Assessing autism at its social and developmental roots: A review of Autism Spectrum Disorder studies using functional near‐infrared spectroscopy
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paper_title: Reduced functional connectivity within and between ‘social’ resting state networks in autism spectrum conditions

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Individuals with autism spectrum conditions (ASC) have difficulties in social interaction and communication, which is reflected in hypoactivation of brain regions engaged in social processing, such as medial prefrontal cortex (mPFC), amygdala and insula. Resting state studies in ASC have identified reduced connectivity of the default mode network (DMN), which includes mPFC, suggesting that other resting state networks incorporating 'social' brain regions may also be abnormal. Using seed-based connectivity and group independent component analysis (ICA) approaches, we looked at resting functional connectivity in ASC between specific 'social' brain regions, as well as within and between whole networks incorporating these regions. We found reduced functional connectivity within the DMN in individuals with ASC, using both ICA and seed-based approaches. Two further networks identified by ICA, the salience network, incorporating the insula and a medial temporal lobe network, incorporating the amygdala, showed reduced inter-network connectivity. This was underlined by reduced seed-based connectivity between the insula and amygdala. The results demonstrate significantly reduced functional connectivity within and between resting state networks incorporating 'social' brain regions. This reduced connectivity may result in difficulties in communication and integration of information across these networks, which could contribute to the impaired processing of social signals in ASC.
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paper_title: A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology

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This year marks the 20th anniversary of functional near-infrared spectroscopy and imaging (fNIRS/fNIRI). As the vast majority of commercial instruments developed until now are based on continuous wave technology, the aim of this publication is to review the current state of instrumentation and methodology of continuous wave fNIRI. For this purpose we provide an overview of the commercially available instruments and address instrumental aspects such as light sources, detectors and sensor arrangements. Methodological aspects, algorithms to calculate the concentrations of oxy- and deoxyhemoglobin and approaches for data analysis are also reviewed. From the single-location measurements of the early years, instrumentation has progressed to imaging initially in two dimensions (topography) and then three (tomography). The methods of analysis have also changed tremendously, from the simple modified Beer-Lambert law to sophisticated image reconstruction and data analysis methods used today. Due to these advances, fNIRI has become a modality that is widely used in neuroscience research and several manufacturers provide commercial instrumentation. It seems likely that fNIRI will become a clinical tool in the foreseeable future, which will enable diagnosis in single subjects.
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paper_title: A failure of left temporal cortex to specialize for language is an early emerging and fundamental property of autism

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Failure to develop normal language comprehension is an early warning sign of autism, but the neural mechanisms underlying this signature deficit are unknown. This is because of an almost complete absence of functional studies of the autistic brain during early development. Using functional magnetic resonance imaging, we previously observed a trend for abnormally lateralized temporal responses to language (i.e. greater activation on the right, rather than the expected left) in a small sample ( n = 12) of sleeping 2–3 year olds with autism in contrast to typically developing children, a finding also reported in autistic adults and adolescents. It was unclear, however, if findings of atypical laterality would be observed in a larger sample, and at even earlier ages in autism, such as around the first birthday. Answers to these questions would provide the foundation for understanding how neurofunctional defects of autism unfold, and provide a foundation for studies using patterns of brain activation as a functional early biomarker of autism. To begin to examine these issues, a prospective, cross-sectional design was used in which brain activity was measured in a large sample of toddlers ( n = 80) during the presentation of a bedtime story during natural sleep. Forty toddlers with autism spectrum disorder and 40 typically developing toddlers ranging in age between 12–48 months participated. Any toddler with autism who participated in the imaging experiment prior to final diagnosis was tracked and diagnoses confirmed at a later age. Results indicated that at-risk toddlers later diagnosed as autistic display deficient left hemisphere response to speech sounds and have abnormally right-lateralized temporal cortex response to language; this defect worsens with age, becoming most severe in autistic 3- and 4-year-olds. Typically developing children show opposite developmental trends with a tendency towards greater temporal cortex response with increasing age and maintenance of left-lateralized activation with age. We have now demonstrated lateralized abnormalities of temporal cortex processing of language in autism across two separate samples, including a large sample of young infants who later are diagnosed with autism, suggesting that this pattern may reflect a fundamental early neural developmental pathology in autism. ::: ::: * Abbreviation ::: : ADOS ::: : autism diagnostic observation schedule ::: ASD ::: : austism spectrum disorder
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paper_title: An information theoretical approach to prefrontal executive function

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The prefrontal cortex subserves executive control – that is, the ability to select actions or thoughts in relation to internal goals. Here, we propose a theory that draws upon concepts from information theory to describe the architecture of executive control in the lateral prefrontal cortex. Supported by evidence from brain imaging in human subjects, the model proposes that action selection is guided by hierarchically ordered control signals, processed in a network of brain regions organized along the anterior–posterior axis of the lateral prefrontal cortex. The theory clarifies how executive control can operate as a unitary function, despite the requirement that information be integrated across multiple distinct, functionally specialized prefrontal regions.
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paper_title: A new research trend in social neuroscience: Towards an interactive‐brain neuroscience

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The ability to flexibly modulate our behaviors in social contexts and to successfully interact with other persons is a fundamental, but pivotal, requirement for human survival. Although previous social neuroscience research with single individuals has contributed greatly to our understanding of the basic mechanisms underlying social perception and social emotions, much of the dynamic nature of interactions between persons remains beyond the reach of single-brain studies. This has led to a growing argument for a shift to the simultaneous measurement of the brain activity of two or more individuals in realistic social interactions-an approach termed "hyperscanning." Although this approach offers important promise in unlocking the brain's role in truly social situations, there are multiple procedural and theoretical questions that require review and analysis. In this paper we discuss this research trend from four aspects: hyperscanning apparatus, experimental task, quantification method, and theoretical interpretation. We also give four suggestions for future research: (a) electroencephalography and near-infrared spectroscopy are useful tools by which to explore the interactive brain in more ecological settings; (b) games are an appropriate method to simulate daily life interactions; (c) transfer entropy may be an important method by which to quantify directed exchange of information between brains; and (d) more explanation is needed of the results of interbrain synchronization itself.
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paper_title: White matter structure in autism: preliminary evidence from diffusion tensor imaging

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Abstract Background Individuals with autism have severe difficulties in social communication and relationships. Prior studies have suggested that abnormal connections between brain regions important for social cognition may contribute to the social deficits seen in autism. Methods In this study, we used diffusion tensor imaging to investigate white matter structure in seven male children and adolescents with autism and nine age-, gender-, and IQ-matched control subjects. Results Reduced fractional anisotropy (FA) values were observed in white matter adjacent to the ventromedial prefrontal cortices and in the anterior cingulate gyri as well as in the temporoparietal junctions. Additional clusters of reduced FA values were seen adjacent to the superior temporal sulcus bilaterally, in the temporal lobes approaching the amygdala bilaterally, in occipitotemporal tracts, and in the corpus callosum. Conclusions Disruption of white matter tracts between regions implicated in social functioning may contribute to impaired social cognition in autism.
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paper_title: Neural Signatures of Autism Spectrum Disorders: Insights into Brain Network Dynamics

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Neuroimaging investigations of autism spectrum disorders (ASDs) have advanced our understanding of atypical brain function and structure, and have recently converged on a model of altered network-level connectivity. Traditional task-based functional magnetic resonance imaging (MRI) and volume-based structural MRI studies have identified widespread atypicalities in brain regions involved in social behavior and other core ASD-related behavioral deficits. More recent advances in MR-neuroimaging methods allow for quantification of brain connectivity using diffusion tensor imaging, functional connectivity, and graph theoretic methods. These newer techniques have moved the field toward a systems-level understanding of ASD etiology, integrating functional and structural measures across distal brain regions. Neuroimaging findings in ASD as a whole have been mixed and at times contradictory, likely due to the vast genetic and phenotypic heterogeneity characteristic of the disorder. Future longitudinal studies of brain development will be crucial to yield insights into mechanisms of disease etiology in ASD sub-populations. Advances in neuroimaging methods and large-scale collaborations will also allow for an integrated approach linking neuroimaging, genetics, and phenotypic data.
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paper_title: A specific hypoactivation of right temporo-parietal junction/posterior superior temporal sulcus in response to socially awkward situations in autism

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People with autism spectrum disorders (ASD) often have difficulty comprehending social situations in the complex, dynamic contexts encountered in the real world. To study the social brain under conditions which approximate naturalistic situations, we measured brain activity with fMRI while participants watched a full-length episode of the sitcom The Office. Having quantified the degree of social awkwardness at each moment of the episode, as judged by an independent sample of controls, we found that both individuals with ASD and control participants showed reliable activation of several brain regions commonly associated with social perception and cognition (e.g., those comprising the “mentalizing network”) during the more awkward moments. However, individuals with ASD showed less activity than controls in a region near right temporo-parietal junction (RTPJ) extending into the posterior end of the right superior temporal sulcus (RSTS). Further analyses suggested that, despite the free-form nature of the experimental design, this group difference was specific to this RTPJ/RSTS area of the mentalizing network; other regions of interest showed similar activity across groups with respect to both location and magnitude. These findings add support to a body of evidence suggesting that RTPJ/RSTS plays a special role in social processes across modalities and may function atypically in individuals with ASD navigating the social world.
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paper_title: Longitudinal Volumetric Brain Changes in Autism Spectrum Disorder Ages 6–35 Years

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Since the impairments associated with autism spectrum disorder (ASD) tend to persist or worsen from childhood into adulthood, it is of critical importance to examine how the brain develops over this growth epoch. We report initial findings on whole and regional longitudinal brain development in 100 male participants with ASD (226 high-quality magnetic resonance imaging [MRI] scans; mean inter-scan interval 2.7 years) compared to 56 typically developing controls (TDCs) (117 high-quality scans; mean inter-scan interval 2.6 years) from childhood into adulthood, for a total of 156 participants scanned over an 8-year period. This initial analysis includes between one and three high-quality scans per participant that have been processed and segmented to date, with 21% having one scan, 27% with two scans, and 52% with three scans in the ASD sample; corresponding percentages for the TDC sample are 30%, 30%, and 40%. The proportion of participants with multiple scans (79% of ASDs and 68% of TDCs) was high in comparison to that of large longitudinal neuroimaging studies of typical development. We provide volumetric growth curves for the entire brain, total gray matter (GM), frontal GM, temporal GM, parietal GM, occipital GM, total cortical white matter (WM), corpus callosum, caudate, thalamus, total cerebellum, and total ventricles. Mean volume of cortical WM was reduced significantly. Mean ventricular volume was increased in the ASD sample relative to the TDCs across the broad age range studied. Decreases in regional mean volumes in the ASD sample most often were due to decreases during late adolescence and adulthood. The growth curve of whole brain volume over time showed increased volumes in young children with autism, and subsequently decreased during adolescence to meet the TDC curve between 10 and 15 years of age. The volume of many structures continued to decline atypically into adulthood in the ASD sample. The data suggest that ASD is a dynamic disorder with complex changes in whole and regional brain volumes that change over time from childhood into adulthood. Autism Res 2015, 8: 82–93. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.
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paper_title: EEG evidence for mirror neuron dysfunction in autism spectrum disorders

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Abstract Autism spectrum disorders (ASD) are largely characterized by deficits in imitation, pragmatic language, theory of mind, and empathy. Previous research has suggested that a dysfunctional mirror neuron system may explain the pathology observed in ASD. Because EEG oscillations in the mu frequency (8–13 Hz) over sensorimotor cortex are thought to reflect mirror neuron activity, one method for testing the integrity of this system is to measure mu responsiveness to actual and observed movement. It has been established that mu power is reduced (mu suppression) in typically developing individuals both when they perform actions and when they observe others performing actions, reflecting an observation/execution system which may play a critical role in the ability to understand and imitate others' behaviors. This study investigated whether individuals with ASD show a dysfunction in this system, given their behavioral impairments in understanding and responding appropriately to others' behaviors. Mu wave suppression was measured in ten high-functioning individuals with ASD and ten age- and gender-matched control subjects while watching videos of (1) a moving hand, (2) a bouncing ball, and (3) visual noise, or (4) moving their own hand. Control subjects showed significant mu suppression to both self and observed hand movement. The ASD group showed significant mu suppression to self-performed hand movements but not to observed hand movements. These results support the hypothesis of a dysfunctional mirror neuron system in high-functioning individuals with ASD.
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paper_title: The Neuroscience of Human Relationships: Attachment and the Developing Social Brain

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As human beings, we cherish our individuality yet we know that we live in constant relationship to others, and that other people play a significant part in regulating our emotional and social behavior. Although this interdependence is a reality of our existence, we are just beginning to understand that we have evolved as social creatures with interwoven brains and biologies. The human brain itself is a social organ and to truly understand being human, we must understand not only how we as whole people exist with others, but how our brains, themselves, exist in relationship to other brains. The first edition of this book tackled these important questions of interpersonal neurobiology-that the brain is a social organ built through experience-using poignant case examples from the author's years of clinical experience. Brain drawings and elegant explanations of social neuroscience wove together emerging findings from the research literature to bring neuroscience to the stories of our lives. Since the publication of the first edition in 2006, the field of social neuroscience has grown at a mind-numbing pace. Technical advances now provide more windows into our inner neural universe and terms like attachment, empathy, compassion, and mindfulness have begun to appear in the scientific literature. Overall, there has been a deepening appreciation for the essential interdependence of brain and mind. More and more parents, teachers, and therapists are asking how brains develop, grow, connect, learn, and heal. The new edition of this book organizes this cutting-edge, abundant research and presents its compelling insights, reflecting a host of significant developments in social neuroscience. Our understanding of mirror neurons and their significance to human relationships has continued to expand and deepen and is discussed here. Additionally, this edition reflects the gradual shift in focus from individual brain structures to functional neural systems-an important and necessary step forward. A great deal of neural overlap has been discovered in brain activation when we are thinking about others and ourselves. This raises many questions including how we come to know others and whether the notion of an "individual self" is anything more than an evolutionary strategy to support our interconnection. In short, we are just beginning to see the larger implications of all neurological processes-how the architecture of the brain can help us to better understand individuals and our relationships. This book gives readers a deeper appreciation of how and why relationships have the power to reshape our brains throughout our life.
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paper_title: Autism Spectrum Disorders According to DSM-IV-TR and Comparison With DSM-5 Draft Criteria: An Epidemiological Study

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Objective The latest definitions of autism spectrum disorders (ASDs) were specified in DSM-IV-TR in 2000. DSM-5 criteria are planned for 2013. Here, we estimated the prevalence of ASDs and autism according to DSM-IV-TR, clarified confusion concerning diagnostic criteria, and evaluated DSM-5 draft criteria for ASD posted by the American Psychiatry Association (APA) in February 2010. Method This was an epidemiological study of 5,484 eight-year-old children in Finland, 4,422 (81%) of them rated via the Autism Spectrum Screening Questionnaire by parents and/or teachers, and 110 examined by using a structured interview, semi-structured observation, IQ measurement, school-day observation, and patient records. Diagnoses were assigned according to DSM-IV-TR criteria and DSM-5 draft criteria in children with a full-scale IQ (FSIQ) ≥50. Patient records were evaluated in children with an FSIQ Results The prevalence of ASDs was 8.4 in 1,000 and that of autism 4.1 in 1,000 according to DSM-IV-TR. Of the subjects with ASDs and autism, 65% and 61% were high-functioning (FSIQ ≥70), respectively. The prevalence of pervasive developmental disorder not otherwise specified was not estimated because of inconsistency in DSM-IV-TR criteria. DSM-5 draft criteria were shown to be less sensitive in regard to identification of subjects with ASDs, particularly those with Asperger's syndrome and some high-functioning subjects with autism. Conclusions DSM-IV-TR helps with the definition of ASDs only up to a point. We suggest modifications to five details of DSM-5 draft criteria posted by the APA in February 2010. Completing revision of DSM criteria for ASDs is a challenging task.
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paper_title: Global Prevalence of Autism and Other Pervasive Developmental Disorders

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We provide a systematic review of epidemiological surveys of autistic disorder and pervasive developmental disorders (PDDs) worldwide. A secondary aim was to consider the possible impact of geographic, cultural/ethnic, and socioeconomic factors on prevalen
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paper_title: Eye tracking in early autism research

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Eye tracking has the potential to characterize autism at a unique intermediate level, with links ‘down’ to underlying neurocognitive networks, as well as ‘up’ to everyday function and dysfunction. Because it is non-invasive and does not require advanced motor responses or language, eye tracking is particularly important for the study of young children and infants. In this article, we review eye tracking studies of young children with autism spectrum disorder (ASD) and children at risk for ASD. Reduced looking time at people and faces, as well as problems with disengagement of attention, appear to be among the earliest signs of ASD, emerging during the first year of life. In toddlers with ASD, altered looking patterns across facial parts such as the eyes and mouth have been found, together with limited orienting to biological motion. We provide a detailed discussion of these and other key findings and highlight methodological opportunities and challenges for eye tracking research of young children with ASD. We conclude that eye tracking can reveal important features of the complex picture of autism.
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paper_title: Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders

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To examine mirror neuron abnormalities in autism, high-functioning children with autism and matched controls underwent fMRI while imitating and observing emotional expressions. Although both groups performed the tasks equally well, children with autism showed no mirror neuron activity in the inferior frontal gyrus (pars opercularis). Notably, activity in this area was inversely related to symptom severity in the social domain, suggesting that a dysfunctional 'mirror neuron system' may underlie the social deficits observed in autism.
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paper_title: Compared to What? Early Brain Overgrowth in Autism and the Perils of Population Norms

