Atypical pattern separation memory and its association with restricted interests and repetitive behaviors in autistic children.

LAY ABSTRACT: Memory challenges remain understudied in childhood autism. Our study investigates one specific aspect of memory function, known as pattern separation memory, in autistic children. Pattern separation memory refers to the critical ability to store unique memories of similar stimuli; however, its role in childhood autism remains largely uncharted. Our study first uncovered that the pattern separation memory was significantly reduced in autistic children, and then showed that reduced memory performance was linked to their symptoms of repetitive, restricted interest and behavior. We also identified distinct subgroups with profiles of reduced and increased generalization for pattern separation memory. More than 72% of autistic children showed a tendency to reduce memory generalization, focusing heavily on unique details of objects for memorization. This focus made it challenging for them to identify commonalities across similar entities. Interestingly, a smaller proportion of autistic children displayed an opposite pattern of increased generalization, marked by challenges in differentiating between similar yet distinct objects. Our findings advance the understanding of memory function in autism and have practical implications for devising personalized learning strategies that align with the unique memory patterns exhibited by autistic children. This study will be of broad interest to researchers in psychology, psychiatry, and brain development as well as teachers, parents, clinicians, and the wider public.

Atypical cognitive training-induced learning and brain plasticity and their relation to insistence on sameness in children with autism.

Children with autism spectrum disorders (ASDs) often display atypical learning styles; however, little is known regarding learning-related brain plasticity and its relation to clinical phenotypic features. Here, we investigate cognitive learning and neural plasticity using functional brain imaging and a novel numerical problem-solving training protocol. Children with ASD showed comparable learning relative to typically developing children but were less likely to shift from rule-based to memory-based strategy. While learning gains in typically developing children were associated with greater plasticity of neural representations in the medial temporal lobe and intraparietal sulcus, learning in children with ASD was associated with more stable neural representations. Crucially, the relation between learning and plasticity of neural representations was moderated by insistence on sameness, a core phenotypic feature of ASD. Our study uncovers atypical cognitive and neural mechanisms underlying learning in children with ASD, and informs pedagogical strategies for nurturing cognitive abilities in childhood autism.

Replicable Patterns of Memory Impairments in Children With Autism and Their Links to Hyperconnected Brain Circuits.

BACKGROUND: Memory impairments have profound implications for social communication and educational outcomes in children with autism spectrum disorder (ASD). However, the precise nature of memory dysfunction in children with ASD and the underlying neural circuit mechanisms remain poorly understood. The default mode network (DMN) is a brain network that is associated with memory and cognitive function, and DMN dysfunction is among the most replicable and robust brain signatures of ASD. METHODS: We used a comprehensive battery of standardized episodic memory assessments and functional circuit analyses in 25 8- to 12-year-old children with ASD and 29 matched typically developing control children. RESULTS: Memory performance was reduced in children with ASD compared with control children. General and face memory emerged as distinct dimensions of memory difficulties in ASD. Importantly, findings of diminished episodic memory in children with ASD were replicated in 2 independent data sets. Analysis of intrinsic functional circuits associated with the DMN revealed that general and face memory deficits were associated with distinct, hyperconnected circuits: Aberrant hippocampal connectivity predicted diminished general memory while aberrant posterior cingulate cortex connectivity predicted diminished face memory. Notably, aberrant hippocampal-posterior cingulate cortex circuitry was a common feature of diminished general and face memory in ASD. CONCLUSIONS: Our results represent a comprehensive appraisal of episodic memory function in children with ASD and identify extensive and replicable patterns of memory reductions in children with ASD that are linked to dysfunction of distinct DMN-related circuits. These findings highlight a role for DMN dysfunction in ASD that extends beyond face memory to general memory function.

Atypical cognitive training-induced learning and brain plasticity and their relation to insistence on sameness in children with autism.

Children with autism spectrum disorders (ASD) often display atypical learning styles, however little is known regarding learning-related brain plasticity and its relation to clinical phenotypic features. Here, we investigate cognitive learning and neural plasticity using functional brain imaging and a novel numerical problem-solving training protocol. Children with ASD showed comparable learning relative to typically developing children but were less likely to shift from rule-based to memory-based strategy. Critically, while learning gains in typically developing children were associated with greater plasticity of neural representations in the medial temporal lobe and intraparietal sulcus, learning in children with ASD was associated with more stable neural representations. Crucially, the relation between learning and plasticity of neural representations was moderated by insistence on sameness, a core phenotypic feature of ASD. Our study uncovers atypical cognitive and neural mechanisms underlying learning in children with ASD, and informs pedagogical strategies for nurturing cognitive abilities in childhood autism.

