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1.  Striatal development in autism: repetitive behaviors and the reward circuitry 
Biological psychiatry  2014;76(5):358-359.
Autism spectrum disorder (ASD) is defined by two essential features – impaired social communication abilities, including deficits with social reciprocity, nonverbal communication and establishing relationships, and by the presence of restricted and repetitive behaviors and interests (RRBIs). Social deficits get the majority of attention both in science and in the popular media, but RRBIs are equally important in understanding autism. Although RRBIs are also seen in typically developing preschoolers, as well as in other psychiatric disorders such as obsessive-compulsive disorder, their impairing and persisting character is a hallmark of ASD1.
Repetitive behaviors are among the first signs of ASD, with significant elevations by the child's first birthday2. Individuals with ASD of all ages and cognitive ability levels display RRBIs to variable degrees, with males usually being more severely affected than females3. Caregivers of individuals with ASD commonly emphasize that RRBIs are among the most challenging facets of the disorder on an everyday basis1. They negatively impact social, cognitive, family functioning and well-being, often leading to increased levels of parental stress and negative parenting styles. While the clinical description and natural history of RRBIs is becoming clear, an understanding of the biological bases of this set of features has only recently begun to emerge4. Better insight into the ontogenesis of RRBIs and their underlying neurobiology is needed not only to inform models of the etiology of ASD, but also to foster the development of new interventions.
In this issue of Biological Psychiatry, Langen et al.5 examine differences in the rate of basal ganglia growth in ASD relative to typically developing children (TDC). Their volumetric analyses focused on developmental trajectories of the ventral striatum (with nucleus accumbens) and dorsal striatum (with caudate nucleus and putamen). These components of the basal ganglia are the major subcortical targets within the frontostriatal behavior control loops that are recognized as likely subserving RRBIs4. This current study is a follow up of this same group's earlier work showing cross sectional differences in growth trajectory. While several labs have previously reported enlargement of the caudate nucleus in ASD, this current study is the first to make repeat morphology measurements, thus overcoming limitations associated with cross sectional analyses. This study involved 86 seven to seventeen year old cases and controls who had 2 MRI anatomical scans approximately 2 and a half years apart on average, allowing a direct test of differential striatal growth. The rate of basal ganglia growth was correlated with the severity of RRBIs as assessed by parent interview at the time of the first MRI scan, corroborating earlier work on the role of the striatum in repetitive behaviors among children with ASD.
Specifically the caudate nucleus showed a growth rate in ASD that was twice as high as the growth rate in TDC (i.e., 4.6% vs. 2.3%). This was independent of overall brain growth, use of psychotropic medications, or other major confounds. Most importantly, more severe RRBIs early in life, particularly insistence on sameness behaviors, such as avoiding trivial changes in routines and environments as well as adhering to compulsions and rituals, were related to faster striatal growth between average ages of about 9 and 12 year old, with large effect sizes (e.g., caudate nucleus: Cohen's d = 0.86). While Langen et al. discuss several complementary explanations for their findings, they conclude that the divergent trajectory of caudate development in relation to RRBIs most likely results from early, and possibly continuing, patterns of repetitive behaviors that shape striatal development – not the other way around.
This new set of data elegantly adds to the notion that the striatum plays a central role in core ASD phenomenology6. However, one question lingers: what cause RRBIs, like insistence on sameness, compulsions and rituals, to become such a force so as to impact the growth trajectory of an evolutionarily ancient brain structure like the caudate nucleus? This question ties in with a long-standing debate among clinicians and scientists concerning the potential functions that the myriad of RRBIs might serve in individuals with ASD. While several plausible ideas have been advanced7, convincing support for any specific one is lacking.
One hypothesis that is gaining increased research attention, however, involves the effects of alterations of the balance between social and nonsocial motivation in reward circuitry on RRBIs8. This model suggests that ASD is in part a disorder of “behavioral dependency” to RRBIs because of the rewarding effects they induce1. Indeed, insistence on sameness and preoccupying restricted interests are reported to be quite pleasurable by affected individuals1. The dorsal striatum with caudate nucleus, in particular, is believed to mediate reward value for purposeful actions5. Functional imaging studies show that the brain's reward circuitry in ASD, particularly striatum and ventral prefrontal cortices, selectively over-reacts to objects that may comprise an intense special interest, whereas it under-reacts to more typical desires such as social reward and money6. This may indicate that the brain in ASD cares less for conventional rewards. It is not yet known if an initial lack of social reward motivation opens the door for enhanced rewarding effects of certain circumscribed objects, topics, and routines, or whether the reverse is true – that the dominating reward effects of nonsocial objects, topic and routines diminishes the reward value of social engagement.
The rewarding effects of RRBIs are thought to be fueled by the preference of those with ASD for predictability in their environment, where they can exercise more control; social encounters are in many ways the antithesis of this, as these are often rapid, hard to control and offer much more variable reinforcement contingencies. When RRBIs are rewarding, their pursuit may be strengthened through reinforcement mechanisms that progressively turn them into rigid and strongly desired habits that are performed almost automatically with little conscious oversight. With this heuristic model, RRBIs are self-reinforcing, and they begin to hijack the normal developmental trajectory of entire repertoires of behaviors. The dorsal (associative) striatum with caudate nucleus dominates these processes4. Thus, an accelerated growth rate of the caudate related to RRBIs, as reported by Langen et al.5, could reflect atypical brain specialization in individuals with ASD9. From early in life the caudate nucleus mediates habitual processes for a wide range of different stimuli and contexts. Across development, however, the caudate may become co-opted by the most rewarding aspects of the environment. This interactive and self-sustaining biobehavioral process – in concert with other mesocorticolimbic functions4 – may shape the growth trajectory of the caudate nucleus and strengthens the occurrence of RRBIs in ASD (Figure 1). On a day-to-day basis, RRBIs interfere with social development and functioning as they may absorb resources typically dedicated to other learning opportunities, including social ones6.
The observation that RRBIs in ASD involve plasticity of the caudate nucleus – one major hub within the frontostriatal circuits that control behavior – is a fascinating advance for our field. It brings us closer to the neurobiological roots of how and why affected individuals develop and maintain this set of challenging behaviors. Follow-up research will need to address several issues to improve upon the approach of the Langen et al study. One critical issue is that researchers need to use more precise behavioral measurement tools10. This could involve item rating scales with greater item density around key concepts, as it is clear to all the ADI-R is sorely lacking in this regard. Also, quantitative motion capture tools are now widely available; deploying these in natural environments seems to us to be extremely promising adjuncts to standard rating scales. Repeat behavioral measurement across time, in sync with repeat brain measurement is an important next step that will enable better characterization of the interplay between RRBIs and brain dynamics. In this regard, multimodal imaging in the same sample is called for, as structural imaging will surely only capture portions of the story. The findings by Langen et al.5 call attention to the importance of RRBIs in autism. Because RRBIs may be rooted in the powerful reward circuitries that motivate a great deal of behavior, strategically targeting the role of reward mechanisms promises to improve treatment practices for limiting the life interfering aspects of RRBIs among individuals with ASD and their families.
doi:10.1016/j.biopsych.2014.07.010
PMCID: PMC4780436  PMID: 25103541
2.  Social and monetary reward processing in autism spectrum disorders 
Molecular Autism  2012;3:7.
