Aging-Related Differences in Structural and Functional Interhemispheric Connectivity.

There is substantial evidence of age-related declines in anatomical connectivity during adulthood, with associated alterations in functional connectivity. But the relation of those functional alterations to the structural reductions is unclear. The complexities of both the structural and the functional connectomes make it difficult to determine such relationships. We pursue this question with methods, based on animal research, that specifically target the interhemispheric connections between the visual cortices. We collect t1- and diffusion-weighted imaging data from which we assess the integrity of the white matter interconnecting the bilateral visual cortices. Functional connectivity between the visual cortices is measured with electroencephalography during the presentation of drifting sinusoidal gratings that agree or conflict across hemifields. Our results show age-related reductions in the integrity of the white matter interconnecting the visual cortices, and age-related increases in the difference in functional interhemispheric lagged coherence between agreeing versus disagreeing visual stimuli. We show that integrity of the white matter in the splenium of the corpus callosum predicts the differences in lagged coherence for the agreeing versus disagreeing stimuli; and that this relationship is mediated by age. These results give new insight into the causal relationship between age and functional connectivity.

Distraction "Hangover": Characterization of the Delayed Return to Baseline Driving Risk After Distracting Behaviors.

OBJECTIVE: We measured how long distraction by a smartphone affects simulated driving behaviors after the tasks are completed (i.e., the distraction hangover). BACKGROUND: Most drivers know that smartphones distract. Trying to limit distraction, drivers can use hands-free devices, where they only briefly glance at the smartphone. However, the cognitive cost of switching tasks from driving to communicating and back to driving adds an underappreciated, potentially long period to the total distraction time. METHOD: Ninety-seven 21- to 78-year-old individuals who self-identified as active drivers and smartphone users engaged in a simulated driving scenario that included smartphone distractions. Peripheral-cue and car-following tasks were used to assess driving behavior, along with synchronized eye tracking. RESULTS: The participants' lateral speed was larger than baseline for 15 s after the end of a voice distraction and for up to 25 s after a text distraction. Correct identification of peripheral cues dropped about 5% per decade of age, and participants from the 71+ age group missed seeing about 50% of peripheral cues within 4 s of the distraction. During distraction, coherence with the lead car in a following task dropped from 0.54 to 0.045, and seven participants rear-ended the lead car. Breadth of scanning contracted by 50% after distraction. CONCLUSION: Simulated driving performance drops dramatically after smartphone distraction for all ages and for both voice and texting. APPLICATION: Public education should include the dangers of any smartphone use during driving, including hands-free.

EEG microstates suggest atypical resting-state network activity in high-functioning children and adolescents with autism spectrum development.

EEG microstates represent transient electrocortical events that reflect synchronized activities of large-scale networks, which allows investigations of brain dynamics with sub-second resolution. We recorded resting EEG from 38 children and adolescents with Autism Spectrum Development (ASD) and 48 age, IQ, sex, and handedness-matched typically developing (TD) participants. The EEG was segmented into a time series of microstates using modified k-means clustering of scalp voltage topographies. The frequency and global explained variance (GEV) of a specific microstate (type C) were significantly lower in the ASD group compared to the TD group while the duration of the same microstate was correlated with the presence of ASD-related behaviors. The duration of this microstate was also positively correlated with participant age in the TD group, but not in the ASD group. Further, the frequency and duration of the microstate were significantly correlated with the overall alpha power only in the TD group. The signal strength and GEV for another microstate (type G) was greater in the ASD group than the TD group, and the associated topographical pattern differed between groups with greater variations in the ASD group. While more work is needed to clarify the underlying neural sources, the existing literature supports associations between the two microstates and the default mode and salience networks. The current study suggests specific alterations of temporal dynamics of the resting cortical network activities as well as their developmental trajectories and relationships to alpha power, which has been proposed to reflect reduced neural inhibition in ASD.

A New Foreperiod Effect on Intertrial Phase Coherence. Part I: Existence and Behavioral Relevance.