Aberrant Emotional Prosody Circuitry Predicts Social Communication Impairments in Children With Autism.

BACKGROUND: Emotional prosody provides acoustical cues that reflect a communication partner's emotional state and is crucial for successful social interactions. Many children with autism have deficits in recognizing emotions from voices; however, the neural basis for these impairments is unknown. We examined brain circuit features underlying emotional prosody processing deficits and their relationship to clinical symptoms of autism. METHODS: We used an event-related functional magnetic resonance imaging task to measure neural activity and connectivity during processing of sad and happy emotional prosody and neutral speech in 22 children with autism and 21 matched control children (7-12 years old). We employed functional connectivity analyses to test competing theoretical accounts that attribute emotional prosody impairments to either sensory processing deficits in auditory cortex or theory of mind deficits instantiated in the temporoparietal junction (TPJ). RESULTS: Children with autism showed specific behavioral impairments for recognizing emotions from voices. They also showed aberrant functional connectivity between voice-sensitive auditory cortex and the bilateral TPJ during emotional prosody processing. Neural activity in the bilateral TPJ during processing of both sad and happy emotional prosody stimuli was associated with social communication impairments in children with autism. In contrast, activity and decoding of emotional prosody in auditory cortex was comparable between autism and control groups and did not predict social communication impairments. CONCLUSIONS: Our findings support a social-cognitive deficit model of autism by identifying a role for TPJ dysfunction during emotional prosody processing. Our study underscores the importance of tuning in to vocal-emotional cues for building social connections in children with autism.

Neural decoding of emotional prosody in voice-sensitive auditory cortex predicts social communication abilities in children.

During social interactions, speakers signal information about their emotional state through their voice, which is known as emotional prosody. Little is known regarding the precise brain systems underlying emotional prosody decoding in children and whether accurate neural decoding of these vocal cues is linked to social skills. Here, we address critical gaps in the developmental literature by investigating neural representations of prosody and their links to behavior in children. Multivariate pattern analysis revealed that representations in the bilateral middle and posterior superior temporal sulcus (STS) divisions of voice-sensitive auditory cortex decode emotional prosody information in children. Crucially, emotional prosody decoding in middle STS was correlated with standardized measures of social communication abilities; more accurate decoding of prosody stimuli in the STS was predictive of greater social communication abilities in children. Moreover, social communication abilities were specifically related to decoding sadness, highlighting the importance of tuning in to negative emotional vocal cues for strengthening social responsiveness and functioning. Findings bridge an important theoretical gap by showing that the ability of the voice-sensitive cortex to detect emotional cues in speech is predictive of a child's social skills, including the ability to relate and interact with others.

A Neurodevelopmental Shift in Reward Circuitry from Mother's to Nonfamilial Voices in Adolescence.

The social worlds of young children primarily revolve around parents and caregivers, who play a key role in guiding children's social and cognitive development. However, a hallmark of adolescence is a shift in orientation toward nonfamilial social targets, an adaptive process that prepares adolescents for their independence. Little is known regarding neurobiological signatures underlying changes in adolescents' social orientation. Using functional brain imaging of human voice processing in children and adolescents (ages 7-16), we demonstrate distinct neural signatures for mother's voice and nonfamilial voices across child and adolescent development in reward and social valuation systems, instantiated in nucleus accumbens and ventromedial prefrontal cortex. While younger children showed greater activity in these brain systems for mother's voice compared with nonfamilial voices, older adolescents showed the opposite effect with increased activity for nonfamilial compared with mother's voice. Findings uncover a critical role for reward and social valuative brain systems in the pronounced changes in adolescents' orientation toward nonfamilial social targets. Our approach provides a template for examining developmental shifts in social reward and motivation in individuals with pronounced social impairments, including adolescents with autism.SIGNIFICANCE STATEMENT Children's social worlds undergo a transformation during adolescence. While socialization in young children revolves around parents and caregivers, adolescence is characterized by a shift in social orientation toward nonfamilial social partners. Here we show that this shift is reflected in neural activity measured from reward processing regions in response to brief vocal samples. When younger children hear their mother's voice, reward processing regions show greater activity compared with when they hear nonfamilial, unfamiliar voices. Strikingly, older adolescents show the opposite effect, with increased activity for nonfamilial compared with mother's voice. Findings identify the brain basis of adolescents' switch in social orientation toward nonfamilial social partners and provides a template for understanding neurodevelopment in clinical populations with social and communication difficulties.