Background
Social motivation theory suggests that deficits in social reward processing underlie social impairments in autism spectrum disorders (ASD). However, the extent to which abnormalities in reward processing generalize to other classes of stimuli remains unresolved. The aim of the current study was to examine if reward processing abnormalities in ASD are specific to social stimuli or can be generalized to other classes of reward. Additionally, we sought to examine the results in the light of behavioral impairments in ASD.
Methods
Participants performed adapted versions of the social and monetary incentive delay tasks. Data from 21 unmedicated right-handed male participants with ASD and 21 age- and IQ-matched controls were analyzed using a factorial design to examine the blood-oxygen-level-dependent (BOLD) response during the anticipation and receipt of both reward types.
Results
Behaviorally, the ASD group showed less of a reduction in reaction time (RT) for rewarded compared to unrewarded trials than the control group. In terms of the fMRI results, there were no significant group differences in reward circuitry during reward anticipation. During the receipt of rewards, there was a significant interaction between group and reward type in the left dorsal striatum (DS). The ASD group showed reduced activity in the DS compared to controls for social rewards but not monetary rewards and decreased activation for social rewards compared to monetary rewards. Controls showed no significant difference between the two reward types. Increased activation in the DS during social reward processing was associated with faster response times for rewarded trials, compared to unrewarded trials, in both groups. This is in line with behavioral results indicating that the ASD group showed less of a reduction in RT for rewarded compared to unrewarded trials. Additionally, de-activation to social rewards was associated with increased repetitive behavior in ASD.
Conclusions
In line with social motivation theory, the ASD group showed reduced activation, compared to controls, during the receipt of social rewards in the DS. Groups did not differ significantly during the processing of monetary rewards. BOLD activation in the DS, during social reward processing, was associated with behavioral impairments in ASD.
doi:10.1186/2040-2392-3-7
PMCID: PMC3499449  PMID: 23014171
Autism; Reward; Social motivation; Striatum; Functional magnetic resonance imaging; fMRI
3.  Response of neural reward regions to food cues in autism spectrum disorders 
Background
One hypothesis for the social deficits that characterize autism spectrum disorders (ASD) is diminished neural reward response to social interaction and attachment. Prior research using established monetary reward paradigms as a test of non-social reward to compare with social reward may involve confounds in the ability of individuals with ASD to utilize symbolic representation of money and the abstraction required to interpret monetary gains. Thus, a useful addition to our understanding of neural reward circuitry in ASD includes a characterization of the neural response to primary rewards.
Method
We asked 17 children with ASD and 18 children without ASD to abstain from eating for at least four hours before an MRI scan in which they viewed images of high-calorie foods. We assessed the neural reward network for increases in the blood oxygenation level dependent (BOLD) signal in response to the food images
Results
We found very similar patterns of increased BOLD signal to these images in the two groups; both groups showed increased BOLD signal in the bilateral amygdala, as well as in the nucleus accumbens, orbitofrontal cortex, and insula. Direct group comparisons revealed that the ASD group showed a stronger response to food cues in bilateral insula along the anterior-posterior gradient and in the anterior cingulate cortex than the control group, whereas there were no neural reward regions that showed higher activation for controls than for ASD.
Conclusion
These results suggest that neural response to primary rewards is not diminished but in fact shows an aberrant enhancement in children with ASD.
doi:10.1186/1866-1955-4-9
PMCID: PMC3436657  PMID: 22958533
4.  Reward system dysfunction in autism spectrum disorders 
Although it has been suggested that social deficits of autism spectrum disorders (ASDs) are related to reward circuitry dysfunction, very little is known about the neural reward mechanisms in ASD. In the current functional magnetic resonance imaging study, we investigated brain activations in response to both social and monetary reward in a group of children with ASD, relative to matched controls. Participants with ASD showed the expected hypoactivation in the mesocorticolimbic circuitry in response to both reward types. In particular, diminished activation in the nucleus accumbens was observed when money, but not when social reward, was at stake, whereas the amygdala and anterior cingulate cortex were hypoactivated within the ASD group in response to both rewards. These data indicate that the reward circuitry is compromised in ASD in social as well as in non-social, i.e. monetary conditions, which likely contributes to atypical motivated behaviour. Taken together, with incentives used in this study sample, there is evidence for a general reward dysfunction in ASD. However, more ecologically valid social reward paradigms are needed to fully understand, whether there is any domain specificity to the reward deficit that appears evident in ASD, which would be most consistent with the ASD social phenotype.
doi:10.1093/scan/nss033
PMCID: PMC3682440  PMID: 22419119
autism spectrum disorders; reward; functional magnetic resonance imaging; limbic system; nucleus accumbens
5.  Impaired Learning of Social Compared to Monetary Rewards in Autism 
A leading hypothesis to explain the social dysfunction in people with autism spectrum disorders (ASD) is that they exhibit a deficit in reward processing and motivation specific to social stimuli. However, there have been few direct tests of this hypothesis to date. Here we used an instrumental reward learning task that contrasted learning with social rewards (pictures of positive and negative faces) against learning with monetary reward (winning and losing money). The two tasks were structurally identical except for the type of reward, permitting direct comparisons. We tested 10 high-functioning people with ASD (7M, 3F) and 10 healthy controls who were matched on gender, age, and education. We found no significant differences between the two groups in terms of overall ability behaviorally to discriminate positive from negative slot machines, reaction-times, and valence ratings, However, there was a specific impairment in the ASD group in learning to choose social rewards, compared to monetary rewards: they had a significantly lower cumulative number of choices of the most rewarding social slot machine, and had a significantly slower initial learning rate for the socially rewarding slot machine, compared to the controls. The findings show a deficit in reward learning in ASD that is greater for social rewards than for monetary rewards, and support the hypothesis of a disproportionate impairment in social reward processing in ASD.
doi:10.3389/fnins.2012.00143
PMCID: PMC3461406  PMID: 23060743
social reward; monetary reward; autism
6.  Preserved reward outcome processing in ASD as revealed by event-related potentials 
Background
Problems with reward system function have been posited as a primary difficulty in autism spectrum disorders. The current study examined an electrophysiological marker of feedback monitoring, the feedback-related negativity (FRN), during a monetary reward task. The study advanced prior understanding by focusing exclusively on a developmental sample, applying rigorous diagnostic characterization and introducing an experimental paradigm providing more subtly different feedback valence (reward versus non-reward instead of reward versus loss).
Methods
Twenty-six children with autism spectrum disorder and 28 typically developing peers matched on age and full-scale IQ played a guessing game resulting in monetary gain (“win”) or neutral outcome (“draw”). ERP components marking early visual processing (N1, P2) and feedback appraisal (FRN) were contrasted between groups in each condition, and their relationships to behavioral measures of social function and dysfunction, social anxiety, and autism symptomatology were explored.
Results
FRN was observed on draw trials relative to win trials. Consistent with prior research, children with ASD exhibited a FRN to suboptimal outcomes that was comparable to typical peers. ERP parameters were unrelated to behavioral measures.
