Journal of Clinical Neuroscience 22 (2015) 664–669
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Increased premotor cortex activation in high functioning autism during action observation Tom J. Perkins a, Richard G. Bittar a,b,c,⇑, Jane A. McGillivray a, Ivanna I. Cox a, Mark A. Stokes a a
Department of Psychology, Faculty of Health, Deakin University, Burwood, VIC, Australia Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia c Precision Brain Spine and Pain Centre, Melbourne, VIC, Australia b
a r t i c l e
i n f o
Article history: Received 22 June 2014 Accepted 1 October 2014
Keywords: Action observation Autism spectrum disorders fMRI Mirror neurons Premotor cortex
a b s t r a c t The mirror neuron (MN) hypothesis of autism has received considerable attention, but to date has produced inconsistent findings. Using functional MRI, participants with high functioning autism or Asperger’s syndrome were compared to typically developing individuals (n = 12 in each group). Participants passively observed hand gestures that included waving, pointing, and grasping. Concerning the MN network, both groups activated similar regions including prefrontal, inferior parietal and superior temporal regions, with the autism group demonstrating significantly greater activation in the dorsal premotor cortex. Concerning other regions, participants with autism demonstrated increased activity in the anterior cingulate and medial frontal gyrus, and reduced activation in calcarine, cuneus, and middle temporal gyrus. These results suggest that during observation of hand gestures, frontal cortex activation is affected in autism, which we suggest may be linked to abnormal functioning of the MN system. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Autism spectrum disorders (ASD) are pervasive, neurodevelopmental conditions, with a prevalence of approximately 1–2% of the population [1,2]. According to the Diagnostic and Statistical Manual V (DSM V) [3], ASD is characterized by anomalies in two key domains: social communication, and repetitive and/or stereotyped patterns of behaviour. At present, the phenotype is broad and illdefined where diagnosis is made on the basis of behavioural presentation. In 1999, two research groups independently suggested that a network of visuomotor cells, mirror neurons (MN), might be a potential biomarker to ASD [4,5]. MN can be distinguished from other motor neurons by discharging both when an individual performs an action (such as reaching for food), and when an individual watches another performing a similar action (such as a friend reaching for some food) [6]. Research using techniques such as functional MRI (fMRI) [7,8], transcranial magnetic stimulation [9] and electroencephalography (EEG) [10] provide indirect evidence that MN constitute a fronto-parieto network in humans. These regions are the premotor cortex (PMC), the pars opercularis of the inferior frontal gyrus, the inferior parietal lobule and the ⇑ Corresponding author. Address: Lower Ground, 115 Cotham Road, Kew, VIC 3101, Australia. Tel.: +61 3 8862 0000. E-mail address: [email protected] (R.G. Bittar). http://dx.doi.org/10.1016/j.jocn.2014.10.007 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
superior temporal sulcus [11–13]. More recent depth electrode research on humans suggests neurons with mirror properties are located in supplementary motor areas and medial temporal areas, in addition to non-significant quantities in the anterior cingulate cortex (ACC) [14]. It has been theorized that MN may be a neural substrate to simulation-based theories of how we understand the actions of other people [15]. This theoretical link has prompted research into the potential role of MN in ASD. To date, EEG research has revealed evidence of both typical [16,17] and atypical [4,18–20] MN response in ASD. Regarding fMRI research, findings have been mixed. During observation of emotional stimuli, there is evidence of reduced [21–23] blood oxygen level dependent (BOLD) response in regions believed to possess MN in ASD compared to typically developing (TD) individuals. In contrast, paradigms requiring observation of non-emotional hand based actions have revealed both increased [24,25] and equivalent [26,27] BOLD responses in mirror regions of ASD compared to TD participants. These studies on hand actions have varied considerably in what stimuli are used as a baseline condition, including a non-moving hand [25], a blank screen [26] and geometric patterns [27], which is likely to contribute to the mixed findings. Using fMRI, the present study will compare BOLD response of participants with high functioning autism and Asperger’s syndrome (HFA/AS) to TD individuals. Videos of goal directed hand actions will be contrasted with still images of a non-moving hand,
T.J. Perkins et al. / Journal of Clinical Neuroscience 22 (2015) 664–669
making the paradigm comparable to previous research which reported a heightened BOLD response in MN regions in ASD [24,25]. Based upon this limited literature, two hypotheses were generated. Firstly, that both groups would demonstrate significantly increased BOLD response in MN regions during observation of hand actions as compared to baseline. Secondly, when contrasting the groups, the HFA/AS group will demonstrate increased BOLD in frontal, parietal and temporal MN areas as compared to TD participants.
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2. Method
waving, and (d) hand–directive actions such as pointing. Participants viewed the videos through a mirror in the scanner, whilst lying supine with their head placed in the coil. The experiment was conducted with a block design, which alternated between experimental and control conditions. Each of the four video tasks was 6 minutes in length, and alternated between 30 second blocks of experimental task and control condition. The control video for all tasks was a picture of a motionless hand, with the exception of the hand–mouth task, which was a picture of an expressionless face [7,8,25]. In each trial, the participant observed six experimental blocks and six control blocks.
