Introduction

Autism was first described by Leo Kanner1 and Hans Asperger2 in a series of clinical case studies. Both clinicians suggested that the conditions now referred to as autism spectrum disorders (ASDs) may have a neurobiological basis. With the relatively recent advent of modern brain imaging techniques, translational psychiatric research has embraced the systematic study of ASDs using these measurement tools to gain insight into the pathophysiology and possible etiology of ASDs. The ultimate promise of these approaches is to improve mechanistic accounts of ASDs as well as provide targets for novel intervention approaches.

ASDs emerge early in life and are generally associated with lifelong disability.3 The defining symptoms of the disorder include social and communicative deficits and restricted and repetitive behaviors and interests.4 Individuals with milder constellations of symptoms are classified as having an ASD, a term that reflects the highly heterogenous array of symptom presentations and that will likely be adopted to characterize individuals with a range of intellectual functioning in the next version of the Diagnostic and Statistical Manual of Mental Disorders.5 Geschwind and Levitt6 illustrated the complexity inherent to understanding the neurobiology of ASDs by suggesting that there are likely many “autisms,” each with non-overlapping etiologies and presentations. Given the highly heterogenous nature of ASDs, it is perhaps not surprising that brain imaging studies have yielded a wide array of candidate brain circuits affected by the disorder. This range of brain endophenotypes is consistent with the challenges associated with identifying genes that cause ASDs: although ASDs have a very strong genetic component, with an estimated heritability as high as 90%,7 the identification of reliable genetic markers remains elusive.

Functional magnetic resonance imaging (fMRI) has proven to be a useful tool to investigate aberrant neurobiological function in ASDs because of its excellent contrast properties, spatial resolution, and temporal resolution. fMRI uses specialized pulse sequences to localize metabolic correlates of neural activity linked to relevant neurocognitive processes. Additionally, unlike positron emission tomography (PET) and single-photon emission computed tomography (SPECT), fMRI does not rely on radiotracers and is noninvasive. The past two decades have witnessed a surge in fMRI research in ASDs, and the goal of this review is to provide an overview of the questions addressed by these studies, to identify consistent patterns across investigations, and to suggest directions for future research.

Task-based functional magnetic resonance imaging

Likely due at least in part to the heterogeneity of symptom expression in ASDs, there is no unifying account of brain dysfunction that explains all the core symptoms of ASDs. Instead, the triad of defining ASD symptoms (ie, impaired social functioning, impaired communication, and restricted and repetitive behaviors and interests) suggests distinct neural systems. Additionally, it is common for some cognitive systems to be spared in individuals with ASDs (eg, even severe cases of ASDs may be accompanied by high intelligence and other so-called “islets of ability”8), suggesting that brain dysfunction in ASDs may be domain-specific. Likewise, task-based fMRI studies of ASDs have taken the piecemeal approach of investigating neurocognitive processes linked to specific symptom domains in relative isolation. Therefore, in this review studies are grouped based on these distinct neurocognitive processes. The clear majority of studies have used tasks that map onto the triad of defining ASD symptoms, and thus studies are first presented based on this trichotomy. However, emerging fMRI data addressing reward processing and resting-state functional connectivity do not clearly fit within these three domains, as thus are given separate sections in this review.

Social cognition

Most functional neuroimaging investigations in ASDs have addressed social perception (the automatic and preconscious processing of social information) and social cognition (processing meaning from emotional and social cues). Task-related fMRI studies addressing social functioning in ASDs have focused on nodes of the socalled “social brain,” including the medial prefrontal cortex, implicated in making inferences about others' intentions, the temporoparietal junction, mediating mentalizing, the posterior superior temporal sulcus, activated by biological motion, the inferior frontal gyrus, involved in emotional judgments, the interparietal sulcus, which guides spatial attention in social contexts, the amygdala, involved in recognizing emotions from facial expressions, the fusiform gyrus, critical for face processing, and the anterior insula, involved in understanding internal states and mimicking social expressions (see ref 9 for a review).

Face processing

Perhaps the richest area of inquiry into social cognition deficits in ASDs has been studies of face processing (Table I). Faces are perhaps the quintessential social stimulus, and infants attend to and recognize faces from very early infancy.10 Studies of face processing in ASDs are theoretically grounded by behavioral evidence of impaired joint attention, eye contact, and face recognition and discrimination in ASDs, as well as impaired social emotional judgments about faces, reduced face emotion recognition and perception, and abnormal eye scanpaths when viewing faces.11,12

Studies investigating face processing in autism spectrum disorders. ASD: Autism Spectrum Disorder; TYP: Neurotypical; †ASD refers to the entire autism sample in a particular study, including high functioning autism, Asperger's syndrome, and pervasive developmental disorder not otherwise specified; *Total number of participants is presented first followed by the number of females in parentheses, if reported; **Not specified; ↓: decreased activation; ↑: increased activation. Abbreviations used in tables: ACC, anterior cingulate cortex; ACG, anterior cingulate gyms; AG, angular gyms; Al, anterior insula; AMY, amygdala; ATL, anterior temporal lobe; BA, Broca's area; BG, basal ganglia; CM, caudate nucleus; DAC, dorsal anterior cingulate; DLPFC, dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex; DN, dentate nucleus; FFA, fusiform face area; FG, fusiform gyms; IC, insular cortex; IFA, inferior frontal area; IFC, inferior frontal cortex; IFG, inferior frontal gyrus; IPL, inferior parietal lobe; ITG, inferior temporal gyrus; LG: lingual gyrus; LSTG, left superior temporal gyrus; MCG, >middle cingulate gyrus; MFC, midfrontaI cortex; MFG, midfrontal gryus; MFL, medial frontal lobes; NAC, nucleus accumbens; OFC, orbitofrental cortex; OFG, orbitofrental gyrus; MPFC, medial prefrontal cortex; MTG, medial temporal gyrus; PO, pars opercularis; PCC, posterior cingulate cortex; PFC, prefrontal cortex; PHG, parahippocampal gyrus; PL, parietal lobe; PMC, premotor cortex; PVC, primary visual cortex; RPVC, right primary visual cortex; SFG, superior frontal gyrus; SPL, superior parietal lobe; STG, superior temporal gyrus; STS, superior temporal sulcus; THAL, thalamus; TL, temporal lobe; TPJ, temporoparietal junction; VS, ventral striatium; VLPFC, ventrolateral prefrontal cortex; VOC, ventral occipital cortex; VMPFC, ventromedial prefrontal cortex; WA, Wernicke's Area