Conclusions
Results of the current study indicate typical patterns of feedback monitoring in the context of monetary reward in ASD. The study extends prior findings of normative feedback monitoring to a sample composed exclusively of children and demonstrates that, as in typical development, individuals with autism exhibit a FRN to suboptimal outcomes, irrespective of neutral or negative valence. Results do not support a pervasive problem with reward system function in ASD, instead suggesting any dysfunction lies in more specific domains, such as social perception, or in response to particular feedback-monitoring contexts, such as self-evaluation of one’s errors.
doi:10.1186/1866-1955-4-16
PMCID: PMC3436639  PMID: 22958616
Autism spectrum disorder; Reward processing; Event-related potentials; Electroencephalography; ERP; EEG; Feedback-related negativity; Medial-frontal negativity
7.  Neural mechanisms of negative reinforcement in children and adolescents with autism spectrum disorders 
Background
Previous research has found accumulating evidence for atypical reward processing in autism spectrum disorders (ASD), particularly in the context of social rewards. Yet, this line of research has focused largely on positive social reinforcement, while little is known about the processing of negative reinforcement in individuals with ASD.
Methods
The present study examined neural responses to social negative reinforcement (a face displaying negative affect) and non-social negative reinforcement (monetary loss) in children with ASD relative to typically developing children, using functional magnetic resonance imaging (fMRI).
Results
We found that children with ASD demonstrated hypoactivation of the right caudate nucleus while anticipating non-social negative reinforcement and hypoactivation of a network of frontostriatal regions (including the nucleus accumbens, caudate nucleus, and putamen) while anticipating social negative reinforcement. In addition, activation of the right caudate nucleus during non-social negative reinforcement was associated with individual differences in social motivation.
Conclusions
These results suggest that atypical responding to negative reinforcement in children with ASD may contribute to social motivational deficits in this population.
doi:10.1186/s11689-015-9107-8
PMCID: PMC4379694  PMID: 25829969
Autism spectrum disorders (ASD); Negative reinforcement; Reward processing; Social motivation; Reward loss; Reward motivation
8.  Mentalizing and motivation neural function during social interactions in autism spectrum disorders☆ 
NeuroImage : Clinical  2013;3:321-331.
Autism Spectrum Disorders (ASDs) are characterized by core deficits in social functions. Two theories have been suggested to explain these deficits: mind-blindness theory posits impaired mentalizing processes (i.e. decreased ability for establishing a representation of others' state of mind), while social motivation theory proposes that diminished reward value for social information leads to reduced social attention, social interactions, and social learning. Mentalizing and motivation are integral to typical social interactions, and neuroimaging evidence points to independent brain networks that support these processes in healthy individuals. However, the simultaneous function of these networks has not been explored in individuals with ASDs. We used a social, interactive fMRI task, the Domino game, to explore mentalizing- and motivation-related brain activation during a well-defined interval where participants respond to rewards or punishments (i.e. motivation) and concurrently process information about their opponent's potential next actions (i.e. mentalizing). Thirteen individuals with high-functioning ASDs, ages 12–24, and 14 healthy controls played fMRI Domino games against a computer-opponent and separately, what they were led to believe was a human-opponent. Results showed that while individuals with ASDs understood the game rules and played similarly to controls, they showed diminished neural activity during the human-opponent runs only (i.e. in a social context) in bilateral middle temporal gyrus (MTG) during mentalizing and right Nucleus Accumbens (NAcc) during reward-related motivation (Pcluster < 0.05 FWE). Importantly, deficits were not observed in these areas when playing against a computer-opponent or in areas related to motor and visual processes. These results demonstrate that while MTG and NAcc, which are critical structures in the mentalizing and motivation networks, respectively, activate normally in a non-social context, they fail to respond in an otherwise identical social context in ASD compared to controls. We discuss implications to both the mind-blindness and social motivation theories of ASD and the importance of social context in research and treatment protocols.
Highlights
•We used an fMRI Domino game to map social networks in high-functioning ASDs.•ASDs did not show MTG increased activation during mentalizing in social context.•ASDs did not show NAcc increased activation for processing reward in social context.•Activation deficits were specific to brain areas involved in social processes.•Results support both the mind-blindness and the social motivation theories of ASDs.
doi:10.1016/j.nicl.2013.09.005
PMCID: PMC3815022  PMID: 24273716
Theory of mind; Reward; Nucleus accumbens; Middle temporal gyrus
9.  Early neural activation during facial affect processing in adolescents with Autism Spectrum Disorder☆ 
NeuroImage : Clinical  2014;7:203-212.
Impaired social interaction is one of the hallmarks of Autism Spectrum Disorder (ASD). Emotional faces are arguably the most critical visual social stimuli and the ability to perceive, recognize, and interpret emotions is central to social interaction and communication, and subsequently healthy social development. However, our understanding of the neural and cognitive mechanisms underlying emotional face processing in adolescents with ASD is limited. We recruited 48 adolescents, 24 with high functioning ASD and 24 typically developing controls. Participants completed an implicit emotional face processing task in the MEG. We examined spatiotemporal differences in neural activation between the groups during implicit angry and happy face processing. While there were no differences in response latencies between groups across emotions, adolescents with ASD had lower accuracy on the implicit emotional face processing task when the trials included angry faces. MEG data showed atypical neural activity in adolescents with ASD during angry and happy face processing, which included atypical activity in the insula, anterior and posterior cingulate and temporal and orbitofrontal regions. Our findings demonstrate differences in neural activity during happy and angry face processing between adolescents with and without ASD. These differences in activation in social cognitive regions may index the difficulties in face processing and in comprehension of social reward and punishment in the ASD group. Thus, our results suggest that atypical neural activation contributes to impaired affect processing, and thus social cognition, in adolescents with ASD.
Highlights
•The ability to recognize and interpret emotions is central to social interaction.•Deficits in social interactions are hallmarks of autism spectrum disorder (ASD).•Adolescents with and without ASD completed an emotional face task in MEG.•MEG data showed atypical neural activity in ASD to both angry and happy faces.•Insula, cingulate, temporal and orbitofrontal activities were particularly affected in the ASD group.
doi:10.1016/j.nicl.2014.11.009
PMCID: PMC4300004  PMID: 25610782
Implicit face processing; Adolescents; Autism Spectrum Disorder; Magnetoencephalography; Affect processing; Anterior cingulate cortex
10.  Effect of Familiarity on Reward Anticipation in Children with and without Autism Spectrum Disorders 
PLoS ONE  2014;9(9):e106667.
Background
Previous research on the reward system in autism spectrum disorders (ASD) suggests that children with ASD anticipate and process social rewards differently than typically developing (TD) children—but has focused on the reward value of unfamiliar face stimuli. Children with ASD process faces differently than their TD peers. Previous research has focused on face processing of unfamiliar faces, but less is known about how children with ASD process familiar faces. The current study investigated how children with ASD anticipate rewards accompanied by familiar versus unfamiliar faces.