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Background Early brain overgrowth (EBO) in autism spectrum disorder (ASD) is among the best replicated biological associations in psychiatry. Most positive reports have compared head circumference (HC) in ASD (an excellent proxy for early brain size) with well-known reference norms. We sought to reappraise evidence for the EBO hypothesis given 1) the recent proliferation of longitudinal HC studies in ASD, and 2) emerging reports that several of the reference norms used to define EBO in ASD may be biased toward detecting HC overgrowth in contemporary samples of healthy children. Methods Systematic review of all published HC studies in children with ASD. Comparison of 330 longitudinally gathered HC measures between birth and 18 months from male children with autism ( n = 35) and typically developing control subjects ( n = 22). Results In systematic review, comparisons with locally recruited control subjects were significantly less likely to identify EBO in ASD than norm-based studies ( p n ~ 75,000). Controlling for known HC norm biases leaves inconsistent support for a subtle, later emerging and subgroup specific pattern of EBO in clinically ascertained ASD versus community control subjects. Conclusions The best-replicated aspects of EBO reflect generalizable HC norm biases rather than disease-specific biomarkers. The potential HC norm biases we detail are not specific to ASD research but apply throughout clinical and academic medicine.
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paper_title: Towards a neuroanatomy of autism: A systematic review and meta-analysis of structural magnetic resonance imaging studies

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Abstract Background Structural brain abnormalities have been described in autism but studies are often small and contradictory. We aimed to identify which brain regions can reliably be regarded as different in autism compared to healthy controls. Method A systematic search was conducted for magnetic resonance imaging studies of regional brain size in autism. Data were extracted and combined using random effects meta-analysis. The modifying effects of age and IQ were investigated using meta-regression. Results The total brain, cerebral hemispheres, cerebellum and caudate nucleus were increased in volume, whereas the corpus callosum area was reduced. There was evidence for a modifying effect of age and IQ on the cerebellar vermal lobules VI–VII and for age on the amygdala. Conclusions Autism may result from abnormalities in specific brain regions and a global lack of integration due to brain enlargement. Inconsistencies in the literature partly relate to differences in the age and IQ of study populations. Some regions may show abnormal growth trajectories.
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paper_title: EEG source imaging

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Abstract Objective: Electroencephalography (EEG) is an important tool for studying the temporal dynamics of the human brain's large-scale neuronal circuits. However, most EEG applications fail to capitalize on all of the data's available information, particularly that concerning the location of active sources in the brain. Localizing the sources of a given scalp measurement is only achieved by solving the so-called inverse problem. By introducing reasonable a priori constraints, the inverse problem can be solved and the most probable sources in the brain at every moment in time can be accurately localized. Methods and Results: Here, we review the different EEG source localization procedures applied during the last two decades. Additionally, we detail the importance of those procedures preceding and following source estimation that are intimately linked to a successful, reliable result. We discuss (1) the number and positioning of electrodes, (2) the varieties of inverse solution models and algorithms, (3) the integration of EEG source estimations with MRI data, (4) the integration of time and frequency in source imaging, and (5) the statistical analysis of inverse solution results. Conclusions and Significance: We show that modern EEG source imaging simultaneously details the temporal and spatial dimensions of brain activity, making it an important and affordable tool to study the properties of cerebral, neural networks in cognitive and clinical neurosciences.
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paper_title: Head circumference and brain size in autism spectrum disorder: A systematic review and meta-analysis

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Macrocephaly and brain overgrowth have been associated with autism spectrum disorder. We performed a systematic review and meta-analysis to provide an overall estimate of effect size and statistical significance for both head circumference and total brain volume in autism. Our literature search strategy identified 261 and 391 records, respectively; 27 studies defining percentages of macrocephalic patients and 44 structural brain imaging studies providing total brain volumes for patients and controls were included in our meta-analyses. Head circumference was significantly larger in autistic compared to control individuals, with 822/5225 (15.7%) autistic individuals displaying macrocephaly. Structural brain imaging studies measuring brain volume estimated effect size. The effect size is higher in low functioning autistics compared to high functioning and ASD individuals. Brain overgrowth was recorded in 142/1558 (9.1%) autistic patients. Finally, we found a significant interaction between age and total brain volume, resulting in larger head circumference and brain size during early childhood. Our results provide conclusive effect sizes and prevalence rates for macrocephaly and brain overgrowth in autism, confirm the variation of abnormal brain growth with age, and support the inclusion of this endophenotype in multi-biomarker diagnostic panels for clinical use.
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paper_title: Why the frontal cortex in autism might be talking only to itself: local over-connectivity but long-distance disconnection

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Although it has long been thought that frontal lobe abnormality must play an important part in generating the severe impairment in higher-order social, emotional and cognitive functions in autism, only recently have studies identified developmentally early frontal lobe defects. At the microscopic level, neuroinflammatory reactions involving glial activation, migration defects and excess cerebral neurogenesis and/or defective apoptosis might generate frontal neural pathology early in development. It is hypothesized that these abnormal processes cause malformation and thus malfunction of frontal minicolumn microcircuitry. It is suggested that connectivity within frontal lobe is excessive, disorganized and inadequately selective, whereas connectivity between frontal cortex and other systems is poorly synchronized, weakly responsive and information impoverished. Increased local but reduced long-distance cortical–cortical reciprocal activity and coupling would impair the fundamental frontal function of integrating information from widespread and diverse systems and providing complex context-rich feedback, guidance and control to lower-level systems.
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paper_title: Autism and the Social Brain: The First-Year Puzzle

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The atypical features of social perception and cognition observed in individuals with a diagnosis of autism have been explained in two different ways. First, domain-specific accounts are based on the assumption that these end-state symptoms result from specific impairments within component structures of the social brain network. Second, domain-general accounts hypothesize that rather than being localized, atypical brain structure and function are widespread, or hypothesize that the apparent social brain differences are the consequence of adaptations to earlier occurring widespread changes in brain function. Critical evidence for resolving this basic issue comes from prospective longitudinal studies of infants at risk for later diagnosis. We highlight selected studies from the newly emerging literature on infants at familial risk for autism to shed light on this issue. Despite multiple reports of possible alterations in brain function in the first year of life, overt behavioral symptoms do not emerge until the second year. Our review reveals only mixed support, within this very early period, for localized deficits in social brain network systems and instead favors the view that atypical development involving perceptual, attentional, motor, and social systems precede the emerging autism phenotype.
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paper_title: fNIRS in the developmental sciences

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With the introduction of functional near-infrared spectroscopy (fNIRS) into the experimental setting, developmental scientists have, for the first time, the capacity to investigate the functional activation of the infant brain in awake, engaged participants. The advantages of fNIRS clearly outweigh the limitations, and a description of how this technology is implemented in infant populations is provided. Most fNIRS research falls into one of three content domains: object processing, processing of biologically and socially relevant information, and language development. Within these domains, there are ongoing debates about the origins and development of human knowledge, making early neuroimaging particularly advantageous. The use of fNIRS has allowed investigators to begin to identify the localization of early object, social, and linguistic knowledge in the immature brain and the ways in which this changes with time and experience. In addition, there is a small but growing body of research that provides insight into the neural mechanisms that support and facilitate learning during the first year of life. At the same time, as with any emerging field, there are limitations to the conclusions that can be drawn on the basis of current findings. We offer suggestions as to how to optimize the use of this technology to answer questions of theoretical and practical importance to developmental scientists. WIREs Cogn Sci 2015, 6:263–283. doi: 10.1002/wcs.1343 ::: ::: ::: ::: For further resources related to this article, please visit the WIREs website. ::: ::: ::: ::: Conflict of interest: The authors have declared no conflicts of interest for this article.
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paper_title: The superior temporal sulcus performs a common function for social and speech perception: Implications for the emergence of autism

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Abstract Within the cognitive neuroscience literature, discussion of the functional role of the superior temporal sulcus (STS) has traditionally been divided into two domains; one focuses on its activity during language processing while the other emphasizes its role in biological motion and social attention, such as eye gaze processing. I will argue that a common process underlying both of these functional domains is performed by the STS, namely analyzing changing sequences of input, either in the auditory or visual domain, and interpreting the communicative significance of those inputs. From a developmental perspective, the fact that these two domains share an anatomical substrate suggests the acquisition of social and speech perception may be linked. In addition, I will argue that because of the STS’ role in interpreting social and speech input, impairments in STS function may underlie many of the social and language abnormalities seen in autism.
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paper_title: A systematic review and meta-analysis of the fMRI investigation of autism spectrum disorders

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Abstract Recent years have seen a rapid increase in the investigation of autism spectrum disorders (ASD) through the use of functional magnetic resonance imaging (fMRI). We carried out a systematic review and ALE meta-analysis of fMRI studies of ASD. A disturbance to the function of social brain regions is among the most well replicated finding. Differences in social brain activation may relate to a lack of preference for social stimuli as opposed to a primary dysfunction of these regions. Increasing evidence points towards a lack of effective integration of distributed functional brain regions and disruptions in the subtle modulation of brain function in relation to changing task demands in ASD. Limitations of the literature to date include the use of small sample sizes and the restriction of investigation to primarily high functioning males with autism.
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paper_title: Involvement of the anterior thalamic radiation in boys with high functioning autism spectrum disorders: A Diffusion Tensor Imaging study

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Abstract Background: Autism has been hypothesized to reflect neuronal disconnection. Several recent reports implicate the key thalamic relay nuclei and cortico-thalamic connectivity in the pathophysiology of autism. Accordingly, we aimed to focus on evaluating the integrity of the thalamic radiation and sought to replicate prior white matter findings in Korean boys with high-functioning autism spectrum disorders (ASD) using Diffusion Tensor Imaging (DTI). Methods: We compared fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in 17 boys with ASD and 17 typically developing controls in the anterior thalamic radiation (ATR), superior thalamic radiation (STR), posterior thalamic radiation (PTR), corpus callosum (CC), uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF). Results: The two groups were group-matched on age, IQ, handedness and head circumference. In whole-brain voxel-wise analyses, FA was significantly reduced and MD was significantly increased in the right ATR, CC, and left UF in subjects with ASD (p
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paper_title: Developmental pathways to autism: A review of prospective studies of infants at risk

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Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders characterized by impairments in social interaction and communication, and the presence of restrictive and repetitive behaviors. Symptoms of ASD likely emerge from a complex interaction between pre-existing neurodevelopmental vulnerabilities and the child's environment, modified by compensatory skills and protective factors. Prospective studies of infants at high familial risk for ASD (who have an older sibling with a diagnosis) are beginning to characterize these developmental pathways to the emergence of clinical symptoms. Here, we review the range of behavioral and neurocognitive markers for later ASD that have been identified in high-risk infants in the first years of life. We discuss theoretical implications of emerging patterns, and identify key directions for future work, including potential resolutions to several methodological challenges for the field. Mapping how ASD unfolds from birth is critical to our understanding of the developmental mechanisms underlying this disorder. A more nuanced understanding of developmental pathways to ASD will help us not only to identify children who need early intervention, but also to improve the range of interventions available to them.
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paper_title: MR Diffusion Tensor Spectroscopy and Imaging 259

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This paper describes a new NMR imaging modality--MR diffusion tensor imaging. It consists of estimating an effective diffusion tensor, Deff, within a voxel, and then displaying useful quantities derived from it. We show how the phenomenon of anisotropic diffusion of water (or metabolites) in anisotropic tissues, measured noninvasively by these NMR methods, is exploited to determine fiber tract orientation and mean particle displacements. Once Deff is estimated from a series of NMR pulsed-gradient, spin-echo experiments, a tissue's three orthotropic axes can be determined. They coincide with the eigenvectors of Deff, while the effective diffusivities along these orthotropic directions are the eigenvalues of Deff. Diffusion ellipsoids, constructed in each voxel from Deff, depict both these orthotropic axes and the mean diffusion distances in these directions. Moreover, the three scalar invariants of Deff, which are independent of the tissue's orientation in the laboratory frame of reference, reveal useful information about molecular mobility reflective of local microstructure and anatomy. Inherently tensors (like Deff) describing transport processes in anisotropic media contain new information within a macroscopic voxel that scalars (such as the apparent diffusivity, proton density, T1, and T2) do not.
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paper_title: Atypical development of white matter microstructure in adolescents with autism spectrum disorders

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Abstract Diffusion tensor imaging (DTI) studies in adolescents with autism spectrum disorders (ASD) indicate aberrant neurodevelopment of frontal white matter (WM), potentially underlying abnormal social cognition and communication in ASD. Here, we further use tract-based spatial statistics (TBSS) to examine the developmental change of WM skeleton (i.e., the most compact whole-brain WM) during adolescence in ASD. This whole-brain DTI used TBSS measures fractional anisotropy (FA) and longitudinal and radial diffusivities in fifty adolescents, 25 ASD and 25 controls. Results show that adolescents with ASD versus controls had significantly reduced FA in the right posterior limb of internal capsule (increased radial diffusivity distally and reduced longitudinal diffusivity centrally). Adolescents with ASD versus controls (covarying for age and IQ) had significantly greater FA in the frontal lobe (reduced radial diffusivity), right cingulate gyrus (reduced radial diffusivity), bilateral insula (reduced radial diffusivity and increased longitudinal diffusivity), right superior temporal gyrus (reduced radial diffusivity), and bilateral middle cerebellar peduncle (reduced radial diffusivity). Notably, a significant interaction with age by group was found in the right paracentral lobule and bilateral superior frontal gyrus as indicated by an age-related FA gain in the controls whilst an age-related FA loss in the ASD. To our knowledge, this is the first study to use TBSS to examine WM in individuals with ASD. Our findings indicate that the frontal lobe exhibits abnormal WM microstructure as well as an aberrant neurodevelopment during adolescence in ASD, which support the frontal disconnectivity theory of autism.
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paper_title: The Autism Diagnostic Observation Schedule-Generic: A Standard Measure of Social and Communication Deficits Associated with the Spectrum of Autism

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The Autism Diagnostic Observation Schedule-Generic (ADOS-G) is a semistructured, stan- dardized assessment of social interaction, communication, play, and imaginative use of ma- terials for individuals suspected of having autism spectrum disorders. The observational sched- ule consists of four 30-minute modules, each designed to be administered to different individuals according to their level of expressive language. Psychometric data are presented for 223 children and adults with Autistic Disorder (autism), Pervasive Developmental Disor- der Not Otherwise Specified (PDDNOS) or nonspectrum diagnoses. Within each module, di- agnostic groups were equivalent on expressive language level. Results indicate substantial in- terrater and test-retest reliability for individual items, excellent interrater reliability within domains and excellent internal consistency. Comparisons of means indicated consistent dif- ferentiation of autism and PDDNOS from nonspectrum individuals, with some, but less con- sistent, differentiation of autism from PDDNOS. A priori operationalization of DSM-IV/ICD- 10 criteria, factor analyses, and ROC curves were used to generate diagnostic algorithms with thresholds set for autism and broader autism spectrum/PDD. Algorithm sensitivities and speci- ficities for autism and PDDNOS relative to nonspectrum disorders were excellent, with mod- erate differentiation of autism from PDDNOS.
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paper_title: Autism: A Very Short Introduction

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1. The autism spectrum 2. Causes of autism 3. Explaining the social impairment 4. Explaining the communication impairment 5. Explaining islets of ability 6. Explaining problems in everyday living 7. Can we explain everything at once?
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paper_title: The use of near-infrared spectroscopy in the study of typical and atypical development

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The use of functional near infrared spectroscopy (fNIRS) has grown exponentially over the past decade, particularly among investigators interested in early brain development. The use of this neuroimaging technique has begun to shed light on the development of a variety of sensory, perceptual, linguistic, and social-cognitive functions. Rather than cast a wide net, in this paper we first discuss typical development, focusing on joint attention, face processing, language, and sensorimotor development. We then turn our attention to infants and children whose development has been compromised or who are at risk for atypical development. We conclude our review by critiquing some of the methodological issues that have plagued the extant literature as well as offer suggestions for future research.
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paper_title: The phenotype and neural correlates of language in autism: An integrative review

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Although impaired communication is one of the defining criteria in autism, linguistic functioning is highly variable among people with this disorder. Accumulating evidence shows that language impairments in autism are more extensive than commonly assumed and described by formal diagnostic criteria and are apparent at various levels. Phenotypically, most people with autism have semantic, syntactic and pragmatic deficits, a smaller number are known to have phonological deficits. Neurophysiologically, abnormal processing of low-level linguistic information points to perceptual difficulties. Also, abnormal high-level linguistic processing of the frontal and temporal language association cortices indicates more self-reliant and less connected neural subsystems. Early sensory impairments and subsequent atypical neural connectivity are likely to play a part in abnormal language acquisition in autism. This paper aims to review the available data on the phenotype of language in autism as well as a number of structural, electrophysiological and functional brain-imaging studies to provide a more integrated view of the linguistic phenotype and its underlying neural deficits, and to provide new directions for research and therapeutic and experimental applications.
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paper_title: Subgrouping the Autism “Spectrum": Reflections on DSM-5