This letter makes scientific and methodological contributions. Scientifically, it demonstrates a new and behaviorally relevant effect of temporal expectation on the phase coherence of the electroencephalogram (EEG). Methodologically, it introduces novel methods to characterize EEG recordings at the single-trial level. Expecting events in time can lead to more efficient behavior. A remarkable finding in the study of temporal expectation is the foreperiod effect on reaction time, that is, the influence on reaction time of the delay between a warning signal and a succeeding imperative stimulus to which subjects are instructed to respond as quickly as possible. Here we study a new foreperiod effect in an audiovisual attention-shifting oddball task in which attention-shift cues directed the attention of subjects to impendent deviant stimuli of a given modality and therefore acted as warning signals for these deviants. Standard stimuli, to which subjects did not respond, were interspersed between warning signals and deviants. We hypothesized that foreperiod durations modulated intertrial phase coherence (ITPC, the degree of phase alignment across multiple trials) evoked by behaviorally irrelevant standards and that these modulations are behaviorally meaningful. Using averaged data, we first observed that ITPC evoked by standards closer to the warning signal was significantly different from that evoked by standards further away from it, establishing a new foreperiod effect on ITPC evoked by standards. We call this effect the standard foreperiod (SFP) effect on ITPC. We reasoned that if the SFP influences ITPC evoked by standards, it should be possible to decode the former from the latter on a trial-by-trial basis. We were able to do so showing that this effect can be observed in single trials. We demonstrated the behavioral relevance of the SFP effect on ITPC by showing significant correlations between its strength and subjects' behavioral performance.

Functional connectivity for an "island of sparing" in autism spectrum disorder: an fMRI study of visual search.

Although autism is usually characterized with respect to sociocommunicative impairments, visual search is known as a domain of relative performance strength in this disorder. This study used functional MRI during visual search in children with autism spectrum disorder (n = 19; mean age = 13;10) and matched typically developing children (n = 19; mean age = 14;0). We selected regions of interest within two attentional networks known to play a crucial role in visual search processes, such as goal-directed selective attention, filtering of irrelevant distractors, and detection of behaviorally-relevant information, and examined activation and connectivity within and between these attentional networks. Additionally, based on prior research suggesting links between visual search abilities and autism symptomatology, we tested for correlations between sociocommunicative impairments and behavioral and neural indices of search. Contrary to many previous functional connectivity magnetic resonance imaging studies of autism that reported functional underconnectivity for task domains of weakness, we found atypically increased connectivity within and between attentional networks in autism. Additionally, we found increased functional connectivity for occipital regions, both locally and for long-distance connections with frontal regions. Both behavioral and neural indices of search were correlated with sociocommunicative impairment in children with autism. This association suggests that strengths in nonsocial visuospatial processing may be related to the development of core autistic sociocommunicative impairments.

Callosal fiber length and interhemispheric connectivity in adults with autism: brain overgrowth and underconnectivity.

Typical adults show an inverse relation between callosal fiber length and degree of interhemispheric connectivity. This has been hypothesized to be a consequence of the influence of conduction delays and cellular costs during development on axonal pruning, both of which increase with fiber length. Autism spectrum disorder (ASD) provides a test of this hypothesis: Children with ASD are known to have enlarged brains; thus, adults with ASD should show reductions in interhemispheric connectivity proportional to their degree of brain overgrowth during development. This prediction was tested by assessing the relation between both the size and structure of the corpus callosum and callosal fiber length, adjusting for intracranial volume, which is thought to reflect maximum brain size achieved during development. Using tractography to estimate the length of callosal fibers emanating from all areas of cortex, and through which region of the corpus callosum they pass, we show that adults with ASD show an inverse relation between callosal fiber length, adjusted for intracranial volume, and callosum size, and a positive relation between adjusted callosal fiber length and radial diffusivity. The results provide support for the hypothesized impact of fiber length during development.

Spatial attention in children with perinatal stroke.

Spatial neglect is a common feature of right hemisphere damage in adults, but less is known about spatial inattention following early brain damage. We used a Posner-based cueing task to examine hemispatial neglect and aspects of attention in children with perinatal stroke in either left (LH) or right hemisphere (RH) and controls. A visual perception task assessed the speed of visual perception. A spatial attention cueing task (the E-task) measured the ability to discriminate the direction of a target stimulus ("E"), when presented on the left or right side of the screen. This task provided indices of performance for attention orienting, disengagement and reorienting. Children with LH lesions had slowed visual perception compared to controls. Children with RH lesions did not demonstrate similar deficits. On the E-task, groups with both LH and RH lesions demonstrated lower accuracy on both left and right sides compared to controls. Children with LH lesions also showed impaired attention orienting and disengagement on left and right sides compared to controls, while children with RH lesions were most impaired in orienting and disengagement on their contralesional side. Children with LH lesions demonstrated more extensive attentional deficits than children with RH lesions. These results suggest that development of spatial attention may require different neural networks than maintenance of attention.

