeded responding on correct trials in individuals with ASDs (Bogte, Flamma, van der Meer, & van Engeland, 2007
; Thakkar et al., 2008
), as well as several findings of general response slowing in individuals with ASDs (Geurts, Verte, Osterlaan, Roeyers, & Sergeant, 2004; Johnson et al., 2007
). Given these contradictions in the literature, studies investigating and comparing speed accuracy tradeoffs and the mechanics of trial-to-trial performance adjustment in different paradigms could help advance our understanding of cognitive control in ASDs.
As hypothesized, fronto-parietal connectivity was inversely related to ADHD symptoms. Like children with ADHD, children with ASDs demonstrated greater response inhibition deficits when external cues were unavailable for use over the long delay period involved in this task. However, while they may show response inhibition deficits in some cases (e.g. Geurts et al., 2004; Solomon, Ozonoff, Cummings, & Carter, 2008), children with ASDs may not exhibit these difficulties when prepotency is not sufficiently strong, or when they do not have clinically significant attention symptoms, and these alternatives should be examined more systematically in future studies.
Our findings add to the recent consensus that ASDs involve fronto-parietal connectivity deficits (Kana et al., 2006; Just et al., 2007
). How might these deficits affect functioning in individuals with ASDs? Parietal cortex has been implicated in storage of spatial information in working memory (Funahashi, Chafee, & Goldman-Rakic, 1993
; Wager & Smith, 2003
), and is sensitive to both rule representation and generally is active when there is a need to control task sets (Brass & von Cramen, 2004; Bunge, 2004
; Crone, Wendelken, Donohue, & Bunge, 2006
). Anterior frontal activation in BA (10) has been associated with a wide range of functions including switching of attention between percepts (Pollman, 2001
), subgoal processing (Braver & Bongiolatti, 2002
), maintaining higher order and/or abstract mental representations of task contingencies (Badre, 2008
; Badre & D’Esposito, 2007
; Botvinick, 2008
; Frank & O’Reilly, 2006
; Koechlin, 2003
), regulating stimulus-oriented versus stimulus-independent processing (Burgess, Dumontheil, & Gilbert, 2007
), and preserving a dynamic balance between controlled and rapid automatic responding (Braver, Reynolds, & Donaldson, 2003
; Brown, Reynolds, & Braver, 2007
). The combination of difficulties in maintaining the task set online, coupled with the inability to retrieve the appropriate rule accords well with the nature of ASD symptoms. An interesting potential line of inquiry is that deficits in the functioning of anterior prefrontal regions could be involved in the pattern of “missing the forest for the trees” or weak central coherence evident in persons with autism. Indeed, several recent studies have raised this possibility (Gilbert, Bird, Brindley, Frith, & Burgess, 2008
; Hill & Bird, 2006
In this study, we did not find ACC activation in either group during the probe phase of the task. Existing behavioral studies suggest that individuals with ASDs exhibit impairments in cognitive control that persist at least until adulthood (Luna, Doll, Hegedus, Minshew, & Sweeney, 2006; Solomon, Ozonoff, Cummings, & Carter, 2008). Frontal and parietal regions are thought to develop throughout adolescence and early adulthood (Luciana, Conklin, Hooper, & Yarger, 2005
; Luna, Garver, Urban, Larzar, & Sweeney, 2004
). However, the ACC may exhibit a more delayed developmental trajectory. For example, Velanova, Wheeler, & Luna (2008)
showed increased activation of the ACC on error versus correct trials in an antisaccade task with development, with peak neural activation onsets occurring later in adults versus children. They suggest that children and adolescents may receive less feedback to guide future performance. A similar argument has been made by Ladouceur, Dahl, & Carter, (2004
, 2007) in a study that examined the development of electrophysiological measures of ACC functioning. These findings may help explain why we did not find significant and expected probed period ACC activation in either typically developing adolescents or those with ASDs, and underscore the great need for additional developmental neuroimaging studies.
Potential limitations of the current study should be discussed. First, we elected to include the 55% of subjects with clinically significant symptoms of ADHD. As we have argued previously (Solomon, Ozonoff, Cummings, & Carter, 2008), co-morbid attention problems are likely part of the autism phenotype, and to exclude such children would preclude us from learning important information about the population as a whole. On the other hand, future studies should look at groups of children with ASDs with and without co-morbid ADHD symptoms to isolate potential differences. Second, we elected to include participants taking SSRIs in the ASD group, given the high percentage of these children taking these medications. Unlike stimulant medications which wash out quickly, SSRI’s would require several weeks, and we could not justify taking this approach in children benefiting from this therapy targeting social anxiety and/or depression. Finally, the POP task is relatively long, and we lost 30% of subjects due to excess motion. Although participants with excess motion came from both groups equally, future studies of cognitive control in ASDs should use briefer tasks in an attempt to reduce the risk that findings are an artifact of a non-representative sample.
In summation, this study provides additional evidence of cognitive control deficits and the first evidence of fronto-parietal connectivity deficits in adolescents with ASDs. We also documented a relationship between reduced fronto-parietal connectivity and ADHD symptoms in individuals with ASDs. Future studies should examine the relationship between these deficits further in an attempt to shed light on issues related to co-morbidity, and the pathophysiology of neurodevelopmental disorders in general.