2.1. Participants
2.3. fMRI acquisition and pre-processing
The present study compared 12 TD participants (mean age = 19.75 years) with 12 individuals who had a previous diagnosis of either autistic disorder or AS (mean age = 18.50 years). Participants with HFA/AS were recruited from various autism support organizations (such as Autism Victoria) and specialist schools (such as Western Autism). In this study, all participants were male, and the age range was from 16–30 years. An experienced clinical psychologist who has worked extensively in the autism field confirmed diagnosis according to DSM IV criteria, as data collection pre-dated the DSM V. More detailed characteristics of this cohort are outlined in a previous manuscript [28].
All MRI were conducted using a 3 Tesla Siemens Tim Trio scanner (Erlangen, Germany) with a birdcage quadrature head-coil. Whole-brain BOLD weighted fMRI images were acquired using a gradient-recalled echo-planar imagine sequence (repetition time = 3.0 s; echo time = 40 ms; slice thickness = 3 mm; slice spacing = 3 mm; flip angle = 60°; field of view = 24 24 cm; 128 128 matrix). All Digital Imaging and Communications in Medicine (DICOM) fMRI were pre-processed using SPM8 (Institute of Neurology, University College, London) and MATLAB (The MathWorks, Natick, MA, USA). For each participant, several preprocessing steps were conducted. This included temporal alignment of slices within each volume to the first slice, rigid-body spatial realignment to correct for motion, spatial normalisation into standard space, re-sampling images into isotropic voxels (2 2 2 mm3), and spatial smoothing with a Gaussian kernel (full width at half maximum = 8 mm). All images were normalized to the standard Montreal Neurological Institute template image of 152 brains.
2.2. Stimuli presentation In this study, four video tasks were recorded for action observation. The tasks were filmed with an 8.9 megapixel Sony camcorder (Nagasaki, Japan), and then edited into 30 seconds blocks using Adobe Premiere (Adobe Systems Incorporated, San Jose, CA, USA). All hand actions were filmed in front of a plain, white background with both male and female models (Fig. 1). The four video tasks involved (a) hand–object manipulations such as grasping a cup, (b) hand–mouth interactions such as bringing a piece of food to the mouth and chewing, (c) hand–communicative actions such as
2.4. fMRI analysis This study implemented a block design analysis in accordance with the general linear model. For each individual, statistical
Fig. 1. The four different hand actions participants observed in the functional MRI as demonstrated by the author T.J.P. (A) Hand–object, (B) hand–mouth, (C) hand–directive, and (D) hand–communicative.
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parametric maps were generated for the following comparisons: hand–object versus baseline; hand–mouth versus baseline; hand– communicative versus baseline; and hand–directive versus baseline. The resultant statistical maps were then pooled together for within groups analysis. Single sample Student’s t-tests were used to examine increases in BOLD between action observation and baseline for TD and HFA/AS groups. Two sample t-tests were then undertaken to contrast differences in BOLD signal between the groups. Localization of both hypothesized and non-hypothesized cortical regions of interest (ROI) was conducted with xjView (http://www. alivelearn.net/xjview8/), a visualization program developed for statistical parametric mapping that represents cortical areas in Montreal Neurological Institute space. xjView utilizes the Wake Forest University PickAtlas database to generate a ROI mask. Several past studies have used xjView to localize ROI [29,30]. The hypothesized ROI for this study were pars opercularis (Brodmann area [BA] 44), the anterior part of the inferior parietal lobule (BA40), the PMC (BA6) and superior temporal sulcus (roughly corresponding to BA22). For all analyses, contrasts were performed on the whole brain using standard threshold criteria [31] with a voxel threshold for statistical significance of p < 0.001. For hypothesized ROI, small volume corrections with a radius of 10 mm were conducted as per previous MN research [32]. Using the aforementioned atlas as a guide, the location of small volume corrections was centered in each ROI, and was the same for within and between group analyses. Following small volume corrections, hypothesized regions were evaluated using cluster-wise significance (p < 0.05, familywise error corrected). For reporting of other significant regions of activation, whole brain cluster level significance with a threshold of p < 0.05 family-wise error corrected was implemented to control for false positives [33].
3. Results 3.1. Within group analysis For both groups a significant signal increase was observed in all hypothesized MN regions, comprised of pre-frontal (pars opercularis, PMC), parietal (supramarginal gyrus) and temporal (superior temporal sulcus) regions. During the hand observation task, several other voxel clusters demonstrated a similar pattern of activation in both groups, corresponding to visual (middle occipital gyrus) and frontal (inferior and middle frontal gyrus) regions. Participants with HFA/AS demonstrated additional significant clusters in temporal (inferior and middle temporal gyrus) parietal (inferior), frontal (operculum), and cerebellar (posterior) areas. In contrast, TD participants demonstrated additional peaks in medial temporal regions (parahippocampus and hippocampus), basal ganglia (putamen, lentiform nucleus) and midline structures (thalamus).
