Shared behavioural impairments in visual perception and place avoidance across different autism models are driven by periaqueductal grey hypoexcitability in Setd5 haploinsufficient mice.

Despite the diverse genetic origins of autism spectrum disorders (ASDs), affected individuals share strikingly similar and correlated behavioural traits that include perceptual and sensory processing challenges. Notably, the severity of these sensory symptoms is often predictive of the expression of other autistic traits. However, the origin of these perceptual deficits remains largely elusive. Here, we show a recurrent impairment in visual threat perception that is similarly impaired in 3 independent mouse models of ASD with different molecular aetiologies. Interestingly, this deficit is associated with reduced avoidance of threatening environments-a nonperceptual trait. Focusing on a common cause of ASDs, the Setd5 gene mutation, we define the molecular mechanism. We show that the perceptual impairment is caused by a potassium channel (Kv1)-mediated hypoexcitability in a subcortical node essential for the initiation of escape responses, the dorsal periaqueductal grey (dPAG). Targeted pharmacological Kv1 blockade rescued both perceptual and place avoidance deficits, causally linking seemingly unrelated trait deficits to the dPAG. Furthermore, we show that different molecular mechanisms converge on similar behavioural phenotypes by demonstrating that the autism models Cul3 and Ptchd1, despite having similar behavioural phenotypes, differ in their functional and molecular alteration. Our findings reveal a link between rapid perception controlled by subcortical pathways and appropriate learned interactions with the environment and define a nondevelopmental source of such deficits in ASD.

Enhanced neural synchronization during social communications between dyads with high autistic traits.

Autism is characterized by atypical social communication styles. To investigate whether individuals with high autistic traits could still have effective social communication among each other, we compared the behavioral patterns and communication quality within 64 dyads of college students paired with both high, both low, and mixed high-low (HL) autistic traits, with their gender matched. Results revealed that the high-high (HH) autistic dyads exhibited atypical behavioral patterns during conversations, including reduced mutual gaze, communicational turns, and emotional sharing compared with the low-low and/or HL autistic dyads. However, the HH autistic dyads displayed enhanced interpersonal neural synchronization during social communications measured by functional near-infrared spectroscopy, suggesting an effective communication style. Besides, they also provided more positive subjective evaluations of the conversations. These findings highlight the potential for alternative pathways to effectively communicate with the autistic community, contribute to a deeper understanding of how high autistic traits influence social communication dynamics among autistic individuals, and provide important insights for the clinical practices for supporting autistic people.

Infants' reorienting efficiency depends on parental autistic traits and predicts future socio-communicative behaviors.

Attentional reorienting is dysfunctional not only in children with autism spectrum disorder (ASD), but also in infants who will develop ASD, thus constituting a potential causal factor of future social interaction and communication abilities. Following the research domain criteria framework, we hypothesized that the presence of subclinical autistic traits in parents should lead to atypical infants' attentional reorienting, which in turn should impact on their future socio-communication behavior in toddlerhood. During an attentional cueing task, we measured the saccadic latencies in a large sample (total enrolled n = 89; final sample n = 71) of 8-month-old infants from the general population as a proxy for their stimulus-driven attention. Infants were grouped in a high parental traits (HPT; n = 23) or in a low parental traits (LPT; n = 48) group, according to the degree of autistic traits self-reported by their parents. Infants (n = 33) were then longitudinally followed to test their socio-communicative behaviors at 21 months. Results show a sluggish reorienting system, which was a longitudinal predictor of future socio-communicative skills at 21 months. Our combined transgenerational and longitudinal findings suggest that the early functionality of the stimulus-driven attentional network-redirecting attention from one event to another-could be directly connected to future social and communication development.

A multimodal interface for speech perception: the role of the left superior temporal sulcus in social cognition and autism.

Multimodal integration is crucial for human interaction, in particular for social communication, which relies on integrating information from various sensory modalities. Recently a third visual pathway specialized in social perception was proposed, which includes the right superior temporal sulcus (STS) playing a key role in processing socially relevant cues and high-level social perception. Importantly, it has also recently been proposed that the left STS contributes to audiovisual integration of speech processing. In this article, we propose that brain areas along the right STS that support multimodal integration for social perception and cognition can be considered homologs to those in the left, language-dominant hemisphere, sustaining multimodal integration of speech and semantic concepts fundamental for social communication. Emphasizing the significance of the left STS in multimodal integration and associated processes such as multimodal attention to socially relevant stimuli, we underscore its potential relevance in comprehending neurodevelopmental conditions characterized by challenges in social communication such as autism spectrum disorder (ASD). Further research into this left lateral processing stream holds the promise of enhancing our understanding of social communication in both typical development and ASD, which may lead to more effective interventions that could improve the quality of life for individuals with atypical neurodevelopment.

