Kevin A. Pelphrey

Functional imaging of numerical processing in adults and 4-y-old children.

Adult humans, infants, pre-school children, and non-human animals appear to share a system of approximate numerical processing for non-symbolic stimuli such as arrays of dots or sequences of tones. Behavioral studies of adult humans implicate a link between these non-symbolic numerical abilities and symbolic numerical processing (e.g., similar distance effects in accuracy and reaction-time for arrays of dots and Arabic numerals). However, neuroimaging studies have remained inconclusive on the neural basis of this link. The intraparietal sulcus (IPS) is known to respond selectively to symbolic numerical stimuli such as Arabic numerals. Recent studies, however, have arrived at conflicting conclusions regarding the role of the IPS in processing non-symbolic, numerosity arrays in adulthood, and very little is known about the brain basis of numerical processing early in development. Addressing the question of whether there is an early-developing neural basis for abstract numerical processing is essential for understanding the cognitive origins of our uniquely human capacity for math and science. Using functional magnetic resonance imaging (fMRI) at 4-Tesla and an event-related fMRI adaptation paradigm, we found that adults showed a greater IPS response to visual arrays that deviated from standard stimuli in their number of elements, than to stimuli that deviated in local element shape. These results support previous claims that there is a neurophysiological link between non-symbolic and symbolic numerical processing in adulthood. In parallel, we tested 4-y-old children with the same fMRI adaptation paradigm as adults to determine whether the neural locus of non-symbolic numerical activity in adults shows continuity in function over development. We found that the IPS responded to numerical deviants similarly in 4-y-old children and adults. To our knowledge, this is the first evidence that the neural locus of adult numerical cognition takes form early in development, prior to sophisticated symbolic numerical experience. More broadly, this is also, to our knowledge, the first cognitive fMRI study to test healthy children as young as 4 y, providing new insights into the neurophysiology of human cognitive development.

Grasping the Intentions of Others: The Perceived Intentionality of an Action Influences Activity in the Superior Temporal Sulcus during Social Perception

An explication of the neural substrates for social perception is an important component in the emerging field of social cognitive neuroscience and is relevant to the field of cognitive neuroscience as a whole. Prior studies from our laboratory have demonstrated that passive viewing of biological motion (Pelphrey, Mitchell, et al., 2003; Puce et al., 1998) activates the posterior superior temporal sulcus (STS) region. Furthermore, recent evidence has shown that the perceived context of observed gaze shifts (Pelphrey, Singerman, et al., 2003; Pelphrey et al., 2004) modulates STS activity. Here, using event-related functional magnetic resonance imaging at 4 T, we investigated brain activity in response to passive viewing of goal- and non-goal- directed reaching-to-grasp movements. Participants viewed an animated character making reaching-to-grasp movements either toward (correct) or away (incorrect) from a blinking dial. Both conditions evoked significant posterior STS activity that was strongly right lateralized. By examining the time course of the blood oxygenation level-dependent response from areas of activation, we observed a functional dissociation. Incorrect trials evoked significantly greater activity in the STS than did correct trials, while an area posterior and inferior to the STS (likely corresponding to the MT/V5 complex) responded equally to correct and incorrect movements. Parietal cortical regions, including the superior parietal lobule and the anterior intraparietal sulcus, also responded equally to correct and incorrect movements, but showed evidence for differential responding based on the hand and arm (left or right) of the animated character used to make the reaching-to-grasp movement. The results of this study further suggest that a region of the right posterior STS is involved in analyzing the intentions of other peoples actions and that activity in this region is sensitive to the context of observed biological motions.

Three Systems of Insular Functional Connectivity Identified with Cluster Analysis

Despite much research on the function of the insular cortex, few studies have investigated functional subdivisions of the insula in humans. The present study used resting-state functional connectivity magnetic resonance imaging (MRI) to parcellate the human insular lobe based on clustering of functional connectivity patterns. Connectivity maps were computed for each voxel in the insula based on resting-state functional MRI (fMRI) data and segregated using cluster analysis. We identified 3 insular subregions with distinct patterns of connectivity: a posterior region, functionally connected with primary and secondary somatomotor cortices; a dorsal anterior to middle region, connected with dorsal anterior cingulate cortex, along with other regions of a previously described control network; and a ventral anterior region, primarily connected with pregenual anterior cingulate cortex. Applying these regions to a separate task data set, we found that dorsal and ventral anterior insula responded selectively to disgusting images, while posterior insula did not. These results demonstrate that clustering of connectivity patterns can be used to subdivide cerebral cortex into anatomically and functionally meaningful subregions; the insular regions identified here should be useful in future investigations on the function of the insula.