3.2. Between groups analysis Regarding MN regions, one hypothesized difference was identified. The HFA/AS group demonstrated significantly greater BOLD signal in a small cluster corresponding to the right PMC (BA6), bordering the precentral gyrus. Among TD participants, no hypothesized regions were more active compared to participants with HFA/AS (Table 1). TD participants also demonstrated significantly increased clusters in right hemisphere visual (cuneus and calcarine gyrus) and temporal (middle temporal gyrus) regions, whilst HFA/ AS participants demonstrated increased BOLD in two right hemisphere frontal regions (rostral ACC and medial frontal gyrus). These significant group differences are depicted in Figure 2.
4. Discussion Using fMRI, the present study contrasted BOLD response of participants with HFA/AS to TD participants whilst observing hand actions. The first hypothesis that both groups would demonstrate a significant BOLD increase in MN regions during action observation compared to baseline was supported. Within group analyses demonstrated signal increases in frontal (BA6, BA44), parietal (BA40) and temporal (BA22) MN regions bilaterally in both groups. Activation in these brain regions whilst observing hand-based gestures supports a number of past neuroimaging studies [7,8]. The second hypothesis that HFA/AS participants would demonstrate increased activation in MN areas was partially supported, with this group demonstrating significantly increased activation in the right PMC compared to TD participants. Although difficult to quantify precisely, this cluster appeared to form part of the dorsal PMC, as this region is estimated to begin at coordinate z = 51 [34], with overlap between z = 30–46 [35]. In the present study, the PMC cluster which demonstrated increased BOLD in the HFA/ AS group had a local maxima at z = 56 (Table 1), making it clearly dorsal by this criteria [34]. The dorsal PMC is considered part of the extended MN system [36], but has been shown to possess MN in single cell research on rhesus monkeys [37,38], and to be active during observation of hand gestures in humans [8]. To our knowledge, only one previous functional imaging study has identified premotor abnormalities in participants with autism [24]. However, previous EEG research provides evidence of atypical premotor activity in individuals with an ASD during observation of hand actions [4,18–20]. These EEG studies found that among those with autism, premotor and parietal MN did not inhibit the mu rhythm when observing hand actions to the same extent as TD participants. It has recently been reported that mu suppression co-varies with BOLD activation in the dorsal PMC [39], which further strengthens the possibility this may be an important area of dysfunction in the mirror network amongst those with an ASD. Although these methods do not quantify what cortical processes may be dysfunctional, it may be linked to abnormal inhibitory processes, as reduced gamma-aminobutyric acid A has been reported in motor regions of ASD populations using transcranial magnetic stimulation [40] and post mortem methods [41,42]. Although a number of studies utilizing hand-based paradigms have reported no difference in activation of MN regions between TD and ASD participants [26,27], a number of methodological differences may contribute to the discrepant findings. Firstly, these two studies used a blank screen [26] and non-biological movement [27] as control conditions, as compared to a static hand and face in the present study. Although it is unclear what contrast is most appropriate for measuring MN regions, this factor is likely to influence the pattern of activation observed. Secondly, the participants in one of these studies [27] had a mean age of 33, considerably older than in the present study. It has recently been reported that changes in BOLD of the inferior frontal gyrus [43] and mu suppression [44] change with increasing age in participants with autism. Finally, these studies utilized a different type of analysis known as stimulus induced suppression. Although more research is necessary to quantify what analyses are most appropriate for investigating MN regions, encouragingly, past research that has used the same contrast of conditions and equivalent analyses have produced similar findings to those herein [24,25]. Nevertheless, the means by which MN regions were measured in the present study is limited. It has previously been recommended that a region should only be considered putatively mirror-related if it demonstrates activation during both observation and execution [45]. In the present study, only action observation was tested, meaning the analyses in this study were less sensitive to
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Table 1 Summary of regions that were significantly different between high functioning autism/Asperger’s syndrome and typically developing groups. For both groups, mirror neurons and other significant regions that were different between the groups are reported Brain region
Side
Number of voxels
MNI coordinates x
Mirror neuron regions Pars opercularis Premotor cortex (BA6)/Precentral gyrus Inferior parietal lobule (BA40) Superior temporal sulcus Other significant regions Calcarine Cuneus/BA18 Middle temporal gyrus/Calcarine Medial frontal gyrus Anterior cingulate (BA24)
R or L R L R or L R or L R R R R R
z score
y
z
34
34
10
296 296 296 641 641
24 18 34 12 12
58 74 60 38 26
56
10 12 10 12 4
NSV 3.96* NSV NSV NSV 4.07* 3.87* 3.57* ⁄⁄⁄ 4.23 ⁄⁄⁄ 4.09
Negative z scores indicate greater activity in the high functioning autism/Asperger’s syndrome than the typically developing group, while positive z scores indicate the reverse. * p < 0.05. ** p < 0.01. ⁄⁄⁄ p < 0.001. BA = Brodmann area, L = left, NSV = no significant voxels, R = right, x = mediolateral coordinate in the Montreal Neurological Institute average brain, y = anteroposterior coordinate in the Montreal Neurological Institute average brain, z = dorsoventral coordinate in the Montreal Neurological Institute average brain, z score = peak z score in cluster.
