Rhythmic attentional sampling in autism.

Individuals diagnosed with autism often display alterations in visual spatial attention toward visual stimuli, but the underlying cause of these differences remains unclear. Recent evidence has demonstrated that covert spatial attention, rather than remaining constant at a cued location, samples stimuli rhythmically at a frequency of 4-8 Hz (theta). Here we tested whether rhythmic sampling of attention is altered in autism. Participants were asked to monitor three locations to detect a brief target presented 300-1200 ms after a spatial cue. Visual attention was oriented to the cue and modified visual processing at the cued location, consistent with previous studies. We measured detection performance at different cue-target intervals when the target occurred at the cued location. Significant oscillations in detection performance were identified using both a traditional time-shuffled approach and a new autoregressive surrogate method developed by Brookshire in 2022. We found that attention enhances behavioral performance rhythmically at the same frequency in both autism and control group at the cued location. However, rhythmic temporal structure was not observed in a subgroup of autistic individuals with co-occurring attention-deficit/hyperactivity disorder (ADHD). Our results imply that intrinsic brain rhythms which organize neural activity into alternating attentional states is functional in autistic individuals, but may be altered in autistic participants who have a concurrent ADHD diagnosis.

Cortical Surface Area Relates to Distinct Computational Properties in Human Visual Perception.

Understanding the relationship between cortical structure and function is essential for elucidating the neural basis of human behavior. However, the impact of cortical structural features on the computational properties of neural circuits remains poorly understood. In this study, we demonstrate that a simple structural feature - cortical surface area (SA) - relates to specific computational properties underlying human visual perception. By combining psychophysical, neuroimaging, and computational modeling approaches, we show that differences in SA in the parietal and frontal cortices are associated with distinct patterns of behavior in a motion perception task. These behavioral differences can be accounted for by specific parameters of a divisive normalization model, suggesting that SA in these regions contributes uniquely to the spatial organization of cortical circuitry. Our findings provide novel evidence linking cortical structure to distinct computational properties and offer a framework for understanding how cortical architecture can impact human behavior.

Late fMRI Response Components Are Altered in Autism Spectrum Disorder.

Disrupted cortical neural inhibition has been hypothesized to be a primary contributor to the pathophysiology of autism spectrum disorder (ASD). This hypothesis predicts that ASD will be associated with an increase in neural responses. We tested this prediction by comparing fMRI response magnitudes to simultaneous visual, auditory, and motor stimulation in ASD and neurotypical (NT) individuals. No increases in the initial transient response in any brain region were observed in ASD, suggesting that there is no increase in overall cortical neural excitability. Most notably, there were widespread fMRI magnitude increases in the ASD response following stimulation offset, approximately 6-8 s after the termination of sensory and motor stimulation. In some regions, the higher fMRI offset response in ASD could be attributed to a lack of an "undershoot"-an often observed feature of fMRI responses believed to reflect inhibitory processing. Offset response magnitude was associated with reaction times (RT) in the NT group and may explain an overall reduced RT in the ASD group. Overall, our results suggest that increases in neural responsiveness are present in ASD but are confined to specific components of the neural response, are particularly strong following stimulation offset, and are linked to differences in RT.

Weaker neural suppression in autism.

Abnormal sensory processing has been observed in autism, including superior visual motion discrimination, but the neural basis for these sensory changes remains unknown. Leveraging well-characterized suppressive neural circuits in the visual system, we used behavioral and fMRI tasks to demonstrate a significant reduction in neural suppression in young adults with autism spectrum disorder (ASD) compared to neurotypical controls. MR spectroscopy measurements revealed no group differences in neurotransmitter signals. We show how a computational model that incorporates divisive normalization, as well as narrower top-down gain (that could result, for example, from a narrower window of attention), can explain our observations and divergent previous findings. Thus, weaker neural suppression is reflected in visual task performance and fMRI measures in ASD, and may be attributable to differences in top-down processing.

Concentrations of Cortical GABA and Glutamate in Young Adults With Autism Spectrum Disorder.

The balance of excitation and inhibition in neural circuits is hypothesized to be increased in autism spectrum disorder, possibly mediated by altered signaling of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), yet empirical evidence in humans is inconsistent. We used edited magnetic resonance spectroscopy (MRS) to quantify signals associated with both GABA and the excitatory neurotransmitter glutamate in multiple regions of the sensory and sensorimotor cortex, including primary visual, auditory, and motor areas in adult individuals with autism and in neurotypical controls. Despite the strong a priori hypothesis of reduced GABA in autism spectrum disorder, we found no group differences in neurometabolite concentrations in any of the examined regions and no correlations of MRS measure with psychophysical visual sensitivity or autism symptomatology. We demonstrate high data quality that is comparable across groups, with a relatively large sample of well-characterized participants, and use Bayesian statistics to corroborate the lack of any group differences. We conclude that levels of GABA and Glx (glutamate, glutamine, and glutathione) in the sensory and sensorimotor cortex, as measured with MRS at 3T, are comparable in adults with autism and neurotypical individuals. Autism Res 2020, 13: 1111-1129. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: γ-Aminobutyric acid (GABA) and glutamate are the main inhibitory and excitatory neurotransmitters in the human brain, respectively, and their balanced interaction is necessary for neural function. Previous research suggests that the GABA and glutamate systems might be altered in autism. In this study, we used magnetic resonance spectroscopy to measure concentrations of these neurotransmitters in the sensory areas in the brains of young adults with autism. In contradiction to the common hypothesis of reduced GABA in autism, we demonstrate that concentrations of both GABA and glutamate, in all the brain regions examined, are comparable in individuals with autism and in neurotypical adults. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Comparison of Multivendor Single-Voxel MR Spectroscopy Data Acquired in Healthy Brain at 26 Sites.