CitationASD*†TYP*†ASD ageTYP ageTask(s)Core findings in ASD group (relative to controls)Conclusions
Ashwin, Baron-Cohen, Wheelwright, O'Riordan, Bullmore, 2007 [163]13 (13)13 (13)31.2 + 9.125.6 + 5.1Viewed facial stimuli known to activate AMY in healthy controlsDifferential activation to faces; ↑ACG, superior temporal cortex; No difference in AMY activation between angry and frightened facesDifferent activation of social brain during face processing; Absence of response to varying emotional intensity of facial stimuli
Bird, Catmur, Silani, Frith, Frith, 2006 [164]16 (14)16 (14)33.3 ± 11.535.3 + 12.1Viewed pairs of stimuli (face/ house) in attended /unattended locationsAttention modulation present only to house images (rather than to both houses and faces)Social stimuli less salient for individuals with ASD
Bookheimer, Wang, Scott, Sigman, Dapretto, 2008 [165]12 (12)12 (12)11.3 ± 4011.9 ± 2.4Inverted or upright face matching↓Frontal cortex across all conditions, particularly left hemisphere, dorsal IFG (i.e. mirror neurons); ↓AMY; ↑PrecuneusFaces processed as objects; Behavioral differences in processing upright vs inverted faces implicates a social rather that visual processing impairment
Corbett, Carmean, Ravizza, et al, 2009 [166]12 (12)15 (13)9.01 ± 13.829.17 ± 1.44Face identify and expression matching↓AMY during expression matching; ↓FG during identity matchingASD recruits frontal and parietal lobes, but not AMY, for face expression matching; ASD processes faces less efficiently and less effectively; AMY fails to provide socio-emotional context during social interactions
Coutanche, Thompson-Schill, Schultz, 2011 [167]12 (12)12 (12)13.9 ± 4.4813.6 ± 3.87Recognition of emotional facial expressionsMulti-voxel pattern analysis classification negatively correlated with symptom severity (activation levels did not); Searchlight analysis across the ventral TL identified regions with relationships between classification performance and symptom severityClinical severity was more classifiable from MVPA than from FG patterns; MVPA can identify regions not found using mean activation, ITG may play a role in ASD face processing
Dalton, Nacewicz, Johnstoner, et al, 2005 [168]Task : 14 (14) Task 2 : 16 (16)Task 1: 12 (12) Task 2: 16 (16)15.9 ± 4.7117.1 ± 2.78(1) Facial emotion discrimination (2) Face recognition↓Bilateral FG, occipital gyri, MFG; ↑Left AMY, OFG; FG and AMY activation correlated with time fixating on eye regions in the ASD groupDiminished gaze fixation may account for FFG hypoactivation results in the literature
Deeley, Daly, Surguladze, et al, 2007 [169]18 (18)9 (9)34 + 1027 ± 5Viewed face stimuli with variable emotional expressionsFusiform, extrastriate hyporesponsiveness across emotion and intensity levelsWhile fusiform and extrastriate regions are activated to social stimuli in ASD, it is less so than in typical development
Greimel, Schulte-Ruther, Kircher, et al, 2010 [170]15 (15), 1115 (15), 9 (9)14.9 ± 1.6, 47.7 ± 5.315.0 ± 1.4, 43.9 ± 5.1Emotion identification in facial stimuli and in self↓FG correlated with social deficits,FG impairment shared between first-degree relatives is a fundamental feature of ASD;
(11) (adolescents, fathers)(adolescents, fathers)(adolescents, fathers)(adolescents, fathers)↓IFG during self-task;
Fathers of ASD performed similarly to fathers of controls, but showedFG impairment during face processing related to empathy deficits
↓FG
Hadjikhani, Joseph, Snyder, et al, 2004 [171]11**10**36 ± 1226 ± 6Viewed faces, objects, and scrambled imagesNo FFA activation differences when viewing facesFace processing abnormalities not due to dysfunction in the FFA, but to abnormalities in surrounding networks involved in social cognition
Hadjikhani, Joseph, Snyder, Tager-Husberg, 2007 [172]10**7**34 ± 1135 ± 12Viewed unemotional facesNo differences in FFA, inferior occipital gyrus activation;Atypical activation in a broader face-processing network outside of FFA and inferior occipital gyrus;
↓Right AMY, IFC, STS, somatosensory cortex, PMC
Suggests mirror neuron system disturbance during face-processing in ASD
Hall, Szeehtman, Nahmias, 2003 [173]8 (8)8 (8)****Emotion and gender recognition tasks↓IFA, FG;Recognition of emotions in ASD achieved through recruitment of brain regions concerned with attention, perceptual knowledge, and categorization
↑right ATL, ACG, THAL
Hall, Doyle, Goldberg, West, Szatman, 2010 [174]12 (12)12(12)31.8**32**Identified gender of subliminally presented images of anxious faces↓FFA;Transmission of social information along subcortical pathways intact, but signaling to downstream structures as well as the mechanisms of subsequent processing are impaired
No AMY differences between groups
Hubl, Bolte, Feineis-Matthews, et al, 2003 [175]10 (10)10 (10)25.3 ± 6.927.7 ± 7.8Viewed faces and complex patterns↓FG, esp during face processing;Deficits in face-specific regions, but overdevelopment in areas of visual search;
↑Medial occipital gyrus, superior parietal lobule, medial frontal gyrus
Predisposed for local processing, rather than global
Humphreys, Hasson, Avidan, Minshew, Behrmann, 2008 [176]13 (13)15 (15)27 ± 1029 ± 10Viewed faces, buildings, objects and patterns in controlled and naturalistic settings↓FFA, occipital face area, STS in response to faces;Differential organization of ventral visual cortex;
No group differences in place-related or object-related processingDevelopmental effects of lower functional connectivity have a more pronounced effect on later-developing systems, like face-processing, than for early-developing systems, like object- and place-processing
Kleinhans, Richards, Sterling, et al,2008 [177]19**21**23.5 ± 7.825.1 ±7.6Viewed familiar faces, housesReduced functional connectivity FFA-AMY, FFA-PCC, FFA-THAL;Abnormal connectivity in limbic system underlies social deficits in ASD
Greater social impairment correlated with worse connectivity FFA-AMY, FFA-right IFC
Kleinhans, Johnson, Richards, et al, 2009 [178]19**20******Viewed neutral facesReduced bilateral AMY habituation;AMY hyperarousal to socially relevant stimuli;
No group differences in FG habituationSustained AMY arousal may contribute to social deficits
Kleinhans, Richards, Weaver, et al, 2010 [179]31 (29)25 (23)23.57 ± 6.623.32 ± 5.15Matched facial expressions of fear or anger↓Left PFC; ↑Occptal lobe;Social anxiety mediates emotional face perception
Social anxiety correlated with ↑right AMY, ↓left middle temporal gyrus, ↓FFA
Kleinhans, Richards, Johnson, et al, 2011 [180]31 (29)25 (23)23.57 ± 6.623.32 ± 5.15Viewed images of faces and housesNo activation in right AMY, right pulvinar, or bilateral superior colliculi to faces;Rapid face identification but failure to engage subcortical brain regions involved in face detection and automatic emotional face processing.
Koshino, Kana, Keller, et al, 2008 [181]11 (11)11 (10)24.5 ± 10.228.7 ± 10.9Working memory tasks using faces↓Inferior left PFC, right posterior temporal;Faces processed as objects;
Activation in a different FFA location;Working memory of faces not mediated by typical frontal regions
Lower FFA-frontal connectivity
Loveland, Steinberg, Pearson, Mansour, Reddoch, 2008 [182]5 (4)4 (3)18 ± 1.317 + 1.1Auditory and visual emotional congruence taskDuring emotion trials, ↓OFt, STG, PHG, posterior cingulate gyrus, occipital gyrusFronto-limbic and superior temporal activity differences during integration of auditory and visual emotional stimuli
Monk, Weng, Wiggins, et al, 2010 [183]12**12**26 ± 627 ± 6Probe detection with different emotional expressions↑Right AMY to emotional faces;Attention must be factored into any model of neural circuitry in ASD;
Greater right AMY and VMPFC coupling;
Weaker positive right AMY and TL couplingOverconnectivity may underlie greater emotional responses in ASD
Morita, Kosaka, Saito, et al, 2011 [184]15 (14)15 (13)23.7 ± 4.323.3 + 3.6Rated photogenicity of faces↓Setf-related activity in PCC;Decoupling between evaluation of self-face images and emotional response;
↓Right IC and lateral OFC to embarrassment;
↓IC activity to self-face images associated with weak coupling between cognitive evaluation and emotional responses to self-faceDysfunction in PCC and IC contributes to lack of self-conscious behaviors in response to self-reflection
Ogai, Matsumoto, Suzuki, et al, 2003 [185]5**9**21.8 ± 5.923.0 ± 5.2Facial expression recognition↓Left insula, left IFG, left putamen during recognition of disgust and fearDifficulty understanding facial expressions in others and, therefore, in manipulating social information
Pelphrey, Morris, McCarthy, Labar, 2007 [186]8 (6)8 (6)24.5 ± 11.524.1 ± 5.6Dynamic and static face processing↓AMY, STS, FG to dynamic facesDysfunctions in these component areas may contribute to problems in social and emotional processing
Perlman, Hudac, Pegors, Minshew, Pelphrey, 2011 [187]12 (11)7 (7)25.5 ± 7.4728.57 ± 5.74Viewed faces while compelled to look at eyesRight FG activity normalized by following predetermined scan paths to eyes, but AMY response unaffectedRather than an underdeveloped FFA as a result of not focusing on faces during development, FFA appears functional;
Impaired mechanism of appropriately directing gaze
Pierce, Muller, Ambrose, Allen, Courchesne, 2001 [188]6 (6)8 (8)29.5 ± 828.3**Face perception with gender identification↓Bilateral FG, left AMY;ASD is associated with aberrant locations of maximal activations to faces
50% of group showed atypical FG activation to faces
Pierce, Haist, Sedaghat, Courchesne, 2004 [189]7 (7)9 (9)27.1 ± 9.2**Familiar versus unfamiliar face processingNo group difference in extent of FFA activation to faces; ↑FFA to familiar faces. Right hemisphere dominance to both types of faces;FFA hypoactivation to faces in ASD may be specific to unfamiliar faces;
Limited response in the posterior cingulate, AMY, MFLASD may be characterized by anomalous FFA modulation by faces, rather than hypoactivation
Pierce, Redcay, 2008 [190]11 (9)11 (9)9.9 ± 2.19.8 ± 1.8Matched faces of mothers, other children, adult strangersNormal FG response to face of mother or other children;Selective reduction in FG activity in response to strangers may be a result to reduced attention and interest in those conditions
↓FG to stranger adult faces
Pinkham, Hopfinger, Peiphrey, Pwen, Penn, 2008 [191]12**12**24.08 ± 5.7127.08 ± 3.99Free-viewing face processing↓Right AMY, FFA;Potential common substrates of impaired social cognition in ASD and schizophrenia
↓Left VLPFC compared to non-paranoid individuals with schizophrenia
Rudie, Shehzad, Hernandez, et al, 2011 [192]23 (21)25 (22)12.6 ± 2.8313.3 ± 96Emotional face processingReduced functional integration; AMY-secondary visual areas, PO-parietal cortex, Reduced segregation AMY-DLPFC, PO-VMPFC;Reduced functional integration and segregation of large-scale brain networks during face viewing
Reduced integration PO-FC, within right NAC
Scherf, Luna, Minshew, Behrmann, 2010 [193]10 (10)10(10)12.2 ± 1.111.2 ± 1.3Vignettes of faces, common objects, houses and scenes of navigation↓FG occipital face area, STS to faces;Selective ventral visual pathway disruption; Face-processing alteration present in early adolescence, Face perception in ASD akin to object perception in typical development
↑Ventral posterior FG to faces
Schultz, Gauthier, Klin, et aI, 2000 [194]14 (14)28 (28) (2 groups of 14)24.08 ± 5.7127.08 ± 3.99Face discrimination↓Right FG;Brain activation in the ASD group during face discrimination was consistent with feature-based strategies
↑Right ITG
Uddin, Davies, Scott, et al, 2008 [195]18 (18)12 (12)13.19 ± 2.6112.23+2.10Judged “self” or “other” for morphed face images↓Right premotor/prefrontal during presentation of “other” facesFunctional dissociation between the representation of self versus others suggests a neural substrate of self-focus and decreased social understanding
Wang, Dapretto, Hariri, Sigman, Bookheimer, 2004 [196]12 (12)12 (12)13.91 ± 2.6112.23 ± 2.10Emotion matching naming↓FG and ↑precuneus during matching facial expressions;Recruited different neural networks and relied on different strategies when processing facial emotion
Lack of modulation by task demands in the AMY
Welchew, Ashwm, Berkouk, et al, 2005 [197]13 (13)13 (13)31.2 ± 5125.6± 5.1Face processingAbnormal AMY-parahippocampal connectivityDifficulty in grasping facial expressions in others and, therefore, in manipulating interpersonally derived information
Weng, Carrasco, Swartz, et al, 2011 [198]22 (17)20 (19)14.36 ± 1714.97 ± 1.95Emotional face processing↑AMY, ventral PFC and striatum, particularly to sad faces;Greater activation in social-emotional processing regions when viewing faces
Negative correlation between age, pubertal status, and AMY activation

In neurotypical participants, the medial-lateral fusiform gyrus (FG) as well as the superior temporal sulcus, amygdala, and orbitofrontal cortex, activate in response to faces.13 The majority of fMRI studies in ASDs indicate FG hypoactivity to faces14-22 and to facial expressions.15,20,23-25 However, other reports suggest no differences in FG activation to familiar faces,26-29 stranger faces in the presence of an attentional cue,30 or when matching upright with inverted faces.31

These apparently inconsistent findings may be reconciled in a number of ways.32,33 The degree of visual attention to faces appears to be a critical factor moderating FG activation to faces in ASDs, with tasks that guide visual attention to faces or analytic approaches that account for point-of-regard resulting in relatively less FG hypoactivation in ASDs.21,30 This conclusion is supported by research indicating that face familiarity moderates FG responses to faces in ASDs28 and that impaired social cognition in ASDs may be mediated, at least in part, by attention to social cues, rather than by deficits in social cue processing per se.31,35 Similarly, lifelong amotivation to interact with faces may result in reduced perceptual skill when processing faces, and, in turn, cause FG hypoactivation to faces in ASDs that is perhaps a downstream consequence of reduced social experience rather than pathognomonic to ASDs.36 Moreover, the FG encodes not only face percepts, but social knowledge as well,37 suggesting that the FG may mediate: (i) the attribution of social meaning to stimuli: (ii) the retrieval of social semantic information; and (iii) self-referential experiences.28 Thus, the disparate results of the face processing literature in ASDs likely reflect the diverse and subtle social processes mediated by the FG and recruited by diverse fMRI tasks.