Fig. 2. (Left to right) Axial, sagittal and coronal functional MRI depiction of regions to demonstrate significantly greater BOLD signal in the HFA/AS group (red), and TD group (blue). Significant clusters are circled in yellow. The HFA/AS group demonstrated significantly greater BOLD in premotor cortex, anterior cingulate cortex, and medial frontal gyrus, whilst the TD group demonstrated significantly greater BOLD in calcarine, cuneus, and middle temporal gyrus. BOLD = blood oxygen level dependent, HFA/AS = high functioning autism/Asperger’s syndrome, TD = typically developing.
the matching mechanism that characterizes MN. However, given that the ROI examined in this study were specified a priori, and based upon past MN research [7,8], it is argued that the observed changes in BOLD at least overlap with MN areas. However, future research utilizing more discerning fMRI measures such as pattern classification [46] will help refine knowledge of (a) the distribution of MN in humans, and (b) their role in ASD. The present study also found that participants with HFA/AS demonstrated increased activity in the rostral ACC and medial
frontal gyrus. Although these regions are typically considered to have a role in executive function [47,48], a recent single cell study in humans with intractable epilepsy revealed MN in the ACC, albeit in non-significant quantities [14]. Moreover, it has been reported the ACC responds to both the experience and observation of pain [49]. A recent meta-analysis of 15 fMRI studies revealed that the rostral ACC is the most common region to demonstrate increased BOLD in ASD during non-social tasks [50], making its functional significance an important focus for future autism research.
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Conversely, TD individuals demonstrated increased BOLD in occipital (calcarine, cuneus) and temporal (middle temporal gyrus) regions compared to those with HFA/AS, which may reflect a difference in visually based processing of hand movements. Surprisingly, there are few studies that have investigated the functional organization of the visual system in individuals with an ASD. There is a small body of evidence that those with autism are less sensitive to visual motion [51–53]. A number of general limitations to this research must be noted. Firstly, combining the four conditions together has the potential to confound the comparisons, and produce low frequency drift in the scanner signal. Although studies have suggested that motion and physiological noises are not responsible for low frequency drift [54], modelling a covariate of no interest may have removed doubt on this potential bias. Secondly, although commonly used, spherical small volume corrections can be crude given the hypothesized ROI do not demonstrate a spherical spatial distribution in the brain. Finally, long echo times can cause signal loss to inferior frontal regions [55]. As this was an area of interest in the present study, an echo time duration of 40 ms may have potentially masked differences in BOLD signal between the groups to this part of the brain. In summary, the present study identified that individuals with HFA/AS possessed increased BOLD in PMC, ACC and medial frontal gyrus during action observation. This contributes to the scarce research that has looked specifically at hand actions, and identified increased activity in frontal MN regions [24,25]. TD participants demonstrated increased BOLD in occipital and temporal regions, which may suggest a difference between the two groups in processing of biological motion [51]. As this field presents with diverse methodologies and data analyses, further work is needed to refine what conditions are most appropriate to measure MN regions, and to clarify the inconsistent findings during observation of hand actions. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgments The authors would like to thank all participants in this study and the MRI radiographers at the Brain Research Institute. The authors would also like to acknowledge the assistance of Danny Flanagan throughout this research, and Shawna Farquarson whose patience and technical expertise was greatly appreciated. References [1] Blumberg S, Bramlett M, Kogan M, et al. Changes in prevalence of parentreported autism spectrum disorder in school-aged US children: 2007 to 2011– 2012. Nat Health Stat Rep 2013;65:1–7. [2] Nygren G, Cederlund M, Sandberg E, et al. The prevalence of autism spectrum disorders in toddlers: a population study of 2-year-old Swedish children. J Autism Dev Disord 2012;42:1491–7. [3] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013. [4] Oberman LM, Hubbard EM, McCleery JP, et al. EEG evidence for mirror neuron dysfunction in autism spectrum disorders. Brain Res Cogn Brain Res 2005;24:190–8. [5] Williams JH, Whiten A, Suddendorf T, et al. Imitation, mirror neurons and autism. Neurosci Biobehav Rev 2001;25:287–95. [6] Rizzolatti G, Craighero L. The mirror-neuron system. Annu Rev Neurosci 2004;27:169–92. [7] Binkofski F, Buccino G. The role of ventral premotor cortex in action execution and action understanding. J Physiol Paris 2006;99:396–405. [8] Buccino G, Lui F, Canessa N, et al. Neural circuits involved in the recognition of actions performed by nonconspecifics: an FMRI study. J Cogn Neurosci 2004;16:114–26.