Attentional networks in children and adolescents with autism spectrum disorder.

BACKGROUND: Individuals diagnosed with autism spectrum disorder (ASD) exhibit lifelong abnormalities in the adaptive allocation of visual attention. The ubiquitous nature of attentional impairments in ASD has led some authors to hypothesize that atypical attentional modulation may be a factor in the development of higher-level sociocommunicative deficits. METHOD: Participants were 20 children with ASD and 20 age- and Nonverbal IQ-matched typically developing (TD) children. We used the Attention Network Test (ANT) to investigate the efficiency and independence of three discrete attentional networks: alerting, orienting, and executive control. Additionally, we sought to investigate the relationship between each attentional network and measures of sociocommunicative symptom severity in children with ASD. RESULTS: Results indicate that the orienting, but not alerting or executive control, networks may be impaired in children with ASD. In contrast to TD children, correlational analyses suggest that the alerting and executive control networks may not function as independently in children with ASD. Additionally, an association was found between the alerting network and social impairment and between the executive control network and IQ in children with ASD. CONCLUSIONS: The results provide further evidence of an impairment in the visuospatial orienting network in ASD and suggest that there may be greater interdependence of alerting and executive control networks in ASD. Furthermore, decreased ability to efficiently modulate levels of alertness was related to increased sociocommunicative deficits, suggesting that domain-general attentional function may be associated with ASD symptomatology.

Neural correlates of verbal and nonverbal semantic integration in children with autism spectrum disorders.

BACKGROUND: Autism is a pervasive developmental disorder characterized by deficits in social-emotional, social-communicative, and language skills. Behavioral and neuroimaging studies have found that children with autism spectrum disorders (ASD) evidence abnormalities in semantic processing, with particular difficulties in verbal comprehension. However, it is not known whether these semantic deficits are confined to the verbal domain or represent a more general problem with semantic processing. The focus of the current study was to investigate verbal and meaningful nonverbal semantic processing in high-functioning children with autism (mean age = 5.8 years) using event-related potentials (ERPs). METHOD: ERPs were recorded while children attended to semantically matching and mismatching picture-word and picture-environmental sound pairs. RESULTS: ERPs of typically developing children exhibited evidence of semantic incongruency detection in both the word and environmental sound conditions, as indexed by elicitation of an N400 effect. In contrast, children with ASD showed an N400 effect in the environmental sound condition but not in the word condition. CONCLUSIONS: These results provide evidence for a deficiency in the automatic activation of semantic representations in children with ASD, and suggest that this deficit is somewhat more selective to, or more severe in, the verbal than the nonverbal domain.

The relation between connection length and degree of connectivity in young adults: a DTI analysis.

Using diffusion tensor imaging and tractography to detail the patterns of interhemispheric connectivity and to determine the length of the connections, and formulae based on histological results to estimate degree of connectivity, we show that connection length is negatively correlated with degree of connectivity in the normal adult brain. The degree of interhemispheric connectivity--the ratio of interhemispheric connections to total corticocortical projection neurons--was estimated for each of 5 subregions of the corpus callosum in 22 normal males between 20 and 45 years of age (mean 31.68; standard deviation 8.75), and the average length of the longest tracts passing through each point of each subregion was calculated. Regression analyses were used to assess the relation between connection length and the degree of connectivity. Connection length was negatively correlated with degree of connectivity in all 5 subregions, and the regression was significant in 4 of the 5, with an average r(2) of 0.255. This is contrasted with previous analyses of the relation between brain size and connectivity, and connection length is shown to be a superior predictor. The results support the hypothesis that cortical networks are optimized to reduce conduction delays and cellular costs.

Brief Report: A Gaming Approach to the Assessment of Attention Networks in Autism Spectrum Disorder and Typical Development.