Mothers adapt their voice during children's adolescent development.

Mothers alter their speech in a stereotypical manner when addressing infants using high pitch, a wide pitch range, and distinct timbral features. Mothers reduce their vocal pitch after early childhood; however, it is not known whether mother's voice changes through adolescence as children become increasingly independent from their parents. Here we investigate the vocal acoustics of 50 mothers of older children (ages 7-16) to determine: (1) whether pitch changes associated with child-directed speech decrease with age; (2) whether other acoustical features associated with child-directed speech change with age; and, (3) the relative contribution of acoustical features in predicting child's age. Results reveal that mothers of older children used lower pitched voices than mothers of younger children, and mother's voice pitch height predicted their child's age. Crucially, these effects were present after controlling for mother's age, accounting for aging-related pitch reductions. Brightness, a timbral feature correlated with pitch height, also showed an inverse relation with child's age but did not improve prediction of child's age beyond that accounted for by pitch height. Other acoustic features did not predict child age. Findings suggest that mother's voice adapts to match their child's developmental progression into adolescence and this adaptation is independent of mother's age.

Epidural labour analgesia and autism spectrum disorder: is the current evidence sufficient to dismiss an association?

Findings from a population-based study using a sibling-matched analysis published in this issue of the British Journal of Anaesthesia indicate that epidural labour analgesia is not associated with an increased risk of autism spectrum disorder. These findings are consistent with those from three other population-based studies that used similar methodological approaches. Cumulatively, these robust, high-quality epidemiological data support the assertion that there is no meaningful association between epidural labour analgesia and autism spectrum disorder in offspring.

Intrinsic functional architecture of the human speech processing network.

Speech engages distributed temporo-fronto-parietal brain regions, however a comprehensive understanding of its intrinsic functional network architecture is lacking. Here we investigate the human speech processing network using the largest sample to date, high temporal resolution resting-state fMRI data, network stability analysis, and theoretically informed models. Network consensus analysis revealed three stable functional modules encompassing: (1) superior temporal plane (STP) and Area Spt, (2) superior temporal sulcus (STS) + ventral frontoparietal cortex, and (3) dorsal frontoparietal cortex. The STS + ventral frontoparietal cortex module showed the highest participation coefficient, and a hub-like organization linking STP with frontoparietal cortical nodes. Node-wise analysis revealed key connectivity features underlying this modular architecture, including a leftward asymmetric connectivity profile, and differential connectivity of STS and STP, with frontoparietal cortex. Our findings, replicated across cohorts, reveal a tripartite functional network architecture supporting speech processing and provide a novel template for future studies.

The visual word form area (VWFA) is part of both language and attention circuitry.

While predominant models of visual word form area (VWFA) function argue for its specific role in decoding written language, other accounts propose a more general role of VWFA in complex visual processing. However, a comprehensive examination of structural and functional VWFA circuits and their relationship to behavior has been missing. Here, using high-resolution multimodal imaging data from a large Human Connectome Project cohort (N = 313), we demonstrate robust patterns of VWFA connectivity with both canonical language and attentional networks. Brain-behavior relationships revealed a striking pattern of double dissociation: structural connectivity of VWFA with lateral temporal language network predicted language, but not visuo-spatial attention abilities, while VWFA connectivity with dorsal fronto-parietal attention network predicted visuo-spatial attention, but not language abilities. Our findings support a multiplex model of VWFA function characterized by distinct circuits for integrating language and attention, and point to connectivity-constrained cognition as a key principle of human brain organization.

A Pivotal Response Treatment Package for Children With Autism Spectrum Disorder: An RCT.

OBJECTIVES: Our aim was to conduct a randomized controlled trial to evaluate a pivotal response treatment package (PRT-P) consisting of parent training and clinician-delivered in-home intervention on the communication skills of children with autism spectrum disorder. METHODS: Forty-eight children with autism spectrum disorder and significant language delay between 2 and 5 years old were randomly assigned to PRT-P (n = 24) or the delayed treatment group (n = 24) for 24 weeks. The effect of treatment on child communication skills was assessed via behavioral coding of parent-child interactions, standardized parent-report measures, and blinded clinician ratings. RESULTS: Analysis of child utterances during the structured laboratory observation revealed that, compared with the delayed treatment group, children in PRT-P demonstrated greater improvement in frequency of functional utterances (F1,41 = 6.07; P = .026; d = 0.61). The majority of parents in the PRT-P group (91%) were able to implement pivotal response treatment (PRT) with fidelity within 24 weeks. Children receiving PRT-P also demonstrated greater improvement on the Brief Observation of Social Communication Change, on the Clinical Global Impressions Improvement subscale, and in number of words used on a parent-report questionnaire. CONCLUSIONS: This is the first 24-week randomized controlled trial in which community treatment is compared with the combination of parent training and clinician-delivered PRT. PRT-P was effective for improving child social communication skills and for teaching parents to implement PRT. Additional research will be needed to understand the optimal combination of treatment settings, intensity, and duration, and to identify child and parent characteristics associated with treatment response.