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The biology of autism cannot yet be used diagnostically, and so—like most psychiatric conditions—autism is defined by behavior [Rett syndrome (Rett's disorder) is diagnosed by incorporating biology, but it has been moved out of the “Autism Spectrum Disorder" category in DSM-5]. The two international psychiatric classification systems (the Diagnostic and Statistical Manual of Mental Disorders [DSM] and the International Classification of Diseases [ICD]) remain useful for making clinical diagnoses, but each time these classification systems are revised, the new definitions inevitably subtly change the nature of how the conditions are construed. While acknowledging concerns about issues such as diagnostic inflation [1] and financial conflicts of interest [2], DSM-5 is now “set in stone" and will be published in May 2013. Although this manual is primarily designed for creating a common language for clinical practice, it is also often used in research settings to define the conditions to be studied. Here we reflect on what the revision may mean for research, and for understanding the nature of autism. ::: ::: New in DSM-5 is the explicit recognition of the “spectrum" nature of autism, subsuming and replacing the DSM-IV Pervasive Developmental Disorder (PDD) categorical subgroups of “autistic disorder," “Asperger's disorder," “pervasive developmental disorder not otherwise specified," and “childhood disintegrative disorder" into a single umbrella term “Autism Spectrum Disorder" (ASD). [Here and throughout we use the term “ASD" because this is what is used in DSM-5. However, in our publications over many years we have opted for the more neutral term “ASC" (Autism Spectrum Conditions) to signal that this is a biomedical diagnosis in which the individual needs support, and which leaves room for areas of strength as well as difficulty, without the somewhat negative overtones of the term “disorder," which implies something is “broken."] DSM-5 characterizes ASD in two behavioral domains (difficulties in social communication and social interaction, and unusually restricted, repetitive behaviors and interests) and is accompanied by a severity scale to capture the “spectrum" nature of ASD. ::: ::: Also new in DSM-5, language development/level is treated as separate from ASD. This means an individual can have ASD with or without a language disorder. Finally, DSM-5 proposes a more inclusive age-of-onset criterion, recognizing that although symptoms should present in early childhood, they may not fully manifest until social demands exceed the capacity of the individual to cope with them. The major rationale behind these changes is to improve reliability [3]. The DSM-5 field trial in North America has shown that ASD diagnosis has reasonable test-retest reliability, with an intraclass Kappa (a statistical measure of reliability) of 0.69 (95% CI 0.58–0.79) [4]. ::: ::: There have been concerns that the DSM-5 criteria may be more stringent than DSM-IV, such that some individuals who qualified for PDD will not meet the new ASD criteria. A series of studies testing the initial [5] and revised draft ASD criteria [6]–[12] showed increased specificity but decreased sensitivity of the DSM-5 draft compared to DSM-IV, and suggested relaxation of the threshold (e.g., fewer numbers of required symptom subdomains) to achieve reasonable sensitivity. However, most of these studies suffer from the weakness of using retrospective datasets and tools developed earlier that may not satisfactorily capture symptoms now included in DSM-5 [13]. One prospective study tested both DSM-IV and DSM-5 criteria against the gold standard of “best-estimate clinical diagnoses" and agreed with the “too-stringent" conclusion in a clinical sample [14]. However, another substantially large retrospective study using data from three existing datasets found few differences between the two systems in sensitivity [15]. ::: ::: In brief, these studies all show that DSM-5 provides better specificity (so reducing false-positive diagnoses), but at the expense of potentially reduced sensitivity, especially for older children, adolescents and adults, individuals without intellectual disability, and individuals who previously met criteria for diagnoses of DSM-IV “Asperger's disorder" or “pervasive developmental disorder not otherwise specified." It remains to be seen in real-life settings how diagnostic practice, service delivery, and prevalence estimates will be affected by applying DSM-5 ASD criteria. In particular, one major nosological issue is to what extent individuals fitting DSM-IV PDD but not DSM-5 ASD diagnoses will end up falling into the newly created diagnosis of “Social (Pragmatic) Communication Disorder" [12],[16]–[18]. Clearly more research needs to be done to provide a thorough and fair evaluation of this revision. ::: ::: Highlighting the dimensional nature of the two cardinal behavioral domains of ASD, as well as the improved organization of symptom descriptions, are excellent features of DSM-5. A unitary label of “ASD" accompanied by individualized assessment of needs for support will likely be useful in clinical settings, especially to guarantee the required levels of support for all individuals “on the spectrum" who will benefit from educational, occupational, social, mental health, and medical interventions (even if they are etiologically, developmentally, and clinically heterogeneous). However, this approach is not useful for research in general, given the known massive heterogeneity within such an omnibus label. Within autism there is a huge variability in terms of behavior (symptom severity and combination), cognition (the range of deficits and assets), and biological mechanisms. Acknowledging heterogeneity has led to the idea that there are many “autisms," with partially distinct etiologies, nested within the umbrella term of “ASD" [19]. Therefore, two critical issues need to be addressed: a clarification of the meaning(s) of the term “spectrum"; and the need for subgrouping.
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paper_title: Structural MRI in Autism Spectrum Disorder

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Magnetic resonance (MR) examination provides a powerful tool for investigating brain structural changes in children with autism spectrum disorder (ASD). We review recent advances in the understanding of structural MR correlates of ASD. We summarize findings from studies based on voxel-based morphometry, surface-based morphometry, tensor-based morphometry, and diffusion-tensor imaging. Finally, we discuss diagnostic models of ASD based on MR-derived features.
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paper_title: Comparison between diagnostic instruments for identifying high-functioning children with autism

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Two instruments for identifying autism in children and adolescents with intellectual abilities in the normal range were compared. Diagnostic tools consisted of the Autism Behavior Checklist (ABC) and the Autism Diagnostic Interview (ADI). The sample was composed of 18 children who were all diagnosed as having either infantile autism or infantile autism, residual state based on DSM-III criteria by a clinical team using observations, parental interviews, and interactions with the children. Only 4 of the children met diagnostic cutoffs for autism on the current ABC but all met criteria for diagnosis on the ABC using parental recall of the child's behavior at 3–5 years of age. The ADI had somewhat greater specificity in that 3 children did not meet criteria for diagnosis although 2 of these children also received ABC scores based on parental recollection that were in the borderline range.
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paper_title: Review of neuroimaging in autism spectrum disorders: what have we learned and where we go from here

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Autism spectrum disorder (ASD) refers to a syndrome of social communication deficits and repetitive behaviors or restrictive interests. It remains a behaviorally defined syndrome with no reliable biological markers. The goal of this review is to summarize the available neuroimaging data and examine their implication for our understanding of the neurobiology of ASD.Although there is variability in the literature on structural magnetic resonance literature (MRI), there is evidence of volume abnormalities in both grey and white matter, with a suggestion of some region-specific differences. Early brain overgrowth is probably the most replicated finding in a subgroup of people with ASD, and new techniques, such as cortical-thickness measurements and surface morphometry have begun to elucidate in more detail the patterns of abnormalities as they evolve with age, and are implicating specific neuroanatomical or neurodevelopmental processes. Functional MRI and diffusion tensor imaging techniques suggest that such volume abnormalities are associated with atypical functional and structural connectivity in the brain, and researchers have begun to use magnetic resonance spectroscopy (MRS) techniques to explore the neurochemical substrate of such abnormalities. The data from multiple imaging methods suggests that ASD is associated with an atypically connected brain. We now need to further clarify such atypicalities, and start interpreting them in the context of what we already know about typical neurodevelopmental processes including migration and organization of the cortex. Such an approach will allow us to relate imaging findings not only to behavior, but also to genes and their expression, which may be related to such processes, and to further our understanding of the nature of neurobiologic abnormalities in ASD.
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paper_title: Network inefficiencies in autism spectrum disorder at 24 months

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Autism spectrum disorder (ASD) is a developmental disorder defined by behavioral symptoms that emerge during the first years of life. Associated with these symptoms are differences in the structure of a wide array of brain regions, and in the connectivity between these regions. However, the use of cohorts with large age variability and participants past the generally recognized age of onset of the defining behaviors means that many of the reported abnormalities may be a result of cascade effects of developmentally earlier deviations. This study assessed differences in connectivity in ASD at the age at which the defining behaviors first become clear. There were 113 24-month-old participants at high risk for ASD, 31 of whom were classified as ASD, and 23 typically developing 24-month-old participants at low risk for ASD. Utilizing diffusion data to obtain measures of the length and strength of connections between anatomical regions, we performed an analysis of network efficiency. Our results showed significantly decreased local and global efficiency over temporal, parietal and occipital lobes in high-risk infants classified as ASD, relative to both low- and high-risk infants not classified as ASD. The frontal lobes showed only a reduction in global efficiency in Broca's area. In addition, these same regions showed an inverse relation between efficiency and symptom severity across the high-risk infants. The results suggest delay or deficits in infants with ASD in the optimization of both local and global aspects of network structure in regions involved in processing auditory and visual stimuli, language and nonlinguistic social stimuli.
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paper_title: Research Review: Constraining heterogeneity: the social brain and its development in autism spectrum disorder

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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. Keywords: Social perception, social cognition, autism, functional neuroimaging, social brain. The considerable heterogeneity in the expression and severity of the core and associated symptoms is a challenge that has hindered progress towards understanding autism spectrum disorder (ASD). To illustrate, within autistic disorder, variability in the social domain ranges from a near absence of interest in interacting with others to more subtle difficulties managing complex social interactions that require an understanding of other people’s goals and intentions and other cues of social context. Similarly, stereotyped and repetitive behaviors range from simple motor stereotypies and/or a preference for sameness to much more complex and elaborate rituals, accompanied by emotional dysregulation or ‘meltdowns’ when these rituals are interrupted. Some individuals with ASD lack basic speech abilities, while others can have language deficits that are mild and limited to language pragmatics. While a majority of individuals with ASD exhibit some level of intellectual impairment, intelligence quotients vary from the severe and profoundly impaired range to well above average.
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paper_title: A systematic review of the diagnostic stability of Autism Spectrum Disorder

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Abstract There is debate in the current literature regarding the permanence of an Autism Spectrum Disorder (ASD) diagnosis. We undertook a systematic review of the diagnostic stability of ASD to summarise current evidence. A comprehensive search strategy was used to identify studies. Participants were children with ASD. Risk of bias was assessed by examining the sample selected, recruitment method, completeness of follow up, timing of diagnosis and blinding. Twenty three studies assessed diagnostic stability with a total of 1466 participants. Fifty three to100% of children still had a diagnosis of Autistic Disorder (AD) and 14–100% of children still had a diagnosis of another form of ASD at follow up. There is some evidence that Autistic Disorder is a reasonably stable diagnosis; however a significant minority of children will no longer meet diagnostic criteria after a period of follow up, particularly those diagnosed in the preschool years with cognitive impairment. Other Autism Spectrum Disorders have very variable stability between studies and clinicians when using this diagnosis need inform parents of its instability. This study supports the stricter diagnostic criteria in DSM-V. There is a need for long term, large population cohort studies measuring diagnostic stability.
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paper_title: Deviant Functional Magnetic Resonance Imaging Patterns of Brain Activity to Speech in 2–3-Year-Old Children with Autism Spectrum Disorder

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Background A failure to develop normal language is one of the most common first signs that a toddler might be at risk for autism. Currently the neural bases underlying this failure to develop language are unknown. Methods In this study, functional magnetic resonance imaging (fMRI) was used to identify the brain regions involved in speech perception in 12 2–3-year-old children with autism spectrum disorder (ASD) during natural sleep. We also recorded fMRI data from two typically developing control groups: a mental age-matched (MA) ( n = 11) and a chronological age-matched (CA) ( n = 12) group. During fMRI data acquisition, forward and backward speech stimuli were presented with intervening periods of no sound presentation. Results Direct statistical comparison between groups revealed significant differences in regions recruited to process speech. In comparison with their MA-matched control subjects, the ASD group showed reduced activity in an extended network of brain regions, which are recruited in typical early language acquisition. In comparison with their CA-matched control subjects, ASD participants showed greater activation primarily within right and medial frontal regions. Laterality analyses revealed a trend toward greater recruitment of right hemisphere regions in the ASD group and left hemisphere regions in the CA group during the forward speech condition. Furthermore, correlation analyses revealed a significant positive relationship between right hemisphere frontal and temporal activity to forward speech and receptive language skill. Conclusions These findings suggest that at 2–3 years, children with ASD might be on a deviant developmental trajectory characterized by a greater recruitment of right hemisphere regions during speech perception.
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paper_title: Online monitoring of the social presence effects in a two-person-like driving video game using near-infrared spectroscopy

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Abstract: We examined how a friend’s presence affects a performer’s prefrontalactivation in daily-life activities using two wireless portable near-infrared spectroscopy(NIRS) devices. Participants played a driving video game either solely in the singlegroup or with a friend in the paired group. The two groups (single and paired) weresubdivided according to their game proﬁciency (low and high). The NIRS data dem-onstrated a signiﬁcant interaction of group by proﬁciency. Low-proﬁciency players inthe paired group showed lower activation than those in the single group, but high-proﬁciency players did not. In the paired group, high-proﬁciency players showedhigher activation than low-proﬁciency players, but not in the single group. Theseresults suggest that NIRS detects social presence effects in everyday situations:decreasing prefrontal activation in low-proﬁciency performers due to tension reduc-tion and increasing prefrontal activation in high-proﬁciency performers due toincreased arousal.Key words: presence of others, near-infrared spectroscopy (NIRS), online monitor-ing, prefrontal cortex (PFC), task proﬁciency.The presence of others (PO) affects an indi-vidual’s mind and performance widely in dailyactivities (Allport, 1924),such as sports,in-classlearning, group work, and playing games.Accordingly, a critical question arises: How canwe predict whether PO will improve or impairour solitary performance? Because of its funda-mental importance on human development andbehavior (Allport, 1954),the effects of PO haveattracted great interest for both theoretical andapplied research for several decades (Aiello D Uziel, 2007).The social presence effects have been previ-ously studied in two main research ﬁelds.Socialfacilitation literature suggests that PO (strangeror friend) generally improves well-learnedtasks and impairs poorly learned tasks as asource of arousal (Zajonc, 1965, 1980). That is,PO generally increases an individual’s arousal,which in turn enhances emission of a habitualresponse from his/her behavioral repertoire. Ina well-learned task, the habitual response isusually the correct one, leading to performanceimprovement,whereas in a poorly learned task,it is usually the incorrect one, leading to perfor-mance impairment.In contrast, social support research has con-sistently revealed that PO does not always func-tion to increase one’s tension; the presenceof a friend may relax an individual in stressful
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paper_title: Prevalence of autism spectrum disorders in an Icelandic birth cohort

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OBJECTIVES ::: A steady increase in the prevalence of autism spectrum disorders (ASD) has been reported in studies based on different methods, requiring adjustment for participation and missing data. Recent studies with high ASD prevalence rates rarely report on co-occurring medical conditions. The aim of the study was to describe the prevalence of clinically confirmed cases of ASD in Iceland and concomitant medical conditions. ::: ::: ::: DESIGN ::: The cohort is based on a nationwide database on ASD among children born during 1994-1998. ::: ::: ::: PARTICIPANTS ::: A total of 267 children were diagnosed with ASD, 197 boys and 70 girls. Only clinically confirmed cases were included. All received physical and neurological examination, standardised diagnostic workup for ASD, as well as cognitive testing. ASD diagnosis was established by interdisciplinary teams. Information on medical conditions and chromosomal testing was obtained by record linkage with hospital registers. ::: ::: ::: SETTING ::: Two tertiary institutions in Iceland. The population registry recorded 22 229 children in the birth cohort. ::: ::: ::: RESULTS ::: Prevalence of all ASD was 120.1/10 000 (95% CI 106.6 to 135.3), for boys 172.4/10 000 (95% CI 150.1 to 198.0) and for girls 64.8/10 000 (95% CI 51.3 to 81.8). Prevalence of all medical conditions was 17.2% (95% CI 13.2 to 22.2), including epilepsy of 7.1% (95% CI 4.6 to 10.8). The proportion of ASD cases with cognitive impairment (intellectual quotient <70) was 45.3%, but only 34.1% were diagnosed with intellectual disability (ID). Children diagnosed earlier or later did not differ on mean total score on a standardised interview for autism. ::: ::: ::: CONCLUSIONS ::: The number of clinically verified cases is larger than in previous studies, yielding a prevalence of ASD on a similar level as found in recent non-clinical studies. The prevalence of co-occurring medical conditions was high, considering the low proportion of ASD cases that also had ID. Earlier detection is clearly desirable in order to provide counselling and treatment.
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paper_title: Advances in autism genetics: on the threshold of a new neurobiology

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Nature Reviews Genetics 9, 341–355 (2008) The first row in Table 1 on page 344 of this Review was incorrect; the corrected version is shown below. The authors apologize for this error.
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paper_title: Comparing symptoms of autism spectrum disorders using the current DSM-IV-TR diagnostic criteria and the proposed DSM-V diagnostic criteria.