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Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Increased premotor cortex activation in high functioning autism during action observation Tom J. Perkins a, Richard G. Bittar a,b,c,⇑, Jane A. McGillivray a, Ivanna I. Cox a, Mark A. Stokes a a
Department of Psychology, Faculty of Health, Deakin University, Burwood, VIC, Australia Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC, Australia c Precision Brain Spine and Pain Centre, Melbourne, VIC, Australia b
a r t i c l e
i n f o
Article history: Received 22 June 2014 Accepted 1 October 2014
Keywords: Action observation Autism spectrum disorders fMRI Mirror neurons Premotor cortex
a b s t r a c t The mirror neuron (MN) hypothesis of autism has received considerable attention, but to date has produced inconsistent findings. Using functional MRI, participants with high functioning autism or Asperger’s syndrome were compared to typically developing individuals (n = 12 in each group). Participants passively observed hand gestures that included waving, pointing, and grasping. Concerning the MN network, both groups activated similar regions including prefrontal, inferior parietal and superior temporal regions, with the autism group demonstrating significantly greater activation in the dorsal premotor cortex. Concerning other regions, participants with autism demonstrated increased activity in the anterior cingulate and medial frontal gyrus, and reduced activation in calcarine, cuneus, and middle temporal gyrus. These results suggest that during observation of hand gestures, frontal cortex activation is affected in autism, which we suggest may be linked to abnormal functioning of the MN system. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Autism spectrum disorders (ASD) are pervasive, neurodevelopmental conditions, with a prevalence of approximately 1–2% of the population [1,2]. According to the Diagnostic and Statistical Manual V (DSM V) [3], ASD is characterized by anomalies in two key domains: social communication, and repetitive and/or stereotyped patterns of behaviour. At present, the phenotype is broad and illdefined where diagnosis is made on the basis of behavioural presentation. In 1999, two research groups independently suggested that a network of visuomotor cells, mirror neurons (MN), might be a potential biomarker to ASD [4,5]. MN can be distinguished from other motor neurons by discharging both when an individual performs an action (such as reaching for food), and when an individual watches another performing a similar action (such as a friend reaching for some food) [6]. Research using techniques such as functional MRI (fMRI) [7,8], transcranial magnetic stimulation [9] and electroencephalography (EEG) [10] provide indirect evidence that MN constitute a fronto-parieto network in humans. These regions are the premotor cortex (PMC), the pars opercularis of the inferior frontal gyrus, the inferior parietal lobule and the ⇑ Corresponding author. Address: Lower Ground, 115 Cotham Road, Kew, VIC 3101, Australia. Tel.: +61 3 8862 0000. E-mail address: [email protected] (R.G. Bittar). http://dx.doi.org/10.1016/j.jocn.2014.10.007 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
superior temporal sulcus [11–13]. More recent depth electrode research on humans suggests neurons with mirror properties are located in supplementary motor areas and medial temporal areas, in addition to non-significant quantities in the anterior cingulate cortex (ACC) [14]. It has been theorized that MN may be a neural substrate to simulation-based theories of how we understand the actions of other people [15]. This theoretical link has prompted research into the potential role of MN in ASD. To date, EEG research has revealed evidence of both typical [16,17] and atypical [4,18–20] MN response in ASD. Regarding fMRI research, findings have been mixed. During observation of emotional stimuli, there is evidence of reduced [21–23] blood oxygen level dependent (BOLD) response in regions believed to possess MN in ASD compared to typically developing (TD) individuals. In contrast, paradigms requiring observation of non-emotional hand based actions have revealed both increased [24,25] and equivalent [26,27] BOLD responses in mirror regions of ASD compared to TD participants. These studies on hand actions have varied considerably in what stimuli are used as a baseline condition, including a non-moving hand [25], a blank screen [26] and geometric patterns [27], which is likely to contribute to the mixed findings. Using fMRI, the present study will compare BOLD response of participants with high functioning autism and Asperger’s syndrome (HFA/AS) to TD individuals. Videos of goal directed hand actions will be contrasted with still images of a non-moving hand,
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making the paradigm comparable to previous research which reported a heightened BOLD response in MN regions in ASD [24,25]. Based upon this limited literature, two hypotheses were generated. Firstly, that both groups would demonstrate significantly increased BOLD response in MN regions during observation of hand actions as compared to baseline. Secondly, when contrasting the groups, the HFA/AS group will demonstrate increased BOLD in frontal, parietal and temporal MN areas as compared to TD participants.
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2. Method
waving, and (d) hand–directive actions such as pointing. Participants viewed the videos through a mirror in the scanner, whilst lying supine with their head placed in the coil. The experiment was conducted with a block design, which alternated between experimental and control conditions. Each of the four video tasks was 6 minutes in length, and alternated between 30 second blocks of experimental task and control condition. The control video for all tasks was a picture of a motionless hand, with the exception of the hand–mouth task, which was a picture of an expressionless face [7,8,25]. In each trial, the participant observed six experimental blocks and six control blocks.