Neuroanatomy of autism: what is the role of the cerebellum?

Autism (or autism spectrum disorder) was initially defined as a psychiatric disorder, with the likely cause maternal behavior (the very destructive "refrigerator mother" theory). It took several decades for research into brain mechanisms to become established. Both neuropathological and imaging studies found differences in the cerebellum in autism spectrum disorder, the most widely documented being a decreased density of Purkinje cells in the cerebellar cortex. The popular interpretation of these results is that cerebellar neuropathology is a critical cause of autism spectrum disorder. We challenge that view by arguing that if fewer Purkinje cells are critical for autism spectrum disorder, then any condition that causes the loss of Purkinje cells should also cause autism spectrum disorder. We will review data on damage to the cerebellum from cerebellar lesions, tumors, and several syndromes (Joubert syndrome, Fragile X, and tuberous sclerosis). Collectively, these studies raise the question of whether the cerebellum really has a role in autism spectrum disorder. Autism spectrum disorder is now recognized as a genetically caused developmental disorder. A better understanding of the genes that underlie the differences in brain development that result in autism spectrum disorder is likely to show that these genes affect the development of the cerebellum in parallel with the development of the structures that do underlie autism spectrum disorder.

Noninvasive brain stimulation in autism: review and outlook for personalized interventions in adult patients.

Noninvasive brain stimulation (NIBS) has been increasingly investigated during the last decade as a treatment option for persons with autism spectrum disorder (ASD). Yet, previous studies did not reach a consensus on a superior treatment protocol or stimulation target. Persons with ASD often suffer from social isolation and high rates of unemployment, arising from difficulties in social interaction. ASD involves multiple neural systems involved in perception, language, and cognition, and the underlying brain networks of these functional domains have been well documented. Aiming to provide an overview of NIBS effects when targeting these neural systems in late adolescent and adult ASD, we conducted a systematic search of the literature starting at 631 non-duplicate publications, leading to six studies corresponding with inclusion and exclusion criteria. We discuss these studies regarding their treatment rationale and the accordingly chosen methodological setup. The results of these studies vary, while methodological advances may allow to explain some of the variability. Based on these insights, we discuss strategies for future clinical trials to personalize the selection of brain stimulation targets taking into account intersubject variability of brain anatomy as well as function.

Differential neural correlates underlying visuospatial versus semantic reasoning in autistic children.

While fronto-posterior underconnectivity has often been reported in autism, it was shown that different contexts may modulate between-group differences in functional connectivity. Here, we assessed how different task paradigms modulate functional connectivity differences in a young autistic sample relative to typically developing children. Twenty-three autistic and 23 typically developing children aged 6 to 15 years underwent functional magnetic resonance imaging (fMRI) scanning while completing a reasoning task with visuospatial versus semantic content. We observed distinct connectivity patterns in autistic versus typical children as a function of task type (visuospatial vs. semantic) and problem complexity (visual matching vs. reasoning), despite similar performance. For semantic reasoning problems, there was no significant between-group differences in connectivity. However, during visuospatial reasoning problems, we observed occipital-occipital, occipital-temporal, and occipital-frontal over-connectivity in autistic children relative to typical children. Also, increasing the complexity of visuospatial problems resulted in increased functional connectivity between occipital, posterior (temporal), and anterior (frontal) brain regions in autistic participants, more so than in typical children. Our results add to several studies now demonstrating that the connectivity alterations in autistic relative to neurotypical individuals are much more complex than previously thought and depend on both task type and task complexity and their respective underlying cognitive processes.

Mapping the differential impact of spontaneous and conversational laughter on brain and mind: an fMRI study in autism.