Amygdala response to faces in ASDs has also been extensively studied, and results in this area are decidedly mixed. There is evidence of no differences in amygdala activation to faces,18 of amygdala hypoactivation during face viewing15,16,26,31,38 and face matching,16 as well as evidence of amygdala hyperactivation to faces39,40 in ASDs, particularly when accounting for gaze time to faces21 (but see ref 41 for an exception). One study reported decreased amygdala habituation to the repeated presentation of faces, suggesting that social deficits in ASDs may be influenced by hyperarousal to faces due to protracted amygdala activation.42

Theory of mind

Theory of mind and mental inferences have been examine in ASDs via fMRI studies that address the ability to infer feeling states and/or intentions (Table II), skills that typically develop during the first 4 or 5 years of life and that are critical for the development of social skills and for successful navigation of the social world.43 Such tasks include images, stories, and animations designed to elicit the attribution of mental states. Results from typically developing individuals indicate with remarkable consistency that theory of mind is mediated by the posterior superior temporal sulcus at the temporoparietal junction, the temporal poles, the amygdala, and dorsal medial and ventrolateral prefrontal cortex.44

Studies investigating theory of mind and mental inference-making in autism spectrum disorders. ASD: Autism Spectrum Disorder; TYP: Neurotypical; †ASD refers to the entire autism sample in a particular study, including high functioning autism, Asperger's syndrome, and pervasive developmental disorder not otherwise specified; *Total number of participants is presented first followed by the number of females in parentheses, if reported; **Not specified; ↓: decreased activation; ↑: increased activation. Abbreviations used in tables: ACC, anterior cingulate cortex; ACG, anterior cingulate gyms; AG, angular gyms; Al, anterior insula; AMY, amygdala; ATL, anterior temporal lobe; BA, Broca's area; BG, basal ganglia; CM, caudate nucleus; DAC, dorsal anterior cingulate; DLPFC, dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex; DN, dentate nucleus; FFA, fusiform face area; FG, fusiform gyms; IC, insular cortex; IFA, inferior frontal area; IFC, inferior frontal cortex; IFG, inferior frontal gyrus; IPL, inferior parietal lobe; ITG, inferior temporal gyrus; LG: lingual gyrus; LSTG, left superior temporal gyrus; MCG, >middle cingulate gyrus; MFC, midfrontaI cortex; MFG, midfrontal gryus; MFL, medial frontal lobes; NAC, nucleus accumbens; OFC, orbitofrental cortex; OFG, orbitofrental gyrus; MPFC, medial prefrontal cortex; MTG, medial temporal gyrus; PO, pars opercularis; PCC, posterior cingulate cortex; PFC, prefrontal cortex; PHG, parahippocampal gyrus; PL, parietal lobe; PMC, premotor cortex; PVC, primary visual cortex; RPVC, right primary visual cortex; SFG, superior frontal gyrus; SPL, superior parietal lobe; STG, superior temporal gyrus; STS, superior temporal sulcus; THAL, thalamus; TL, temporal lobe; TPJ, temporoparietal junction; VS, ventral striatium; VLPFC, ventrolateral prefrontal cortex; VOC, ventral occipital cortex; VMPFC, ventromedial prefrontal cortex; WA, Wernicke's Area

CitationASD*†TYP*†ASD ageTYP ageTask(s)Core findings in ASD group (relative to controls)Conclusions
Baron-Cohen, Ring, Wheelwright, et al, 1999 [199]6 (4)12 (6)26.3 ± 2.125.5 ±2.8Inferred mental states from images of eyes↑Frontal-temporal regions;Supports amygdala theory of autism
↓AMY
Castelli, Frith, Happe, Frith, 2002 [200]10**10**33 ± 7.625 ± 4.8Viewed animated sequence of geometric shapes↓MPFC, STS, temporal poles;Possible neurofunctional explanation for impaired mentalizing
Decreased extrastriate functional connectivity
Dapretto, Davies, Pfeifer, et al, 2006 [201]10 (9)9 (9)12.05 ± 2.512.38 ± 2.22Imitation and observation of emotional expressions↓IFG;Dysfunctional mirror neuron system may underlie social deficits in autism
Mirror neuron activity inversely related to social symptom severity
Kaiser, Hudac, Shultz, et al, 2010 [202]25 (20)17 (12) (no sibling with ASD);11.8 ± 3.610.9 ± 3.1 (no sibling with ASD);Viewed biological motion clips and scrambled motion clipsDiffered in right AMY, VMPFC, left VLPFC, right posterior STS, bilateral FG;Identifies non-overlapping regions associated with ASD phenotypes and ASD genetic vulnerability in the absence of ASD symptoms
20 (9) (sibling with ASD)11.3 ± 28 (sibIing with ASD)Controls without ASD sibling differed from other two groups in left DLPFC, right ITG, bilateral FG, CG; Controls with ASD sibling differed from other two groups in right posterior STS, VMPFC
Hadjikhani, Joseph, Manoach, et al, 2009 [203]9**11 (8)30 ± 1131 ± 14Emotion processing of body expressionsNo differential brain activation to bodies expressing fear compared with neutral bodies;Emotion perception deficits in ASD may be due to compromised processing of the emotional component of observed actions
↓FC, Al to emotionally neutral bodies
Pitskel, Boiling, Hudac et al, 2011 [204]15(15)14 (13)23.4 ± 6.924.2 ± 7.4Viewed direct and averted gaze of virtual human face↓Right TPJ, right Al, left lateral OC;Brain mechanisms underlying processing gaze direction in ASD
↑ Left DLPFC
Konishi, Nakajima, Uchida, et al, 1999 [205]18 (12)18 (12)38.6 ± 12.433.0 ± 10.7Imitation inhibition taskImitation scores correlated with ↓medial PFC, TPJHighlights contribution of hyperimitation to reduced social cognition
Pelphrey, Morris, McCarthy, 2005 [206]10 (9)9 (8)23.2 ± 9.923.4 ± 5.8Viewing congruent and incongruent eye gaze shifts↓STS on incongruent trialsLack of STS modulation to congruent and incongruent gaze shifts contributes to eye gaze processing deficits
Silani, Bird, Brindley, et al, 2008 [207]15 (13)15 (13)36.6 ± 11.733.7 ± 10.3Emotion introspection task↓Self-reflection/ mentalizing regions (MPPC, ACC, precuneus, inferior OFC, temporal poles, cerebellum) during self introspection;Alexithymia and empathy deficits linked to anomalous Al actvity
Al activity predicted alexithymia and empathy in both groups
Wang, Lee, Sigman, Dapretto, 2007 [208]18 (18)18 (18)12.4 ± 2.911.8 ± 1.9Processed potentially ironic remarks↓MPFC, right STG to irony; MPFC activity in ASD modulated by instructions to attend to faces and tones of voice;MPFC mediates understanding the intentions of others
MPFC activity inversely related to symptom severity in ASD group
Wicker, Fonlupt, Hubert et al, 2008 [209]12 (11)14 (14)27 ± 1123 ± 10Emotion and age discrimination↓DMPFC, right VLPFC, right STG;Abnormal connectivity between structures of the social brain could explain social deficits in ASD
Abnormal connectivity between AMY, VLPFC, DLPFC, posterior occipital-temporal regions

The amygdala plays a critical role in multiple aspects of mentalizing, including determining emotional states of others from facial expressions,45 and a number of studies have reported aberrant amygdala activation in ASDs during tasks requiring inferring mental states from pictures of eyes46,47 and judging facial expressions,23 suggesting that the amygdala may fail to assign emotional relevance to social stimuli in ASDs. Other studies, however, have reported that ASDs are characterized by amygdala hyperactivity during face viewing48 and anticipation,49 suggesting that the so-called “amygdala theory of autism” may reflect impaired amygdala modulation rather than simply hypoactivation in social contexts.