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Abstract The American Psychiatric Association has proposed major revisions for the diagnostic category encompassing Autism Spectrum Disorders (ASD), which will reportedly increase the specificity and maintain the sensitivity of diagnoses. As a result, the aim of the current study was to compare symptoms of ASD in children and adolescents ( N = 208) who met criteria for ASD according to only the DSM-IV-TR to those who met criteria according to the forthcoming version of the DSM and to those that were typically developing. Participants comprising the DSM-IV-TR and DSM-V groups did not score significantly different from each other on overall autism symptoms, but both groups scored significantly different from the control group. However significant differences emerged between the DSM-IV-TR and DSM-V groups in the core domain of nonverbal communication/socialization. Implications of the results and the proposed changes to the ASD diagnostic category are discussed.
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paper_title: The Implications of Brain Connectivity in the Neuropsychology of Autism

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Autism is a neurodevelopmental disorder that has been associated with atypical brain functioning. Functional connectivity MRI (fcMRI) studies examining neural networks in autism have seen an exponential rise over the last decade. Such investigations have led to the characterization of autism as a distributed neural systems disorder. Studies have found widespread cortical underconnectivity, local overconnectivity, and mixed results suggesting disrupted brain connectivity as a potential neural signature of autism. In this review, we summarize the findings of previous fcMRI studies in autism with a detailed examination of their methodology, in order to better understand its potential and to delineate the pitfalls. We also address how a multimodal neuroimaging approach (incorporating different measures of brain connectivity) may help characterize the complex neurobiology of autism at a global level. Finally, we also address the potential of neuroimaging-based markers in assisting neuropsychological assessment of autism. The quest for a neural marker for autism is still ongoing, yet new findings suggest that aberrant brain connectivity may be a promising candidate.
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paper_title: Functional connectivity in the first year of life in infants at-risk for autism: a preliminary near-infrared spectroscopy study

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Background: Autism spectrum disorder (ASD) has been called a “developmental disconnection syndrome,” however the majority of the research examining connectivity in ASD has been conducted exclusively with older children and adults. Yet, prior ASD research suggests that perturbations in neurodevelopmental trajectories begin as early as the first year of life. Prospective longitudinal studies of infants at risk for ASD may provide a window into the emergence of these aberrant patterns of connectivity. The current study employed functional connectivity near-infrared spectroscopy (NIRS) in order to examine the development of intra- and inter-hemispheric functional connectivity in high- and low-risk infants across the first year of life. Methods: NIRS data were collected from 27 infants at high risk for autism (HRA) and 37 low-risk comparison (LRC) infants who contributed a total of 116 data sets at 3-, 6-, 9-, and 12-months. At each time point, HRA and LRC groups were matched on age, sex, head circumference, and Mullen Scales of Early Learning scores. Regions of interest (ROI) were selected from anterior and posterior locations of each hemisphere. The average time course for each ROI was calculated and correlations for each ROI pair were computed. Differences in functional connectivity were examined in a cross-sectional manner. Results: At 3-months, HRA infants showed increased overall functional connectivity compared to LRC infants. This was the result of increased connectivity for intra- and inter-hemispheric ROI pairs. No significant differences were found between HRA and LRC infants at 6- and 9-months. However, by 12-months, HRA infants showed decreased connectivity relative to LRC infants.
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paper_title: Brain-to-brain coupling: a mechanism for creating and sharing a social world

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Cognition materializes in an interpersonal space. The emergence of complex behaviors requires the coordination of actions among individuals according to a shared set of rules. Despite the central role of other individuals in shaping one's mind, most cognitive studies focus on processes that occur within a single individual. We call for a shift from a single-brain to a multi-brain frame of reference. We argue that in many cases the neural processes in one brain are coupled to the neural processes in another brain via the transmission of a signal through the environment. Brain-to-brain coupling constrains and shapes the actions of each individual in a social network, leading to complex joint behaviors that could not have emerged in isolation.
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paper_title: Early brain enlargement and elevated extra-axial fluid in infants who develop autism spectrum disorder

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Prospective studies of infants at risk for autism spectrum disorder have provided important clues about the early behavioural symptoms of autism spectrum disorder. Diagnosis of autism spectrum disorder, however, is not currently made until at least 18 months of age. There is substantially less research on potential brain-based differences in the period between 6 and 12 months of age. Our objective in the current study was to use magnetic resonance imaging to identify any consistently observable brain anomalies in 6–9 month old infants who would later develop autism spectrum disorder. We conducted a prospective infant sibling study with longitudinal magnetic resonance imaging scans at three time points (6–9, 12–15, and 18–24 months of age), in conjunction with intensive behavioural assessments. Fifty-five infants (33 ‘high-risk’ infants having an older sibling with autism spectrum disorder and 22 ‘low-risk’ infants having no relatives with autism spectrum disorder) were imaged at 6–9 months; 43 of these (27 high-risk and 16 low-risk) were imaged at 12–15 months; and 42 (26 high-risk and 16 low-risk) were imaged again at 18–24 months. Infants were classified as meeting criteria for autism spectrum disorder, other developmental delays, or typical development at 24 months or later (mean age at outcome: 32.5 months). Compared with the other two groups, infants who developed autism spectrum disorder ( n = 10) had significantly greater extra-axial fluid at 6–9 months, which persisted and remained elevated at 12–15 and 18–24 months. Extra-axial fluid is characterized by excessive cerebrospinal fluid in the subarachnoid space, particularly over the frontal lobes. The amount of extra-axial fluid detected as early as 6 months was predictive of more severe autism spectrum disorder symptoms at the time of outcome. Infants who developed autism spectrum disorder also had significantly larger total cerebral volumes at both 12–15 and 18–24 months of age. This is the first magnetic resonance imaging study to prospectively evaluate brain growth trajectories from infancy in children who develop autism spectrum disorder. The presence of excessive extra-axial fluid detected as early as 6 months and the lack of resolution by 24 months is a hitherto unreported brain anomaly in infants who later develop autism spectrum disorder. This is also the first magnetic resonance imaging evidence of brain enlargement in autism before age 2. These findings raise the potential for the use of structural magnetic resonance imaging to aid in the early detection of children at risk for autism spectrum disorder or other neurodevelopmental disorders. ::: ::: * Abbreviations ::: : ADOS ::: : Autism Diagnostic Observation Schedule ::: ASD ::: : autism spectrum disorder
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paper_title: Centrality of Social Interaction in Human Brain Function

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People are embedded in social interaction that shapes their brains throughout lifetime. Instead of emerging from lower-level cognitive functions, social interaction could be the default mode via which humans communicate with their environment. Should this hypothesis be true, it would have profound implications on how we think about brain functions and how we dissect and simulate them. We suggest that the research on the brain basis of social cognition and interaction should move from passive spectator science to studies including engaged participants and simultaneous recordings from the brains of the interacting persons.
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paper_title: Hypersensitivity to acoustic change in children with autism: Electrophysiological evidence of left frontal cortex dysfunctioning

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Exaggerated reactions to even small changes in the environment and abnormal behaviors in response to auditory stimuli are frequently observed in children with autism (CWA). Brain mechanisms involved in the automatic detection of auditory frequency change were studied using scalp potential and scalp current density (SCD) mapping of mismatch negativity (MMN) in 15 CWA matched with 15 healthy children. Compared with the response in controls, MMN recorded at the Fz site in CWA showed significantly shorter latency and was followed by a P3a wave. Mapping of potentials indicated significant intergroup differences. Moreover, SCD mapping demonstrated the dynamics of the different MMN generators: Although temporal component was evidenced bilaterally in both groups, it occurred earlier on the left hemisphere in CWA, preceded by an abnormal early left frontal component. The electrophysiological pattern reported here emphasized a left frontal cortex dysfunctioning that might also be implicated in cognitive and behavioral impairment characteristic, of this complex neurodevelopmental disorder.
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paper_title: Autism, Language Disorder, and Social (Pragmatic) Communication Disorder: DSM-V and Differential Diagnoses

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1. Mark D. Simms, MD, MPH* ::: 2. Xing Ming Jin, MD† ::: ::: ::: ::: ::: 1. *Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI. ::: ::: 2. †Department of Pediatrics, Jiao Tong University School of Medicine, Shanghai, Peoples Republic of China. ::: ::: The recent revision of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-V) included refinements to the diagnostic criteria for autism spectrum disorders and language disorders and introduced a new entity, social (pragmatic) communication disorder. Clinicians should become familiar with these changes and understand how to apply this new knowledge in clinical practice. ::: ::: After completing this article, readers should be able to: ::: ::: 1. Know the revised criteria for autistic spectrum disorders and language disorders and the diagnostic criteria for social (pragmatic) communication disorder. ::: ::: 2. Understand the clinical similarities and difference of these disorders. ::: ::: 3. Know the differences in the long-term prognosis of these disorders. ::: ::: 4. Be familiar with some relatively common “nonspecific” behaviors that should not be confused with specific developmental disorders. ::: ::: The past decade has witnessed an explosion in public and professional awareness of autism and autistic spectrum disorders (ASDs). Once considered to be a rare disorder, ASD now has a reported prevalence rate of slightly more than 1% among United States children. (1) Although the cause of this increased prevalence is not certain, greater awareness has likely resulted in improved recognition. This has been accompanied by increased research on autism focused on its cause and effective interventions for young children. Autism treatment programs are now widely available in school and community settings. ::: ::: At the same time, childhood language disorders, which are more common than ASDs, have remained relatively unknown publicly and professionally. At kindergarten entry, approximately 7% to 8% of children have evidence of a language impairment (2) and are at significant risk for difficulty with language-based learning tasks and social adaptation as they progress through school. The most …
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paper_title: In search of biomarkers for autism: scientific, social and ethical challenges

paper_content:

There is widespread hope that the discovery of valid biomarkers for autism will both reveal the causes of autism and enable earlier and more targeted methods for diagnosis and intervention. However, growing enthusiasm about recent advances in this area of autism research needs to be tempered by an awareness of the major scientific challenges and the important social and ethical concerns arising from the development of biomarkers and their clinical application. Collaborative approaches involving scientists and other stakeholders must combine the search for valid, clinically useful autism biomarkers with efforts to ensure that individuals with autism and their families are treated with respect and understanding.
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paper_title: Connectivity in Autism: A Review of MRI Connectivity Studies.

paper_content:

Learning ObjectiveAfter participating in this activity, learners should be better able to:Assess the resting state and diffusion tensor imaging connectivity literature regarding subjects with autism spectrum disorder.AbstractAutism spectrum disorder (ASD) affects 1 in 50 children between the ages of
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paper_title: Neural bases of gaze and emotion processing in children with autism spectrum disorders

paper_content:

Abnormal eye contact is a core symptom of autism spectrum disorders (ASD), though little is understood of the neural bases of gaze processing in ASD. Competing hypotheses suggest that individuals with ASD avoid eye contact due to the anxiety-provoking nature of direct eye gaze or that eye-gaze cues hold less interest or significance to children with ASD. The current study examined the effects of gaze direction on neural processing of emotional faces in typically developing (TD) children and those with ASD. While undergoing functional magnetic resonance imaging (fMRI), 16 high-functioning children and adolescents with ASD and 16 TD controls viewed a series of faces depicting emotional expressions with either direct or averted gaze. Children in both groups showed significant activity in visual-processing regions for both direct and averted gaze trials. However, there was a significant group by gaze interaction such that only TD children showed reliably greater activity in ventrolateral prefrontal cortex for direct versus averted gaze. The ASD group showed no difference between direct and averted gaze in response to faces conveying negative emotions. These results highlight the key role of eye gaze in signaling communicative intent and suggest altered processing of the emotional significance of direct gaze in children with ASD.
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paper_title: Autism as a disorder of neural information processing: directions for research and targets for therapy*

paper_content:

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which they feed, is hampered by the large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging, and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself.
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paper_title: The neural basis of functional brain imaging signals

paper_content:

The haemodynamic responses to neural activity that underlie the blood-oxygen-level-dependent (BOLD) signal used in functional magnetic resonance imaging (fMRI) of the brain are often assumed to be driven by energy use, particularly in presynaptic terminals or glia. However, recent work has suggested that most brain energy is used to power postsynaptic currents and action potentials rather than presynaptic or glial activity and, furthermore, that haemodynamic responses are driven by neurotransmitter-related signalling and not directly by the local energy needs of the brain. A firm understanding of the BOLD response will require investigation to be focussed on the neural signalling mechanisms controlling blood flow rather than on the locus of energy use.
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paper_title: Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2016

paper_content:

PROBLEM/CONDITION ::: Autism spectrum disorder (ASD). ::: ::: ::: PERIOD COVERED ::: 2016. ::: ::: ::: DESCRIPTION OF SYSTEM ::: The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active surveillance program that provides estimates of the prevalence of ASD among children aged 8 years whose parents or guardians live in 11 ADDM Network sites in the United States (Arizona, Arkansas, Colorado, Georgia, Maryland, Minnesota, Missouri, New Jersey, North Carolina, Tennessee, and Wisconsin). Surveillance is conducted in two phases. The first phase involves review and abstraction of comprehensive evaluations that were completed by medical and educational service providers in the community. In the second phase, experienced clinicians who systematically review all abstracted information determine ASD case status. The case definition is based on ASD criteria described in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. ::: ::: ::: RESULTS ::: For 2016, across all 11 sites, ASD prevalence was 18.5 per 1,000 (one in 54) children aged 8 years, and ASD was 4.3 times as prevalent among boys as among girls. ASD prevalence varied by site, ranging from 13.1 (Colorado) to 31.4 (New Jersey). Prevalence estimates were approximately identical for non-Hispanic white (white), non-Hispanic black (black), and Asian/Pacific Islander children (18.5, 18.3, and 17.9, respectively) but lower for Hispanic children (15.4). Among children with ASD for whom data on intellectual or cognitive functioning were available, 33% were classified as having intellectual disability (intelligence quotient [IQ] ≤70); this percentage was higher among girls than boys (40% versus 32%) and among black and Hispanic than white children (47%, 36%, and 27%, respectively). Black children with ASD were less likely to have a first evaluation by age 36 months than were white children with ASD (40% versus 45%). The overall median age at earliest known ASD diagnosis (51 months) was similar by sex and racial and ethnic groups; however, black children with IQ ≤70 had a later median age at ASD diagnosis than white children with IQ ≤70 (48 months versus 42 months). ::: ::: ::: INTERPRETATION ::: The prevalence of ASD varied considerably across sites and was higher than previous estimates since 2014. Although no overall difference in ASD prevalence between black and white children aged 8 years was observed, the disparities for black children persisted in early evaluation and diagnosis of ASD. Hispanic children also continue to be identified as having ASD less frequently than white or black children. ::: ::: ::: PUBLIC HEALTH ACTION ::: These findings highlight the variability in the evaluation and detection of ASD across communities and between sociodemographic groups. Continued efforts are needed for early and equitable identification of ASD and timely enrollment in services.
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paper_title: Three-dimensional probabilistic anatomical cranio-cerebral correlation via the international 10–20 system oriented for transcranial functional brain mapping

paper_content:

Abstract The recent advent of multichannel near-infrared spectroscopy (NIRS) has expanded its technical potential for human brain mapping. However, NIRS measurement has a technical drawback in that it measures cortical activities from the head surface without anatomical information of the object to be measured. This problem is also found in transcranial magnetic stimulation (TMS) that transcranially activates or inactivates the cortical surface. To overcome this drawback, we examined cranio-cerebral correlation using magnetic resonance imaging (MRI) via the guidance of the international 10–20 system for electrode placement, which had originally been developed for electroencephalography. We projected the 10–20 standard cranial positions over the cerebral cortical surface. After examining the cranio-cerebral correspondence for 17 healthy adults, we normalized the 10–20 cortical projection points of the subjects to the standard Montreal Neurological Institute (MNI) and Talairach stereotactic coordinates and obtained their probabilistic distributions. We also expressed the anatomical structures for the 10–20 cortical projection points probabilistically. Next, we examined the distance between the cortical surface and the head surface along the scalp and created a cortical surface depth map. We found that the locations of 10–20 cortical projection points in the standard MNI or Talairach space could be estimated with an average standard deviation of 8 mm. This study provided an initial step toward establishing a three-dimensional probabilistic anatomical platform that enables intra- and intermodal comparisons of NIRS and TMS brain imaging data.
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paper_title: A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology

paper_content:

This year marks the 20th anniversary of functional near-infrared spectroscopy and imaging (fNIRS/fNIRI). As the vast majority of commercial instruments developed until now are based on continuous wave technology, the aim of this publication is to review the current state of instrumentation and methodology of continuous wave fNIRI. For this purpose we provide an overview of the commercially available instruments and address instrumental aspects such as light sources, detectors and sensor arrangements. Methodological aspects, algorithms to calculate the concentrations of oxy- and deoxyhemoglobin and approaches for data analysis are also reviewed. From the single-location measurements of the early years, instrumentation has progressed to imaging initially in two dimensions (topography) and then three (tomography). The methods of analysis have also changed tremendously, from the simple modified Beer-Lambert law to sophisticated image reconstruction and data analysis methods used today. Due to these advances, fNIRI has become a modality that is widely used in neuroscience research and several manufacturers provide commercial instrumentation. It seems likely that fNIRI will become a clinical tool in the foreseeable future, which will enable diagnosis in single subjects.
---
paper_title: Functional near‐infrared optical imaging: Utility and limitations in human brain mapping

paper_content:

Although near-infrared spectroscopy (NIRS) was developed as a tool for clinical monitoring of tissue oxygenation, it also has potential for neuroimaging. A wide range of different NIRS instruments have been developed, and instruments for continuous intensity measurements with fixed spacing [continuous wave (CW)-type instruments], which are most readily available commercially, allow us to see dynamic changes in regional cerebral blood flow in real time. However, quantification, which is necessary for imaging of brain functions, is impossible with these CW-type instruments. Over the past 20 years, many different approaches to quantification have been tried, and several multichannel time-resolved and frequency-domain instruments are now in common use for imaging. Although there are still many problems with this technique, such as incomplete knowledge of how light propagates through the head, NIRS will not only open a window on brain physiology for subjects who have rarely been examined until now, but also provide a new direction for functional mapping studies.
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paper_title: Time domain functional NIRS imaging for human brain mapping

paper_content:

This review is aimed at presenting the state-of-the-art of time domain (TD) functional near-infrared spectroscopy (fNIRS). We first introduce the physical principles, the basics of modeling and data analysis. Basic instrumentation components (light sources, detection techniques, and delivery and collection systems) of a TD fNIRS system are described. A survey of past, existing and next generation TD fNIRS systems used for research and clinical studies is presented. Performance assessment of TD fNIRS systems and standardization issues are also discussed. Main strengths and weakness of TD fNIRS are highlighted, also in comparison with continuous wave (CW) fNIRS. Issues like quantification of the hemodynamic response, penetration depth, depth selectivity, spatial resolution and contrast-to-noise ratio are critically examined, with the help of experimental results performed on phantoms or in vivo. Finally we give an account on the technological developments that would pave the way for a broader use of TD fNIRS in the neuroimaging community.
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paper_title: Frontal Lobe Activation during Object Permanence: Data from Near-Infrared Spectroscopy

paper_content:

Abstract The ability to create and hold a mental schema of an object is one of the milestones in cognitive development. Developmental scientists have named the behavioral manifestation of this competence object permanence. Convergent evidence indicates that frontal lobe maturation plays a critical role in the display of object permanence, but methodological and ethical constrains have made it difficult to collect neurophysiological evidence from awake, behaving infants. Near-infrared spectroscopy provides a noninvasive assessment of changes in oxy- and deoxyhemoglobin and total hemoglobin concentration within a prescribed region. The evidence described in this report reveals that the emergence of object permanence is related to an increase in hemoglobin concentration in frontal cortex.
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paper_title: A brief review on the history of human functional near-infrared spectroscopy (fNIRS) development and fields of application

paper_content:

article i nfo Functional near-infrared spectroscopy Functional near-infrared topography Hemodynamic response Optical imaging Cortical activation This review is aimed at celebrating the upcoming 20th anniversary of the birth of human functional near- infrared spectroscopy (fNIRS). After the discovery in 1992 that the functional activation of the human cerebral cortex (due to oxygenation and hemodynamic changes) can be explored by NIRS, human functional brain mapping research has gained a new dimension. fNIRS or optical topography, or near-infrared imaging or diffuse optical imaging is used mainly to detect simultaneous changes in optical properties of the human cortex from multiple measurement sites and displays the results in the form of a map or image over a specific area. In order to place current fNIRS research in its proper context, this paper presents a brief historical overview of the events that have shaped the present status of fNIRS. In particular, technological progresses of fNIRS are highlighted (i.e. from single-site to multi-site functional cortical measurements (images)), introduction of the commercial multi-channel systems, recent commercial wireless instrumentation and more advanced prototypes.
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paper_title: Beyond the Visible—Imaging the Human Brain with Light

paper_content:

Optical approaches to investigate cerebral function and metabolism have long been applied in invasive studies. From the neuron cultured in vitro to the exposed cortex in the human during neurosurgical procedures, high spatial resolution can be reached and several processes such as membrane potential, cell swelling, metabolism of mitochondrial chromophores, and vascular response can be monitored, depending on the respective preparation. The authors focus on an extension of optical methods to the noninvasive application in the human. Starting with the pioneering work of Jobsis 25 years ago, near-infrared spectroscopy (NIRS) has been used to investigate functional activation of the human cerebral cortex. Recently, several groups have started to use imaging systems that allow the generation of images of a larger area of the subject's head and, thereby, the production of maps of cortical oxygenation changes. Such images have a much lower spatial resolution compared with the invasively obtained optical images. The noninvasive NIRS images, however, can be obtained in undemanding set-ups that can be easily combined with other functional methods, in particular EEG. Moreover, NIRS is applicable to bedside use. The authors briefly review some of the abundant literature on intrinsic optical signals and the NIRS imaging studies of the past few years. The weaknesses and strengths of the approach are critically discussed. The authors conclude that NIRS imaging has two major advantages: it can address issues concerning neurovascular coupling in the human adult and can extend functional imaging approaches to the investigation of the diseased brain.
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paper_title: A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology

paper_content:

This year marks the 20th anniversary of functional near-infrared spectroscopy and imaging (fNIRS/fNIRI). As the vast majority of commercial instruments developed until now are based on continuous wave technology, the aim of this publication is to review the current state of instrumentation and methodology of continuous wave fNIRI. For this purpose we provide an overview of the commercially available instruments and address instrumental aspects such as light sources, detectors and sensor arrangements. Methodological aspects, algorithms to calculate the concentrations of oxy- and deoxyhemoglobin and approaches for data analysis are also reviewed. From the single-location measurements of the early years, instrumentation has progressed to imaging initially in two dimensions (topography) and then three (tomography). The methods of analysis have also changed tremendously, from the simple modified Beer-Lambert law to sophisticated image reconstruction and data analysis methods used today. Due to these advances, fNIRI has become a modality that is widely used in neuroscience research and several manufacturers provide commercial instrumentation. It seems likely that fNIRI will become a clinical tool in the foreseeable future, which will enable diagnosis in single subjects.
---
paper_title: Functional near‐infrared optical imaging: Utility and limitations in human brain mapping

paper_content:

Although near-infrared spectroscopy (NIRS) was developed as a tool for clinical monitoring of tissue oxygenation, it also has potential for neuroimaging. A wide range of different NIRS instruments have been developed, and instruments for continuous intensity measurements with fixed spacing [continuous wave (CW)-type instruments], which are most readily available commercially, allow us to see dynamic changes in regional cerebral blood flow in real time. However, quantification, which is necessary for imaging of brain functions, is impossible with these CW-type instruments. Over the past 20 years, many different approaches to quantification have been tried, and several multichannel time-resolved and frequency-domain instruments are now in common use for imaging. Although there are still many problems with this technique, such as incomplete knowledge of how light propagates through the head, NIRS will not only open a window on brain physiology for subjects who have rarely been examined until now, but also provide a new direction for functional mapping studies.
---
paper_title: Sustained decrease in oxygenated hemoglobin during video games in the dorsal prefrontal cortex: A NIRS study of children

paper_content:

Abstract Traditional neuroimaging studies have mainly focused on brain activity derived from a simple stimulus and task. Therefore, little is known about brain activity during daily operations. In this study, we investigated hemodynamic changes in the dorsal prefrontal cortex (DPFC) during video games as one of daily amusements, using near infrared spectroscopy technique. It was previously reported that oxygenated hemoglobin (oxyHb) in adults' DPFC decreased during prolonged game playing time. In the present study, we examined whether similar changes were observed in children. Twenty children (7–14 years old) participated in our study, but only 13 of them were eventually subject to analysis. They played one or two commercially available video games; namely a fighting and a puzzle game, for 5 min. We used changes in concentration of oxyHb as an indicator of brain activity and consequently, most of the children exhibited a sustained game-related oxyHb decrease in DPFC. Decrease patterns of oxyHb in children during video game playing time did not differ from those in adults. There was no significant correlation between ages or game performances and changes in oxyHb. These findings suggest that game-related oxyHb decrease in DPFC is a common phenomenon to adults and children at least older than 7 years old, and we suggest that this probably results from attention demand from the video games rather than from subject's age and performance.
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paper_title: Motion artifacts in functional near-infrared spectroscopy: a comparison of motion correction techniques applied to real cognitive data.

paper_content:

Motion artifacts are a significant source of noise in many functional near-infrared spectroscopy (fNIRS) experiments. Despite this, there is no well-established method for their removal. Instead, functional trials of fNIRS data containing a motion artifact are often rejected completely. However, in most experimental circumstances the number of trials is limited, and multiple motion artifacts are common, particularly in challenging populations. Many methods have been proposed recently to correct for motion artifacts, including principle component analysis, spline interpolation, Kalman filtering, wavelet filtering and correlation-based signal improvement. The performance of different techniques has been often compared in simulations, but only rarely has it been assessed on real functional data. Here, we compare the performance of these motion correction techniques on real functional data acquired during a cognitive task, which required the participant to speak aloud, leading to a low-frequency, low-amplitude motion artifact that is correlated with the hemodynamic response. To compare the efficacy of these methods, objective metrics related to the physiology of the hemodynamic response have been derived. Our results show that it is always better to correct for motion artifacts than reject trials, and that wavelet filtering is the most effective approach to correcting this type of artifact, reducing the area under the curve where the artifact is present in 93% of the cases. Our results therefore support previous studies that have shown wavelet filtering to be the most promising and powerful technique for the correction of motion artifacts in fNIRS data. The analyses performed here can serve as a guide for others to objectively test the impact of different motion correction algorithms and therefore select the most appropriate for the analysis of their own fNIRS experiment.
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paper_title: Interpretation of near-infrared spectroscopy signals: a study with a newly developed perfused rat brain model.

paper_content:

Using a newly developed perfused rat brain model, we examined direct effects of each change in cerebral blood flow (CBF) and oxygen metabolic rate on cerebral hemoglobin oxygenation to interpret near-infrared spectroscopy signals. Changes in CBF and total hemoglobin (tHb) were in parallel, although tHb showed no change when changes in CBF were small (< or =10%). Increasing CBF caused an increase in oxygenated hemoglobin (HbO(2)) and a decrease in deoxygenated hemoglobin (deoxy-Hb). Decreasing CBF was accompanied by a decrease in HbO(2), whereas changes in direction of deoxy-Hb were various. Cerebral blood congestion caused increases in HbO(2), deoxy-Hb, and tHb. Administration of pentylenetetrazole without increasing the flow rate caused increases in HbO(2) and tHb with a decrease in deoxy-Hb. There were no significant differences in venous oxygen saturation before vs. during seizure. These results suggest that, in activation studies with near-infrared spectroscopy, HbO(2) is the most sensitive indicator of changes in CBF, and the direction of changes in deoxy-Hb is determined by the degree of changes in venous blood oxygenation and volume.
---
paper_title: A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology

paper_content:

This year marks the 20th anniversary of functional near-infrared spectroscopy and imaging (fNIRS/fNIRI). As the vast majority of commercial instruments developed until now are based on continuous wave technology, the aim of this publication is to review the current state of instrumentation and methodology of continuous wave fNIRI. For this purpose we provide an overview of the commercially available instruments and address instrumental aspects such as light sources, detectors and sensor arrangements. Methodological aspects, algorithms to calculate the concentrations of oxy- and deoxyhemoglobin and approaches for data analysis are also reviewed. From the single-location measurements of the early years, instrumentation has progressed to imaging initially in two dimensions (topography) and then three (tomography). The methods of analysis have also changed tremendously, from the simple modified Beer-Lambert law to sophisticated image reconstruction and data analysis methods used today. Due to these advances, fNIRI has become a modality that is widely used in neuroscience research and several manufacturers provide commercial instrumentation. It seems likely that fNIRI will become a clinical tool in the foreseeable future, which will enable diagnosis in single subjects.
---
paper_title: A new research trend in social neuroscience: Towards an interactive‐brain neuroscience

paper_content:

The ability to flexibly modulate our behaviors in social contexts and to successfully interact with other persons is a fundamental, but pivotal, requirement for human survival. Although previous social neuroscience research with single individuals has contributed greatly to our understanding of the basic mechanisms underlying social perception and social emotions, much of the dynamic nature of interactions between persons remains beyond the reach of single-brain studies. This has led to a growing argument for a shift to the simultaneous measurement of the brain activity of two or more individuals in realistic social interactions-an approach termed "hyperscanning." Although this approach offers important promise in unlocking the brain's role in truly social situations, there are multiple procedural and theoretical questions that require review and analysis. In this paper we discuss this research trend from four aspects: hyperscanning apparatus, experimental task, quantification method, and theoretical interpretation. We also give four suggestions for future research: (a) electroencephalography and near-infrared spectroscopy are useful tools by which to explore the interactive brain in more ecological settings; (b) games are an appropriate method to simulate daily life interactions; (c) transfer entropy may be an important method by which to quantify directed exchange of information between brains; and (d) more explanation is needed of the results of interbrain synchronization itself.
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paper_title: Functional near Infrared Spectroscopy in Psychiatry: A Critical Review

paper_content:

This review deals with the utilisation of functional near infrared (fNIR) spectroscopy for an in vivo assessment of activation changes in brain tissue, which has broadened the range of non-invasive functional imaging methods within the field of neuroscientific research. Due to its simple and quick applicability as well as the absence of side effects, fNIR spectroscopy is particularly well tolerated by psychiatric patients and can hence markedly contribute to the understanding of the neurobiological basis of psychiatric disorders. The optical, light-based method emits near infrared wavelengths of about 700–1000 nm, which are able to penetrate the scalp and skull, into the head. Because near infrared light is distinctively absorbed by the chromophores oxy-haemoglobin (O2Hb) and deoxy-haemoglobin (HHb), the measured relative amount of reflected NIR light can indicate regional oxygenation patterns in cortical brain tissue with a depth resolution of, on average, 1.5 cm and a spatial resolution of about 2–3 cm. Validity and reliability of fNIR spectroscopy measurements to assess task-related cognitive activation have been repeatedly confirmed among healthy subjects. Beyond that, the application of fNIR spectroscopy to detect altered cortical oxygenation in psychiatric patients during cognitive tasks has been greatly intensified over the last two decades. In this context, hypo-frontality, a decrease in frontal lobe activity that is associated with a number of clinical symptoms and psychiatric disorders, has been demonstrated in a wide range of fNIR spectroscopy studies with psychiatric patients. Despite its variety of beneficial properties, the most apparent disadvantages of NIR spectroscopy compared to other imaging techniques are its limited spatial as well as depth resolution and its restriction to cortical areas. Although multimodal approaches based on simultaneous application of NIR spectroscopy combined with other imaging techniques initially revealed promising results, further technical development and a broadened implementation of combined measurements are necessary in order to uncover distinct brain activity alterations in different psychiatric disorders. In addition to the need for further technical improvement of the method, broad and longitudinal applications of fNIR spectroscopy measurements in psychiatric research are required in order to identify robust diagnostic markers which are required to establish NIR spectroscopy as a valid inter-individual screening instrument in psychiatry.
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paper_title: Reduced interhemispheric functional connectivity of children with autism spectrum disorder: evidence from functional near infrared spectroscopy studies

paper_content:

Autism spectrum disorder (ASD) is a neuro-developmental disorder, which has been associated with atypical neural synchronization. In this study, functional near infrared spectroscopy (fNIRS) was used to study the differences in functional connectivity in bilateral inferior frontal cortices (IFC) and bilateral temporal cortices (TC) between ASD and typically developing (TD) children between 8 and 11 years of age. As the first report of fNIRS study on the resting state functional connectivity (RSFC) in children with ASD, ten children with ASD and ten TD children were recruited in this study for 8 minute resting state measurement. Compared to TD children, children with ASD showed reduced interhemispheric connectivity in TC. Children with ASD also showed significantly lower local connectivity in bilateral temporal cortices. In contrast to TD children, children with ASD did not show typical patterns of symmetry in functional connectivity in temporal cortex. These results support the feasibility of using the fNIRS method to assess atypical functional connectivity of cortical responses of ASD and its potential application in diagnosis.
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paper_title: Interpretation of near-infrared spectroscopy signals: a study with a newly developed perfused rat brain model.

paper_content:

Using a newly developed perfused rat brain model, we examined direct effects of each change in cerebral blood flow (CBF) and oxygen metabolic rate on cerebral hemoglobin oxygenation to interpret near-infrared spectroscopy signals. Changes in CBF and total hemoglobin (tHb) were in parallel, although tHb showed no change when changes in CBF were small (< or =10%). Increasing CBF caused an increase in oxygenated hemoglobin (HbO(2)) and a decrease in deoxygenated hemoglobin (deoxy-Hb). Decreasing CBF was accompanied by a decrease in HbO(2), whereas changes in direction of deoxy-Hb were various. Cerebral blood congestion caused increases in HbO(2), deoxy-Hb, and tHb. Administration of pentylenetetrazole without increasing the flow rate caused increases in HbO(2) and tHb with a decrease in deoxy-Hb. There were no significant differences in venous oxygen saturation before vs. during seizure. These results suggest that, in activation studies with near-infrared spectroscopy, HbO(2) is the most sensitive indicator of changes in CBF, and the direction of changes in deoxy-Hb is determined by the degree of changes in venous blood oxygenation and volume.
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paper_title: fNIRS in the developmental sciences

paper_content:

With the introduction of functional near-infrared spectroscopy (fNIRS) into the experimental setting, developmental scientists have, for the first time, the capacity to investigate the functional activation of the infant brain in awake, engaged participants. The advantages of fNIRS clearly outweigh the limitations, and a description of how this technology is implemented in infant populations is provided. Most fNIRS research falls into one of three content domains: object processing, processing of biologically and socially relevant information, and language development. Within these domains, there are ongoing debates about the origins and development of human knowledge, making early neuroimaging particularly advantageous. The use of fNIRS has allowed investigators to begin to identify the localization of early object, social, and linguistic knowledge in the immature brain and the ways in which this changes with time and experience. In addition, there is a small but growing body of research that provides insight into the neural mechanisms that support and facilitate learning during the first year of life. At the same time, as with any emerging field, there are limitations to the conclusions that can be drawn on the basis of current findings. We offer suggestions as to how to optimize the use of this technology to answer questions of theoretical and practical importance to developmental scientists. WIREs Cogn Sci 2015, 6:263–283. doi: 10.1002/wcs.1343 ::: ::: ::: ::: For further resources related to this article, please visit the WIREs website. ::: ::: ::: ::: Conflict of interest: The authors have declared no conflicts of interest for this article.
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paper_title: Coupled oxygenation oscillation measured by NIRS and intermittent cerebral activation on EEG in premature infants

paper_content:

Abstract Electroencephalography of premature neonates shows a physiological discontinuity of electrical activity during quiet sleep. Near infrared spectroscopy (NIRS) shows spontaneous oscillations of hemoglobin oxygenation and volume. Similar oscillations are visible in term neonates and adults, with NIRS and other functional imaging techniques (fMRI, Doppler, etc.), but are generally thought to result from vasomotion and to be a physiological artifact of limited interest. The origin and possible relationship to neuronal activity of the baseline changes in the NIRS signal have not been established. We carried out simultaneous EEG–NIRS recordings on six healthy premature neonates and four premature neonates presenting neurological distress, to determine whether changes in the concentration of cerebral oxy- and deoxy- and total hemoglobin were related to the occurrence of spontaneous bursts of cerebral electric activity. Bursts of electroencephalographic activity in neonates during quiet sleep were found to be coupled to a transient stereotyped hemodynamic response involving a decrease in oxy-hemoglobin concentration, sometimes beginning a few seconds before the onset of electroencephalographic activity, followed by an increase, and then a return to baseline. This pattern could be either part of the baseline oscillations or superimposed changes to this baseline, influencing its shape and phase. The temporal patterns of NIRS parameters present an unique configuration, and tend to be different between our healthy and pathological subjects. Studies of physiological activities and of the effects of intrinsic regulation on the NIRS signal should increase our understanding of these patterns and EEG–NIRS studies should facilitate the integration of NIRS into the set of clinical tools used in neurology.
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paper_title: The use of near-infrared spectroscopy in the study of typical and atypical development

paper_content:

The use of functional near infrared spectroscopy (fNIRS) has grown exponentially over the past decade, particularly among investigators interested in early brain development. The use of this neuroimaging technique has begun to shed light on the development of a variety of sensory, perceptual, linguistic, and social-cognitive functions. Rather than cast a wide net, in this paper we first discuss typical development, focusing on joint attention, face processing, language, and sensorimotor development. We then turn our attention to infants and children whose development has been compromised or who are at risk for atypical development. We conclude our review by critiquing some of the methodological issues that have plagued the extant literature as well as offer suggestions for future research.
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paper_title: Low resolution brain electromagnetic tomography (LORETA) functional imaging in acute, neuroleptic-naive, first-episode, productive schizophrenia

paper_content:

Functional imaging of brain electrical activity was performed in nine acute, neuroleptic-naive, first-episode, productive patients with schizophrenia and 36 control subjects. Low-resolution electromagnetic tomography (LORETA, three-dimensional images of cortical current density) was computed from 19-channel of electroencephalographic (EEG) activity obtained under resting conditions, separately for the different EEG frequencies. Three patterns of activity were evident in the patients: (1) an anterior, near-bilateral excess of delta frequency activity; (2) an anterior-inferior deficit of theta frequency activity coupled with an anterior-inferior left-sided deficit of alpha-1 and alpha-2 frequency activity; and (3) a posterior-superior right-sided excess of beta-1, beta-2 and beta-3 frequency activity. Patients showed deviations from normal brain activity as evidenced by LORETA along an anterior-left-to-posterior-right spatial axis. The high temporal resolution of EEG makes it possible to specify the deviations not only as excess or deficit, but also as inhibitory, normal and excitatory. The patients showed a dis-coordinated brain functional state consisting of inhibited prefrontal/frontal areas and simultaneously overexcited right parietal areas, while left anterior, left temporal and left central areas lacked normal routine activity. Since all information processing is brain-state dependent, this dis-coordinated state must result in inadequate treatment of (externally or internally generated) information.
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paper_title: Near-infrared spectroscopy: A report from the McDonnell infant methodology consortium

paper_content:

Near-infrared spectroscopy (NIRS) is a new and increasingly widespread brain imaging technique, particularly suitable for young infants. The laboratories of the McDonnell Con- sortium have contributed to the technological development and research applications of this technique for nearly a decade. The present paper provides a general introduction to the technique as well as a detailed report of the methodological innovations developed by the Consortium. The basic principles of NIRS and some of the existing developmental stud- ies are reviewed. Issues concerning technological improvements, parameter optimization, possible experimental designs and data analysis techniques are discussed and illustrated by novel empirical data.
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paper_title: Time courses of brain activation and their implications for function: A multichannel near-infrared spectroscopy study during finger tapping

paper_content:

The time courses of brain activation were monitored during a finger tapping task using multichannel near-infrared spectroscopy with a time resolution of 0.1 s in 30 healthy volunteers. Task-induced brain activations were demonstrated as significant increases in oxygenated hemoglobin concentration ([oxy-Hb]) in a broad area around the motor cortex and significant decreases in deoxygenated hemoglobin concentration ([deoxy-Hb]) in a more restricted area, with a large degree of activation in the contralateral hemisphere. The time courses of the [oxy-Hb] changes varied depending on channel location: sustained activation across the task period in the motor cortex, transient activation during the initial segments of the task period in the somatosensory cortex, and accumulating activation along the task period in the frontal lobe. These characteristics are assumed to reflect the functional roles of the brain structures during the task period, that is, the execution, sensory monitoring, and maintenance of finger tapping.
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paper_title: Response Inhibition Impairment in High Functioning Autism and Attention Deficit Hyperactivity Disorder: Evidence from Near-Infrared Spectroscopy Data

paper_content:

BACKGROUND ::: Response inhibition, an important domain of executive function (EF), involves the ability to suppress irrelevant or interfering information and impulses. Previous studies have shown impairment of response inhibition in high functioning autism (HFA) and attention deficit hyperactivity disorder (ADHD), but more recent findings have been inconsistent. To date, almost no studies have been conducted using functional imaging techniques to directly compare inhibitory control between children with HFA and those with ADHD. ::: ::: ::: METHOD ::: Nineteen children with HFA, 16 age- and intelligence quotient (IQ)-matched children with ADHD, and 16 typically developing (TD) children were imaged using functional near-infrared spectroscopy (NIRS) while performing Go/No-go and Stroop tasks. ::: ::: ::: RESULTS ::: Compared with the TD group, children in both the HFA and ADHD groups took more time to respond during the No-go blocks, with reaction time longest for HFA and shortest for TD. Children in the HFA and ADHD groups also made a greater number of reaction errors in the No-go blocks than those in the TD group. During the Stroop task, there were no significant differences between these three groups in reaction time and omission errors. Both the HFA and ADHD groups showed a higher level of inactivation in the right prefrontal cortex (PFC) during the No-go blocks, relative to the TD group. However, no significant differences were found between groups in the levels of oxyhemoglobin concentration in the PFC during the Stroop task. ::: ::: ::: CONCLUSION ::: Functional brain imaging using NIRS showed reduced activation in the right PFC in children with HFA or ADHD during an inhibition task, indicating that inhibitory dysfunction is a shared feature of both HFA and ADHD.
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paper_title: Neurobehavioral and hemodynamic evaluation of Stroop and reverse Stroop interference in children with attention-deficit/hyperactivity disorder

paper_content:

Failure of executive function (EF) is a core symptom of attention-deficit/hyperactivity disorder (ADHD). However, various results have been reported and sufficient evidence is lacking. In the present study, we evaluated the characteristics of children with ADHD using the Stroop task (ST) and reverse Stroop task (RST) that reflects the inhibition function of EF. We compared children with ADHD, typically developing children (TDC), and children with autism spectrum disorder (ASD), which is more difficult to discriminate from ADHD. A total of 10 children diagnosed with ADHD, 15 TDC, and 11 children diagnosed with ASD, all matched by age, sex, language ability, and intelligence quotient, participated in this study. While each subject performed computer-based ST and RST with a touch panel, changes in oxygenated hemoglobin (oxy-Hb) were measured in the prefrontal cortex (PFC) by near-infrared spectroscopy (NIRS) to correlate test performance with neural activity. Behavioral performance significantly differed among 3 groups during RST but not during ST. The ADHD group showed greater color interference than the TDC group. In addition, there was a negative correlation between right lateral PFC (LPFC) activity and the severity of attention deficit. Children with ADHD exhibit several problems associated with inhibition of color, and this symptom is affected by low activities of the right LPFC. In addition, it is suggested that low hemodynamic activities in this area are correlated with ADHD.
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paper_title: Inhibition and the Validity of the Stroop Task for Children with Autism

paper_content:

Findings are mixed concerning inhibition in autism. Using the classic Stroop, children with autism (CWA) often outperform typically developing children (TDC). A classic Stroop and a chimeric animal Stroop were used to explore the validity of the Stroop task as a test of inhibition for CWA. During the classic Stroop, children ignored the word and named the ink colour, then vice versa. Although CWA showed less interference than TDC when colour naming, both groups showed comparable interference when word reading. During the chimeric animal task, children ignored bodies of animals and named heads, and vice versa; the groups performed comparably. Findings confirm that lower reading comprehension affects Stroop interference in CWA, potentially leading to inaccurate conclusions concerning inhibition in CWA.
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paper_title: Cortical activation during attention to sound in autism spectrum disorders.

paper_content:

Abstract Individuals with autism spectrum disorders (ASDs) can demonstrate hypersensitivity to sounds as well as a lack of awareness of them. Several functional imaging studies have suggested an abnormal response in the auditory cortex of such subjects, but it is not known whether these subjects have dysfunction in the auditory cortex or are simply not listening. We measured changes in blood oxygenated hemoglobin (OxyHb) in the prefrontal and temporal cortices using near-infrared spectroscopy during various listening and ignoring tasks in 11 ASD and 12 control subjects. Here we show that the auditory cortex in ASD subjects responds to sounds fully during attention. OxyHb in the auditory cortex increased with intentional listening but not with ignoring of the same auditory stimulus in a similar fashion in both groups. Cortical responses differed not in the auditory but in the prefrontal region between the ASD and control groups. Thus, unawareness to sounds in ASD could be interpreted as due to inattention rather than dysfunction of the auditory cortex. Difficulties in attention control may account for the contrary behaviors of hypersensitivity and unawareness to sound in ASD.
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paper_title: Atypicalities in Cortical Structure, Handedness, and Functional Lateralization for Language in Autism Spectrum Disorders

paper_content:

Language is typically a highly lateralized function, with atypically reduced or reversed lateralization linked to language impairments. Given the diagnostic and prognostic role of impaired language for autism spectrum disorders (ASDs), this paper reviews the growing body of literature that examines patterns of lateralization in individuals with ASDs. Including research from structural and functional imaging paradigms, and behavioral evidence from investigations of handedness, the review confirms that atypical lateralization is common in people with ASDs. The evidence indicates reduced structural asymmetry in fronto-temporal language regions, attenuated functional activation in response to language and pre-linguistic stimuli, and more ambiguous (mixed) hand preferences, in individuals with ASDs. Critically, the evidence emphasizes an intimate relationship between atypical lateralization and language impairment, with more atypical asymmetries linked to more substantive language impairment. Such evidence highlights opportunities for the identification of structural and functional biomarkers of ASDs, affording the potential for earlier diagnosis and intervention implementation.
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paper_title: Reduced interhemispheric functional connectivity of children with autism spectrum disorder: evidence from functional near infrared spectroscopy studies

paper_content:

Autism spectrum disorder (ASD) is a neuro-developmental disorder, which has been associated with atypical neural synchronization. In this study, functional near infrared spectroscopy (fNIRS) was used to study the differences in functional connectivity in bilateral inferior frontal cortices (IFC) and bilateral temporal cortices (TC) between ASD and typically developing (TD) children between 8 and 11 years of age. As the first report of fNIRS study on the resting state functional connectivity (RSFC) in children with ASD, ten children with ASD and ten TD children were recruited in this study for 8 minute resting state measurement. Compared to TD children, children with ASD showed reduced interhemispheric connectivity in TC. Children with ASD also showed significantly lower local connectivity in bilateral temporal cortices. In contrast to TD children, children with ASD did not show typical patterns of symmetry in functional connectivity in temporal cortex. These results support the feasibility of using the fNIRS method to assess atypical functional connectivity of cortical responses of ASD and its potential application in diagnosis.
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paper_title: Anterior Prefrontal Hemodynamic Connectivity in Conscious 3- to 7-Year-Old Children with Typical Development and Autism Spectrum Disorder

paper_content:

Socio-communicative impairments are salient features of autism spectrum disorder (ASD) from a young age. The anterior prefrontal cortex (aPFC), or Brodmann area 10, is a key processing area for social function, and atypical development of this area is thought to play a role in the social deficits in ASD. It is important to understand these brain functions in developing children with ASD. However, these brain functions have not yet been well described under conscious conditions in young children with ASD. In the present study, we focused on the brain hemodynamic functional connectivity between the right and the left aPFC in children with ASD and typically developing (TD) children and investigated whether there was a correlation between this connectivity and social ability. Brain hemodynamic fluctuations were measured non-invasively by near-infrared spectroscopy (NIRS) in 3- to 7-year-old children with ASD (n = 15) and gender- and age-matched TD children (n = 15). The functional connectivity between the right and the left aPFC was assessed by measuring the coherence for low-frequency spontaneous fluctuations (0.01 – 0.10 Hz) during a narrated picture-card show. Coherence analysis demonstrated that children with ASD had a significantly higher inter-hemispheric connectivity with 0.02-Hz fluctuations, whereas a power analysis did not demonstrate significant differences between the two groups in terms of low frequency fluctuations (0.01 – 0.10 Hz). This aberrant higher connectivity in children with ASD was positively correlated with the severity of social deficit, as scored with the Autism Diagnostic Observation Schedule. This is the first study to demonstrate aberrant brain functional connectivity between the right and the left aPFC under conscious conditions in young children with ASD.
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paper_title: Functional connectivity in the first year of life in infants at-risk for autism: a preliminary near-infrared spectroscopy study

paper_content:

Background: Autism spectrum disorder (ASD) has been called a “developmental disconnection syndrome,” however the majority of the research examining connectivity in ASD has been conducted exclusively with older children and adults. Yet, prior ASD research suggests that perturbations in neurodevelopmental trajectories begin as early as the first year of life. Prospective longitudinal studies of infants at risk for ASD may provide a window into the emergence of these aberrant patterns of connectivity. The current study employed functional connectivity near-infrared spectroscopy (NIRS) in order to examine the development of intra- and inter-hemispheric functional connectivity in high- and low-risk infants across the first year of life. Methods: NIRS data were collected from 27 infants at high risk for autism (HRA) and 37 low-risk comparison (LRC) infants who contributed a total of 116 data sets at 3-, 6-, 9-, and 12-months. At each time point, HRA and LRC groups were matched on age, sex, head circumference, and Mullen Scales of Early Learning scores. Regions of interest (ROI) were selected from anterior and posterior locations of each hemisphere. The average time course for each ROI was calculated and correlations for each ROI pair were computed. Differences in functional connectivity were examined in a cross-sectional manner. Results: At 3-months, HRA infants showed increased overall functional connectivity compared to LRC infants. This was the result of increased connectivity for intra- and inter-hemispheric ROI pairs. No significant differences were found between HRA and LRC infants at 6- and 9-months. However, by 12-months, HRA infants showed decreased connectivity relative to LRC infants.
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paper_title: Neural Processing of Facial Identity and Emotion in Infants at High-Risk for Autism Spectrum Disorders

paper_content:

Deficits in face processing and social impairment are core characteristics of autism spectrum disorder. The present work examined 7 month-old infants at high risk for developing autism and typically developing controls at low risk, using a face perception task designed to differentiate between the effects of face identity and facial emotions on neural response using functional Near Infrared Spectroscopy (fNIRS). In addition, we employed independent component analysis (ICA), as well as a novel method of condition-related component selection and classification to identify group differences in hemodynamic waveforms and response distributions associated with face and emotion processing. The results indicate similarities of waveforms, but differences in the magnitude, spatial distribution, and timing of responses between groups. These early differences in local cortical regions and the hemodynamic response may, in turn, contribute to differences in patterns of functional connectivity.
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paper_title: The Link between Social Cognition and Self-referential Thought in the Medial Prefrontal Cortex

paper_content:

The medial prefrontal cortex (mPFC) has been implicated in seemingly disparate cognitive functions, such as understanding the minds of other people and processing information about the self. This functional overlap would be expected if humans use their own experiences to infer the mental states of others, a basic postulate of simulation theory. Neural activity was measured while participants attended to either the mental or physical aspects of a series of other people. To permit a test of simulation theory's prediction that inferences based on self-reflection should only be made for similar others, targets were subsequently rated for their degree of similarity to self. Parametric analyses revealed a region of the ventral mPFC—previously implicated in self-referencing tasks—in which activity correlated with perceived self/other similarity, but only for mentalizing trials. These results suggest that self-reflection may be used to infer the mental states of others when they are sufficiently similar to self.
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paper_title: Neuroimaging in autism spectrum disorders: 1H-MRS and NIRS study.

paper_content:

Using proton magnetic resonance spectroscopy (1H-MRS), we measured chemical metabolites in the left amygdala and the bilateral orbito-frontal cortex (OFC) in children with autism spectrum disorders (ASD). The concentrations of N-acetylaspartate (NAA) in these regions of ASD were significantly decreased compared to those in the control group. In the autistic patients, the NAA concentrations in these regions correlated with their social quotient. These findings suggest the presence of neuronal dysfunction in the amygdala and OFC in ASD. Dysfunction in the amygdala and OFCmay contribute to the pathogenesis of ASD.We performed a near-infrared spectroscopy (NIRS) study to evaluate the mirror neuron system in children with ASD. The concentrations of oxygenated hemoglobin (oxy-Hb) were measured with frontal probes using a 34-channel NIRS machine while the subjects imitated emotional facial expressions. The increments in the concentration of oxy-Hb in the pars opercularis of the inferior frontal gyrus in autistic subjects were significantly lower than those in the controls. However, the concentrations of oxy-Hb in this area were significantly elevated in autistic subjects after they were trained to imitate emotional facial expressions. The results suggest that mirror neurons could be activated by repeated imitation in children with ASD.
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paper_title: Self-face recognition in children with autism spectrum disorders: A near-infrared spectroscopy study

paper_content:

It is assumed that children with autism spectrum disorders (ASD) have specificities for self-face recognition, which is known to be a basic cognitive ability for social development. In the present study, we investigated neurological substrates and potentially influential factors for self-face recognition of ASD patients using near-infrared spectroscopy (NIRS). The subjects were 11 healthy adult men, 13 normally developing boys, and 10 boys with ASD. Their hemodynamic activities in the frontal area and their scanning strategies (eye-movement) were examined during self-face recognition. Other factors such as ASD severities and self-consciousness were also evaluated by parents and patients, respectively. Oxygenated hemoglobin levels were higher in the regions corresponding to the right inferior frontal gyrus than in those corresponding to the left inferior frontal gyrus. In two groups of children these activities reflected ASD severities, such that the more serious ASD characteristics corresponded with lower activity levels. Moreover, higher levels of public self-consciousness intensified the activities, which were not influenced by the scanning strategies. These findings suggest that dysfunction in the right inferior frontal gyrus areas responsible for self-face recognition is one of the crucial neural substrates underlying ASD characteristics, which could potentially be used to evaluate psychological aspects such as public self-consciousness.
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paper_title: Atypical neural self-representation in autism

paper_content:

The ‘self’ is a complex multidimensional construct deeply embedded and in many ways defined by our relations with the social world. Individuals with autism are impaired in both self-referential and other-referential social cognitive processing. Atypical neural representation of the self may be a key to understanding the nature of such impairments. Using functional magnetic resonance imaging we scanned adult males with an autism spectrum condition and age and IQ-matched neurotypical males while they made reflective mentalizing or physical judgements about themselves or the British Queen. Neurotypical individuals preferentially recruit the middle cingulate cortex and ventromedial prefrontal cortex in response to self compared with other-referential processing. In autism, ventromedial prefrontal cortex responded equally to self and other, while middle cingulate cortex responded more to other-mentalizing than self-mentalizing. These atypical responses occur only in areas where self-information is preferentially processed and does not affect areas that preferentially respond to other-referential information. In autism, atypical neural self-representation was also apparent via reduced functional connectivity between ventromedial prefrontal cortex and areas associated with lower level embodied representations, such as ventral premotor and somatosensory cortex. Furthermore, the magnitude of neural self-other distinction in ventromedial prefrontal cortex was strongly related to the magnitude of early childhood social impairments in autism. Individuals whose ventromedial prefrontal cortex made the largest distinction between mentalizing about self and other were least socially impaired in early childhood, while those whose ventromedial prefrontal cortex made little to no distinction between mentalizing about self and other were the most socially impaired in early childhood. These observations reveal that the atypical organization of neural circuitry preferentially coding for self-information is a key mechanism at the heart of both self-referential and social impairments in autism.
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paper_title: Functional connectivity in the first year of life in infants at-risk for autism: a preliminary near-infrared spectroscopy study

paper_content:

Background: Autism spectrum disorder (ASD) has been called a “developmental disconnection syndrome,” however the majority of the research examining connectivity in ASD has been conducted exclusively with older children and adults. Yet, prior ASD research suggests that perturbations in neurodevelopmental trajectories begin as early as the first year of life. Prospective longitudinal studies of infants at risk for ASD may provide a window into the emergence of these aberrant patterns of connectivity. The current study employed functional connectivity near-infrared spectroscopy (NIRS) in order to examine the development of intra- and inter-hemispheric functional connectivity in high- and low-risk infants across the first year of life. Methods: NIRS data were collected from 27 infants at high risk for autism (HRA) and 37 low-risk comparison (LRC) infants who contributed a total of 116 data sets at 3-, 6-, 9-, and 12-months. At each time point, HRA and LRC groups were matched on age, sex, head circumference, and Mullen Scales of Early Learning scores. Regions of interest (ROI) were selected from anterior and posterior locations of each hemisphere. The average time course for each ROI was calculated and correlations for each ROI pair were computed. Differences in functional connectivity were examined in a cross-sectional manner. Results: At 3-months, HRA infants showed increased overall functional connectivity compared to LRC infants. This was the result of increased connectivity for intra- and inter-hemispheric ROI pairs. No significant differences were found between HRA and LRC infants at 6- and 9-months. However, by 12-months, HRA infants showed decreased connectivity relative to LRC infants.
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paper_title: How Would You Feel versus How Do You Think She Would Feel? A Neuroimaging Study of Perspective-Taking with Social Emotions

paper_content:

Perspective-taking is a complex cognitive process involved in social cognition. This positron emission tomography (PET) study investigated by means of a factorial design the interaction between the emotional and the perspective factors. Participants were asked to adopt either their own (first person) perspective or the (third person) perspective of their mothers in response to situations involving social emotions or to neutral situations. The main effect of third-person versus first-person perspective resulted in hemodynamic increase in the medial part of the superior frontal gyrus, the left superior temporal sulcus, the left temporal pole, the posterior cingulate gyrus, and the right inferior parietal lobe. A cluster in the postcentral gyrus was detected in the reverse comparison. The amygdala was selectively activated when subjects were processing social emotions, both related to self and other. Interaction effects were identified in the left temporal pole and in the right postcentral gyrus. These results support our prediction that the frontopolar, the somatosensory cortex, and the right inferior parietal lobe are crucial in the process of self/other distinction. In addition, this study provides important building blocks in our understanding of social emotion processing and human empathy.
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paper_title: Perceptual inconstancy in early infantile autism. The syndrome of early infant autism and its variants including certain cases of childhood schizophrenia.

paper_content:

WITHIN the decade since the syndrome of early infantile autism was first described by Kanner, 1-2 terms such as childhood schizophrenia, 3 atypical children, 4 children with unusual sensitivities, 5 and symbiotic psychosis 6 were used to conceptualize similar, yet apparently distinctive clinical entities. The tendency to create separate entities was reinforced by a desire for diagnostic specificity and accuracy and etiologic preference. As the symptomatology in these children varies both with the severity of the illness and age, it has been possible to emphasize distinctive clusters of symptoms and relate these to particular theories of causation. For instance, the predominance of disturbances of relating coupled with the prevailing belief in the 1940's and 1950's that specific syndromes in children must be outgrowths of specific parental behaviors or attitudes 7 led to attempts to implicate the parents in the development of early infantile autism. The
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paper_title: Neural Processing of Facial Identity and Emotion in Infants at High-Risk for Autism Spectrum Disorders

paper_content:

Deficits in face processing and social impairment are core characteristics of autism spectrum disorder. The present work examined 7 month-old infants at high risk for developing autism and typically developing controls at low risk, using a face perception task designed to differentiate between the effects of face identity and facial emotions on neural response using functional Near Infrared Spectroscopy (fNIRS). In addition, we employed independent component analysis (ICA), as well as a novel method of condition-related component selection and classification to identify group differences in hemodynamic waveforms and response distributions associated with face and emotion processing. The results indicate similarities of waveforms, but differences in the magnitude, spatial distribution, and timing of responses between groups. These early differences in local cortical regions and the hemodynamic response may, in turn, contribute to differences in patterns of functional connectivity.
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paper_title: Usefulness of near-infrared spectroscopy to detect brain dysfunction in children with autism spectrum disorder when inferring the mental state of others

paper_content:

Aims ::: ::: The purpose of this study was to examine the usefulness of near-infrared spectroscopy (NIRS) for identifying abnormalities in prefrontal brain activity in children with autism spectrum disorders (ASD) as they inferred the mental states of others. ::: ::: ::: ::: Methods ::: ::: The subjects were 16 children with ASD aged between 8 and 14 years and 16 age-matched healthy control children. Oxygenated hemoglobin concentration was measured in the subject's prefrontal brain region on NIRS during tasks expressing a person's mental state (MS task) and expressing an object's characteristics (OC task). ::: ::: ::: ::: Results ::: ::: There was a significant main effect of group (ASD vs control), with the control group having more activity than the ASD group. But there was no significant main effect of task (MS task vs OC task) or hemisphere (right vs left). Significant interactions of task and group were found, with the control group showing more activity than the ASD group during the MS task relative to the OC task. ::: ::: ::: ::: Conclusions ::: ::: NIRS showed that there was lower activity in the prefrontal brain area when children with ASD performed MS tasks. Therefore, clinicians might be able to use NIRS and these tasks for conveniently detecting brain dysfunction in children with ASD related to inferring mental states, in the clinical setting.
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paper_title: Perception of Complex Sounds: Abnormal Pattern of Cortical Activation in Autism

paper_content:

OBJECTIVE: Bilateral temporal hypoperfusion at rest was recently described in autism. In normal adults, these regions are activated by listening to speech-like sounds. To investigate auditory cortical processing in autism, the authors performed a positron emission tomography activation study. METHOD: Regional cerebral blood flow was measured in five autistic adults and eight comparison subjects during rest and while listening to speech-like sounds. RESULTS: Similar to the comparison subjects, autistic patients showed a bilateral activation of the superior temporal gyrus. However, an abnormal pattern of hemispheric activation was observed in the autistic group. The volume of activation was larger on the right side in the autistic patients, whereas the reverse pattern was found in the comparison group. The direct comparison between the two groups showed that the right middle frontal gyrus exhibited significantly greater activation in the autistic group. Conversely, the left temporal areas exhibited less act...
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paper_title: Autistic Traits and Brain Activation during Face-to-Face Conversations in Typically Developed Adults

paper_content:

Background ::: Autism spectrum disorders (ASD) are characterized by impaired social interaction and communication, restricted interests, and repetitive behaviours. The severity of these characteristics is posited to lie on a continuum that extends into the general population. Brain substrates underlying ASD have been investigated through functional neuroimaging studies using functional magnetic resonance imaging (fMRI). However, fMRI has methodological constraints for studying brain mechanisms during social interactions (for example, noise, lying on a gantry during the procedure, etc.). In this study, we investigated whether variations in autism spectrum traits are associated with changes in patterns of brain activation in typically developed adults. We used near-infrared spectroscopy (NIRS), a recently developed functional neuroimaging technique that uses near-infrared light, to monitor brain activation in a natural setting that is suitable for studying brain functions during social interactions. ::: ::: ::: Methodology ::: We monitored regional cerebral blood volume changes using a 52-channel NIRS apparatus over the prefrontal cortex (PFC) and superior temporal sulcus (STS), 2 areas implicated in social cognition and the pathology of ASD, in 28 typically developed participants (14 male and 14 female) during face-to-face conversations. This task was designed to resemble a realistic social situation. We examined the correlations of these changes with autistic traits assessed using the Autism-Spectrum Quotient (AQ). ::: ::: ::: Principal Findings ::: Both the PFC and STS were significantly activated during face-to-face conversations. AQ scores were negatively correlated with regional cerebral blood volume increases in the left STS during face-to-face conversations, especially in males. ::: ::: ::: Conclusions ::: Our results demonstrate successful monitoring of brain function during realistic social interactions by NIRS as well as lesser brain activation in the left STS during face-to-face conversations in typically developed participants with higher levels of autistic traits.
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paper_title: Autism, the superior temporal sulcus and social perception

paper_content:

The most common clinical sign of autism spectrum disorders (ASD) is social interaction impairment, which is associated with communication deficits and stereotyped behaviors. Based on recent brain-imaging results, our hypothesis is that abnormalities in the superior temporal sulcus (STS) are highly implicated in ASD. STS abnormalities are characterized by decreased gray matter concentration, rest hypoperfusion and abnormal activation during social tasks. STS anatomical and functional anomalies occurring during early brain development could constitute the first step in the cascade of neural dysfunction underlying ASD. We will focus this review on the STS, which has been highly implicated in social cognition. We will review recent data on the contribution of the STS to normal social cognition and review brain-imaging data implicating this area in ASD. This review is part of the INMED/TINS special issue Nature and nurture in brain development and neurological disorders, based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).
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paper_title: Differences in Neural Correlates of Speech Perception in 3 Month Olds at High and Low Risk for Autism Spectrum Disorder

paper_content:

In this study, we investigated neural precursors of language acquisition as potential endophenotypes of autism spectrum disorder (ASD) in 3-month-old infants at high and low familial ASD risk. Infants were imaged using functional near-infrared spectroscopy while they listened to auditory stimuli containing syllable repetitions; their neural responses were analyzed over left and right temporal regions. While female low risk infants showed initial neural activation that decreased over exposure to repetition-based stimuli, potentially indicating a habituation response to repetition in speech, female high risk infants showed no changes in neural activity over exposure. This finding may indicate a potential neural endophenotype of language development or ASD specific to females at risk for the disorder.
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paper_title: The superior temporal sulcus performs a common function for social and speech perception: Implications for the emergence of autism

paper_content:

Abstract Within the cognitive neuroscience literature, discussion of the functional role of the superior temporal sulcus (STS) has traditionally been divided into two domains; one focuses on its activity during language processing while the other emphasizes its role in biological motion and social attention, such as eye gaze processing. I will argue that a common process underlying both of these functional domains is performed by the STS, namely analyzing changing sequences of input, either in the auditory or visual domain, and interpreting the communicative significance of those inputs. From a developmental perspective, the fact that these two domains share an anatomical substrate suggests the acquisition of social and speech perception may be linked. In addition, I will argue that because of the STS’ role in interpreting social and speech input, impairments in STS function may underlie many of the social and language abnormalities seen in autism.
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paper_title: Most genetic risk for autism resides with common variation

paper_content:

Joseph Buxbaum and colleagues use an epidemiological sample from Sweden to investigate the genetic architecture of autism spectrum disorders. They conclude that most inherited risk for autism is determined by common variation and that rare variation explains a smaller fraction of total heritability.
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paper_title: Research Review: Constraining heterogeneity: the social brain and its development in autism spectrum disorder

paper_content:

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. Keywords: Social perception, social cognition, autism, functional neuroimaging, social brain. The considerable heterogeneity in the expression and severity of the core and associated symptoms is a challenge that has hindered progress towards understanding autism spectrum disorder (ASD). To illustrate, within autistic disorder, variability in the social domain ranges from a near absence of interest in interacting with others to more subtle difficulties managing complex social interactions that require an understanding of other people’s goals and intentions and other cues of social context. Similarly, stereotyped and repetitive behaviors range from simple motor stereotypies and/or a preference for sameness to much more complex and elaborate rituals, accompanied by emotional dysregulation or ‘meltdowns’ when these rituals are interrupted. Some individuals with ASD lack basic speech abilities, while others can have language deficits that are mild and limited to language pragmatics. While a majority of individuals with ASD exhibit some level of intellectual impairment, intelligence quotients vary from the severe and profoundly impaired range to well above average.
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paper_title: The neonate brain detects speech structure

paper_content:

What are the origins of the efficient language learning abilities that allow humans to acquire their mother tongue in just a few years very early in life? Although previous studies have identified different mechanisms underlying the acquisition of auditory and speech patterns in older infants and adults, the earliest sensitivities remain unexplored. To address this issue, we investigated the ability of newborns to learn simple repetition-based structures in two optical brain-imaging experiments. In the first experiment, 22 neonates listened to syllable sequences containing immediate repetitions (ABB; e.g., “mubaba,” “penana”), intermixed with random control sequences (ABC; e.g., “mubage,” “penaku”). We found increased responses to the repetition sequences in the temporal and left frontal areas, indicating that the newborn brain differentiated the two patterns. The repetition sequences evoked greater activation than the random sequences during the first few trials, suggesting the presence of an automatic perceptual mechanism to detect repetitions. In addition, over the subsequent trials, activation increased further in response to the repetition sequences but not in response to the random sequences, indicating that recognition of the ABB pattern was enhanced by repeated exposure. In the second experiment, in which nonadjacent repetitions (ABA; e.g., “bamuba,” “napena”) were contrasted with the same random controls, no discrimination was observed. These findings suggest that newborns are sensitive to certain input configurations in the auditory domain, a perceptual ability that might facilitate later language development.
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paper_title: Sibling Recurrence and the Genetic Epidemiology of Autism

paper_content:

Objective:Although the symptoms of autism exhibit quantitative distributions in nature, estimates of recurrence risk in families have never previously considered or incorporated quantitative characterization of the autistic phenotype among siblings. Method:The authors report the results of quantitative characterization of 2,920 children from 1,235 families participating in a national volunteer register, with at least one child clinically affected by an autism spectrum disorder and at least one full biological sibling. Results:A traditionally defined autism spectrum disorder in an additional child occurred in 10.9% of the families. An additional 20% of nonautism-affected siblings had a history of language delay, one-half of whom exhibited autistic qualities of speech. Quantitative characterization using the Social Responsiveness Scale supported previously reported aggregation of a wide range of subclinical (quantitative) autistic traits among otherwise unaffected children in multiple-incidence families and...
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paper_title: Behavioral manifestations of autism in the first year of life

paper_content:

In the interest of more systematically documenting the early signs of autism, and of testing specific hypotheses regarding their underlying neurodevelopmental substrates, we have initiated a longitudinal study of high-risk infants, all of whom have an older sibling diagnosed with an autistic spectrum disorder. Our sample currently includes 150 infant siblings, including 65 who have been followed to age 24 months, who are the focus of this paper. We have also followed a comparison group of low-risk infants. Our measures include a novel observational scale (the first, to our knowledge, that is designed to assess autism-specific behavior in infants), a computerized visual orienting task, and standardized measures of temperament, cognitive and language development. Our preliminary results indicate that by 12 months of age, siblings who are later diagnosed with autism may be distinguished from other siblings and low-risk controls on the basis of: (1) several specific behavioral markers, including atypicalities in eye contact, visual tracking, disengagement of visual attention, orienting to name, imitation, social smiling, reactivity, social interest and affect, and sensory-oriented behaviors; (2) prolonged latency to disengage visual attention; (3) a characteristic pattern of early temperament, with marked passivity and decreased activity level at 6 months, followed by extreme distress reactions, a tendency to fixate on particular objects in the environment, and decreased expression of positive affect by 12 months; and (4) delayed expressive and receptive language. We discuss these findings in the context of various neural networks thought to underlie neurodevelopmental abnormalities in autism, including poor visual orienting. Over time, as we are able to prospectively study larger numbers and to examine interrelationships among both early-developing behaviors and biological indices of interest, we hope this work will advance current understanding of the neurodevelopmental origins of autism.
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paper_title: Dissociable Roles of the Superior Temporal Sulcus and the Intraparietal Sulcus in Joint Attention: A Functional Magnetic Resonance Imaging Study

paper_content:

Previous imaging work has shown that the superior temporal sulcus (STS) region and the intraparietal sulcus (IPS) are specifically activated during the passive observation of shifts in eye gaze [Pelphrey, K. A., Singerman, J. D., Allison, T., & McCarthy, G. Brain activation evoked by perception of gaze shifts: The influence of context. Neuropsychologia, 41, 156170, 2003; Hoffman, E. A., & Haxby, J. V. Distinct representations of eye gaze and identity in the distributed human neural system for face perception. Nature Neuroscience, 3, 8084, 2000; Puce, A., Allison, T., Bentin, S., Gore, J. C., & McCarthy, G. Temporal cortex activation in humans viewing eye and mouth movements. Journal of Neuroscience, 18, 21882199, 1998; Wicker, B., Michel, F., Henaff, M. A., & Decety, J. Brain regions involved in the perception of gaze: A PET study. Neuroimage, 8, 221227, 1998]. Are the same brain regions also involved in extracting gaze direction in order to establish joint attention? In an event-related functional magnetic resonance imaging experiment, healthy human subjects actively followed the directional cue provided by the eyes of another person toward an object in space or, in the control condition, used a nondirectional symbolic cue to make an eye movement toward an object in space. Our results show that the posterior part of the STS region and the cuneus are specifically involved in extracting and using detailed directional information from the eyes of another person to redirect one's own gaze and establish joint attention. The IPS, on the other hand, seems to be involved in encoding spatial direction and mediating shifts of spatial attention independent of the type of cue that triggers this process.
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paper_title: A new research trend in social neuroscience: Towards an interactive‐brain neuroscience