Spontaneous and conversational laughter are important socio-emotional communicative signals. Neuroimaging findings suggest that non-autistic people engage in mentalizing to understand the meaning behind conversational laughter. Autistic people may thus face specific challenges in processing conversational laughter, due to their mentalizing difficulties. Using fMRI, we explored neural differences during implicit processing of these two types of laughter. Autistic and non-autistic adults passively listened to funny words, followed by spontaneous laughter, conversational laughter, or noise-vocoded vocalizations. Behaviourally, words plus spontaneous laughter were rated as funnier than words plus conversational laughter, and the groups did not differ. However, neuroimaging results showed that non-autistic adults exhibited greater medial prefrontal cortex activation while listening to words plus conversational laughter, than words plus genuine laughter, while autistic adults showed no difference in medial prefrontal cortex activity between these two laughter types. Our findings suggest a crucial role for the medial prefrontal cortex in understanding socio-emotionally ambiguous laughter via mentalizing. Our study also highlights the possibility that autistic people may face challenges in understanding the essence of the laughter we frequently encounter in everyday life, especially in processing conversational laughter that carries complex meaning and social ambiguity, potentially leading to social vulnerability. Therefore, we advocate for clearer communication with autistic people.

Atypical functional connectivity between the amygdala and visual, salience regions in infants with genetic liability for autism.

The amygdala undergoes a period of overgrowth in the first year of life, resulting in enlarged volume by 12 months in infants later diagnosed with ASD. The overgrowth of the amygdala may have functional consequences during infancy. We investigated whether amygdala connectivity differs in 12-month-olds at high likelihood (HL) for ASD (defined by having an older sibling with autism), compared to those at low likelihood (LL). We examined seed-based connectivity of left and right amygdalae, hypothesizing that the HL and LL groups would differ in amygdala connectivity, especially with the visual cortex, based on our prior reports demonstrating that components of visual circuitry develop atypically and are linked to genetic liability for autism. We found that HL infants exhibited weaker connectivity between the right amygdala and the left visual cortex, as well as between the left amygdala and the right anterior cingulate, with evidence that these patterns occur in distinct subgroups of the HL sample. Amygdala connectivity strength with the visual cortex was related to motor and communication abilities among HL infants. Findings indicate that aberrant functional connectivity between the amygdala and visual regions is apparent in infants with genetic liability for ASD and may have implications for early differences in adaptive behaviors.

Patterns of spontaneous neural activity associated with social communication abilities among infants and toddlers showing signs of autism.

Early disruptions to social communication development, including delays in joint attention and language, are among the earliest markers of autism spectrum disorder (autism, henceforth). Although social communication differences are a core feature of autism, there is marked heterogeneity in social communication-related development among infants and toddlers exhibiting autism symptoms. Neural markers of individual differences in joint attention and language abilities may provide important insight into heterogeneity in autism symptom expression during infancy and toddlerhood. This study examined patterns of spontaneous electroencephalography (EEG) activity associated with joint attention and language skills in 70 community-referred 12- to 23-month-olds with autism symptoms and elevated scores on an autism diagnostic instrument. Data-driven cluster-based permutation analyses revealed significant positive associations between relative alpha power (6-9 Hz) and concurrent response to joint attention skills, receptive language, and expressive language abilities. Exploratory analyses also revealed significant negative associations between relative alpha power and measures of core autism features (i.e., social communication difficulties and restricted/repetitive behaviors). These findings shed light on the neural mechanisms underlying typical and atypical social communication development in emerging autism and provide a foundation for future work examining neural predictors of social communication growth and markers of intervention response.

Age, not autism, influences multisensory integration of speech stimuli among adults in a McGurk/MacDonald paradigm.

Differences between autistic and non-autistic individuals in perception of the temporal relationships between sights and sounds are theorized to underlie difficulties in integrating relevant sensory information. These, in turn, are thought to contribute to problems with speech perception and higher level social behaviour. However, the literature establishing this connection often involves limited sample sizes and focuses almost entirely on children. To determine whether these differences persist into adulthood, we compared 496 autistic and 373 non-autistic adults (aged 17 to 75 years). Participants completed an online version of the McGurk/MacDonald paradigm, a multisensory illusion indicative of the ability to integrate audiovisual speech stimuli. Audiovisual asynchrony was manipulated, and participants responded both to the syllable they perceived (revealing their susceptibility to the illusion) and to whether or not the audio and video were synchronized (allowing insight into temporal processing). In contrast with prior research with smaller, younger samples, we detected no evidence of impaired temporal or multisensory processing in autistic adults. Instead, we found that in both groups, multisensory integration correlated strongly with age. This contradicts prior presumptions that differences in multisensory perception persist and even increase in magnitude over the lifespan of autistic individuals. It also suggests that the compensatory role multisensory integration may play as the individual senses decline with age is intact. These findings challenge existing theories and provide an optimistic perspective on autistic development. They also underline the importance of expanding autism research to better reflect the age range of the autistic population.

Electrophysiological correlates of self-related processing in adults with autism.

