To our knowledge, this is the first fMRI study to explore the neural activation and connectivity associated with simple motor execution in children with autism. The results are remarkable for a relative dissociation of cerebral and cerebellar motor regions between children with HFA and their TD peers. While both groups displayed the expected predominant activations in cortical and subcortical regions critical to motor execution (e.g. contralateral pericentral gyrus and ipsilateral cerebellum), children in the TD group showed greater activation in the ipsilateral anterior cerebellum, as well as additional activation in the anterior lobe of the contralateral cerebellum (lobules IV/V) that was absent in the HFA group. The TD findings are consistent with prior imaging studies of basic finger movements in normal adults (Rijntjes et al
; Grodd et al
; Nitschke et al
; Thickbroom et al
; Habas et al
), including the finding of significant, though lesser, activation in the posterior lobule. In contrast, exploratory whole brain analyses revealed greater cerebral activation in the HFA group, located in the SMA proper, which is consistent with findings of increased premotor activation during cued finger sequencing in adults with autism (Muller et al
). This observed pattern of decreased cerebellar activation and increased premotor activation in the HFA group is both distinctive and robust, with interesting implications for further exploration.
There are several potential explanations for the observed cerebral/cerebellar dissociation. First, it is possible that the HFA group's increased frontal activation and failure to recruit cerebellar regions results directly from anatomical or functional abnormalities in those regions. Consistent with this, adults with ASD were found to show increased frontal activation compared with controls during executive tasks, with structural analyses revealing associated decreases in grey-matter density in those areas (Schmitz et al
). Moreover, cerebellar abnormalities are a common finding in post-mortem studies (Williams et al
; Ritvo et al
; Bailey et al
; Kemper and Bauman, 2002
), with several studies demonstrating direct associations between behavioural functioning and cerebellar integrity (Pierce and Courchesne, 2001
; Akshoomoff et al
; Kates et al
The lesser anterior cerebellar activation in our HFA group may also reflect those subjects’ relative inability to shift responsibility of continued motor execution from premotor regions associated with effortful movement to those associated with over-learned or habitual movement. Several studies in normal adults have demonstrated stage-dependent activation in various motor regions, leading to the suggestion that the cerebellum may be preferentially involved in automatic or ‘learned’ motor execution (Seitz et al
; Burnod and Duffose, 1991
; Doyon et al
; Shadmehr and Holcomb, 1997
; Krebs et al
; Muller et al
). In fact, for simple, repeated single digit tapping that requires much less in-scanner learning, adults with autism show the opposite pattern of fMRI activation with decreased premotor (Muller et al
) and increased ipsilateral cerebellar (Allen et al
Efficient neuro-functioning is predicated upon the automatization of learned or habitual outputs. From a developmental perspective, deficits in automatization and motor sequence learning might explain impairments in motor coordination commonly reported in autism (Jansiewicz et al
), as well as abnormal and delayed acquisition of motor gestures important for social communication (Gidley Larson and Mostofsky, 2006
Learning-dependent shifts in motor control depend on the integrity of connections between cortical and subcortical regions. Inefficient, or less organized, neural activation (Muller et al
; Turner et al
) has proven to be a relatively consistent finding in neuroimaging studies of adults with autism, with motor studies revealing greater variability, with scattered activation extending beyond sites typically dedicated to basic movement in both frontal regions and the cerebellum (Muller et al
; Turner et al
). As such, aberrant neural organization may be a broad neurofunctional or neuroanatomic characteristic of the disorder. This functional disorganization has been attributed to a ‘local overconnectivity’ and ‘long-distance underconnectivity’ of neural circuits in individuals with autism, leading to lesser integration of remote cortical areas (Minshew et al
; Herbert et al
; Happe and Frith, 2006
). Anatomic imaging studies reveal increased volume of outer ‘radiate’ white matter volumes comprising localized connections to be the primary contributor to overall brain volume increases in boys with autism (Herbert et al
) and recent findings revealed increased volume of primary motor cortex white matter to be a highly robust predictor of impaired motor function in children with HFA (Mostofsky et al
Consistent with this, we found that children with HFA show decreased functional connectivity across nearly the entire network of regions activated during both RHFS and LHFS. The failure of our HFA group to recruit cerebellar regions and their greater reliance instead on premotor cortical regions during finger sequencing, combined with the observed decreased functional connectivity within motor networks that include cerebellar and premotor regions, suggests that autism-associated deficits in motor execution may result from anomalous long-tract connections within the fronto–cerebello–thalamo–frontal network. Further, HFA-associated reductions in functional connectivity within this motor control network were more robust during finger sequencing than during rest, suggesting that decreased connectivity is particularly evident while the network is active (during motor execution). Indeed, it is worth noting that, as shown in , motor task performance often drives inter-regional correlations in autism below what they are during rest. This might suggest that, given the relative underconnectivity between these distant brain regions, with increasing task demand, it may be more efficient for children with autism to utilize these regions as independent processors, rather than to have them work in concert.