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The ability to flexibly modulate our behaviors in social contexts and to successfully interact with other persons is a fundamental, but pivotal, requirement for human survival. Although previous social neuroscience research with single individuals has contributed greatly to our understanding of the basic mechanisms underlying social perception and social emotions, much of the dynamic nature of interactions between persons remains beyond the reach of single-brain studies. This has led to a growing argument for a shift to the simultaneous measurement of the brain activity of two or more individuals in realistic social interactions-an approach termed "hyperscanning." Although this approach offers important promise in unlocking the brain's role in truly social situations, there are multiple procedural and theoretical questions that require review and analysis. In this paper we discuss this research trend from four aspects: hyperscanning apparatus, experimental task, quantification method, and theoretical interpretation. We also give four suggestions for future research: (a) electroencephalography and near-infrared spectroscopy are useful tools by which to explore the interactive brain in more ecological settings; (b) games are an appropriate method to simulate daily life interactions; (c) transfer entropy may be an important method by which to quantify directed exchange of information between brains; and (d) more explanation is needed of the results of interbrain synchronization itself.
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paper_title: Cortical activation during attention to sound in autism spectrum disorders.

paper_content:

Abstract Individuals with autism spectrum disorders (ASDs) can demonstrate hypersensitivity to sounds as well as a lack of awareness of them. Several functional imaging studies have suggested an abnormal response in the auditory cortex of such subjects, but it is not known whether these subjects have dysfunction in the auditory cortex or are simply not listening. We measured changes in blood oxygenated hemoglobin (OxyHb) in the prefrontal and temporal cortices using near-infrared spectroscopy during various listening and ignoring tasks in 11 ASD and 12 control subjects. Here we show that the auditory cortex in ASD subjects responds to sounds fully during attention. OxyHb in the auditory cortex increased with intentional listening but not with ignoring of the same auditory stimulus in a similar fashion in both groups. Cortical responses differed not in the auditory but in the prefrontal region between the ASD and control groups. Thus, unawareness to sounds in ASD could be interpreted as due to inattention rather than dysfunction of the auditory cortex. Difficulties in attention control may account for the contrary behaviors of hypersensitivity and unawareness to sound in ASD.
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paper_title: Development of a neurofeedback protocol targeting the frontal pole using near‐infrared spectroscopy

paper_content:

Aim ::: Neurofeedback has been studied with the aim of controlling cerebral activity. Near-infrared spectroscopy is a non-invasive neuroimaging technique used for measuring hemoglobin concentration changes in cortical surface areas with high temporal resolution. Thus, near-infrared spectroscopy may be useful for neurofeedback, which requires real-time feedback of repeated brain activation measurements. However, no study has specifically targeted neurofeedback, using near-infrared spectroscopy, in the frontal pole cortex. ::: ::: Methods ::: We developed an original near-infrared spectroscopy neurofeedback system targeting the frontal pole cortex. Over a single day of testing, each healthy participant (n = 24) received either correct or incorrect (Sham) feedback from near-infrared spectroscopy signals, based on a crossover design. ::: ::: Results ::: Under correct feedback conditions, significant activation was observed in the frontal pole cortex (P = 0.000073). Additionally, self-evaluation of control and metacognitive beliefs were associated with near-infrared spectroscopy signals (P = 0.006). ::: ::: Conclusion ::: The neurofeedback system developed in this study might be useful for developing control of frontal pole cortex activation.
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paper_title: Neuroimaging in autism spectrum disorders: 1H-MRS and NIRS study.

paper_content:

Using proton magnetic resonance spectroscopy (1H-MRS), we measured chemical metabolites in the left amygdala and the bilateral orbito-frontal cortex (OFC) in children with autism spectrum disorders (ASD). The concentrations of N-acetylaspartate (NAA) in these regions of ASD were significantly decreased compared to those in the control group. In the autistic patients, the NAA concentrations in these regions correlated with their social quotient. These findings suggest the presence of neuronal dysfunction in the amygdala and OFC in ASD. Dysfunction in the amygdala and OFCmay contribute to the pathogenesis of ASD.We performed a near-infrared spectroscopy (NIRS) study to evaluate the mirror neuron system in children with ASD. The concentrations of oxygenated hemoglobin (oxy-Hb) were measured with frontal probes using a 34-channel NIRS machine while the subjects imitated emotional facial expressions. The increments in the concentration of oxy-Hb in the pars opercularis of the inferior frontal gyrus in autistic subjects were significantly lower than those in the controls. However, the concentrations of oxy-Hb in this area were significantly elevated in autistic subjects after they were trained to imitate emotional facial expressions. The results suggest that mirror neurons could be activated by repeated imitation in children with ASD.
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paper_title: Near-infrared spectroscopy (NIRS) neurofeedback as a treatment for children with attention deficit hyperactivity disorder (ADHD)—a pilot study

paper_content:

In this pilot study near-infrared spectroscopy (NIRS) neurofeedback was investigated as a new method for the treatment of ADHD. Oxygenated hemoglobin in the prefrontal cortex of children with ADHD was measured and fed back. 12 sessions of NIRS-neurofeedback were compared to the intermediate outcome after 12 sessions of EEG-neurofeedback (slow cortical potentials, SCP) and 12 sessions of EMG-feedback (muscular activity of left and right musculus supraspinatus). The task was either to increase or decrease hemodynamic activity in the prefrontal cortex (NIRS), to produce positive or negative shifts of SCP (EEG) or to increase or decrease muscular activity (EMG). In each group nine children with ADHD, aged 7 to 10 years, took part. Changes in parents’ ratings of ADHD symptoms were assessed before and after the 12 sessions and compared within and between groups. For the NIRS-group additional teachers’ ratings of ADHD symptoms, parents’ and teachers’ ratings of associated behavioral symptoms, childrens’ self reports on quality of life and a computer based attention task were conducted before, 4 weeks and 6 months after training. As primary outcome, ADHD symptoms decreased significantly 4 weeks and 6 months after the NIRS training, according to parents’ ratings. In teachers’ ratings of ADHD symptoms there was a significant reduction 4 weeks after the training. The performance in the computer based attention test improved significantly. Within-group comparisons after 12 sessions of NIRS-, EEG- and EMG-training revealed a significant reduction in ADHD symptoms in the NIRS-group and a trend for EEG- and EMG-groups. No significant differences for symptom reduction were found between the groups. Despite the limitations of small groups and the comparison of a completed with two uncompleted interventions, the results of this pilot study are promising. NIRS-neurofeedback could be a time-effective treatment for ADHD and an interesting new option to consider in the treatment of ADHD.
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paper_title: Self-face recognition in children with autism spectrum disorders: A near-infrared spectroscopy study

paper_content:

It is assumed that children with autism spectrum disorders (ASD) have specificities for self-face recognition, which is known to be a basic cognitive ability for social development. In the present study, we investigated neurological substrates and potentially influential factors for self-face recognition of ASD patients using near-infrared spectroscopy (NIRS). The subjects were 11 healthy adult men, 13 normally developing boys, and 10 boys with ASD. Their hemodynamic activities in the frontal area and their scanning strategies (eye-movement) were examined during self-face recognition. Other factors such as ASD severities and self-consciousness were also evaluated by parents and patients, respectively. Oxygenated hemoglobin levels were higher in the regions corresponding to the right inferior frontal gyrus than in those corresponding to the left inferior frontal gyrus. In two groups of children these activities reflected ASD severities, such that the more serious ASD characteristics corresponded with lower activity levels. Moreover, higher levels of public self-consciousness intensified the activities, which were not influenced by the scanning strategies. These findings suggest that dysfunction in the right inferior frontal gyrus areas responsible for self-face recognition is one of the crucial neural substrates underlying ASD characteristics, which could potentially be used to evaluate psychological aspects such as public self-consciousness.
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paper_title: Weak network efficiency in young children with Autism Spectrum Disorder: Evidence from a functional near-infrared spectroscopy study

paper_content:

Abstract Functional near infrared spectroscopy (fNIRS) is particularly suited for the young population and ecological measurement. However, thus far, not enough effort has been given to the clinical diagnosis of young children with Autism Spectrum Disorder (ASD) by using fNIRS. The current study provided some insights into the quantitative analysis of functional networks in young children (ages 4.8–8.0 years old) with and without ASD and, in particular, investigated the network efficiency and lobe-level connectivity of their functional networks while watching a cartoon. The main results included that: (i) Weak network efficiency was observed in young children with ASD, even for a wide range of threshold for the binarization of functional networks; (ii) A maximum classification accuracy rate of 83.3% was obtained for all participants by using the k-means clustering method with network efficiencies as the feature parameters; and (iii) Weak lobe-level inter-region connections were uncovered in the right prefrontal cortex, including its linkages with the left prefrontal cortex and the bilateral temporal cortex. Such results indicate that the right prefrontal cortex might make a major contribution to the psychopathology of young children with ASD at the functional network architecture level, and at the functional lobe-connectivity level, respectively.
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paper_title: Fundamental Components of Attention

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A mechanistic understanding of attention is necessary for the elucidation of the neurobiological basis of conscious experience. This chapter presents a framework for thinking about attention that facilitates the analysis of this cognitive process in terms of underlying neural mechanisms. Four processes are fundamental to attention: working memory, top-down sensitivity control, competitive selection, and automatic bottom-up filtering for salient stimuli. Each process makes a distinct and essential contribution to attention. Voluntary control of attention involves the first three processes (working memory, top-down sensitivity control, and competitive selection) operating in a recurrent loop. Recent results from neurobiological research on attention are discussed within this framework.
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paper_title: Distinctive activation patterns under intrinsically versus extrinsically driven cognitive loads in prefrontal cortex: A near-infrared spectroscopy study using a driving video game

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Abstract To investigate the neural bases of intrinsically and extrinsically driven cognitive loads in daily life, we measured repetitively prefrontal activation in three (one control and two experimental) groups during a driving video game using near-infrared spectroscopy. The control group drove to goal four times with distinct route-maps illustrating default turning points. In contrast, the memory group drove the memorized default route without a route-map, and the emergency group drove with a route-map, but was instructed to change the default route by an extrinsically given verbal command (turn left or right) as an envisioned emergency. The predictability of a turning point in the route in each group was relatively different: due to extrinsic dictate of others in the emergency group, intrinsic memory in the memory group, and route-map aid in the control group. We analyzed concentration changes of oxygenated hemoglobin (CoxyHb) in the three critical periods (pre-turning, actual-turning, and post-turning). The emergency group showed a significantly increasing pattern of CoxyHb throughout the three periods, and a significant reduction in CoxyHb throughout the repetitive trials, but the memory group did not, even though both experimental groups showed higher activation than the control group in the pre-turning period. These results suggest that the prefrontal cortex differentiates the intrinsically (memory) and the extrinsically (dictate of others) driven cognitive loads according to the predictability of turning behavior, although the two types of cognitive loads commonly show increasing activation in the pre-turning period as the preparation effect.
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paper_title: An Integrative Theory of Prefrontal Cortex Function

paper_content:

▪ Abstract The prefrontal cortex has long been suspected to play an important role in cognitive control, in the ability to orchestrate thought and action in accordance with internal goals. Its neural basis, however, has remained a mystery. Here, we propose that cognitive control stems from the active maintenance of patterns of activity in the prefrontal cortex that represent goals and the means to achieve them. They provide bias signals to other brain structures whose net effect is to guide the flow of activity along neural pathways that establish the proper mappings between inputs, internal states, and outputs needed to perform a given task. We review neurophysiological, neurobiological, neuroimaging, and computational studies that support this theory and discuss its implications as well as further issues to be addressed
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paper_title: Atypical attentional networks and the emergence of autism

paper_content:

The sociocommunicative impairments that define autism spectrum disorder (ASD) are not present at birth but emerge gradually over the first two years of life. In typical development, basic attentional processes may provide a critical foundation for sociocommunicative abilities. Therefore early attentional dysfunction in ASD may result in atypical development of social communication. Prior research has demonstrated that persons with ASD exhibit early and lifelong impairments in attention. The primary aim of this paper is to provide a review of the extant research on attention in ASD using a framework of functionally independent attentional networks as conceptualized by Posner and colleagues: the alerting, orienting and executive control networks (Posner and Petersen, 1990 ; Petersen and Posner, 2012). The neural substrates and typical development of each attentional network are briefly discussed, a review of the ASD attention literature is presented, and a hypothesis is proposed that links aberrant attentional mechanisms, specifically impaired disengagement of attention, with the emergence of core ASD symptoms.
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paper_title: Cross-Brain Neurofeedback: Scientific Concept and Experimental Platform

paper_content:

The present study described a new type of multi-person neurofeedback with the neural synchronization between two participants as the direct regulating target, termed as “cross-brain neurofeedback.” As a first step to implement this concept, an experimental platform was built on the basis of functional near-infrared spectroscopy, and was validated with a two-person neurofeedback experiment. This novel concept as well as the experimental platform established a framework for investigation of the relationship between multiple participants' cross-brain neural synchronization and their social behaviors, which could provide new insight into the neural substrate of human social interactions.
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paper_title: Near-infrared spectroscopy based neurofeedback training increases specific motor imagery related cortical activation compared to sham feedback

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Abstract In the present study we implemented a real-time feedback system based on multichannel near-infrared spectroscopy (NIRS). Prior studies indicated that NIRS-based neurofeedback can enhance motor imagery related cortical activation. To specify these prior results and to confirm the efficacy of NIRS-based neurofeedback, we examined changes in blood oxygenation level collected in eight training sessions. One group got real feedback about their own brain activity ( N = 9) and one group saw a playback of another person’s feedback recording ( N = 8). All participants performed motor imagery of a right hand movement. Real neurofeedback induced specific and focused brain activation over left motor areas. This focal brain activation became even more specific over the eight training sessions. In contrast, sham feedback led to diffuse brain activation patterns over the whole cortex. These findings can be useful when training patients with focal brain lesions to increase activity of specific brain areas for rehabilitation purpose.
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paper_title: Neurofeedback Using Real-Time Near-Infrared Spectroscopy Enhances Motor Imagery Related Cortical Activation

paper_content:

Accumulating evidence indicates that motor imagery and motor execution share common neural networks. Accordingly, mental practices in the form of motor imagery have been implemented in rehabilitation regimes of stroke patients with favorable results. Because direct monitoring of motor imagery is difficult, feedback of cortical activities related to motor imagery (neurofeedback) could help to enhance efficacy of mental practice with motor imagery. To determine the feasibility and efficacy of a real-time neurofeedback system mediated by near-infrared spectroscopy (NIRS), two separate experiments were performed. Experiment 1 was used in five subjects to evaluate whether real-time cortical oxygenated hemoglobin signal feedback during a motor execution task correlated with reference hemoglobin signals computed off-line. Results demonstrated that the NIRS-mediated neurofeedback system reliably detected oxygenated hemoglobin signal changes in real-time. In Experiment 2, 21 subjects performed motor imagery of finger movements with feedback from relevant cortical signals and irrelevant sham signals. Real neurofeedback induced significantly greater activation of the contralateral premotor cortex and greater self-assessment scores for kinesthetic motor imagery compared with sham feedback. These findings suggested the feasibility and potential effectiveness of a NIRS-mediated real-time neurofeedback system on performance of kinesthetic motor imagery. However, these results warrant further clinical trials to determine whether this system could enhance the effects of mental practice in stroke patients.
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Title: Assessing autism at its social and developmental roots: A review of Autism Spectrum Disorder studies using functional near-infrared spectroscopy

Section 1: Introduction
Description 1: Introduce Autism Spectrum Disorder (ASD), its challenges, and the significance of early diagnosis and treatment. Mention the limitations of current behavioral and neuroimaging methods, and propose fNIRS as a promising alternative.

Section 2: Review: two puzzles in current ASD study
Description 2: Provide an overview of previous brain imaging approaches (fMRI and EEG) and introduce the main targets of current fNIRS studies, focusing on two major puzzles: ASD in the developing baby brain and the social brain and brain-to-brain interactions.

Section 3: Puzzle one: ASD in the developing baby brain
Description 3: Discuss studies investigating cerebral structure and function in children with ASD, highlighting deficiencies in executive control, speech processing, auditory processing, and social cognition.

Section 4: Puzzle two: the social brain and brain-to-brain interactions
Description 4: Explore social difficulties in communication and interaction, emphasizing the need for multi-brain "hyperscanning" paradigms to better understand social cognition and neural coupling in ASD.

Section 5: Basic principles of fNIRS
Description 5: Describe the functional near-infrared spectroscopy (fNIRS) technique, including its operation, key modalities, and advantages over traditional neuroimaging methods.

Section 6: Key modalities in fNIRS application
Description 6: Outline various fNIRS device setups, emission and reception methods, and data assessment techniques used in studies.

Section 7: fNIRS data assessment and focus
Description 7: Explain the data preprocessing steps, typical measures of neural activity assessed in fNIRS studies, and the experimental paradigms used.

Section 8: fNIRS studies on ASD
Description 8: Review current fNIRS studies on ASD, categorized into non-social difficulties, atypical brain connectivity, and social difficulties in interaction and communication.

Section 9: Non-social difficulties
Description 9: Summarize fNIRS studies exploring executive function deficits, sensory perception issues, and auditory processing abnormalities in children with ASD.

Section 10: Atypical brain connectivity
Description 10: Detail fNIRS studies on functional connectivity in the brain, discussing findings from both infant and older children populations.

Section 11: Social difficulties in interaction and communication
Description 11: Discuss research on self-other distinction, face processing, visual and auditory social cue recognition, and theory of mind, highlighting deficits observed in ASD.

Section 12: Communication deficits
Description 12: Examine fNIRS studies investigating communication difficulties in ASD, focusing on speech perception and neural precursors of communication.

Section 13: Discussion and conclusion
Description 13: Summarize the findings of reviewed fNIRS studies, discuss their implications for understanding ASD, and propose future research directions and potential applications of fNIRS in ASD intervention and treatment.