The term "self-bias" refers to the human propensity to prioritize self- over other-related stimuli and is believed to influence various stages of the processing stream. By means of event-related potentials (ERPs), it was recently shown that the self-bias in a shape-label matching task modulates early as well as later phases of information processing in neurotypicals. Recent claims suggest autism-related deficits to specifically impact later stages of self-related processing; however, it is unclear whether these claims hold based on current findings. Using the shape-label matching task while recording ERPs in individuals with autism can clarify which stage of self-related processing is specifically affected in this condition. Therefore, this study sought to investigate the temporal course of self-related processing in adults with and without autism. Thirty-two adults with autism and 27 neurotypicals completed a shape-label matching task while ERPs were concomitantly recorded. At the behavioral level, results furnished evidence for a comparable self-bias across groups, with no differences in task performance between adults with and without autism. At the ERP level, the two groups showed a similar self-bias at early stages of self-related information processing (the N1 component). Conversely, the autism group manifested a lessened differentiation between self- and other-related stimuli at later stages (the parietal P3 component). In line with recent claims of later phases of self-related processing being altered in autism, we found an equivalent self-bias between groups at an early, sensory stage of processing, yet a strongly diminished self-bias at a later, cognitive stage in adults with autism.

Stabilizing axin leads to optic nerve hypoplasia in a mouse model of autism.

Autism spectrum disorder (ASD) is a group of neurodevelopment disorders characterized by deficits in social interaction and communication, and repetitive or stereotyped behavior. Autistic children are more likely to have vision problems, and ASD is unusually common among blind people. However, the mechanisms behind the vision disorders in autism are unclear. Stabilizing WNT-targeted scaffold protein Axin2 by XAV939 during embryonic development causes overproduction of cortical neurons and leads to autistic-like behaviors in mice. In this study, we investigated the relationship between vision abnormality and autism using an XAV939-induced mouse model of autism. We found that the mice receiving XAV939 had decreased amplitude of bright light-adaptive ERG. The amplitudes and latency of flash visual evoked potential recorded from XAV939-treated mice were lower and longer, respectively than in the control mice, suggesting that XAV939 inhibits visual signal processing and conductance. Anatomically, the diameters of RGC axons were reduced when Axin2 was stabilized during the development, and the optic fibers had defective myelin sheaths and reduced oligodendrocytes. The results suggest that the WNT signaling pathway is crucial for optic nerve development. This study provides experimental evidence that conditions interfering with brain development may also lead to visual problems, which in turn might exaggerate the autistic features in humans.

Editorial Perspective: Bridging the translational neuroscience gap in autism - development of the 'shiftability' paradigm.

Clinical trials of pharmacological candidates targeting the core features of autism have largely failed. This is despite evidence linking differences in multiple neurochemical systems to brain function in autism. While this has in part been explained by the heterogeneity of the autistic population, the field has largely relied upon association studies to link brain chemistry to function. The only way to directly establish that a neurotransmitter or neuromodulator is involved in a candidate brain function is to change it and observe a shift in that function. This experimental approach dominates preclinical neuroscience, but not human studies. There is little direct experimental evidence describing how neurochemical systems modulate information processing in the living human brain. Thus, our understanding of how neurochemical differences contribute to neurodiversity is limited, impeding our ability to translate findings from animal studies into humans. Here, we introduce our 'shiftability' paradigm, an approach to bridge the translational gap in autism research. We provide an overview of the guiding principles and methodologies we use to directly test the hypothesis that neurochemical systems function differently in autistic and non-autistic individuals.

The roles of sensory hyperreactivity and hyporeactivity in understanding infant fearfulness and emerging autistic traits.