Attentional impairments are among the earliest identifiable features of autism spectrum disorders (ASDs). Three attention networks have been extensively studied using the attention network test (ANT), but this long and repetitive task may pose challenges for individuals with ASDs. The AttentionTrip was developed as a more engaging measure of attention network efficiency. In 20 adults with ASDs and 20 typically developing controls, both tasks produced typical network scores (all p < .003, all Cohen's d > 0.78). Reaction time was less variable in the AttentionTrip than the ANT, possibly reflecting improved task engagement. Although the AttentionTrip elicited more consistent responses throughout an experimental session, anomalously low split-half reliability for its executive control network suggests that some changes may be needed.

Atypical Relationships Between Spontaneous EEG and fMRI Activity in Autism.

Autism spectrum disorders (ASDs) have been linked to atypical communication among distributed brain networks. However, despite decades of research, the exact nature of these differences between typically developing (TD) individuals and those with ASDs remains unclear. ASDs have been widely studied using resting-state neuroimaging methods, including both functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). However, little is known about how fMRI and EEG measures of spontaneous brain activity are related in ASDs. In the present study, two cohorts of children and adolescents underwent resting-state EEG (n = 38 per group) or fMRI (n = 66 ASD, 57 TD), with a subset of individuals in both the EEG and fMRI cohorts (n = 17 per group). In the EEG cohort, parieto-occipital EEG alpha power was found to be reduced in ASDs. In the fMRI cohort, blood oxygen level-dependent (BOLD) power was regionally increased in right temporal regions and there was widespread overconnectivity between the thalamus and cortical regions in the ASD group relative to the TD group. Finally, multimodal analyses indicated that while TD children showed consistently positive relationships between EEG alpha power and regional BOLD power, these associations were weak or negative in ASDs. These findings suggest atypical links between alpha rhythms and regional BOLD activity in ASDs, possibly implicating neural substrates and processes that coordinate thalamocortical regulation of the alpha rhythm.

Brief Report: Cross-Modal Capture: Preliminary Evidence of Inefficient Filtering in Children with Autism Spectrum Disorder.

This study investigates how task-irrelevant auditory information is processed in children with autism spectrum disorder (ASD). Eighteen children with ASD and 19 age- and IQ-matched typically developing (TD) children were presented with semantically-congruent and incongruent picture-sound pairs, and in separate tasks were instructed to attend to only visual or both audio-visual sensory channels. Preliminary results showed that when required to attend to both modalities, both groups were equally slowed for semantically-incongruent compared to congruent pairs. However, when asked to attend to only visual information, children with ASD were disproportionally slowed by incongruent auditory information, suggesting that they may have more difficulty filtering task-irrelevant cross-modal information. Correlational analyses showed that this inefficient cross-modal attentional filtering was related to greater sociocommunicative impairment.

Dopaminergic hypo-activity and reduced theta-band power in autism spectrum disorder: A resting-state EEG study.

BACKGROUND: Prior studies using a variety of methodologies have reported inconsistent dopamine (DA) findings in individuals with autism spectrum disorder (ASD), ranging from dopaminergic hypo- to hyper-activity. Theta-band power derived from scalp-recorded electroencephalography (EEG), which may be associated with dopamine levels in frontal cortex, has also been shown to be atypical in ASD. The present study examined spontaneous eye-blink rate (EBR), an indirect, non-invasive measure of central dopaminergic activity, and theta power in children with ASD to determine: 1) whether ASD may be associated with atypical DA levels, and 2) whether dopaminergic dysfunction may be associated with aberrant theta-band activation. METHOD: Participants included thirty-two children with ASD and thirty-two age-, IQ-, and sex-matched typically developing (TD) children. Electroencephalography and eye-tracking data were acquired while participants completed an eyes-open resting-state session. Blinks were counted and EBR was determined by dividing blink frequency by session duration and theta power (4-7.5 Hz) was extracted from midline leads. RESULTS: Eye-blink rate and theta-band activity were significantly reduced in children with ASD as compared to their TD peers. For all participants, greater midline theta power was associated with increased EBR (related to higher DA levels). CONCLUSIONS: These results suggest that ASD may be associated with dopaminergic hypo-activity, and that this may contribute to atypical theta-band power. Lastly, EBR may be a useful tool to non-invasively index dopamine levels in ASD and could potentially have many clinical applications, including selecting treatment options and monitoring treatment response.

A developmental ERP study of verbal and non-verbal semantic processing.