Another brain region that has received scrutiny in fMRI studies of theory of mind in ASDs is the posterior superior temporal sulcus, a region recruited during tasks that involve interpreting other's mental states from biological motion cues.50 There are reports of posterior superior temporal sulcus hypoactivation while processing incongruent eye gaze shifts,51 while viewing direct and averted gaze,52 during intentional attribution to animated sequences of geometric figures,53 and during speech perception.54 A recent study of children with ASDs and their unaffected siblings found that activation in posterior superior temporal sulcus (as well as the amygdala and ventromedial prefrontal cortex) during biological motion perception differentiated children with ASDs both from their unaffected siblings and from matched control participants, suggesting that activation of this region may be related to phenotypic expression of social deficits in ASDs rather than genetic liability.55

Another area of inquiry has been functioning of the mirror neuron system (including, in humans, the pars opercularis in the inferior frontal gyrus). This system is active during imitation, action observation, intention understanding, and understanding emotional states of others.56 The inferior frontal gyrus has been reported to be relatively less active in ASDs during imitation and observation of faces57-59 and during imitation and observation of emotional expressions in ASDs,48,60 suggesting that mirror neuron dysfunction may account for social deficits in ASDs, though this contention has been questioned.61 Additionally, a recent metaanalysis of fMRI studies of social processing in ASDs revealed hypoactivation of the right anterior insula across studies (but see ref 62 for an exception), a region that is believed to be a relay station for projections from the IFG to the amygdala.63

Cognitive control

Restricted and repetitive behaviors and interests constitute a multifaceted symptom domain in ASDs that comprises both lower-order motoric repetitive behaviors (eg, body rocking, hand flapping) as well as higher-order cognitive manifestations (eg, a need for predictability).64 Because fMRI requires minimal motion from research subjects, cognitive manifestations of restricted and repetitive behaviors have been the focus of fMRI research. Such studies have mostly relied on tasks requiring cognitive control because of linkages between deficits on neuropsychological cognitive control tasks and symptoms of restricted and repetitive behaviors and interests in ASDs.65

Animal lesion and nonclinical human neuroimaging studies indicate that cognitive control is mediated by frontostriatal brain systems, including the lateral prefrontal cortex, the inferior frontal cortex (including the insular cortex), the anterior cingulate cortex, the intraparietal sulcus, and the striatum.66 Functional MRI studies of cognitive control in ASDs have revealed anomalous activation in frontostriatal brain regions (Table III), including inferior and middle frontal gyri, dorsal anterior cingulate cortex, and the basal ganglia during cognitive control tasks. Such findings have been reported using go/no-go, Stroop, and switching tasks,67 tasks that require interference inhibition,68-72 response monitoring,73 novelty detection,74-75 spatial attention,68 working memory,76,77 and saccadic eye movements.78 These findings have been interpreted to reflect deficits in behavioral inhibition and/or generation of adaptive behaviors linked to the expression of restricted and repetitive behavior and interests. Although the direction of effects has varied across studies (ie, frontostriatal hyperactivation vs hypoactivation), likely due to task demands and analysis methods, anomalous frontostriatal activation during tasks requiring cognitive control has been a consistent result in ASD samples, with the majority of findings indicating frontostriatal hyperactivation that has been interpreted to reflect a neurof unctional compensatory mechanisms to overcome cortical inefficiency.70

Studies investigating cognitive control in autism spectrum disorders. ASD: Autism Spectrum Disorder; TYP: Neurotypical; †ASD refers to the entire autism sample in a particular study, including high functioning autism, Asperger's syndrome, and pervasive developmental disorder not otherwise specified; *Total number of participants is presented first followed by the number of females in parentheses, if reported; **Not specified; ↓: decreased activation; ↑: increased activation. Abbreviations used in tables: ACC, anterior cingulate cortex; ACG, anterior cingulate gyms; AG, angular gyms; Al, anterior insula; AMY, amygdala; ATL, anterior temporal lobe; BA, Broca's area; BG, basal ganglia; CM, caudate nucleus; DAC, dorsal anterior cingulate; DLPFC, dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex; DN, dentate nucleus; FFA, fusiform face area; FG, fusiform gyms; IC, insular cortex; IFA, inferior frontal area; IFC, inferior frontal cortex; IFG, inferior frontal gyrus; IPL, inferior parietal lobe; ITG, inferior temporal gyrus; LG: lingual gyrus; LSTG, left superior temporal gyrus; MCG, >middle cingulate gyrus; MFC, midfrontaI cortex; MFG, midfrontal gryus; MFL, medial frontal lobes; NAC, nucleus accumbens; OFC, orbitofrental cortex; OFG, orbitofrental gyrus; MPFC, medial prefrontal cortex; MTG, medial temporal gyrus; PO, pars opercularis; PCC, posterior cingulate cortex; PFC, prefrontal cortex; PHG, parahippocampal gyrus; PL, parietal lobe; PMC, premotor cortex; PVC, primary visual cortex; RPVC, right primary visual cortex; SFG, superior frontal gyrus; SPL, superior parietal lobe; STG, superior temporal gyrus; STS, superior temporal sulcus; THAL, thalamus; TL, temporal lobe; TPJ, temporoparietal junction; VS, ventral striatium; VLPFC, ventrolateral prefrontal cortex; VOC, ventral occipital cortex; VMPFC, ventromedial prefrontal cortex; WA, Wernicke's Area

CitationASD*†TYP*†ASD ageTYP ageTask(s)Core findings in ASD group (relative to controls)Conclusions
Allen, Courchesne, 2003 [210]8 (7)8 (7)26.89 ± 8.5926.77 ± 8.22Motor control and attentional control↑Motor regions; ↓Cerebellar attentionDevelopmental cerebellar abnormality has differential functional implications for cognitive and motor systems
Allen, MuIIer, Courchesne, 2004 [211]8 (7)8 (7)26.89 ± 8.5926.77 ± 8.22Repeated button pressing↓lpsilateral anterior cerebellar hemisphereCerebellar dysfunction that is a reflection of abnormal anatomy
Agam, Joseph, Barton, Manoach, 2010 [212]11**14**28 ± 1027 ± 8Antisaccade task↑Frontal eye field, dorsal ACC; Functional neural abnormalities in volitional ocular-motor control linked to repetitive behaviors
Both findings associated with repetitive behavior symptoms
Belmonte, Yurgelun-Tedd, 2003 [213]6 (5)6 (5)32.7 ± 9.827.2 ± 4.4Bilateral visual spatial attention task↓Left VOC;Neurofunctional basis of impaired selective attention
↑Left IPS
Damarla, Keller, Kana, et al, 2010 [214]13 (11)13 (13)19 ± 5.522.1 ± 4.25Embedded figures task↓Left DLPFC, inferior parietal areas;Cortical underconnectivity despite preserved visuospatial performance
↑Visuospatial areas;
Decreased frontal - visuospatial connectivity
Dichter, Belger, 2007 [215]17 (16)15 (14)22.9 ± 5.224.6 ± 6.5Flanker task (interference inhibition)↓Prefrontal, parietal regions during the incongruent social condition onlySocial stimuli interfere with brain regions mediating cognitive control
Dichter, Belger, 2008 [216]12 (12)22 (22)23.2 ± 5.825.1 ± 6.0Flanker task intermixed with high and low arousal images↓Right MFG on conflict trials preceded by high arousal images onlyAbnormal modulation of regions mediating cognitive control in context of high arousal
Dichter, Felder, Bodf ish, 2009 [217]15 (14)19 (18)23.3 ± 11.128.0 ± 7.9Oddball target detection task with social and non-social targets↑Right IFG, DMPFC to social targets,DMPFC hyper activation during cognitive control of social stimuli contributes to expression of social deficits
DMPFC activation to social targets predicted severity of social impairments
Gilbert, Bird, Brindley, Frith, Burgess, 2008 [218]14 (11)18 (13)38 ± 1332 ± 8(1) Random response generation taskTask 1: ↓Cerebellum, left lateral temporal cortex;Impaired cognitive control in is associated with task-specific functional changes
(2) Selected stimulus-oriented vs stimulus-independent thoughtTask 2: ↑MediaI rostral PFC
Gilbert, Meuwese, Towgood, Frith, Burgess, 2003 [219]16 (14)16 (12)32 ± 7.731 ±5.7(1) Stimulus-oriented spatial taskSimilar activation patterns;Abnormal functional specialization within medial rostral PFC
(2) Stimulus-independent spatial taskMulti-voxel similarity analyses revealed found abnormal functional specialization within medial rostral PFC
Gomot, Belmonte, Bullmore, Bernard, Baron-Cohen, 2008 [220]12 (12)12 (12)13.5 ± 1.613.8 ± 1Auditory novelty detection↑Right PFC-premotor, left inferior parietal regionsCognitive control associated with activation of a more widespread network of regions
Haist, Adamo, Westerfield, Courchesne, Townsend, 2005 [221]8 (8)8 (8)23.4 ± 11.425.6 ± 12.5Spatial attention task↓Frontal, parietal, occipital, within the IPL;Deficit in automatic spatial attention abilities and aberrant voluntary spatial attention skills
↑SPL and extrastriate cortex
Just, Cherkassky, Keller, Kana, Minshew, 2007 [222]18 (17)18 (15)27.1 ± 11.924.5 ± 9.9Tower of London taskSimilar activation in DLPFC between groups;Cognitive control deficits may be preferentially linked to lower cortical integration of information
Lower frontal-parietal connectivity
Kana, Keller, Minshew, Just, 2007 [223]12 (11)12 (11)26.8 ± 7.722.5 ± 3.2Go/No-go task↓Left ACG, left precuneus, right AG, premotor areas;Inhibition circuitry is activated atypically and is less synchronized, leaving inhibition to be accomplished by strategic control rather than automatically
Lower connectivity between ACS, MCG, right MFG, IFG, inferior parietal regions
Keehn, Brenner, Palmer, Lincoln, MuIIer, 2008 [224]9 (9)13 (13)15.1 ± 2.614.1 ± 2.1Visual search task↑Occipital and frontoparietal regionsEnhanced discrimination and increased top-down modulation of attentional processes
Kennedy, Redcay, Courchesne, 2006 [225]12**14**25.49 ± 9.6126.07 ± 7.95Counting Stroop taskDecreased deactivation of resting network regions (MPFC/rostral ACC, PCC)Lack of deactivation indicates abnormal internally directed processes at rest and may be compensatory
Lee, Yerys, Della Rosa, et aI, 2003 [226]12 (9)12 (8)10.17 ± 1.5711.01 ± 1.78Go/No-go taskAge-moderated decreased connectivity in IFC, motor planning regionsAtypical developmental connectivity trajectories for IFC with other neural regions supporting response inhibition
Lee, Foss-Feig, Henderson et al, 2007 [227]17 (12)14 (11)10.37 ± 1.5210.85 ± 1.47Embedded figures task↑Dorsomedial premotor, left superior parietal, right occipital cortexReduced cortical activation suggests that disembedded visual processing is performed sparingly
Liu, Cherkassky, Minshew, Just, 2011 [228]15 (14)15 (15)25.2 ± 7.626.3 ± 8.2(1) Line-counting task (2) Judged whether a 3D object was possible↓Medial frontal to possibility task,Less effort for lower-level processing,
Decreased frontal-posterior connectivityReduced global-to-local interferences
Luna, Minshew, Garver, et al, 2002 [229]11 (9)6 (6)32.3 ± 9.330.3 ± 11.8(1) Spatial working memory taskTask 1: ↓DLPFC, PCC;Neurofunctional basis of impaired working memory
(2) Guided saccade taskTask 2: no differences
Manjaly, Bruning, Neuf ang et al,12**12**14.4 ± 2.714.3 ± 2.7Embedded figures task↑Right PVC, bilateral extrastriate areasEnhanced local processing in early visual areas rather than impaired
2007 [230]global processing
Mizuno, Villa lobos, Davies, Dahl,8 (8)8 (8)28.4 ± 8.928.1 ± 8.3Visuomotor coordination taskIncreased functional connectivity in left insula, right postcentral gyrus,Underconnectivity hypothesis unsupported;
Muller, 2008 [231]MFGSubcortico-cortical connectivity may be hyperfunctional, potentially
compensating for reduced cortico-cortical connectivity
Muller, Kleinhans, Kemmotsu, Pierce,8 (8)8 (8)28.4 ± 8.928.1 ± 8.36-digit sequence learning↑PFC posterior parietal cortexDisturbances incerebello-thalamocortical pathways
Courchesne, 2003 [232]
Muller, Cauich, Rabio, Mizuno,8 (8)8 (8)28.4 ± 8.928.1 ± 8.38-digit sequence learning↑Right pericentral and PMC;Atypical use of the primary sensory and premotor cortices during
Courchesne, 2004 [233]Delayed activation of BA 3, 4, 6learning
Muller, Pierce, Ambrose, Allen,8 (8)8 (8)28.4 ± 8.928.1 ± 8.3Visual stimulation using finger movements↓Contralateral periolandic cortex, BG, THAL, bilateral supplementary;Abnormal functional variability and less distinct regional activation
Courchesne, 2001 [234]motor area, ipsilateral cerebellum, bilateral DLPFCpatterns
↑Postenor cortex, PFC, extrastnrite regions
Noonan, Haist, Muller, 2003 [235]10 (10)10 (10)23 ± 9.925.8 ± 9.9Source recognition taskIncreased connectivity between left MFC-left superior parietalAn inefficiency in optimizing network connections during task
regionsperformance
Ring, Baron-Cohen, Wheelwright, et al,6 (4)12 (6)26.3 ± 2.125.5 ± 2.8Embedded figures task↓Right DLPFC, bilateral parietal cortex;Object feature analysis, rather than working memory systems, are
1999 [236]↑Right ventral occipitotemporal cortexused for local processing and visual search in autism
Solomon, Ozonoff, Ursu, et al,22 (17)23 (18)15.2 ± 1.716.0 ± 2.0Preparing to overcome prepotency task↓Anterior frontal, parietal occipital regions;Fronto-parietal connectivity deficits contribute to ADHD symptoms
2009 [237]Decreased frontal/parietal/occipital connectivity related to ADHD symptomsin autism
Schmitz, Rubia, Daly, et al, 2006 [238]10 (10)12 (12)38 ± 939 ± 6(1) Go/No-go taskTask 1: ↑left IFG, OFGCognitive control associated with increased brain activity in
(2) Stroop taskTask 2: ↑left insula, AMY-hippocampal junction;multiple regions
(3) Cognitive set shiftingTask 3: ↑PL
Shafritz, Dichter, laranek, Belger,18 (16)15 (13)22.3 ± 8.724.3 ± 6.2Oddball target detection task↓Frontal, striatal, and parietal regions;Cognitive control deficits and repetitive behaviors might be
2008 [239]ACC activation correlated with repetitive behavior symptomsassociated with dysfunctions in neural circuitry
Silk, Rinehart, Bradshaw et al,7 (7)9 (9)14.7 ± 2.915.0 ± 1.8Mental rotation task↓lateral and medial PMC, DLPFC, ACG, CNDysfunctional frontostriatal networks during cognitive control
2006 [240]
Takarae, Minshew, Luna, Sweeney,13**14**24.5 ± 7.726.6 ± 7.8Saccadic eye movement paradigms↑DLPFC, CN, medial THAL, ACC, PCC, right DNCognitive control regions may compensate for lower-level
2007 [241]processing difficulties
Thakkar, Polli, Joseph, et al, 2008 [242]12 (10)14 (8)30 ± 1127 ± 8Anti-saccade task↑Rostral ACC,Rostral ACC abnormalities contribute to repetitive behaviors
Reduced fractional anisotropy in white matter underlying rostral ACC;
Repetitive behaviors correlated with rostral ACC activation