Methods
The stimulus preceding negativity (SPN) of the event-related potential (ERP) was utilized to measure reward anticipation. Participants were 6- to 10-year-olds with (N = 14) and without (N = 14) ASD. Children were presented with rewards accompanied by incidental face or non-face stimuli that were either familiar (caregivers) or unfamiliar. All non-face stimuli were composed of scrambled face elements in the shape of arrows, controlling for visual properties.
Results
No significant differences between familiar versus unfamiliar faces were found for either group. When collapsing across familiarity, TD children showed larger reward anticipation to face versus non-face stimuli, whereas children with ASD did not show differential responses to these stimulus types. Magnitude of reward anticipation to faces was significantly correlated with behavioral measures of social impairment in the ASD group.
Conclusions
The findings do not provide evidence for differential reward anticipation for familiar versus unfamiliar face stimuli in children with or without ASD. These findings replicate previous work suggesting that TD children anticipate rewards accompanied by social stimuli more than rewards accompanied by non-social stimuli. The results do not support the idea that familiarity normalizes reward anticipation in children with ASD. Our findings also suggest that magnitude of reward anticipation to faces is correlated with levels of social impairment for children with ASD.
doi:10.1371/journal.pone.0106667
PMCID: PMC4153666  PMID: 25184524
11.  Common and distinct neural features of social and non-social reward processing in autism and social anxiety disorder 
Autism spectrum disorders (ASDs) and social anxiety disorder (SAD) are both characterized by social dysfunction, but no study to date has compared neural responses to social rewards in ASDs and SAD. Neural responses during social and non-social reward anticipation and outcomes were examined in individuals with ASD (n = 16), SAD (n = 15) and a control group (n = 19) via functional magnetic resonance imaging. Analyses modeling all three groups revealed increased nucleus accumbens (NAc) activation in SAD relative to ASD during monetary reward anticipation, whereas both the SAD and ASD group demonstrated decreased bilateral NAc activation relative to the control group during social reward anticipation. During reward outcomes, the SAD group did not differ significantly from the other two groups in ventromedial prefrontal cortex activation to either reward type. Analyses comparing only the ASD and SAD groups revealed greater bilateral amygdala activation to social rewards in SAD relative to ASD during both anticipation and outcome phases, and the magnitude of left amygdala hyperactivation in the SAD group during social reward anticipation was significantly correlated with the severity of trait anxiety symptoms. Results suggest reward network dysfunction to both monetary and social rewards in SAD and ASD during reward anticipation and outcomes, but that NAc hypoactivation during monetary reward anticipation differentiates ASD from SAD.
doi:10.1093/scan/nss146
PMCID: PMC3980795  PMID: 23223206
autism; social anxiety disorder; nucleus accumbens; ventromedial prefrontal cortex; functional magnetic resonance imaging; reward
12.  Distinct effects of ASD and ADHD symptoms on reward anticipation in participants with ADHD, their unaffected siblings and healthy controls: a cross-sectional study 
Molecular Autism  2015;6:48.
Background
Autism spectrum disorder (ASD) traits are continuously distributed throughout the population, and ASD symptoms are also frequently observed in patients with attention-deficit/hyperactivity disorder (ADHD). Both ASD and ADHD have been linked to alterations in reward-related neural processing. However, whether both symptom domains interact and/or have distinct effects on reward processing in healthy and ADHD populations is currently unknown.
Methods
We examined how variance in ASD and ADHD symptoms in individuals with ADHD and healthy participants was related to the behavioural and neural response to reward during a monetary incentive delay (MID) task. Participants (mean age: 17.7 years, range: 10–28 years) from the NeuroIMAGE study with a confirmed diagnosis of ADHD (n = 136), their unaffected siblings (n = 83), as well as healthy controls (n = 105) performed an MID task in a magnetic resonance imaging (MRI) scanner. ASD and ADHD symptom scores were used as predictors of the neural response to reward anticipation and reward receipt. Behavioural responses were modeled using linear mixed models; neural responses were analysed using FMRIB’s Software Library (FSL) proprietary mixed effects analysis (FLAMEO).
Results
ASD and ADHD symptoms were associated with alterations in BOLD activity during reward anticipation, but not reward receipt. Specifically, ASD scores were related to increased insular activity during reward anticipation across the sample. No interaction was found between this effect and the presence of ADHD, suggesting that ASD symptoms had no differential effect in ADHD and healthy populations. ADHD symptom scores were associated with reduced dorsolateral prefrontal activity during reward anticipation. No interactions were found between the effects of ASD and ADHD symptoms on reward processing.
Conclusions
Variance in ASD and ADHD symptoms separately influence neural processing during reward anticipation in both individuals with (an increased risk of) ADHD and healthy participants. Our findings therefore suggest that both symptom domains affect reward processing through distinct mechanisms, underscoring the importance of multidimensional and multimodal assessment in psychiatry.
Electronic supplementary material
The online version of this article (doi:10.1186/s13229-015-0043-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13229-015-0043-y
PMCID: PMC4551566  PMID: 26322219
ADHD; ASD; Reward; Reward anticipation; Comorbidity
13.  Reward circuitry function in autism spectrum disorders 
Social interaction deficits and restricted repetitive behaviors and interests that characterize autism spectrum disorders (ASDs) may both reflect aberrant functioning of brain reward circuits. However, no neuroimaging study to date has investigated the integrity of reward circuits using an incentive delay paradigm in individuals with ASDs. In the present study, we used functional magnetic resonance imaging to assess blood-oxygen level-dependent activation during reward anticipation and outcomes in 15 participants with an ASD and 16 matched control participants. Brain activation was assessed during anticipation of and in response to monetary incentives and object image incentives previously shown to be visually salient for individuals with ASDs (e.g. trains, electronics). Participants with ASDs showed decreased nucleus accumbens activation during monetary anticipation and outcomes, but not during object anticipation or outcomes. Group × reward-type-interaction tests revealed robust interaction effects in bilateral nucleus accumbens during reward anticipation and in ventromedial prefrontal cortex during reward outcomes, indicating differential responses contingent on reward type in these regions. Results suggest that ASDs are characterized by reward-circuitry hypoactivation in response to monetary incentives but not in response to autism-relevant object images. The clinical implications of the double dissociation of reward type and temporal phase in reward circuitry function in ASD are discussed.
doi:10.1093/scan/nsq095
PMCID: PMC3277365  PMID: 21148176
autism; reward; nucleus accumbens; anticipation; functional magnetic resonance imaging
14.  Brain function and gaze-fixation during facial emotion processing in fragile-X and autism 
This research focuses on the relationship between fragile X syndrome (FXS) and autism spectrum disorders (ASD). Both of these populations have a tendency to avoid looking others in the eye, along with difficulties in communication with others and tend to be socially withdrawn. While it is clear that FXS and ASD share some common abnormal behaviors, the underlying brain mechanisms associated with the social and emotional deficits in these groups remain unclear. We showed pictures of emotional and non-emotional human faces to these groups while in a magnetic resonance scanner (MRI). We collected images of brain function along with measures of where on the faces the individuals were looking (e.g. eyes or mouth). The FXS group showed a similar yet less abnormal pattern of where they were looking on the face compared to the ASD group. The FXS group also showed a similar pattern of decreased brain function in the area of the brain typically used when looking at faces, the fusiform gyrus (FG). The amount of activation in the FG was associated with how much time the FXS and ASD individuals looked at the eyes, the more they looked at the eyes, the greater the FG activation. The FXS group also displayed more brain activation than both the ASD group and a group of typically developing control subjects in brain areas that might suggest increased task difficulty for the FXS group. These group differences in brain activation are important as they suggest there is some overlap in areas of brain function in FXS and ASD when looking at faces, but that these two groups also have unique activation in other brain areas. These findings largely support the idea that ASD characteristics in FXS are associated with partially different patterns of brain activation when looking at human faces compared to individuals with ASD.