A limitation of the current study is the potential for the behavioural differences between groups to have driven the observed neural activation. While the pre-scanning motor exam suggested no difference in rate of finger apposition, the TD group did have a higher number of taps during imaging of RHFS and LHFS (significant only for LHFS). To address this, the data were reanalysed covarying for number of finger taps; the results did not change, suggesting that the fMRI findings could not be accounted for by differences in finger-sequencing speed.
Some of the children with HFA were taking psychoactive medications, and the potential impact of this cannot be discounted. Future investigations might benefit from exclusion of children taking medications, though this would have a detrimental impact on recruitment of numbers sufficient to examine group differences using BOLD fMRI. With sufficient numbers, comparisons of subjects with autism on/off medications could be applied to future studies.
One particular strength of this study is the use of a study-specific template to normalize the functional data into standardized space. Spatial normalization of paediatric brains to a standard adult template is problematic, since paediatric brains differ from adult brains in both regional and global size and composition (Casey et al
; Courchesne et al
). Additionally, the use of a standard template is especially problematic in disorders such as autism, which have been associated with differences in cerebral volume and composition (Courchesne et al
). As it has been shown that utilizing custom paediatric templates for normalization in paediatric populations improves the quality of normalization (Wilke et al
., 2002), our use of a customized study-specific template allowed us to minimize artefacts due to poor normalization.
Though the aetiology of autism is yet unknown, the pervasiveness of symptoms across modalities suggests that impairments are likely not limited to a single system and that neurological onset is likely quite early. As such, careful examination of the neurologic underpinnings of motor dysfunction in autism may provide insight into mechanisms within parallel systems important for cognitive and behavioural control (Gidley Larson and Mostofsky, 2006
). Further, as one of the earliest identifiable traits, motor impairment may serve a principal role in the behavioural phenotype of the disorder, with broad downstream effects across other domains; i.e. early deficits in basic motor abilities may impede the development of compound motor skills and social gestures, contributing to the defining behavioural features of the disorder. Receptive language far outpaces expressive language in many children with autism (Gernsbacher et al
) and motor dysfunction might also contribute to delays in productive speech. Indeed, neural systems important for procedural acquisition of motor skills appear to also be critical for language and social development. It follows that abnormalities in these systems may contribute not only to impaired motor skill acquisition in children with autism, but also to impaired communicative and social development (Mostofsky et al
; Walenski et al
). As evidence, recent findings reveal the clearest predictor of optimal outcome in toddlers diagnosed with an autism spectrum disorder is motor skills at age 2 years (Sutera et al
). As such, continued investigation of the neural mechanisms underlying motor development in children with autism is critical to our ongoing understanding of the disorder, as well as the design of effective early interventions. The current study reflects the initial attempts to do so, beginning with a targeted exploration of a simple form of motor execution.