Communication

Investigations of communication deficits in ASDs have focused predominantly on brain regions mediating language perception, comprehension, and generation. The left hemisphere is typically language-dominant, and speech production is mediated by Broca's area at the junction of the frontal, parietal, and temporal lobes, whereas speech comprehension is mediated by Wernicke's area in the posterior temporal lobe.79 Heschl's gyrus, in the dorsal temporal lobe, contains primary auditory cortex as well as the angular gyrus, involved in higher-order language comprehension and cross-modal integration, and the inferior parietal lobule, involved in processing semantic content.80

fMRI studies of communication functions in ASDs have used tasks requiring listening to speech sounds,54,81,82 sentence comprehension,83-85 verbal fluency,86 pragmatic language comprehension,87 semantic judgments,88 responsenaming,89 and viewing body gestures90-91 (Table IV). Overall, findings indicate differential lateralization patterns in ASDs (ie, reduced left > right lateralization),82,84,86,87,89 decreased synchrony of brain regions processing language,83,92 decreased automaticity of language processing,93 greater neurofunctional deficits for speech than songs,94 and recruitment of brain regions that do not typically process language.83,95-97 A recent methodological innovation in the domain of language-based fMRI studies in ASDs has been to present speech stimuli to veryyoung children with ASDs (as young as 12 months old) while asleep.82,98 Although the diagnostic stability of ASDs for children in this age range must be considered, this approach has the potential to leverage task-based fMRI in far younger children with ASDs to examine altered developmental trajectories associated with impaired receptive language skills. Additionally, sleep fMRI would appear to be well suited to studying early emerging functional brain activation properties linked to speech processing in infant high-risk paradigms.

Studies investigating communication in autism spectrum disorders. ASD: Autism Spectrum Disorder; TYP: Neurotypical; †ASD refers to the entire autism sample in a particular study, including high functioning autism, Asperger's syndrome, and pervasive developmental disorder not otherwise specified; *Total number of participants is presented first followed by the number of females in parentheses, if reported; **Not specified; ↓: decreased activation; ↑: increased activation. Abbreviations used in tables: ACC, anterior cingulate cortex; ACG, anterior cingulate gyms; AG, angular gyms; Al, anterior insula; AMY, amygdala; ATL, anterior temporal lobe; BA, Broca's area; BG, basal ganglia; CM, caudate nucleus; DAC, dorsal anterior cingulate; DLPFC, dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex; DN, dentate nucleus; FFA, fusiform face area; FG, fusiform gyms; IC, insular cortex; IFA, inferior frontal area; IFC, inferior frontal cortex; IFG, inferior frontal gyrus; IPL, inferior parietal lobe; ITG, inferior temporal gyrus; LG: lingual gyrus; LSTG, left superior temporal gyrus; MCG, >middle cingulate gyrus; MFC, midfrontaI cortex; MFG, midfrontal gryus; MFL, medial frontal lobes; NAC, nucleus accumbens; OFC, orbitofrental cortex; OFG, orbitofrental gyrus; MPFC, medial prefrontal cortex; MTG, medial temporal gyrus; PO, pars opercularis; PCC, posterior cingulate cortex; PFC, prefrontal cortex; PHG, parahippocampal gyrus; PL, parietal lobe; PMC, premotor cortex; PVC, primary visual cortex; RPVC, right primary visual cortex; SFG, superior frontal gyrus; SPL, superior parietal lobe; STG, superior temporal gyrus; STS, superior temporal sulcus; THAL, thalamus; TL, temporal lobe; TPJ, temporoparietal junction; VS, ventral striatium; VLPFC, ventrolateral prefrontal cortex; VOC, ventral occipital cortex; VMPFC, ventromedial prefrontal cortex; WA, Wernicke's Area