Objective:
Fragile X syndrome (FXS) is the most commonly known genetic disorder associated with autism spectrum disorder (ASD). Overlapping features in these populations include gaze aversion, communication deficits, and social withdrawal. Although the association between FXS and ASD has been well documented at the behavioral level, the underlying neural mechanisms associated with the social/emotional deficits in these groups remain unclear.
Method:
We collected functional brain images and eye-gaze fixations from 9 individuals with FXS and 14 individuals with idiopathic ASD, as well as 15 typically developing (TD) individuals, while they performed a facial-emotion discrimination task.
Results:
The FXS group showed a similar yet less aberrant pattern of gaze-fixations compared to the ASD group. The FXS group also showed fusiform gyrus (FG) hypoactivation compared to the TD control group. Activation in FG was strongly and positively associated with average eye fixation and negatively associated with ASD characteristics in the FXS group. The FXS group displayed significantly greater activation than both the TD control and ASD groups in the left hippocampus (HIPP), left superior temporal gyrus (STG), right insula (INS), and left post-central gyrus (PCG).
Conclusions:
These group differences in brain activation are important as they suggest unique underlying face-processing neural circuitry in FXS versus idiopathic ASD, largely supporting the hypothesis that ASD characteristics in FXS and idiopathic ASD reflect partially divergent impairments at the neural level, at least in FXS individuals without a co-morbid diagnosis of ASD.
doi:10.1002/aur.32
PMCID: PMC2679695  PMID: 19360673
fragile X syndrome; autism; face processing; brain function; fMRI
15.  Social ‘wanting’ dysfunction in autism: neurobiological underpinnings and treatment implications 
Most behavioral training regimens in autism spectrum disorders (ASD) rely on reward-based reinforcement strategies. Although proven to significantly increase both cognitive and social outcomes and successfully reduce aberrant behaviors, this approach fails to benefit a substantial number of affected individuals. Given the enormous amount of clinical and financial resources devoted to behavioral interventions, there is a surprisingly large gap in our knowledge of the basic reward mechanisms of learning in ASD. Understanding the mechanisms for reward responsiveness and reinforcement-based learning is urgently needed to better inform modifications that might improve current treatments. The fundamental goal of this review is to present a fine-grained literature analysis of reward function in ASD with reference to a validated neurobiological model of reward: the ‘wanting’/’liking’ framework. Despite some inconsistencies within the available literature, the evaluation across three converging sets of neurobiological data (neuroimaging, electrophysiological recordings, and neurochemical measures) reveals good evidence for disrupted reward-seeking tendencies in ASD, particularly in social contexts. This is most likely caused by dysfunction of the dopaminergic–oxytocinergic ‘wanting’ circuitry, including the ventral striatum, amygdala, and ventromedial prefrontal cortex. Such a conclusion is consistent with predictions derived from diagnostic criteria concerning the core social phenotype of ASD, which emphasize difficulties with spontaneous self-initiated seeking of social encounters (that is, social motivation). Existing studies suggest that social ‘wanting’ tendencies vary considerably between individuals with ASD, and that the degree of social motivation is both malleable and predictive of intervention response. Although the topic of reward responsiveness in ASD is very new, with much research still needed, the current data clearly point towards problems with incentive-based motivation and learning, with clear and important implications for treatment. Given the reliance of behavioral interventions on reinforcement-based learning principles, we believe that a systematic focus on the integrity of the reward system in ASD promises to yield many important clues, both to the underlying mechanisms causing ASD and to enhancing the efficacy of existing and new interventions.
doi:10.1186/1866-1955-4-10
PMCID: PMC3436671  PMID: 22958468
Autism spectrum disorders; Reward; Social motivation; Ventral striatum; Ventromedial prefrontal cortex; Amygdala; Dopamine; Oxytocin; Opioids; Treatment
16.  Girls’ Challenging Social Experiences in Early Adolescence Predict Neural Response to Rewards and Depressive Symptoms1 
Developmental models of psychopathology posit that exposure to social stressors may confer risk for depression in adolescent girls by disrupting neural reward circuitry. The current study tested this hypothesis by examining the relationship between early adolescent social stressors and later neural reward processing and depressive symptoms. Participants were 120 girls from an ongoing longitudinal study of precursors to depression across adolescent development. Low parental warmth, peer victimization, and depressive symptoms were assessed when the girls were 11 and 12 years old, and participants completed a monetary reward guessing fMRI task and assessment of depressive symptoms at age 16. Results indicate that low parental warmth was associated with increased response to potential rewards in the medial prefrontal cortex (mPFC), striatum, and amygdala, whereas peer victimization was associated with decreased response to potential rewards in the mPFC. Furthermore, concurrent depressive symptoms were associated with increased reward anticipation response in mPFC and striatal regions that were also associated with early adolescent psychosocial stressors, with mPFC and striatal response mediating the association between social stressors and depressive symptoms. These findings are consistent with developmental models that emphasize the adverse impact of early psychosocial stressors on neural reward processing and risk for depression in adolescence.
doi:10.1016/j.dcn.2013.12.003
PMCID: PMC3960334  PMID: 24397999
parental warmth; peer victimization; reward; fMRI; adolescence; depression
17.  Association between the oxytocin receptor (OXTR) gene and mesolimbic responses to rewards 
Molecular Autism  2014;5:7.
Background
There has been significant progress in identifying genes that confer risk for autism spectrum disorders (ASDs). However, the heterogeneity of symptom presentation in ASDs impedes the detection of ASD risk genes. One approach to understanding genetic influences on ASD symptom expression is to evaluate relations between variants of ASD candidate genes and neural endophenotypes in unaffected samples. Allelic variations in the oxytocin receptor (OXTR) gene confer small but significant risk for ASDs for which the underlying mechanisms may involve associations between variability in oxytocin signaling pathways and neural response to rewards. The purpose of this preliminary study was to investigate the influence of allelic variability in the OXTR gene on neural responses to monetary rewards in healthy adults using functional magnetic resonance imaging (fMRI).
Methods
The moderating effects of three single nucleotide polymorphisms (SNPs) (rs1042778, rs2268493 and rs237887) of the OXTR gene on mesolimbic responses to rewards were evaluated using a monetary incentive delay fMRI task.
Results
T homozygotes of the rs2268493 SNP demonstrated relatively decreased activation in mesolimbic reward circuitry (including the nucleus accumbens, amygdala, insula, thalamus and prefrontal cortical regions) during the anticipation of rewards but not during the outcome phase of the task. Allelic variation of the rs1042778 and rs237887 SNPs did not moderate mesolimbic activation during either reward anticipation or outcomes.