To clarify how different the processing of verbal information is from the processing of meaningful non-verbal information, the present study characterized the developmental changes in neural responses to words and environmental sounds from pre-adolescence (7-9 years) through adolescence (12-14 years) to adulthood (18-25 years). Children and adults' behavioral and electrophysiological responses (the N400 effect of event-related potentials) were compared during the processing of words and environmental sounds presented in semantically matching and mismatching picture contexts. Behavioral accuracy of picture-sound matching improved until adulthood, while reaction time measures leveled out by age 12. No major electrophysiological changes in the N400 effect were observed between pre-adolescence and adolescence. When compared to adults, children demonstrated significant maturational changes including longer latencies and larger amplitudes of the N400 effect. Interestingly, these developmental differences were driven by stimulus type: the Environmental Sound N400 effect decreased in latency from adolescence to adulthood, while no age effects were observed in response to Words. Thus, while the semantic processing of single words is well established by 7 years of age, the processing of environmental sounds continues to improve throughout development.

A novel approach to training attention and gaze in ASD: A feasibility and efficacy pilot study.

In addition to the social, communicative and behavioral symptoms that define the disorder, individuals with ASD have difficulty re-orienting attention quickly and accurately. Similarly, fast re-orienting saccadic eye movements are also inaccurate and more variable in both endpoint and timing. Atypical gaze and attention are among the earliest symptoms observed in ASD. Disruption of these foundation skills critically affects the development of higher level cognitive and social behavior. We propose that interventions aimed at these early deficits that support social and cognitive skills will be broadly effective. We conducted a pilot clinical trial designed to demonstrate the feasibility and preliminary efficacy of using gaze-contingent video games for low-cost in-home training of attention and eye movement. Eight adolescents with ASD participated in an 8-week training, with pre-, mid- and post-testing of eye movement and attention control. Six of the eight adolescents completed the 8 weeks of training and all six showed improvement in attention (orienting, disengagement) and eye movement control or both. All game systems remained intact for the duration of training and all participants could use the system independently. We delivered a robust, low-cost, gaze-contingent game system for home use that, in our pilot training sample, improved the attention orienting and eye movement performance of adolescent participants in 8 weeks of training. We are currently conducting a clinical trial to replicate these results and to examine what, if any, aspects of training transfer to more real-world tasks. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 546-554, 2018.

Multimodal approaches to functional connectivity in autism spectrum disorders: An integrative perspective.

Atypical functional connectivity has been implicated in autism spectrum disorders (ASDs). However, the literature to date has been largely inconsistent, with mixed and conflicting reports of hypo- and hyper-connectivity. These discrepancies are partly due to differences between various neuroimaging modalities. Functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and magnetoencephalography (MEG) measure distinct indices of functional connectivity (e.g., blood-oxygenation level-dependent [BOLD] signal vs. electrical activity). Furthermore, each method has unique benefits and disadvantages with respect to spatial and temporal resolution, vulnerability to specific artifacts, and practical implementation. Thus far, functional connectivity research on ASDs has remained almost exclusively unimodal; therefore, interpreting findings across modalities remains a challenge. Multimodal integration of fMRI, EEG, and MEG data is critical in resolving discrepancies in the literature, and working toward a unifying framework for interpreting past and future findings. This review aims to provide a theoretical foundation for future multimodal research on ASDs. First, we will discuss the merits and shortcomings of several popular theories in ASD functional connectivity research, using examples from the literature to date. Next, the neurophysiological relationships between imaging modalities, including their relationship with invasive neural recordings, will be reviewed. Finally, methodological approaches to multimodal data integration will be presented, and their future application to ASDs will be discussed. Analyses relating transient patterns of neural activity ("states") are particularly promising. This strategy provides a comparable measure across modalities, captures complex spatiotemporal patterns, and is a natural extension of recent dynamic fMRI research in ASDs. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 456-473, 2018.

Electroencephalographic brain dynamics following manually responded visual targets.