Quantitative analysis of heterogeneity in academic achievement of children with autism.

Autism spectrum disorders (ASD) represent a quintessential example of a clinical population with diverse symptom presentations and marked variation in cognitive abilities. However, the extent literature lacks rigorous quantitative procedures for characterizing heterogeneity of cognitive abilities in these individuals. Here we employ novel clustering and cross-validation procedures to investigate the stability of heterogeneous patterns of cognitive abilities in reading and math in a relatively large sample (N=114) of children with ASD and matched controls (N=96). Our analysis revealed a unique profile of heterogeneity in ASD, consisting of a low-achieving subgroup with poor math skills compared to reading, and a high-achieving subgroup who showed superior math skills compared to reading. Verbal and central executive working memory skills further differentiated these subgroups. Findings provide insights into distinct profiles of academic achievement in children with ASD, with implications for educational practice and intervention, and provide a novel framework for quantifying heterogeneity in the disorder.

Neural signatures of co-occurring reading and mathematical difficulties.

Impaired abilities in multiple domains is common in children with learning difficulties. Co-occurrence of low reading and mathematical abilities (LRLM) appears in almost every second child with learning difficulties. However, little is known regarding the neural bases of this combination. Leveraging a unique and tightly controlled sample including children with LRLM, isolated low reading ability (LR), and isolated low mathematical ability (LM), we uncover a distinct neural signature in children with co-occurring low reading and mathematical abilities differentiable from LR and LM. Specifically, we show that LRLM is neuroanatomically distinct from both LR and LM based on reduced cortical folding of the right parahippocampal gyrus, a medial temporal lobe region implicated in visual associative learning. LRLM children were further distinguished from LR and LM by patterns of intrinsic functional connectivity between parahippocampal gyrus and brain circuitry underlying reading and numerical quantity processing. Our results critically inform cognitive and neural models of LRLM by implicating aberrations in both domain-specific and domain-general brain regions involved in reading and mathematics. More generally, our results provide the first evidence for distinct multimodal neural signatures associated with LRLM, and suggest that this population displays an independent phenotype of learning difficulty that cannot be explained simply as a combination of isolated low reading and mathematical abilities.

Individual Differences in Human Auditory Processing: Insights From Single-Trial Auditory Midbrain Activity in an Animal Model.

Auditory-evoked potentials are classically defined as the summations of synchronous firing along the auditory neuraxis. Converging evidence supports a model whereby timing jitter in neural coding compromises listening and causes variable scalp-recorded potentials. Yet the intrinsic noise of human scalp recordings precludes a full understanding of the biological origins of individual differences in listening skills. To delineate the mechanisms contributing to these phenomena, in vivo extracellular activity was recorded from inferior colliculus in guinea pigs to speech in quiet and noise. Here we show that trial-by-trial timing jitter is a mechanism contributing to auditory response variability. Identical variability patterns were observed in scalp recordings in human children, implicating jittered timing as a factor underlying reduced coding of dynamic speech features and speech in noise. Moreover, intertrial variability in human listeners is tied to language development. Together, these findings suggest that variable timing in inferior colliculus blurs the neural coding of speech in noise, and propose a consequence of this timing jitter for human behavior. These results hint both at the mechanisms underlying speech processing in general, and at what may go awry in individuals with listening difficulties.

Population responses in primary auditory cortex simultaneously represent the temporal envelope and periodicity features in natural speech.