2.1. Participants
2.3. fMRI acquisition and pre-processing
The present study compared 12 TD participants (mean age = 19.75 years) with 12 individuals who had a previous diagnosis of either autistic disorder or AS (mean age = 18.50 years). Participants with HFA/AS were recruited from various autism support organizations (such as Autism Victoria) and specialist schools (such as Western Autism). In this study, all participants were male, and the age range was from 16–30 years. An experienced clinical psychologist who has worked extensively in the autism field confirmed diagnosis according to DSM IV criteria, as data collection pre-dated the DSM V. More detailed characteristics of this cohort are outlined in a previous manuscript [28].
All MRI were conducted using a 3 Tesla Siemens Tim Trio scanner (Erlangen, Germany) with a birdcage quadrature head-coil. Whole-brain BOLD weighted fMRI images were acquired using a gradient-recalled echo-planar imagine sequence (repetition time = 3.0 s; echo time = 40 ms; slice thickness = 3 mm; slice spacing = 3 mm; flip angle = 60°; field of view = 24 24 cm; 128 128 matrix). All Digital Imaging and Communications in Medicine (DICOM) fMRI were pre-processed using SPM8 (Institute of Neurology, University College, London) and MATLAB (The MathWorks, Natick, MA, USA). For each participant, several preprocessing steps were conducted. This included temporal alignment of slices within each volume to the first slice, rigid-body spatial realignment to correct for motion, spatial normalisation into standard space, re-sampling images into isotropic voxels (2 2 2 mm3), and spatial smoothing with a Gaussian kernel (full width at half maximum = 8 mm). All images were normalized to the standard Montreal Neurological Institute template image of 152 brains.
2.2. Stimuli presentation In this study, four video tasks were recorded for action observation. The tasks were filmed with an 8.9 megapixel Sony camcorder (Nagasaki, Japan), and then edited into 30 seconds blocks using Adobe Premiere (Adobe Systems Incorporated, San Jose, CA, USA). All hand actions were filmed in front of a plain, white background with both male and female models (Fig. 1). The four video tasks involved (a) hand–object manipulations such as grasping a cup, (b) hand–mouth interactions such as bringing a piece of food to the mouth and chewing, (c) hand–communicative actions such as
2.4. fMRI analysis This study implemented a block design analysis in accordance with the general linear model. For each individual, statistical
Fig. 1. The four different hand actions participants observed in the functional MRI as demonstrated by the author T.J.P. (A) Hand–object, (B) hand–mouth, (C) hand–directive, and (D) hand–communicative.
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parametric maps were generated for the following comparisons: hand–object versus baseline; hand–mouth versus baseline; hand– communicative versus baseline; and hand–directive versus baseline. The resultant statistical maps were then pooled together for within groups analysis. Single sample Student’s t-tests were used to examine increases in BOLD between action observation and baseline for TD and HFA/AS groups. Two sample t-tests were then undertaken to contrast differences in BOLD signal between the groups. Localization of both hypothesized and non-hypothesized cortical regions of interest (ROI) was conducted with xjView (http://www. alivelearn.net/xjview8/), a visualization program developed for statistical parametric mapping that represents cortical areas in Montreal Neurological Institute space. xjView utilizes the Wake Forest University PickAtlas database to generate a ROI mask. Several past studies have used xjView to localize ROI [29,30]. The hypothesized ROI for this study were pars opercularis (Brodmann area [BA] 44), the anterior part of the inferior parietal lobule (BA40), the PMC (BA6) and superior temporal sulcus (roughly corresponding to BA22). For all analyses, contrasts were performed on the whole brain using standard threshold criteria [31] with a voxel threshold for statistical significance of p < 0.001. For hypothesized ROI, small volume corrections with a radius of 10 mm were conducted as per previous MN research [32]. Using the aforementioned atlas as a guide, the location of small volume corrections was centered in each ROI, and was the same for within and between group analyses. Following small volume corrections, hypothesized regions were evaluated using cluster-wise significance (p < 0.05, familywise error corrected). For reporting of other significant regions of activation, whole brain cluster level significance with a threshold of p < 0.05 family-wise error corrected was implemented to control for false positives [33].
3. Results 3.1. Within group analysis For both groups a significant signal increase was observed in all hypothesized MN regions, comprised of pre-frontal (pars opercularis, PMC), parietal (supramarginal gyrus) and temporal (superior temporal sulcus) regions. During the hand observation task, several other voxel clusters demonstrated a similar pattern of activation in both groups, corresponding to visual (middle occipital gyrus) and frontal (inferior and middle frontal gyrus) regions. Participants with HFA/AS demonstrated additional significant clusters in temporal (inferior and middle temporal gyrus) parietal (inferior), frontal (operculum), and cerebellar (posterior) areas. In contrast, TD participants demonstrated additional peaks in medial temporal regions (parahippocampus and hippocampus), basal ganglia (putamen, lentiform nucleus) and midline structures (thalamus).