Scalp-recorded electroencephalographic (EEG) signals produced by partial synchronization of cortical field activity mix locally synchronous electrical activities of many cortical areas. Analysis of event-related EEG signals typically assumes that poststimulus potentials emerge out of a flat baseline. Signals associated with a particular type of cognitive event are then assessed by averaging data from each scalp channel across trials, producing averaged event-related potentials (ERPs). ERP averaging, however, filters out much of the information about cortical dynamics available in the unaveraged data trials. Here, we studied the dynamics of cortical electrical activity while subjects detected and manually responded to visual targets, viewing signals retained in ERP averages not as responses of an otherwise silent system but as resulting from event-related alterations in ongoing EEG processes. We applied infomax independent component analysis to parse the dynamics of the unaveraged 31-channel EEG signals into maximally independent processes, then clustered the resulting processes across subjects by similarities in their scalp maps and activity power spectra, identifying nine classes of EEG processes with distinct spatial distributions and event-related dynamics. Coupled two-cycle postmotor theta bursts followed button presses in frontal midline and somatomotor clusters, while the broad postmotor "P300" positivity summed distinct contributions from several classes of frontal, parietal, and occipital processes. The observed event-related changes in local field activities, within and between cortical areas, may serve to modulate the strength of spike-based communication between cortical areas to update attention, expectancy, memory, and motor preparation during and after target recognition and speeded responding.

Autism, Attention, and Alpha Oscillations: An Electrophysiological Study of Attentional Capture.

BACKGROUND: Autism spectrum disorder (ASD) is associated with deficits in adaptively orienting attention to behaviorally-relevant information. Neural oscillatory activity plays a key role in brain function and provides a high-resolution temporal marker of attention dynamics. Alpha band (8-12 Hz) activity is associated with both selecting task-relevant stimuli and filtering task-irrelevant information. METHODS: The present study used electroencephalography (EEG) to examine alpha-band oscillatory activity associated with attentional capture in nineteen children with ASD and twenty-one age- and IQ-matched typically developing (TD) children. Participants completed a rapid serial visual presentation paradigm designed to investigate responses to behaviorally-relevant targets and contingent attention capture by task-irrelevant distractors, which either did or did not share a behaviorally-relevant feature. Participants also completed six minutes of eyes-open resting EEG. RESULTS: In contrast to their TD peers, children with ASD did not evidence posterior alpha desynchronization to behaviorally-relevant targets. Additionally, reduced target-related desynchronization and poorer target detection were associated with increased ASD symptomatology. TD children also showed behavioral and electrophysiological evidence of contingent attention capture, whereas children with ASD showed no behavioral facilitation or alpha desynchronization to distractors that shared a task-relevant feature. Lastly, children with ASD had significantly decreased resting alpha power, and for all participants increased resting alpha levels were associated with greater task-related alpha desynchronization. CONCLUSIONS: These results suggest that in ASD under-responsivity and impairments in orienting to salient events within their environment are reflected by atypical EEG oscillatory neurodynamics, which may signify atypical arousal levels and/or an excitatory/inhibitory imbalance.

Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial.

OBJECTIVE: No drug is yet approved to treat the core symptoms of autism spectrum disorder (ASD). Low-dose suramin was effective in the maternal immune activation and Fragile X mouse models of ASD. The Suramin Autism Treatment-1 (SAT-1) trial was a double-blind, placebo-controlled, translational pilot study to examine the safety and activity of low-dose suramin in children with ASD. METHODS: Ten male subjects with ASD, ages 5-14 years, were matched by age, IQ, and autism severity into five pairs, then randomized to receive a single, intravenous infusion of suramin (20 mg/kg) or saline. The primary outcomes were ADOS-2 comparison scores and Expressive One-Word Picture Vocabulary Test (EOWPVT). Secondary outcomes were the aberrant behavior checklist, autism treatment evaluation checklist, repetitive behavior questionnaire, and clinical global impression questionnaire. RESULTS: Blood levels of suramin were 12 ± 1.5 µmol/L (mean ± SD) at 2 days and 1.5 ± 0.5 µmol/L after 6 weeks. The terminal half-life was 14.7 ± 0.7 days. A self-limited, asymptomatic rash was seen, but there were no serious adverse events. ADOS-2 comparison scores improved by -1.6 ± 0.55 points (n = 5; 95% CI = -2.3 to -0.9; Cohen's d = 2.9; P = 0.0028) in the suramin group and did not change in the placebo group. EOWPVT scores did not change. Secondary outcomes also showed improvements in language, social interaction, and decreased restricted or repetitive behaviors. INTERPRETATION: The safety and activity of low-dose suramin showed promise as a novel approach to treatment of ASD in this small study.