Conclusions
This preliminary study suggests that the OXTR SNP rs2268493, which has been previously identified as an ASD risk gene, moderates mesolimbic responses during reward anticipation. Given previous findings of decreased mesolimbic activation during reward anticipation in ASD, the present results suggest that OXTR may confer ASD risk via influences on the neural systems that support reward anticipation.
doi:10.1186/2040-2392-5-7
PMCID: PMC3922109  PMID: 24485285
Autism spectrum disorder (ASD); Oxytocin; Oxytocin receptor; Genetics; Neuroimaging; Reward; Motivation; Mesolimbic; Functional magnetic resonance imaging (fMRI); Single nucleotide polymorphism (SNP)
18.  Atypical Neural Networks for Social Orienting in Autism Spectrum Disorders 
NeuroImage  2011;56(1):354-362.
Autism spectrum disorders (ASD) are characterized by significant social impairments, including deficits in orienting attention following social cues. Behavioral studies investigating social orienting in ASD, however, have yielded mixed results, as the use of naturalistic paradigms typically reveals clear deficits whereas computerized laboratory experiments often report normative behavior. The present study is the first to examine the neural mechanisms underlying social orienting in ASD in order to provide new insight into the social attention impairments that characterize this disorder. Using fMRI, we examined the neural correlates of social orienting in children and adolescents with ASD and in a matched sample of typically developing (TD) controls while they performed a spatial cueing paradigm with social (eye gaze) and nonsocial (arrow) cues. Cues were either directional (indicating left or right) or neutral (indicating no direction), and directional cues were uninformative of the upcoming target location in order to engage automatic processes by minimizing expectations. Behavioral results demonstrated intact orienting effects for social and nonsocial cues, with no differences between groups. The imaging results, however, revealed clear group differences in brain activity. When attention was directed by social cues compared to nonsocial cues, the TD group showed increased activity in frontoparietal attention networks, visual processing regions, and the striatum, whereas the ASD group only showed increased activity in the superior parietal lobule. Significant group × cue type interactions confirmed greater responsivity in task-relevant networks for social cues than nonsocial cues in TD as compared to ASD, despite similar behavioral performance. These results indicate that, in the autistic brain, social cues are not assigned the same privileged status as they are in the typically developing brain. These findings provide the first empirical evidence that the neural circuitry involved in social orienting is disrupted in ASD and highlight that normative behavioral performance in a laboratory setting may reflect compensatory mechanisms rather than intact social attention.
doi:10.1016/j.neuroimage.2011.02.031
PMCID: PMC3091391  PMID: 21334443
autism; attention; functional magnetic resonance imaging; gaze; social cue
19.  Abnormal Brain Activity in Social Reward Learning in Children with Autism Spectrum Disorder: An fMRI Study 
Yonsei Medical Journal  2015;56(3):705-711.
Purpose
We aimed to determine whether Autism Spectrum Disorder (ASD) would show neural abnormality of the social reward system using functional MRI (fMRI).
Materials and Methods
27 ASDs and 12 typically developing controls (TDCs) participated in this study. The social reward task was developed, and all participants performed the task during fMRI scanning.
Results
ASDs and TDCs with a social reward learning effect were selected on the basis of behavior data. We found significant differences in brain activation between the ASDs and TDCs showing a social reward learning effect. Compared with the TDCs, the ASDs showed reduced activity in the right dorsolateral prefrontal cortex, right orbitofrontal cortex, right parietal lobe, and occipital lobe; however, they showed increased activity in the right parahippocampal gyrus and superior temporal gyrus.
Conclusion
These findings suggest that there might be neural abnormality of the social reward learning system of ASDs. Although this study has several potential limitations, it presents novel findings in the different neural mechanisms of social reward learning in children with ASD and a possible useful biomarker of high-functioning ASDs.
doi:10.3349/ymj.2015.56.3.705
PMCID: PMC4397440  PMID: 25837176
ASDs; social reward leaning; fMRI
20.  Functional and structural connectivity of frontostriatal circuitry in Autism Spectrum Disorder 
Abnormalities in frontostriatal circuitry potentially underlie the two core deficits in Autism Spectrum Disorder (ASD); social interaction and communication difficulties and restricted interests and repetitive behaviors. Whilst a few studies have examined connectivity within this circuitry in ASD, no previous study has examined both functional and structural connectivity within the same population. The present study provides the first exploration of both functional and structural frontostriatal connectivity in ASD. Twenty-eight right-handed Caucasian male ASD (17.28 ± 3.57 years) and 27 right-handed male, age and IQ matched controls (17.15 ± 3.64 years) took part in the study. Resting state functional connectivity was carried out on 21 ASD and control participants, and tractography was carried out on 22 ASD and 24 control participants, after excluding subjects for excessive motion and poor data quality. Functional connectivity analysis was carried out between the frontal cortex and striatum after which tractography was performed between regions that showed significant group differences in functional connectivity. The ASD group showed increased functional connectivity between regions in the frontal cortex [anterior cingulate cortex (ACC), middle frontal gyrus (MFG), paracingulate gyrus (Pcg) and orbitofrontal cortex (OFC)], and striatum [nucleus accumbens (NAcc) and caudate]. Increased functional connectivity between ACC and caudate was associated with deactivation to social rewards in the caudate, as previously reported in the same participants. Greater connectivity between the right MFG and caudate was associated with higher restricted interests and repetitive behaviors and connectivity between the bilateral Pcg and NAcc, and the right OFC and NAcc, was negatively associated with social and communicative deficits. Although tracts were reliably constructed for each subject, there were no group differences in structural connectivity. Results are in keeping with previously reported increased corticostriatal functional connectivity in ASD.
doi:10.3389/fnhum.2013.00430
PMCID: PMC3734372  PMID: 23964221
Autism Spectrum Disorder; connectivity; frontostriatal; striatum; fMRI; DTI; social reward
21.  Non-Specialist Psychosocial Interventions for Children and Adolescents with Intellectual Disability or Lower-Functioning Autism Spectrum Disorders: A Systematic Review 
PLoS Medicine  2013;10(12):e1001572.
In a systematic review, Brian Reichow and colleagues assess the evidence that non-specialist care providers in community settings can provide effective interventions for children and adolescents with intellectual disabilities or lower-functioning autism spectrum disorders.
Please see later in the article for the Editors' Summary
Background
The development of effective treatments for use by non-specialists is listed among the top research priorities for improving the lives of people with mental illness worldwide. The purpose of this review is to appraise which interventions for children with intellectual disabilities or lower-functioning autism spectrum disorders delivered by non-specialist care providers in community settings produce benefits when compared to either a no-treatment control group or treatment-as-usual comparator.