3.2. Between groups analysis Regarding MN regions, one hypothesized difference was identified. The HFA/AS group demonstrated significantly greater BOLD signal in a small cluster corresponding to the right PMC (BA6), bordering the precentral gyrus. Among TD participants, no hypothesized regions were more active compared to participants with HFA/AS (Table 1). TD participants also demonstrated significantly increased clusters in right hemisphere visual (cuneus and calcarine gyrus) and temporal (middle temporal gyrus) regions, whilst HFA/ AS participants demonstrated increased BOLD in two right hemisphere frontal regions (rostral ACC and medial frontal gyrus). These significant group differences are depicted in Figure 2.
4. Discussion Using fMRI, the present study contrasted BOLD response of participants with HFA/AS to TD participants whilst observing hand actions. The first hypothesis that both groups would demonstrate a significant BOLD increase in MN regions during action observation compared to baseline was supported. Within group analyses demonstrated signal increases in frontal (BA6, BA44), parietal (BA40) and temporal (BA22) MN regions bilaterally in both groups. Activation in these brain regions whilst observing hand-based gestures supports a number of past neuroimaging studies [7,8]. The second hypothesis that HFA/AS participants would demonstrate increased activation in MN areas was partially supported, with this group demonstrating significantly increased activation in the right PMC compared to TD participants. Although difficult to quantify precisely, this cluster appeared to form part of the dorsal PMC, as this region is estimated to begin at coordinate z = 51 [34], with overlap between z = 30–46 [35]. In the present study, the PMC cluster which demonstrated increased BOLD in the HFA/ AS group had a local maxima at z = 56 (Table 1), making it clearly dorsal by this criteria [34]. The dorsal PMC is considered part of the extended MN system [36], but has been shown to possess MN in single cell research on rhesus monkeys [37,38], and to be active during observation of hand gestures in humans [8]. To our knowledge, only one previous functional imaging study has identified premotor abnormalities in participants with autism [24]. However, previous EEG research provides evidence of atypical premotor activity in individuals with an ASD during observation of hand actions [4,18–20]. These EEG studies found that among those with autism, premotor and parietal MN did not inhibit the mu rhythm when observing hand actions to the same extent as TD participants. It has recently been reported that mu suppression co-varies with BOLD activation in the dorsal PMC [39], which further strengthens the possibility this may be an important area of dysfunction in the mirror network amongst those with an ASD. Although these methods do not quantify what cortical processes may be dysfunctional, it may be linked to abnormal inhibitory processes, as reduced gamma-aminobutyric acid A has been reported in motor regions of ASD populations using transcranial magnetic stimulation [40] and post mortem methods [41,42]. Although a number of studies utilizing hand-based paradigms have reported no difference in activation of MN regions between TD and ASD participants [26,27], a number of methodological differences may contribute to the discrepant findings. Firstly, these two studies used a blank screen [26] and non-biological movement [27] as control conditions, as compared to a static hand and face in the present study. Although it is unclear what contrast is most appropriate for measuring MN regions, this factor is likely to influence the pattern of activation observed. Secondly, the participants in one of these studies [27] had a mean age of 33, considerably older than in the present study. It has recently been reported that changes in BOLD of the inferior frontal gyrus [43] and mu suppression [44] change with increasing age in participants with autism. Finally, these studies utilized a different type of analysis known as stimulus induced suppression. Although more research is necessary to quantify what analyses are most appropriate for investigating MN regions, encouragingly, past research that has used the same contrast of conditions and equivalent analyses have produced similar findings to those herein [24,25]. Nevertheless, the means by which MN regions were measured in the present study is limited. It has previously been recommended that a region should only be considered putatively mirror-related if it demonstrates activation during both observation and execution [45]. In the present study, only action observation was tested, meaning the analyses in this study were less sensitive to
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Table 1 Summary of regions that were significantly different between high functioning autism/Asperger’s syndrome and typically developing groups. For both groups, mirror neurons and other significant regions that were different between the groups are reported Brain region
Side
Number of voxels
MNI coordinates x
Mirror neuron regions Pars opercularis Premotor cortex (BA6)/Precentral gyrus Inferior parietal lobule (BA40) Superior temporal sulcus Other significant regions Calcarine Cuneus/BA18 Middle temporal gyrus/Calcarine Medial frontal gyrus Anterior cingulate (BA24)
R or L R L R or L R or L R R R R R
z score
y
z
34
34
10
296 296 296 641 641
24 18 34 12 12
58 74 60 38 26
56
10 12 10 12 4
NSV 3.96* NSV NSV NSV 4.07* 3.87* 3.57* ⁄⁄⁄ 4.23 ⁄⁄⁄ 4.09
Negative z scores indicate greater activity in the high functioning autism/Asperger’s syndrome than the typically developing group, while positive z scores indicate the reverse. * p < 0.05. ** p < 0.01. ⁄⁄⁄ p < 0.001. BA = Brodmann area, L = left, NSV = no significant voxels, R = right, x = mediolateral coordinate in the Montreal Neurological Institute average brain, y = anteroposterior coordinate in the Montreal Neurological Institute average brain, z = dorsoventral coordinate in the Montreal Neurological Institute average brain, z score = peak z score in cluster.