BACKGROUND: Existing evidence indicates that atypical sensory reactivity is a core characteristic of autism, and has been linked to both anxiety (and its putative infant precursor of fearfulness) and repetitive behaviours. However, most work has used cross-sectional designs and not considered the differential roles of hyperreactivity and hyporeactivity to sensory inputs, and is thus limited in specificity. METHODS: 161 infants with and without an elevated likelihood of developing autism and attention-deficit hyperactivity disorder (ADHD) were followed from 10 to 36 months of age. Parents rated an infant precursor of later anxiety (fearfulness) using the Infant Behaviour Questionnaire at 10 and 14 months, and the Early Childhood Behavioural Questionnaire at 24 months, and sensory hyperreactivity and hyporeactivity at 10, 14 and 24 months using the Infant Toddler Sensory Profile. Domains of autistic traits (restrictive and repetitive behaviours; RRB, and social communication interaction, SCI) were assessed using the parent-rated Social Responsiveness Scale at 36 months. Cross-lagged models tested (a) paths between fearfulness and hyperreactivity at 10-24 months, and from fearfulness and hyperreactivity to later autism traits, (b) the specificity of hyperreactivity effects by including hyporeactivity as a correlated predictor. RESULTS: Hyperreactivity at 14 months was positively associated with fearfulness at 24 months, and hyperreactivity at 24 months was positively associated with SCI and RRB at 36 months. When hyporeactivity was included in the model, paths between hyperreactivity and fearfulness remained, but paths between hyperreactivity and autistic traits became nonsignificant. CONCLUSIONS: Our findings indicate that alterations in early sensory reactivity may increase the likelihood of showing fearfulness in infancy, and relate to later social interactions and repetitive behaviours, particularly in individuals with a family history of autism or ADHD.

Testing the social motivation theory of autism: the role of co-occurring anxiety.

BACKGROUND: The Social Motivation Theory proposes that social reward processing differences underlie autism. However, low social motivation has also been linked to higher anxiety. Given the co-occurrence between autism and anxiety, it is possible that anxiety drives the association between social motivation and autistic characteristics. This study tests the mechanisms underlying the association between social motivation and autistic traits. METHODS: Participants were 165 adolescents (71 male), aged 10-16 years, from the Mapping profiles of cognition, motivation and attention in childhood (C-MAPS) study, enriched for autistic traits (70 participants with an autism diagnosis, 37 male). Participants completed a battery of online experimental tasks, including a Choose-a-Movie social motivation task and social cognition measures (theory of mind; emotion recognition), alongside parent-reported child anxiety and autistic traits. RESULTS: Higher social motivation was significantly associated with lower autistic traits (ß = -.26, p < .001). Controlling for social cognition did not change the association between social motivation and autistic traits. Controlling for anxiety did significantly reduce the strength of the association (unstandardized coefficient change: p = .003), although social motivation remained associated with autistic traits (ß = -.16, p = .004). Post hoc analyses demonstrated differential sex-effects: The association between social motivation and autistic traits was significant only in the females (ß = -.38, p < .001), as was the attenuation by anxiety (unstandardized coefficient change: p < .001). CONCLUSIONS: The association between social motivation and autistic traits could be partially attributed to co-occurring anxiety. Sex-specific effects found in females may be due to environmental factors such as increased social demands in adolescent female relationships. Results are consistent with self-report by autistic individuals who do not identify as having reduced social motivation.

Gender diversity is correlated with dimensional neurodivergent traits but not categorical neurodevelopmental diagnoses in children.

BACKGROUND: Gender clinic and single-item questionnaire-based data report increased co-occurrence of gender diversity and neurodevelopmental conditions. The nuances of these associations are under-studied. We used a transdiagnostic approach, combining categorical and dimensional characterization of neurodiversity, to further the understanding of its associations with gender diversity in identity and expression in children. METHODS: Data from 291 children (Autism N = 104, ADHD N = 104, Autism + ADHD N = 17, neurotypical N = 66) aged 4-12 years enrolled in the Province of Ontario Neurodevelopmental Network were analyzed. Gender diversity was measured multi-dimensionally using a well-validated parent-report instrument, the Gender Identity Questionnaire for Children (GIQC). We used gamma regression models to determine the significant correlates of gender diversity among age, puberty, sex-assigned-at-birth, categorical neurodevelopmental diagnoses, and dimensional neurodivergent traits (using the Social Communication Questionnaire and the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Rating Scales). Internalizing and externalizing problems were included as covariates. RESULTS: Neither a categorical diagnosis of autism nor ADHD significantly correlated with current GIQC-derived scores. Instead, higher early-childhood dimensional autistic social-communication traits correlated with higher current overall gender incongruence (as defined by GIQC-14 score). This correlation was potentially moderated by sex-assigned-at-birth: greater early-childhood autistic social-communication traits were associated with higher current overall gender incongruence in assigned-males-at-birth, but not assigned-females-at-birth. For fine-grained gender diversity domains, greater autistic restricted-repetitive behavior traits were associated with greater diversity in gender identity across sexes-assigned-at-birth; greater autistic social-communication traits were associated with lower stereotypical male expression across sexes-assigned-at-birth. CONCLUSIONS: Dimensional autistic traits, rather than ADHD traits or categorical neurodevelopmental diagnoses, were associated with gender diversity domains across neurodivergent and neurotypical children. The association between early-childhood autistic social-communication traits and overall current gender diversity was most evident in assigned-males-at-birth. Nuanced interrelationships between neurodivergence and gender diversity should be better understood to clarify developmental links and to offer tailored support for neurodivergent and gender-diverse populations.