When Strangers Pass Processing of Mutual and Averted Social Gaze in the Superior Temporal Sulcus

Using functional magnetic resonance imaging (fMRI), we investigated brain activity evoked by mutual and averted gaze in a compelling and commonly experienced social encounter. Through virtual-reality goggles, subjects viewed a man who walked toward them and shifted his neutral gaze either toward (mutual gaze) or away (averted gaze) from them. Robust activity was evoked in the superior temporal sulcus (STS) and fusiform gyrus (FFG). For both conditions, STS activity was strongly right lateralized. Mutual gaze evoked greater activity in the STS than did averted gaze, whereas the FFG responded equivalently to mutual and averted gaze. Thus, we show that the STS is involved in processing social information conveyed by shifts in gaze within an overtly social context. This study extends understanding of the role of the STS in social cognition and social perception by demonstrating that it is highly sensitive to the context in which a human action occurs.

Neural bases for impaired social cognition in schizophrenia and autism spectrum disorders

Schizophrenia and autism both feature significant impairments in social cognition and social functioning, but the specificity and mechanisms of these deficits remain unknown. Recent research suggests that social cognitive deficits in both disorders may arise from dysfunctions in the neural systems that underlie social cognition. We explored the neural activation of discrete brain regions implicated in social cognitive and face processing in schizophrenia subgroups and autism spectrum disorders during complex social judgments of faces. Twelve individuals with autism spectrum disorders (ASD), 12 paranoid individuals with schizophrenia (P-SCZ), 12 non-paranoid individuals with schizophrenia (NP-SCZ), and 12 non-clinical healthy controls participated in this cross sectional study. Neural activation, as indexed by blood oxygenation level dependent (BOLD) contrast, was measured in a priori regions of interest while individuals rated faces for trustworthiness. All groups showed significant activation of a social cognitive network including the amygdala, fusiform face area (FFA), superior temporal sulcus (STS), and ventrolateral prefrontal cortex (VLPFC) while completing a task of complex social cognition (i.e. trustworthiness judgments). ASD and P-SCZ individuals showed significantly reduced neural activation in the right amygdala, FFA, and left VLPFC as compared to controls and in the left VLPFC as compared to NP-SCZ individuals during this task. These findings lend support to models hypothesizing well-defined neural substrates of social cognition and suggest a specific neural mechanism that may underlie social cognitive impairments in both autism and paranoid schizophrenia.

FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders

Autism spectrum disorder (ASD) is a disorder of brain development. Most cases lack a clear etiology or genetic basis, and the difficulty of re-enacting human brain development has precluded understanding of ASD pathophysiology. Here we use three-dimensional neural cultures (organoids) derived from induced pluripotent stem cells (iPSCs) to investigate neurodevelopmental alterations in individuals with severe idiopathic ASD. While no known underlying genomic mutation could be identified, transcriptome and gene network analyses revealed upregulation of genes involved in cell proliferation, neuronal differentiation, and synaptic assembly. ASD-derived organoids exhibit an accelerated cell cycle and overproduction of GABAergic inhibitory neurons. Using RNA interference, we show that overexpression of the transcription factor FOXG1 is responsible for the overproduction of GABAergic neurons. Altered expression of gene network modules and FOXG1 are positively correlated with symptom severity. Our data suggest that a shift toward GABAergic neuron fate caused by FOXG1 is a developmental precursor of ASD.