CitationASD*†TYP*†ASD ageTYP ageTask(s)Core findings in ASD group (relative to controls)Conclusions
Anderson, Lange, Froehlich, et al,26 (26)15 (15)21.5 ± 6.422.5 ± 6.3(1) Thought about a described word↓Left posterior insula, bilateral receptive language areas,Posterior insula implicated in receptive language impairments
2010 [243](2) Filled in missing word in a sentenceReceptive language correlated with activation of posterior left WA;
Verbal IQ correlated with activation of bilateral BA, PFC, lateral PMC
Boddaert, Belin, Chabane, et al,5 (4)8 (8)19.1 ± 4.521.9 ± 3.3Listened to speech-like sounds↑ Right MFGAbnormal auditory cortical processing implicated in language
2003 [244]impairments
Catarino, Luke, Waldman, et aI,12 (12)12(12)27.0 ± 1034.0 ± 13Detected semantic incongruities withinMore spatially restricted activation pattern (only left IFG, left ACC,impaired integration of multiple neural networks related to
2011 [245]written sentencesright FG)difficulties in use of context
Eigsti, Schuh, Mend, Schultz, Paul,16**11******Processed linguistic stimuli that varied inAffective and grammatical prosodic cues prompted more general-Language processing less automatic;
2011 [246]emotional and semantic contentized activationLinkages between ToM and language processing deficits,
Increased reliance on executive control regions for speech processing
Eyler, Pierce, Courchesne, 2012 [247]40 (40)40 (40)32. 0 mo ±25.6 mo ± 9.6Listened to story with complex, simple, or↓Left hemisphere to speech sounds (worsens with age).Lateralized abnormalities of temporal cortex processing of
10.2backward speech during sleepAbnormally right-lateralized temporal cortex to language (worsenslanguage in toddlers with autism
with age)
Grezes, Wicker, Berthoz, de Gelder,12 (10)12 (12)26.6 ± 10.421.0 ± 1.6Viewed fearful or neutral body language↓AMY, IFG, PMC to fearful gesturesDysfunction in this network may impact the communication deficits
2009 [248]present in autism
Groen, Tesink, Petersson, et al,16 (12)26 (21)15.3 ± 1.615.7 ± 1.7Sentences congruent or incongruent to↓Left IFG for sentences requiring integration of speaker information;ASD recruits left IFG atypically in language tasks that demand
2010 [249]speakerNo difference for semantic- and world-knowledge sentencesintegration of social information
Hadjikhani et al, 2009 [203]12 (9)11 (11)30 ± 1135 ± 12Recognition of emotional bodies↓lFC, Al in response to emotionally neutral gesturesIdentifies neural mechanisms of impaired affect communication
Harris, Chabris, Clark, et al, 2006 [250]14 (14)22 (22)36 ± 1231 ± 9Semantic and perceptual word processingDuring semantic processing, ↓BA, ↑WA;Abnormal Braca's area development that may be linked with
Diminished activation difference between concrete and abstract wordslanguage deficits
Hesling, Dilharreguy, Peppe, et al,8 (8)8 (8)23.± 38 ± 2.1023.05 ± 2.02Listened to speech stimulus involvingAbnormal neural network for prosodic speech perception in leftProsodic impairments could not only result from activation pattern
2010 [251]variable intonation, rhythm, focus andsupra marginal gyrus;abnormalities, but also from an inability to inhibit default network
affectAbsence of deactivation patterns in default mode
Just, Cherkassky, Keller, Minshew,17 (13)17 (12)28.0 ± 13.328.6 ± 10.7Identified agent or object in each sentence↑WA;Decreased information synchronization across the language
2004 [252]↓BA;processing network
Decreased functional connectivity between contributing cortical areas
Kana, Keller, Cherkassky, Minshew,12 (11)13 (12)22.5 ± 8.820.3 ± 4.0Processed sentences with high or lowLanguage and spatial centers not as synchronized,Under-integration of language and imagery;
Just, 2006 [253]imagery content↑Parietal and occipital regions during low-imagery sentencesReliance on visualization to support language comprehension
Kana, Wadsworth, 2012 [254]16 (16)16 (16)20.0 ± 6.4321.6 ± 2.70Processed sentences with puns↑Overall, particularly in right hemisphere and posterior areas duringAltered neural route in language comprehension in general, and
pun comprehension;figurative language in particular
↓Left hemisphere
Kleinhans, Muller, Cohen, Courchesne,14 (14)14**23.79 ± 3.5822.41 ± 8.67(1) Letter fluency task;↑Right frontal and right superior TL during letter fluency task;Reduced hemispheric differentiation for certain verbal fluency
2008 [255](2) Category fluency taskDecreased lateralization of activation patterns during letter fluency,tasks; abnormal functional organization may contribute to the
but not to categorylanguage impairments
Knaus, Silver, Lindgren, Hadjikhani,12 (12)12 (12)15.46 ± 2.4814.94 ± 2.71Reading version of response-naming task↑BA;Decreased efficiency of semantic processing
Tager-FIusberg, 2008 [256]Reduced BA left lateralization
Knaus, Silver, Kennedy, et aI, 2010 [257]14 (14)20 (20)16.83 ± 2.3514.43 ± 2.47(1) Response-naming task;Atypical language laterality more prevalent in the ASD groupLanguage laterality may be a novel way to subdivide samples,
(2) Control letter-judgment taskresulting in more homogenous groups
Lai, Schneider, Schwarzenberger,39 (35)15 (10)12.4 ± 4.712.13 ± 4.34Listened to speech
Hirsch, 2011 [258]↓Mean amplitude and spread of activity in STGPossible neurofunctional correlate of language impairment
Lai, Fantazatos, Schneider, Hirsch,36 (32)21 (14)9.61 ± 4.0410.72 ± 4.42Listened to speech and songs↓Left IFG during speech;Functional systems that process speech and song more effectively
2012 [259]↑Left IFG during songs;engaged for song than for speech
Increased left IFG-STG connectivity for songs;
Increased frontal-posterior connectivity
Mizuno, Liu, Williams, et al, 2011 [260]15 (14)15 (15)24.7 ± 7.824.7 ± 7.7Linguistic perspective-taking task requiring↑Right Al, precuneus;Higher activation compensates for decreased connectivity during
deictic shiftingDecreased right Al-precuneus connectivitydeictic shifting
Redcay, Courchesne, 2008 [261]12 (12)23 (17)34.9 mo ±19.8 mo ± 4.2Listened to forward and backward speech↓Extended network recruited in typical early language acquisition,Children with ASDs may be on a deviant developmental trajectory
7.4↑Medial, right GC;characterized by greater recruitment of right hemisphere regions
↑Right hemisphere to forward speechduring speech perception
Redcay, Dodell-Feder, Mavros, et al,13 (10)14 (11)28.0 ± 7.0527.0 ± 5.68Interactive face-to-face joint attention↓Left posterior STS, DMPFC during joint attention;Failure of developmental neural specialization in STS and DMPFC
2012 [262]game↑Posterior STS during solo attentionduring joint attention
Sahyoun, Belliveau, Soulieres,12 (10)12 (9)13.3 ± 2.4513.3 ± 2.07Pictorial reasoning with visuospatial processing, semantic↑Occipito-parietal, ventral temporal areas;Greater visual mediation of language processing
Schwartz, Mody, 2010 [263]processing, or bothReduced inferior frontal - ventral temporal and middle temporal
connectivity
Scott-Van Zeeland, McNealy, Wang, et al,18 (18)18 (18)12.62 ± 2.511.64 ± 1.58Listened to two artificial languages and a↑Frorto-temporal-parietal, as number of cues to word boundariesAbnormalities in neural regions subserving language-related
2010 [264]random speech streamincreased;learning;
No learning-related increases for artificial languages in BG, left temCommunicative impairments linked to decreased sensitivity to the
poroparietal cortex;statistical and speech cues in language
Communicative impairment correlated with signal increases in these
regions to artificial languages
Tesink, Buitelaar, Petersson, et al,24 (16)24 (16)26.3 ± 6.326.2 ± 6.0Speaker inference task↑Right IFG for speaker-incongruent sentences,Compensatory mechanisms during implicit low-level inferential
2009 [265]Absence of VMPFC modulation to incongruent sentencesprocesses in spoken language
Tesink, Buitelaar, Petersson, et al,24 (16)24 (16)26.3 ± 6.326.2 ± 6.0Integrated contextual information during↓Left, right IFG for sentences with world knowledge anomalyReduced integrative capacity of stored knowledge;
2011 [266]auditory language comprehensionDifficulties with exception handling
Vaidya, Foss-Feig, Shook, et al,15 (11)18 (14)10.78 ± 1.2910.96 ± 1.26Responded to target word in presence ofCongruent regions associated with attention to gaze (left STS, PMC)Atypical functional anatomy to social and nonsocial communicative
2011 [267]congruent or incongruent arrow oractivated to arrows;cues
averted gazeIncongruent regions associated with arrows (ACC, left DLPFC, right
CN) activated to gaze

Reward processing

The social-communication deficits that characterize ASDs may reflect decreased motivation to engage in social behaviors in early childhood. This decreased motivation may result in fewer experiences with the social environment,99 further compounding social-communicative deficits.100 Reward processing is mediated primarily by dopaminergic projections from the ventral tegmental area to the striatum, orbitofrontal cortex, ventromedial prefrontal cortex, and the anterior cingulate cortex, forming a mesolimbic dopamine reward pathway.101 Emerging evidence suggests that the neural circuits that mediate reward processing may have evolved, at least in part, to facilitate social attachment,102 and reward mechanisms serve to encode and consolidate positive memories of social experiences, facilitating social functioning abilities hypothesized to be impaired in ASDs.103

Reward processing deficits in ASDs have been assessed in six fMRI studies to date (Table V). Schmitz and colleagues104 reported decreased left anterior cingulate gyrus and left midfrontal gyrus activation to rewarded trials during a sustained attention task in ASDs and that anterior cingulate gyrus activation predicted social symptom severity. Scott-Van Zeeland and colleagues105 reported ventral striatal hypoactivation during social and nonsocial learning in ASDs. During a rewarded go/no-go paradigm, Kohls and colleagues106 found ventral striatal hypoactivation to monetary rewards and amygdala and anterior cingulate cortex hypoactivation to monetary and social rewards in children with ASDs. Cascio and colleagues107 reported increased bilateral insula and anterior cingulate cortex activation to images of food in children with ASDs who had fasted for at least 4 hours. Two studies by Dichter and colleagues,49,108 using incentive delay tasks, found decreased nucleus accumbens activation during monetary anticipation, bilateral amygdala hyperactivation during face anticipation that predicted social symptom severity (Figure 1), insular cortex hyperactivation during face outcomes, and ventromedial prefrontal cortex hyperactivation while viewing images related to circumscribed interests in ASDs. Taken together, these results suggest that reward network dysfunction in ASDs may not be constrained to responses to social rewards, but rather may be characterized by anomalous responsivity that is contingent on the type of reward processed. When considered in light of empirical findings of dysfunctional reward circuitry in a number of psychiatric conditions, including substance use disorders, schizophrenia, affective disorders, and attention deficit/hyperactivity disorder, abnormal mesolimbic responses to rewards appears to be a common endophenotype that may cut across diagnostic boundaries.109