Modeling intra-individual inter-trial EEG response variability in autism.

Autism spectrum disorder (autism) is a prevalent neurodevelopmental condition characterized by early emerging impairments in social behavior and communication. EEG represents a powerful and non-invasive tool for examining functional brain differences in autism. Recent EEG evidence suggests that greater intra-individual trial-to-trial variability across EEG responses in stimulus-related tasks may characterize brain differences in autism. Traditional analysis of EEG data largely focuses on mean trends of the trial-averaged data, where trial-level analysis is rarely performed due to low neural signal to noise ratio. We propose to use nonlinear (shape-invariant) mixed effects (NLME) models to study intra-individual inter-trial EEG response variability using trial-level EEG data. By providing more precise metrics of response variability, this approach could enrich our understanding of neural disparities in autism and potentially aid the identification of objective markers. The proposed multilevel NLME models quantify variability in the signal's interpretable and widely recognized features (e.g., latency and amplitude) while also regularizing estimation based on noisy trial-level data. Even though NLME models have been studied for more than three decades, existing methods cannot scale up to large data sets. We propose computationally feasible estimation and inference methods via the use of a novel minorization-maximization (MM) algorithm. Extensive simulations are conducted to show the efficacy of the proposed procedures. Applications to data from a large national consortium find that children with autism have larger intra-individual inter-trial variability in P1 latency in a visual evoked potential (VEP) task, compared to their neurotypical peers.

Loss of protein tyrosine phosphatase receptor delta PTPRD increases the number of cortical neurons, impairs synaptic function and induces autistic-like behaviors in adult mice.

BACKGROUND: The brain cortex is responsible for many higher-level cognitive functions. Disruptions during cortical development have long-lasting consequences on brain function and are associated with the etiology of brain disorders. We previously found that the protein tyrosine phosphatase receptor delta Ptprd, which is genetically associated with several human neurodevelopmental disorders, is essential to cortical brain development. Loss of Ptprd expression induced an aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRß in neural precursor cells. However, whether these alterations have long-lasting consequences in adulthood remains unknown. RESULTS: Here, we found that in Ptprd+/- or Ptprd-/- mice, the developmental increase of excitatory neurons persists through adulthood, affecting excitatory synaptic function in the medial prefrontal cortex. Likewise, heterozygosity or homozygosity for Ptprd also induced an increase of inhibitory cortical GABAergic neurons and impaired inhibitory synaptic transmission. Lastly, Ptprd+/- or Ptprd-/- mice displayed autistic-like behaviors and no learning and memory impairments or anxiety. CONCLUSIONS: These results indicate that loss of Ptprd has long-lasting effects on cortical neuron number and synaptic function that may aberrantly impact ASD-like behaviors.

The Physiological and Clinical-Behavioral Effects of Heart Rate Variability Biofeedback in Adolescents with Autism: A Pilot Randomized Controlled Trial.

Adolescents with autism present lower levels of cardiac vagal modulation. It was hypothesized that Heart Rate Variability Biofeedback (HRVB) increases cardiac vagal modulation in adolescents with autism, resulting in positive effects on physiological and psychosocial parameters. It was also hypothesized that home-based HRVB training is feasible. In a single-blind, randomized sham-controlled pilot trial, adolescents with autism performed supervised HRVB (n = 24) or sham training (n = 20). Subsequently, half of the adolescents received HRVB training at home, whereas the other subset did not practice. Physiological, cortisol and behavioral data were collected during stress-provoking assessments before and after each training period. Supervised HRVB resulted in a late increase in cardiac vagal modulation in adolescents with autism. Heart rate increased and cortisol decreased significantly immediately after supervised HRVB, but none of these effects remained after follow-up. Following supervised HRVB, no significant change in psychosocial functioning was found. Home-based HRVB was feasible, adolescents reported lower symptoms of stress, but a significant decrease in compliance rate was found. HRVB is feasible and effective in adolescents with autism given the late-emerging increases in cardiac vagal modulation and decrease in stress symptoms. Replicating this study with a larger sample and further exploration of the working mechanisms of HRVB are recommended. ClinicalTrials.gov , NCT04628715.