Methods and Findings
We systematically searched electronic databases through 24 June 2013 to locate prospective controlled studies of psychosocial interventions delivered by non-specialist providers to children with intellectual disabilities or lower-functioning autism spectrum disorders. We screened 234 full papers, of which 34 articles describing 29 studies involving 1,305 participants were included. A majority of the studies included children exclusively with a diagnosis of lower-functioning autism spectrum disorders (15 of 29, 52%). Fifteen of twenty-nine studies (52%) were randomized controlled trials and just under half of all effect sizes (29 of 59, 49%) were greater than 0.50, of which 18 (62%) were statistically significant. For behavior analytic interventions, the best outcomes were shown for development and daily skills; cognitive rehabilitation, training, and support interventions were found to be most effective for improving developmental outcomes, and parent training interventions to be most effective for improving developmental, behavioral, and family outcomes. We also conducted additional subgroup analyses using harvest plots. Limitations include the studies' potential for performance bias and that few were conducted in lower- and middle-income countries.
Conclusions
The findings of this review support the delivery of psychosocial interventions by non-specialist providers to children who have intellectual disabilities or lower-functioning autism spectrum disorders. Given the scarcity of specialists in many low-resource settings, including many lower- and middle-income countries, these findings may provide guidance for scale-up efforts for improving outcomes for children with developmental disorders or lower-functioning autism spectrum disorders.
Protocol Registration
PROSPERO CRD42012002641
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Newborn babies are helpless, but over the first few years of life, they acquire motor (movement) skills, language (communication) skills, cognitive (thinking) skills, and social (interpersonal interaction) skills. Individual aspects of these skills are usually acquired at specific ages, but children with a development disorder such as an autism spectrum disorder (ASD) or intellectual disability (mental retardation) fail to reach these “milestones” because of impaired or delayed brain maturation. Autism, Asperger syndrome, and other ASDs (also called pervasive developmental disorders) affect about 1% of the UK and US populations and are characterized by abnormalities in interactions and communication with other people (reciprocal socio-communicative interactions; for example, some children with autism reject physical affection and fail to develop useful speech) and a restricted, stereotyped, repetitive repertoire of interests (for example, obsessive accumulation of facts about unusual topics). About half of individuals with an ASD also have an intellectual disability—a reduced overall level of intelligence characterized by impairment of the skills that are normally acquired during early life. Such individuals have what is called lower-functioning ASD.
Why Was This Study Done?
Most of the children affected by developmental disorders live in low- and middle-income countries where there are few services available to help them achieve their full potential and where little research has been done to identify the most effective treatments. The development of effective treatments for use by non-specialists (for example, teachers and parents) is necessary to improve the lives of people with mental illnesses worldwide, but particularly in resource-limited settings where psychiatrists, psychologists, and other specialists are scarce. In this systematic review, the researchers investigated which psychosocial interventions for children and adolescents with intellectual disabilities or lower-functioning ASDs delivered by non-specialist providers in community settings produce improvements in development, daily skills, school performance, behavior, or family outcomes when compared to usual care (the control condition). A systematic review identifies all the research on a given topic using predefined criteria; psychosocial interventions are defined as therapy, education, training, or support aimed at improving behavior, overall development, or specific life skills without the use of drugs.
What Did the Researchers Do and Find?
The researchers identified 29 controlled studies (investigations with an intervention group and a control group) that examined the effects of various psychosocial interventions delivered by non-specialist providers to children (under 18 years old) who had a lower-functioning ASD or intellectual disability. The researchers retrieved information on the participants, design and methods, findings, and intervention characteristics for each study, and calculated effect sizes—a measure of the effectiveness of a test intervention relative to a control intervention—for several outcomes for each intervention. Across the studies, three-quarters of the effect size estimates were positive, and nearly half were greater than 0.50; effect sizes of less than 0.2, 0.2–0.5, and greater than 0.5 indicate that an intervention has no, a small, or a medium-to-large effect, respectively. For behavior analytic interventions (which aim to improve socially significant behavior by systematically analyzing behavior), the largest effect sizes were seen for development and daily skills. Cognitive rehabilitation, training, and support (interventions that facilitates the relearning of lost or altered cognitive skills) produced good improvements in developmental outcomes such as standardized IQ tests in children aged 6–11 years old. Finally, parental training interventions (which teach parents how to provide therapy services for their child) had strong effects on developmental, behavioral, and family outcomes.
What Do These Findings Mean?
Because few of the studies included in this systematic review were undertaken in low- and middle-income countries, the review's findings may not be generalizable to children living in resource-limited settings. Moreover, other characteristics of the included studies may limit the accuracy of these findings. Nevertheless, these findings support the delivery of psychosocial interventions by non-specialist providers to children who have intellectual disabilities or a lower-functioning ASD, and indicate which interventions are likely to produce the largest improvements in developmental, behavioral, and family outcomes. Further studies are needed, particularly in low- and middle-income countries, to confirm these findings, but given that specialists are scarce in many resource-limited settings, these findings may help to inform the implementation of programs to improve outcomes for children with intellectual disabilities or lower-functioning ASDs in low- and middle-income countries.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001572.
This study is further discussed in a PLOS Medicine Perspective by Bello-Mojeed and Bakare
The US Centers for Disease Control and Prevention provides information (in English and Spanish) on developmental disabilities, including autism spectrum disorders and intellectual disability
The US National Institute of Mental Health also provides detailed information about autism spectrum disorders, including the publication “A Parent's Guide to Autism Spectrum Disorder”
Autism Speaks, a US non-profit organization, provides information about all aspects of autism spectrum disorders and includes information on the Autism Speaks Global Autism Public Health Initiative
The National Autistic Society, a UK charity, provides information about all aspects of autism spectrum disorders and includes personal stories about living with these conditions
The UK National Health Service Choices website has an interactive guide to child development and information about autism and Asperger syndrome, including personal stories, and about learning disabilities
The UK National Institute for Health and Care Excellence provides clinical guidelines for the management and support of children with autism spectrum disorders
The World Health Organization provides information on its Mental Health Gap Action Programme (mhGAP), which includes recommendations on the management of developmental disorders by non-specialist providers; the mhGAP Evidence Resource Center provides evidence reviews for parent skills training for management of children with intellectual disabilities and pervasive developmental disorders and interventions for management of children with intellectual disabilities
PROSPERO, an international prospective register of systematic reviews, provides more information about this systematic review
doi:10.1371/journal.pmed.1001572
PMCID: PMC3866092  PMID: 24358029
22.  Neural selectivity for communicative auditory signals in Phelan-McDermid syndrome 
Background
Phelan-McDermid syndrome (PMS), a neurodevelopmental disorder caused by deletion or mutation in the SHANK3 gene, is one of the more common single-locus causes of autism spectrum disorder (ASD). PMS is characterized by global developmental delay, hypotonia, delayed or absent speech, increased risk of seizures, and minor dysmorphic features. Impairments in language and communication are one of the most consistent characteristics of PMS. Although there is considerable overlap in the social communicative deficits associated with PMS and ASD, there is a dearth of data on underlying abnormalities at the level of neural systems in PMS. No controlled neuroimaging studies of PMS have been reported to date. The goal of this study was to examine the neural circuitry supporting the perception of auditory communicative signals in children with PMS as compared to idiopathic ASD (iASD).
Methods
Eleven children with PMS and nine comparison children with iASD were scanned using functional magnetic resonance imaging (fMRI) under light sedation. The fMRI paradigm was a previously validated passive auditory task, which presented communicative (e.g., speech, sounds of agreement, disgust) and non-communicative vocalizations (e.g., sneezing, coughing, yawning).