Figure 1.
Figure 1. Individuals with autism spectrum disorders demonstrated bilateral amygdala hyperactivation during the anticipation of social rewards (left), and activation magnitude predicted social impairments (right). This pattern was not evident during the actual presentation of social rewards, or in response to other types of rewards. This and related findings suggest that the functional integrity of brain reward systems in autism spectrum disorders is contingent on both the type of reward processed and the temporal phase of the reward response. ADOS, Autism Diagnostic Observation Schedule. Adapted from ref 49: Dichter GS, Richey JA, Rittenberg AM, Sabatino A, Bodfish JW. Reward circuitry function in autism during face anticipation and outcomes. J Autism Dev Disord. 2012;42:147-160. Copyright © Springer 2012

Studies investigating reward processing in autism spectrum disorders. ASD: Autism Spectrum Disorder; TYP: Neurotypical; †ASD refers to the entire autism sample in a particular study, including high functioning autism, Asperger's syndrome, and pervasive developmental disorder not otherwise specified; *Total number of participants is presented first followed by the number of females in parentheses, if reported; **Not specified; ↓: decreased activation; ↑: increased activation. Abbreviations used in tables: ACC, anterior cingulate cortex; ACG, anterior cingulate gyms; AG, angular gyms; Al, anterior insula; AMY, amygdala; ATL, anterior temporal lobe; BA, Broca's area; BG, basal ganglia; CM, caudate nucleus; DAC, dorsal anterior cingulate; DLPFC, dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex; DN, dentate nucleus; FFA, fusiform face area; FG, fusiform gyms; IC, insular cortex; IFA, inferior frontal area; IFC, inferior frontal cortex; IFG, inferior frontal gyrus; IPL, inferior parietal lobe; ITG, inferior temporal gyrus; LG: lingual gyrus; LSTG, left superior temporal gyrus; MCG, >middle cingulate gyrus; MFC, midfrontaI cortex; MFG, midfrontal gryus; MFL, medial frontal lobes; NAC, nucleus accumbens; OFC, orbitofrental cortex; OFG, orbitofrental gyrus; MPFC, medial prefrontal cortex; MTG, medial temporal gyrus; PO, pars opercularis; PCC, posterior cingulate cortex; PFC, prefrontal cortex; PHG, parahippocampal gyrus; PL, parietal lobe; PMC, premotor cortex; PVC, primary visual cortex; RPVC, right primary visual cortex; SFG, superior frontal gyrus; SPL, superior parietal lobe; STG, superior temporal gyrus; STS, superior temporal sulcus; THAL, thalamus; TL, temporal lobe; TPJ, temporoparietal junction; VS, ventral striatium; VLPFC, ventrolateral prefrontal cortex; VOC, ventral occipital cortex; VMPFC, ventromedial prefrontal cortex; WA, Wernicke's Area

CitationASD*†TYP*†ASD ageTYP ageTask(s)Core findings in ASD group (relative to controls)Conclusions
Cascio, Foss-Feig, Heacock, et al,17 (17)23**12.8 ± 2.513.2 ± 3.4Viewed images of high-calorie foods after↑Bilateral insula along anterior-posterior gradient;Abnormally enhanced neural response to primary rewards in ASD
2012 [268]fasting↑ACC to food cues
Dichter, Richey, Rittenberg,16 (14)20 (14)26.0 ± 9.125.4 ± 7.0Incentive delay task with monetary and↓NAC, OFC during monetary anticipation;Domain-general reward circuitry dysfunction, atypical amygdala
2012 [269]social rewards↑Right insula to face incentives;activation to social rewards may contribute to social symptom
↑Bilateral AMY during face anticipation that correlated with socialseverity in ASD
symptoms
Dichter, Felder, Green, et al, 2012 [270]15 (15)16 (16)30.1 ± 11.627.5 ± 7.5Incentive delay task with monetary↓NAC during monetary anticipation and outcomes;Reward circuitry hypoactwation to monetary incentives but hyper-
rewards and rewards related to↑VMPFC to circumscribed interests incentivesactivation to circumscribed interests in ASD. Possible neural mecha-
circumscribed interestsnism of circumscribed interests in ASD
Kohls, Schulte-Ruther, Nehrkorn,15 (15)17 (17)14.6 ± 3.313.9 ± 3.0Go/no-go task with social vs. monetary↓Midbrain, THAL, AMY, striatium, ACC to both rewards;Domain-general reward system dysfunction in ASD
et al, 2012 [271]rewards↓NAC to monetary reward, but not social reward
Schmitz, Rubia, van Amelswoort,10 (10)10 (10)37.8 ± 738.2 ± 6Rewarded continuous performance task↑Left ACG during reward trials that correlated with social symptomReward achievement associated with abnormal activation in areas
et al, 2008 [272]severity;responsible for attention and arousal in ASD
Scott-Van Zeeland, Dapretto,16 (16)16 (16)12.4 ± 2.1412.3 ± 1.76Implicit learning task with social vs.↓VS to both social and monetary rewards (more pronounced toDiminished neural responses during social reward learning may
Ghahremani, 2010 [273]monetary rewardssocial rewards.contribute to social learning impairments in ASD

Functional connectivity

Whereas task-based fMRI studies focus on activity within specific brain regions evoked by cognitive tasks, studies of functional connectivity speak to the temporal dynamics of brain network activity. Hie integrity of brain connections affects integration and synchronization of information processing, and the study of functional connectivity in ASDs addresses circuitry-level questions believed to be central to dysfunction in ASDs.6 There is a confluence of evidence that ASDs are characterized by decreased connectivity, in particular between frontal and posterior-temporal cortical systems that play key roles in processing social-affective information.110 Although initial studies highlighted cortical underconnectivity in ASDs, more recent data suggests that ASDs may be characterized by both local overconnectivity and longdistance underconnectivity. It has been suggested that a cortical underconnectivity account of ASDs may address heterogeneity as well as broad information processing deficits in general, rather than the expression of specific core symptoms.111

Task-based functional connectivity

The majority of task-based studies in ASDs have documented reduced functional connectivity between frontal and parietal regions75,83,112 as well as between frontal and temporal and/or occipital regions.69,113 Tasks have included language comprehension,83,88,97 cognitive control,69,75,114 mentalizing,53,113,115 social processing,113 working memory,116 and visuospatial processing.112 A number of these studies have also indicated smaller and less synchronized cortical networks in ASDs.116-117 It should be noted, however, that some task-based studies have found long-range over-connectivity between subcortical and cortical regions118-119 as well as between frontal and temporal regions.120-122 Other studies have examined connectivity during task-related paradigms by filtering out taskrelated activity to examine connectivity patterns that are task-independent, and found evidence of decreased123-124 and increased118-121 functional connectivity.

Resting-state functional connectivity

Relatively fewer studies have examined brain connectivity in ASDs during resting state fMRI scans (Table VI). Cherkassky and colleagues125 reported decreased frontalposterior default network connectivity during task-based inter-trail intervals (see also refs 126-128) while others have found lower default-mode network connectivity at rest125,128-131 in ASDs. There are also reports of decreased connectivity between the anterior and posterior insula and a number of social processing brain regions in ASDs75,114,116 and less coherent endogenous low-frequency oscillations across multiple cortical and subcortical regions in ASDs.132 von dem Hagen and colleagues133 reported reduced functional connectivity within and between resting state networks incorporating “social brain regions” including the insula and amygdala within the default-mode and salience networks, respectively, and Di Martino and colleagues134 reported increased connectivity between multiple striatal regions and striatal hyperconnectivity with the pons. Monk and colleagues127 reported positive correlations between repetitive behavior symptoms and resting state connectivity between posterior cingulate cortex and the right parahippocampal gyrus in adults with ASDs, despite increased connectivity between the posterior cingulate cortex, the right temporal lobe, and the right parahippocampal gyrus, although Weng and collègues128 found correlations between social and repetitive behavior symptoms and a number of resting connectivity metrics in adolescents with ASDs.

Studies investigating resting state connectivity in autism spectrum disorders. ASD: Autism Spectrum Disorder; TYP: Neurotypical; †ASD refers to the entire autism sample in a particular study, including high functioning autism, Asperger's syndrome, and pervasive developmental disorder not otherwise specified; *Total number of participants is presented first followed by the number of females in parentheses, if reported; **Not specified; ↓: decreased activation; ↑: increased activation. Abbreviations used in tables: ACC, anterior cingulate cortex; ACG, anterior cingulate gyms; AG, angular gyms; Al, anterior insula; AMY, amygdala; ATL, anterior temporal lobe; BA, Broca's area; BG, basal ganglia; CM, caudate nucleus; DAC, dorsal anterior cingulate; DLPFC, dorsolateral prefrontal cortex; DMPFC, dorsomedial prefrontal cortex; DN, dentate nucleus; FFA, fusiform face area; FG, fusiform gyms; IC, insular cortex; IFA, inferior frontal area; IFC, inferior frontal cortex; IFG, inferior frontal gyrus; IPL, inferior parietal lobe; ITG, inferior temporal gyrus; LG: lingual gyrus; LSTG, left superior temporal gyrus; MCG, >middle cingulate gyrus; MFC, midfrontaI cortex; MFG, midfrontal gryus; MFL, medial frontal lobes; NAC, nucleus accumbens; OFC, orbitofrental cortex; OFG, orbitofrental gyrus; MPFC, medial prefrontal cortex; MTG, medial temporal gyrus; PO, pars opercularis; PCC, posterior cingulate cortex; PFC, prefrontal cortex; PHG, parahippocampal gyrus; PL, parietal lobe; PMC, premotor cortex; PVC, primary visual cortex; RPVC, right primary visual cortex; SFG, superior frontal gyrus; SPL, superior parietal lobe; STG, superior temporal gyrus; STS, superior temporal sulcus; THAL, thalamus; TL, temporal lobe; TPJ, temporoparietal junction; VS, ventral striatium; VLPFC, ventrolateral prefrontal cortex; VOC, ventral occipital cortex; VMPFC, ventromedial prefrontal cortex; WA, Wernicke's Area