Neural signatures of autism

Functional magnetic resonance imaging of brain responses to biological motion in children with autism spectrum disorder (ASD), unaffected siblings (US) of children with ASD, and typically developing (TD) children has revealed three types of neural signatures: (i) state activity, related to the state of having ASD that characterizes the nature of disruption in brain circuitry; (ii) trait activity, reflecting shared areas of dysfunction in US and children with ASD, thereby providing a promising neuroendophenotype to facilitate efforts to bridge genomic complexity and disorder heterogeneity; and (iii) compensatory activity, unique to US, suggesting a neural system–level mechanism by which US might compensate for an increased genetic risk for developing ASD. The distinct brain responses to biological motion exhibited by TD children and US are striking given the identical behavioral profile of these two groups. These findings offer far-reaching implications for our understanding of the neural systems underlying autism.

Perception of dynamic changes in facial affect and identity in autism

Despite elegant behavioral descriptions of abnormalities for processing emotional facial expressions and biological motion in autism, identification of the neural mechanisms underlying these abnormalities remains a critical and largely unmet challenge. We compared brain activity with dynamic and static facial expressions in participants with and without high-functioning autism using event-related functional magnetic resonance imaging (fMRI) and three classes of face stimuli-emotion morphs (fearful and angry), identity morphs and static images (fearful, angry and neutral). We observed reduced activity in the amygdala (AMY) and fusiform gyrus (FFG) to dynamic emotional expressions in people with autism. There was also a lack of modulation by dynamic compared with static emotional expressions of social brain regions including the AMY, posterior superior temporal sulcus (STS) region and FFG. We observed equivalent emotion and identity morph-evoked activity in participants with and without autism in a region corresponding to the expected location of the more generally motion-sensitive area MT or V5. We conclude that dysfunctions in key components of the human face processing system including the AMY, FFG and posterior STS region are present in individuals with high-functioning autism, and this dysfunction might contribute to the deficits in processing emotional facial expressions.

Anorexia Nervosa and Autism Spectrum Disorders: Guided Investigation of Social Cognitive Endophenotypes.

Death by suicide occurs in a disproportionate percentage of individuals with anorexia nervosa (AN), with a standardized mortality ratio indicating a 57-fold greater risk of death from suicide relative to an age-matched cohort. Longitudinal studies indicate impaired social functioning increases risk for fatal outcomes, while social impairment persists following recovery. Study of social cognition in AN may elucidate impaired processes that may influence therapeutic efficacy. Symptoms of autism spectrum disorders (ASD) are overrepresented in those who evidence a chronic course. Relative to that in AN, social information processing in ASD is well characterized and may inform systematic study in AN. This article (a) reviews impaired interpersonal processes in AN, (b) compares the phenotype of AN with that of ASD, (c) highlights deficits of social cognitive disturbance in ASD relative to AN, and (d) proposes a new framework to understand the interaction of individuals with AN with their social context.

Oxytocin enhances brain function in children with autism

Significance This article presents our discovery that intranasal administration of oxytocin enhances activity in the brain for socially meaningful stimuli and attenuates its response to nonsocially meaningful stimuli in children with autism spectrum disorder (ASD) as measured via functional MRI. We also identified a relationship between changes in salivary oxytocin following administration and enhancements in brain function. These discoveries are particularly important given the urgent need for treatments that target the core social dysfunction in ASD. The functional neural attunement we demonstrated might facilitate social learning, thus potentially bringing about long-term change in neural systems and subsequent behavioral improvements. Our results illustrate the power of a translational neuroscience approach to facilitate the development of pharmacological interventions for neurodevelopmental disorders like ASD. Following intranasal administration of oxytocin (OT), we measured, via functional MRI, changes in brain activity during judgments of socially (Eyes) and nonsocially (Vehicles) meaningful pictures in 17 children with high-functioning autism spectrum disorder (ASD). OT increased activity in the striatum, the middle frontal gyrus, the medial prefrontal cortex, the right orbitofrontal cortex, and the left superior temporal sulcus. In the striatum, nucleus accumbens, left posterior superior temporal sulcus, and left premotor cortex, OT increased activity during social judgments and decreased activity during nonsocial judgments. Changes in salivary OT concentrations from baseline to 30 min postadministration were positively associated with increased activity in the right amygdala and orbitofrontal cortex during social vs. nonsocial judgments. OT may thus selectively have an impact on salience and hedonic evaluations of socially meaningful stimuli in children with ASD, and thereby facilitate social attunement. These findings further the development of a neurophysiological systems-level understanding of mechanisms by which OT may enhance social functioning in children with ASD.