Fig. 2. (Left to right) Axial, sagittal and coronal functional MRI depiction of regions to demonstrate significantly greater BOLD signal in the HFA/AS group (red), and TD group (blue). Significant clusters are circled in yellow. The HFA/AS group demonstrated significantly greater BOLD in premotor cortex, anterior cingulate cortex, and medial frontal gyrus, whilst the TD group demonstrated significantly greater BOLD in calcarine, cuneus, and middle temporal gyrus. BOLD = blood oxygen level dependent, HFA/AS = high functioning autism/Asperger’s syndrome, TD = typically developing.
the matching mechanism that characterizes MN. However, given that the ROI examined in this study were specified a priori, and based upon past MN research [7,8], it is argued that the observed changes in BOLD at least overlap with MN areas. However, future research utilizing more discerning fMRI measures such as pattern classification [46] will help refine knowledge of (a) the distribution of MN in humans, and (b) their role in ASD. The present study also found that participants with HFA/AS demonstrated increased activity in the rostral ACC and medial
frontal gyrus. Although these regions are typically considered to have a role in executive function [47,48], a recent single cell study in humans with intractable epilepsy revealed MN in the ACC, albeit in non-significant quantities [14]. Moreover, it has been reported the ACC responds to both the experience and observation of pain [49]. A recent meta-analysis of 15 fMRI studies revealed that the rostral ACC is the most common region to demonstrate increased BOLD in ASD during non-social tasks [50], making its functional significance an important focus for future autism research.
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Conversely, TD individuals demonstrated increased BOLD in occipital (calcarine, cuneus) and temporal (middle temporal gyrus) regions compared to those with HFA/AS, which may reflect a difference in visually based processing of hand movements. Surprisingly, there are few studies that have investigated the functional organization of the visual system in individuals with an ASD. There is a small body of evidence that those with autism are less sensitive to visual motion [51–53]. A number of general limitations to this research must be noted. Firstly, combining the four conditions together has the potential to confound the comparisons, and produce low frequency drift in the scanner signal. Although studies have suggested that motion and physiological noises are not responsible for low frequency drift [54], modelling a covariate of no interest may have removed doubt on this potential bias. Secondly, although commonly used, spherical small volume corrections can be crude given the hypothesized ROI do not demonstrate a spherical spatial distribution in the brain. Finally, long echo times can cause signal loss to inferior frontal regions [55]. As this was an area of interest in the present study, an echo time duration of 40 ms may have potentially masked differences in BOLD signal between the groups to this part of the brain. In summary, the present study identified that individuals with HFA/AS possessed increased BOLD in PMC, ACC and medial frontal gyrus during action observation. This contributes to the scarce research that has looked specifically at hand actions, and identified increased activity in frontal MN regions [24,25]. TD participants demonstrated increased BOLD in occipital and temporal regions, which may suggest a difference between the two groups in processing of biological motion [51]. As this field presents with diverse methodologies and data analyses, further work is needed to refine what conditions are most appropriate to measure MN regions, and to clarify the inconsistent findings during observation of hand actions. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgments The authors would like to thank all participants in this study and the MRI radiographers at the Brain Research Institute. The authors would also like to acknowledge the assistance of Danny Flanagan throughout this research, and Shawna Farquarson whose patience and technical expertise was greatly appreciated. References [1] Blumberg S, Bramlett M, Kogan M, et al. Changes in prevalence of parentreported autism spectrum disorder in school-aged US children: 2007 to 2011– 2012. Nat Health Stat Rep 2013;65:1–7. [2] Nygren G, Cederlund M, Sandberg E, et al. The prevalence of autism spectrum disorders in toddlers: a population study of 2-year-old Swedish children. J Autism Dev Disord 2012;42:1491–7. [3] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013. [4] Oberman LM, Hubbard EM, McCleery JP, et al. EEG evidence for mirror neuron dysfunction in autism spectrum disorders. Brain Res Cogn Brain Res 2005;24:190–8. [5] Williams JH, Whiten A, Suddendorf T, et al. Imitation, mirror neurons and autism. Neurosci Biobehav Rev 2001;25:287–95. [6] Rizzolatti G, Craighero L. The mirror-neuron system. Annu Rev Neurosci 2004;27:169–92. [7] Binkofski F, Buccino G. The role of ventral premotor cortex in action execution and action understanding. J Physiol Paris 2006;99:396–405. [8] Buccino G, Lui F, Canessa N, et al. Neural circuits involved in the recognition of actions performed by nonconspecifics: an FMRI study. J Cogn Neurosci 2004;16:114–26.
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