CitationASD*†TYP*†ASD ageTYP ageTask(s)Core findings in ASD group (relative to controls)Conclusions
Anderson, Nielsen, Froehlich, et al,40 (40)40 (40)22.7 ± 7.421.6 ± 7.48' resting scan with eyes openNegatively correlated ROI pairs showed decreased anticorrelation inWeaker inhibitory connections, particularly for long connections;
2011 [274]ASD;Resting state fMRI may be feasible as a diagnostic classifier for ASD
Greatest connectivity differences in default mode network, superior
parietal lobule, FG and Al
Cherkassky, Kana, Keller, Just,57 (53)57 (52)24.0 ± 10.624.0 ± 9Periods of rest during task-based scansDecreased connectivity in resting-state networks despite similar vol-Resting state underconnectivity in ASD
2006 [275](duration not specified)ume and organization;
Decreased posterior-anterior connectivity
Di Martinet, Kelly, Grzadzinski, et al,20 (17)20 (14)10.4 ± 1.710.9±1.66' 38'' resting scan with eyes openIncreased connectivity between striatal subregions and heteromodalIncreased connectivity in ectopic circuits reflects alternate trajectory
2011 [276]associative and limbic cortex;
Increased pons-striatum and pons-insula connectivityof development, rather than immaturity of circuits
Kennedy, Courchesne, 2008 [277]13 (13)12 (12)26.9 ± 12.327.5 ± 10.97' 10'' resting scan with eyes openReduced default mode network connectivityAltered functional organization of the network involved in social
and emotional processing
Lai, Lombardo, Chakrabarti, et al,18 (18)33 (33)26.9 ± 7.428.4 ± 6.113' 39'' resting scan with eyes dosed (onlyMore randomness in midline structures,ASD associated with small but significant shift towards randomness
2010 [278]last 512 of 625 volumes analyzed).medial temporal structures, lateral temporal and parietal structures, insula, AMY, BG, THAL, IFG;in endogenous brain oscillations
Social symptoms negatively correlated with randomness in retrosple-
nial and right anterior IC
Monk, Peltier, Wiggins, et aI,12 (11)12 (10)26 ± 5.9327 ± 6.110' resting scan with eyes openDecreased PCC-SFG connectivity;Altered intrinsic connectivity that was associated with core
2009 [279]Increased connectivity between PCC and right TL and right PHG;symptoms
Social symptoms correlated with PCC-SFG connectivity, repetitive
behaviors correlated with PCC - right PHG connectivity
Paakki, Rahko, Long et al, 2010 [280]28 (20)27 (18)14.58 ± 1.6214.49 ± 1.517' 36'' resting scan with eyes openDecreased regional homogeneity in right STS, right IFS, right MFG,Right-dominant alterations of resting state activity
bilateral cerebellum, right insula, right postcentral gyrus;
Increased regional homogeneity in right THAL, left 1FG, left anterior
subcallosal gyrus, bilateral cerebellar lobule VIII
von dem Hagen, Stoyanowa,18 (18)25 (25)30 ± 825 ± 610' resting scan with eyes openDecreased default mode network connectivity;Reduced connectivity in networks involved with the “social brain”,
Baron-Cohen, Calder,2012 [281]Decreased connectivity in salience network (includes insula) and aMay be implicated in difficulties with communication and informa-
medial TL network (includes AMY)tion integration
Weng, Wiggins, Peltier, et al,16 (14)15 (14)15.0 ± 1.4516.0 ± 1.4410' resting scan with eyes openDecreased connectivity in 9 of 11 default mode areas;Decreased default mode network connectivity in adolescents with
2010 [282]Social and repetitive behavior symptoms correlated with decreasedASDs than in adults with ASDs
connectivity in parts of default mode network;
Communication correlated with increased connectivity in parts of
default mode network
Wiggins, Peltier, Ashmoff et al, 201139 (32)41 (33)14.0 ± 2.0815.3 ± 2.410' resting scan with eyes openDecreased connectivity between posterior hub of default networkDifferent developmental trajectory of default mode network
[283]and right SFG;
Less increase in connectivity with age

Structural MRI

Functional MRI results should ultimately be considered within a broader neuroimaging literature addressing brain structure and white matter connectivity in ASDs. Structural MRI yields information about brain anatomy, including gray- and white-matter volumes as well as gyrus and sulcus development, and this approach is wellsuited for studies seeking to predict future ASDs diagnoses in infants. Very briefly, the structural MRI literature indicates accelerated brain growth during earlydevelopment in ASDs.135,136 There are reports of significantly large head circumference137 and brain volume in children with autism.138 Longitudinal studies indicate that ASDs are characterized by an early transient period of postnatal brain overgrowth evident in 70% of children with ASDs before age 2 that is not present in adolescence and adulthood.139-140 Evidence of enlarged total brain size in ASDs is accompanied by studies showing smaller cerebellar vermis,141,142 amygdala, and hippocampus.138 Increased brain size in young children with ASDs has also been linked to increased frontal lobe white matter143 followed by reduced white matter in early and late adolescence and adulthood.144,145

Diffusion tensor imaging

Because the contrast properties of structural MRI are suboptimal for differentiating still-myelinating white matter from surrounding gray matter in children,146 diffusion tensor imaging (DTI), a measure of microstructural properties of white matter fibers, has emerged as a valuable tool to assess white-matter structure in very young samples.147 There is evidence of widespread abnormalities in white-matter fiber tract integrity in ASDs, but the extent and developmental course of these differences remains unclear.148-151 Two- to three-year-old children with ASDs are characterized by increased fractional anisotropy (an index of white matter fiber density) in the frontal lobes and in the corpus callosum,152 but in 5-year-old children with ASDs fractional anisotropy was reduced in frontal lobe tracts and no different from controls in tracts connecting frontal and posterior regions.153 In 10- to 18-year-old children with ASDs, there is evidence of reduced fractional anisotropy in frontal-posterior tracts154 and in hemispheric fractional anisotropy lateralization in the arcuate fasciculus,155,156 but fractional anisotropy was found to be reduced in adolescents with ASDs in prefrontal cortex and tempoparietal junction.157 It thus appears that young children with ASDs are characterized by increased fractional anisotropy- in brain areas mediating social communication, whereas adolescents and adults with ASDs are characterized by generally lower fractional anisotropy, a pattern that recapitulates patterns of brain overgrowth discussed earlier.

Finally, a prospective DTI study of 6- to 24-month-old infants at high-risk of developing ASDs found that fractional anisotropy trajectories for 12 of 15 fiber tracts examined differed between infants who later were identified as having an ASDs and those who did not. Infants who went on to have a diagnosis of an ASD had fiber tracts characterized by higher fractional anisotropy at 6 months of age, slower change between 6 and 24 months of age, and lower fractional anisotropy at 24 months of age.158

Summary

The goal of this review is to highlight consistencies in the ASD fMRI literature. Given the array of imaging tasks reviewed, it is perhaps not surprising that findings are heterogenous. Despite variations in findings, there is a sufficient degree of consistency to draw a number of substantive conclusions. Studies of social processes have generally found evidence of hypoactivation in nodes of the “social brain,” including the medial prefrontal cortex, the inferior frontal gyrus and the anterior insula, the posterior superior temporal sulcus, the interparietal sulcus, the amygdala, and the fusiform gyrus. Studies addressing cognitive control, designed to address neural mechanisms underlying restricted and repetitive behaviors and interests, have converged on aberrant frontostriatal functioning in ASDs, specifically in inferior and middle frontal gyri, anterior cingulate cortex, and the basal ganglia. Communication impairments in ASDs have been linked to differential patterns of language function lateralization, decreased synchrony- of brain regions processing language, and recruitment of brain regions that do not typically processing language. Reward processing studies have highlighted mesolimbic and mesocortical impairments when processing both social and nonsocial incentives in ASDs. Finally, task-based functional connectivity studies in ASDs have reported local overconnectivity and long-distance (ie, between frontal and posterior regions) underconnectivity-, whereas resting state connectivity studies indicate decreased anterior-posterior connectivity and less coherent endogenous low-frequency oscillations across multiple regions.

Future directions

Most studies reviewed here focus on adulthood or adolescence, yet ASDs are present from very early childhood. It will be critical to address developmental profiles in children with ASDs to disambiguate proximal effects of altered brain function from downstream effects on learning and motivation. There also may be critical periods during early development when brain dysfunction creates a predisposition to develop a number of disorders, and understanding factors that influence these processes will be essential for the prevention of symptom onset. Indeed, emerging techniques allow for functional brain imaging in children as young as 12 months old, and future studies that focus on young samples are needed. Additionally, most studies reviewed here contain small samples, and larger samples will be needed to identify meaningful subgroups and track developmental profiles. Given the high costs associated with brain imaging and challenges recruiting large pediatric patient samples, it will be critical to leverage available bioinformatics tools to facilitate data sharing across research groups. Such tools are under development159 and the National Institutes of Health recently established a database for sharing ASDs neuroimaging data.160

There is also a need to move to designs that incorporate psychiatric comparisons to delineate brain activation patterns in ASDs that diverge and converge with other disorders characterized by social communication impairments and repetitive behaviors. Similarly, ASDs are commonly comorbid with other psychiatric and neurodevelopmental conditions,161 possibly due to shared genetic etiology and common socioenvironmental determinants, and thus it will be important to examine ASD samples with and without comorbid conditions to refine our understanding of neural endophenotypes in ASDs. Finally, the literature reviewed here is cross-sectional. Though these studies have elucidated aberrant patterns of brain activation in ASDs, these paradigms have rarelybeen applied to longitudinal treatment outcome studies aimed at understanding mechanisms of action of treatment response in ASDs. As neuroimaging and data-sharing techniques evolve, functional brain imaging will continue to improve our understanding of the pathophysiology of ASDs, with the ultimate goal of improved ASD identification and treatment.162