Results
Previous research has shown that the superior temporal gyrus (STG) responds selectively to communicative vocal signals in typically developing children and adults. Here, selective activity for communicative relative to non-communicative vocalizations was detected in the right STG in the PMS group, but not in the iASD group. The PMS group also showed preferential activity for communicative vocalizations in a range of other brain regions associated with social cognition, such as the medial prefrontal cortex (MPFC), insula, and inferior frontal gyrus. Interestingly, better orienting toward social sounds was positively correlated with selective activity in the STG and other “social brain” regions, including the MPFC, in the PMS group. Finally, selective MPFC activity for communicative sounds was associated with receptive language level in the PMS group and expressive language in the iASD group.
Conclusions
Despite shared behavioral features, children with PMS differed from children with iASD in their neural response to communicative vocal sounds and showed relative strengths in this area. Furthermore, the relationship between clinical characteristics and neural selectivity also differed between the two groups, suggesting that shared ASD features may partially reflect different neurofunctional abnormalities due to differing etiologies.
Electronic supplementary material
The online version of this article (doi:10.1186/s11689-016-9138-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s11689-016-9138-9
PMCID: PMC4763436  PMID: 26909118
23.  Of mice and monkeys: using non-human primate models to bridge mouse- and human-based investigations of autism spectrum disorders 
The autism spectrum disorders (ASDs) arise from a diverse array of genetic and environmental origins that disrupt the typical developmental trajectory of neural connectivity and synaptogenesis. ASDs are marked by dysfunctional social behavior and cognition, among other deficits. Greater understanding of the biological substrates of typical social behavior in animal models will further our understanding of the etiology of ASDs. Despite the precision and tractability of molecular genetics models of ASDs in rodents, these organisms lack the complexity of human social behavior, thus limiting their impact on understanding ASDs to basic mechanisms. Non-human primates (NHPs) provide an attractive, complementary model for ASDs, due in part to the complexity and dynamics of social structures, reliance on vision for social signaling, and deep homology in brain circuitry mediating social behavior and reward. This knowledge is based on a rich literature, compiled over 50 years of observing primate behavior in the wild, which, in the case of rhesus macaques, is complemented by a large body of research characterizing neuronal activity during cognitive behavior. Several recent developments in this field are directly relevant to ASDs, including how the brain represents the perceptual features of social stimuli, how social information influences attention processes in the brain, and how the value of social interaction is computed. Because the symptoms of ASDs may represent extreme manifestations of traits that vary in intensity within the general population, we will additionally discuss ways in which nonhuman primates also show variation in social behavior and reward sensitivity. In cases where variation in species-typical behavior is analogous to similar variations in human behavior, we believe that study of the neural circuitry underlying this variation will provide important insights into the systems-level mechanisms contributing to ASD pathology.
doi:10.1186/1866-1955-4-21
PMCID: PMC3445833  PMID: 22958282
Autism; Asperger’s; Non-human primate; Monkey
24.  Constraining Heterogeneity: The Social Brain and its Development in Autism Spectrum Disorder 
The expression of autism spectrum disorder (ASD) is highly heterogeneous, owing to the complex interactions between genes, the brain, and behavior throughout development. Here we present a model of ASD that implicates an early and initial failure to develop the specialized functions of one or more of the set of neuroanatomical structures involved in social information processing (i.e., the “social brain”). From this early and primary disruption, abnormal brain development is canalized because the individual with an ASD must develop in a highly social world without the specialized neural systems that would ordinarily allow him or her to partake in the fabric of social life, which is woven from the thread of opportunities for social reciprocity and the tools of social engagement. This brain canalization gives rise to other characteristic behavioral deficits in ASD including deficits in communication, restricted interests, and repetitive behaviors. We propose that focused efforts to explore the brain mechanisms underlying the core, pathognomic deficits in the development of mechanisms for social engagement in ASD will greatly elucidate our understanding and treatment of this complex, devastating family of neurodevelopmental disorders. In particular, developmental studies (i.e., longitudinal studies of young children with and without ASD, as well as infants at increased risk for being identified with ASD) of the neural circuitry supporting key aspects of social information processing are likely to provide important insights into the underlying components of the full-syndrome of ASD. These studies could also contribute to the identification of developmental brain endophenotypes to facilitate genetic studies. The potential for this kind of approach is illustrated via examples of functional neuroimaging research from our own laboratory implicating the posterior superior temporal sulcus (STS) as a key player in the set of neural structures giving rise to ASD.
doi:10.1111/j.1469-7610.2010.02349.x
PMCID: PMC3096715  PMID: 21244421
25.  Early sex differences are not autism-specific: A Baby Siblings Research Consortium (BSRC) study 
Molecular Autism  2015;6:32.
Background
The increased male prevalence of autism spectrum disorder (ASD) may be mirrored by the early emergence of sex differences in ASD symptoms and cognitive functioning. The female protective effect hypothesis posits that ASD recurrence and symptoms will be higher among relatives of female probands. This study examined sex differences and sex of proband differences in ASD outcome and in the development of ASD symptoms and cognitive functioning among the high-risk younger siblings of ASD probands and low-risk children.
Methods
Prior to 18 months of age, 1824 infants (1241 high-risk siblings, 583 low-risk) from 15 sites were recruited. Hierarchical generalized linear model (HGLM) analyses of younger sibling and proband sex differences in ASD recurrence among high-risk siblings were followed by HGLM analyses of sex differences and group differences (high-risk ASD, high-risk non-ASD, and low-risk) on the Mullen Scales of Early Learning (MSEL) subscales (Expressive and Receptive Language, Fine Motor, and Visual Reception) at 18, 24, and 36 months and Autism Diagnostic Observation Schedule (ADOS) domain scores (social affect (SA) and restricted and repetitive behaviors (RRB)) at 24 and 36 months.
Results
Of 1241 high-risk siblings, 252 had ASD outcomes. Male recurrence was 26.7 % and female recurrence 10.3 %, with a 3.18 odds ratio. The HR-ASD group had lower MSEL subscale scores and higher RRB and SA scores than the HR non-ASD group, which had lower MSEL subscale scores and higher RRB scores than the LR group. Regardless of group, males obtained lower MSEL subscale scores, and higher ADOS RRB scores, than females. There were, however, no significant interactions between sex and group on either the MSEL or ADOS. Proband sex did not affect ASD outcome, MSEL subscale, or ADOS domain scores.
Conclusions
A 3.2:1 male:female odds ratio emerged among a large sample of prospectively followed high-risk siblings. Sex differences in cognitive performance and repetitive behaviors were apparent not only in high-risk children with ASD, but also in high-risk children without ASD and in low-risk children. Sex differences in young children with ASD do not appear to be ASD-specific but instead reflect typically occurring sex differences seen in children without ASD. Results did not support a female protective effect hypothesis.
Electronic supplementary material
The online version of this article (doi:10.1186/s13229-015-0027-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13229-015-0027-y
PMCID: PMC4455973  PMID: 26045943
Sex differences; High-risk siblings; Symptom severity; Development; Longitudinal

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