Speech perception relies on a listener's ability to simultaneously resolve multiple temporal features in the speech signal. Little is known regarding neural mechanisms that enable the simultaneous coding of concurrent temporal features in speech. Here we show that two categories of temporal features in speech, the low-frequency speech envelope and periodicity cues, are processed by distinct neural mechanisms within the same population of cortical neurons. We measured population activity in primary auditory cortex of anesthetized guinea pig in response to three variants of a naturally produced sentence. Results show that the envelope of population responses closely tracks the speech envelope, and this cortical activity more closely reflects wider bandwidths of the speech envelope compared to narrow bands. Additionally, neuronal populations represent the fundamental frequency of speech robustly with phase-locked responses. Importantly, these two temporal features of speech are simultaneously observed within neuronal ensembles in auditory cortex in response to clear, conversation, and compressed speech exemplars. Results show that auditory cortical neurons are adept at simultaneously resolving multiple temporal features in extended speech sentences using discrete coding mechanisms.

Neural circuits underlying mother's voice perception predict social communication abilities in children.

The human voice is a critical social cue, and listeners are extremely sensitive to the voices in their environment. One of the most salient voices in a child's life is mother's voice: Infants discriminate their mother's voice from the first days of life, and this stimulus is associated with guiding emotional and social function during development. Little is known regarding the functional circuits that are selectively engaged in children by biologically salient voices such as mother's voice or whether this brain activity is related to children's social communication abilities. We used functional MRI to measure brain activity in 24 healthy children (mean age, 10.2 y) while they attended to brief (<1 s) nonsense words produced by their biological mother and two female control voices and explored relationships between speech-evoked neural activity and social function. Compared to female control voices, mother's voice elicited greater activity in primary auditory regions in the midbrain and cortex; voice-selective superior temporal sulcus (STS); the amygdala, which is crucial for processing of affect; nucleus accumbens and orbitofrontal cortex of the reward circuit; anterior insula and cingulate of the salience network; and a subregion of fusiform gyrus associated with face perception. The strength of brain connectivity between voice-selective STS and reward, affective, salience, memory, and face-processing regions during mother's voice perception predicted social communication skills. Our findings provide a novel neurobiological template for investigation of typical social development as well as clinical disorders, such as autism, in which perception of biologically and socially salient voices may be impaired.

Brain State Differentiation and Behavioral Inflexibility in Autism.

Autism spectrum disorders (ASDs) are characterized by social impairments alongside cognitive and behavioral inflexibility. While social deficits in ASDs have extensively been characterized, the neurobiological basis of inflexibility and its relation to core clinical symptoms of the disorder are unknown. We acquired functional neuroimaging data from 2 cohorts, each consisting of 17 children with ASDs and 17 age- and IQ-matched typically developing (TD) children, during stimulus-evoked brain states involving performance of social attention and numerical problem solving tasks, as well as during intrinsic, resting brain states. Effective connectivity between key nodes of the salience network, default mode network, and central executive network was used to obtain indices of functional organization across evoked and intrinsic brain states. In both cohorts examined, a machine learning algorithm was able to discriminate intrinsic (resting) and evoked (task) functional brain network configurations more accurately in TD children than in children with ASD. Brain state discriminability was related to severity of restricted and repetitive behaviors, indicating that weak modulation of brain states may contribute to behavioral inflexibility in ASD. These findings provide novel evidence for a potential link between neurophysiological inflexibility and core symptoms of this complex neurodevelopmental disorder.

Underconnectivity between voice-selective cortex and reward circuitry in children with autism.

Individuals with autism spectrum disorders (ASDs) often show insensitivity to the human voice, a deficit that is thought to play a key role in communication deficits in this population. The social motivation theory of ASD predicts that impaired function of reward and emotional systems impedes children with ASD from actively engaging with speech. Here we explore this theory by investigating distributed brain systems underlying human voice perception in children with ASD. Using resting-state functional MRI data acquired from 20 children with ASD and 19 age- and intelligence quotient-matched typically developing children, we examined intrinsic functional connectivity of voice-selective bilateral posterior superior temporal sulcus (pSTS). Children with ASD showed a striking pattern of underconnectivity between left-hemisphere pSTS and distributed nodes of the dopaminergic reward pathway, including bilateral ventral tegmental areas and nucleus accumbens, left-hemisphere insula, orbitofrontal cortex, and ventromedial prefrontal cortex. Children with ASD also showed underconnectivity between right-hemisphere pSTS, a region known for processing speech prosody, and the orbitofrontal cortex and amygdala, brain regions critical for emotion-related associative learning. The degree of underconnectivity between voice-selective cortex and reward pathways predicted symptom severity for communication deficits in children with ASD. Our results suggest that weak connectivity of voice-selective cortex and brain structures involved in reward and emotion may impair the ability of children with ASD to experience speech as a pleasurable stimulus, thereby impacting language and social skill development in this population. Our study provides support for the social motivation theory of ASD.