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Bumetanide has received much interest as a potential pharmacological modulator of the putative imbalance in excitatory/inhibitory (E/I) signaling that is thought to characterize autism spectrum conditions. Yet, currently, no studies of bumetanide efficacy have used an outcome measure that is modeled to depend on E/I balance in the brain. In this manuscript, we present the first causal study of the effect of bumetanide on an objective marker of E/I balance in the brain, binocular rivalry, which we have previously shown to be sensitive to pharmacological manipulation of GABA. Using a within-subjects placebo-control crossover design study, we show that, contrary to expectation, acute administration of bumetanide does not alter binocular rivalry dynamics in neurotypical adult individuals. Neither changes in response times nor response criteria can account for these results. These results raise important questions about the efficacy of acute bumetanide administration for altering E/I balance in the human brain, and highlight the importance of studies using objective markers of the underlying neural processes that drugs hope to target.

An imbalance between excitatory/inhibitory neurotransmission has been posited as a central characteristic of the neurobiology of autism [1], inspired in part by the striking prevalence of seizures among individuals with the disorder [2]. Evidence supporting this hypothesis has specifically implicated the signaling pathway of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), in this putative imbalance: GABA receptor genes have been associated with autism in linkage and copy number variation studies [3-7], fewer GABA receptor subunits have been observed in the post-mortem tissue of autistic individuals [8, 9], and GABAergic signaling is disrupted across heterogeneous mouse models of autism [10]. Yet, empirical evidence supporting this hypothesis in humans is lacking, leaving a gulf between animal and human studies of the condition. Here, we present a direct link between GABA signaling and autistic perceptual symptomatology. We first demonstrate a robust, replicated autistic deficit in binocular rivalry [11], a basic visual function that is thought to rely on the balance of excitation/inhibition in visual cortex [12-15]. Then, using magnetic resonance spectroscopy, we demonstrate a tight linkage between binocular rivalry dynamics in typical participants and both GABA and glutamate levels in the visual cortex. Finally, we show that the link between GABA and binocular rivalry dynamics is completely and specifically absent in autism. These results suggest a disruption in inhibitory signaling in the autistic brain and forge a translational path between animal and human models of the condition.

Individuals with autism are often characterized as 'seeing the trees, but not the forest'-attuned to individual details in the visual world at the expense of the global percept they compose. Here, we tested the extent to which global processing deficits in autism reflect impairments in (i) primary visual processing; or (ii) decision-formation, using an archetypal example of global perception, coherent motion perception. In an event-related functional MRI experiment, 43 intelligence quotient and age-matched male participants (21 with autism, age range 15-27 years) performed a series of coherent motion perception judgements in which the amount of local motion signals available to be integrated into a global percept was varied by controlling stimulus viewing duration (0.2 or 0.6 s) and the proportion of dots moving in the correct direction (coherence: 4%, 15%, 30%, 50%, or 75%). Both typical participants and those with autism evidenced the same basic pattern of accuracy in judging the direction of motion, with performance decreasing with reduced coherence and shorter viewing durations. Critically, these effects were exaggerated in autism: despite equal performance at the long duration, performance was more strongly reduced by shortening viewing duration in autism (P0.015) and decreasing stimulus coherence (P0.008). To assess the neural correlates of these effects we focused on the responses of primary visual cortex and the middle temporal area, critical in the early visual processing of motion signals, as well as a region in the intraparietal sulcus thought to be involved in perceptual decision-making. The behavioural results were mirrored in both primary visual cortex and the middle temporal area, with a greater reduction in response at short, compared with long, viewing durations in autism compared with controls (both P0.018). In contrast, there was no difference between the groups in the intraparietal sulcus (P0.574). These findings suggest that reduced global motion perception in autism is driven by an atypical response early in visual processing and may reflect a fundamental perturbation in neural circuitry.

Autism has traditionally been regarded as a disorder of the social brain. Recent reports of differences in visual perception have challenged this notion, but little evidence for altered visual processing in the autistic brain exists. We have previously observed slower behaviorally reported rates of a basic visual phenomenon, binocular rivalry, in autism [1, 2]. During rivalry, two images-one presented to each eye-vie for awareness, alternating back and forth in perception. This competition is modeled to rely, in part, on the balance of excitation and inhibition in visual cortex [3-8], which may be altered in autism [2, 9-14]. Yet direct neural evidence for this potential marker of excitation/inhibition (E/I) balance in autism is lacking. Here, we report a striking alteration in the neural dynamics of binocular rivalry in individuals with autism. Participants viewed true and simulated frequency-tagged binocular rivalry displays while steady-state visually evoked potentials (SSVEPs) were measured over occipital cortex using electroencephalography (EEG). First, we replicate our prior behavioral findings of slower rivalry and reduced perceptual suppression in individuals with autism compared with controls. Second, we provide direct neural evidence for slower rivalry in autism compared with controls, which strongly predicted individuals' behavioral switch rates. Finally, using neural data alone, we were able to predict autism symptom severity (ADOS) and correctly classify individuals' diagnostic status (autistic versus control; 87% accuracy). These findings clearly implicate atypical visual processing in the neurobiology of autism. Down the road, this paradigm may serve as a non-verbal marker of autism for developmental and cross-species research.

Enhanced perception of detail has long been regarded a hallmark of autism spectrum conditions (ASC), but its origins are unknown. Normal sensitivity on all fundamental perceptual measures—visual acuity, contrast discrimination, and flicker detection—is strongly established in the literature. If individuals with ASC do not have superior low-level vision, how is perception of detail enhanced? We argue that this apparent paradox can be resolved by considering visual attention, which is known to enhance basic visual sensitivity, resulting in greater acuity and lower contrast thresholds. Here, we demonstrate that the focus of attention and concomitant enhancement of perception are sharper in human individuals with ASC than in matched controls. Using a simple visual acuity task embedded in a standard cueing paradigm, we mapped the spatial and temporal gradients of attentional enhancement by varying the distance and onset time of visual targets relative to an exogenous cue, which obligatorily captures attention. Individuals with ASC demonstrated a greater fall-off in performance with distance from the cue than controls, indicating a sharper spatial gradient of attention. Further, this sharpness was highly correlated with the severity of autistic symptoms in ASC, as well as autistic traits across both ASC and control groups. These findings establish the presence of a form of “tunnel vision” in ASC, with far-reaching implications for our understanding of the social and neurobiological aspects of autism.

Enhanced spatial processing of local visual details has been reported in individuals with autism spectrum conditions (ASC), and crowding is postulated to be a mechanism that may produce this ability. However, evidence for atypical crowding in ASC is mixed, with some studies reporting a complete lack of crowding in autism and others reporting a typical magnitude of crowding between individuals with and without ASC. Here, we aim to disambiguate these conflicting results by testing both the magnitude and the spatial extent of crowding in individuals with ASC (N = 25) and age- and IQ-matched controls (N = 23) during an orientation discrimination task. We find a strong crowding effect in individuals with and without ASC, which falls off as the distance between target and flanker is increased. Both the magnitude and the spatial range of this effect were comparable between individuals with and without ASC. We also find typical (uncrowded) orientation discrimination thresholds in individuals with ASC. These findings suggest that the spatial extent of crowding is unremarkable in ASC, and is therefore unlikely to account for the visual symptoms reported in individuals with the diagnosis.

An imbalance between cortical excitation and inhibition is a central component of many models of autistic neurobiology. We tested a potential behavioral footprint of this proposed imbalance using binocular rivalry, a visual phenomenon in which perceptual experience is thought to mirror the push and pull of excitatory and inhibitory cortical dynamics. In binocular rivalry, two monocularly presented images compete, leading to a percept that alternates between them. In a series of trials, we presented separate images of objects (e.g., a baseball and a broccoli) to each eye using a mirror stereoscope and asked human participants with autism and matched control subjects to continuously report which object they perceived, or whether they perceived a mixed percept. Individuals with autism demonstrated a slower rate of binocular rivalry alternations than matched control subjects, with longer durations of mixed percepts and an increased likelihood to revert to the previously perceived object when exiting a mixed percept. Critically, each of these findings was highly predictive of clinical measures of autistic symptomatology. Control “playback” experiments demonstrated that differences in neither response latencies nor response criteria could account for the atypical dynamics of binocular rivalry we observed in autistic spectrum conditions. Overall, these results may provide an index of atypical cortical dynamics that may underlie both the social and nonsocial symptoms of autism.

Vision in Autism Spectrum Conditions (ASC) is characterized by enhanced perception of local elements, but impaired perception of global percepts. Deficits in coherent motion perception seem to support this characterization, but the roots and robustness of such deficits remain unclear. We aimed to investigate the dynamics of the perceptual decision-making network known to support coherent motion perception. In a series of forced-choice coherent motion perception tests, we parametrically varied a single stimulus dimension, viewing duration, to test whether the rate at which evidence is accumulated towards a global decision is atypical in ASC. 40 adult participants (20 ASC) performed a classic motion discrimination task, manually indicating the global direction of motion in a random-dot kinematogram across a range of coherence levels (2-75%) and stimulus-viewing durations (200-1500 ms). We report a deficit in global motion perception at short viewing durations in ASC. Critically, however, we found that increasing the amount of time over which motion signals could be integrated reduced the magnitude of the deficit, such that at the longest duration there was no difference between the ASC and control groups. Further, the deficit in motion integration at the shortest duration was significantly associated with the severity of autistic symptoms in our clinical population, and was independent from measures of intelligence. These results point to atypical integration of motion signals during the construction of a global percept in ASC. Based on the neural correlates of decision-making in global motion perception our findings suggest the global motion deficit observed in ASC could reflect a slower or more variable response from the primary motion area of the brain or longer accumulation of evidence towards a decision-bound in parietal areas.