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted Pboot). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N-acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol (Pboot > .90), N-acetylaspartate and N-acetylaspartylglutamate (Pboot = .13), or glutamate and glutamine (Pboot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (Pboot = .08), aspartate (Pboot > .90), glutathione (Pboot > .90), or lactate (Pboot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article.

Response Dissociation in Hierarchical Cortical Circuits: a Unique Feature of Autism Spectrum Disorder.

A prominent hypothesis regarding the pathophysiology of autism is that an increase in the balance between neural excitation and inhibition results in an increase in neural responses. However, previous reports of population-level response magnitude in individuals with autism have been inconsistent. Critically, network interactions have not been considered in previous neuroimaging studies of excitation and inhibition imbalance in autism. In particular, a defining characteristic of cortical organization is its hierarchical and interactive structure; sensory and cognitive systems are comprised of networks where later stages inherit and build upon the processing of earlier input stages, and also influence and shape earlier stages by top-down modulation. Here we used the well established connections of the human visual system to examine response magnitudes in a higher-order motion processing region [middle temporal area (MT+)] and its primary input region (V1). Simple visual stimuli were presented to adult individuals with autism spectrum disorders (ASD; n = 24, mean age 23 years, 8 females) and neurotypical controls (n = 24, mean age 22, 8 females) during fMRI scanning. We discovered a strong dissociation of fMRI response magnitude between region MT+ and V1 in individuals with ASD: individuals with high MT+ responses had attenuated V1 responses. The magnitude of MT+ amplification and of V1 attenuation was associated with autism severity, appeared to result from amplified suppressive feedback from MT+ to V1, and was not present in neurotypical controls. Our results reveal the potential role of altered hierarchical network interactions in the pathophysiology of ASD.SIGNIFICANCE STATEMENT An imbalance between neural excitation and inhibition, resulting in increased neural responses, has been suggested as a pathophysiological pathway to autism, but direct evidence from humans is lacking. In the current study we consider the role of interactions between stages of sensory processing when testing increased neural responses in individuals with autism. We used the well known hierarchical structure of the visual motion pathway to demonstrate dissociation in the fMRI response magnitude between adjacent stages of processing in autism: responses are attenuated in a primary visual area but amplified in a subsequent higher-order area. This response dissociation appears to rely on enhanced suppressive feedback between regions and reveals a previously unknown cortical network alteration in autism.

The time course of different surround suppression mechanisms.

What we see depends on the spatial context in which it appears. Previous work has linked the suppression of perceived contrast by surrounding stimuli to reduced neural responses in early visual cortex. This surround suppression depends on at least two separable neural mechanisms, "low-level" and "higher level," which can be differentiated by their response characteristics. We used electroencephalography to demonstrate for the first time that human occipital neural responses show evidence of these two suppression mechanisms. Eighteen adults (10 women, 8 men) each participated in three experimental sessions, in which they viewed visual stimuli through a mirror stereoscope. The first session was used to identify the C1 component, while the second and third comprised the main experiment. Event-related potentials were measured in response to center gratings either with no surround or with surrounding gratings oriented parallel or orthogonal, and presented in either the same eye (monoptic) or the opposite eye (dichoptic). We found that the earliest component of an event-related potential (C1; ∼60 ms) was suppressed by surrounding stimuli, but that suppression did not depend on surround configuration. This suggests a suppression mechanism that is not tuned for relative orientation acting on the earliest cortical response to the target. A later response component (N1; ∼160 ms) showed stronger suppression for parallel and monoptic surrounds, consistent with our earlier psychophysical results and a second form of suppression that is binocular and orientation tuned. We conclude that these two forms of surround suppression have distinct response time courses in the human visual system, which can be differentiated using electrophysiology.

Big GABA II: Water-referenced edited MR spectroscopy at 25 research sites.

Accurate and reliable quantification of brain metabolites measured in vivo using 1H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T1-weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels.

Glutamatergic facilitation of neural responses in MT enhances motion perception in humans.

There is large individual variability in human neural responses and perceptual abilities. The factors that give rise to these individual differences, however, remain largely unknown. To examine these factors, we measured fMRI responses to moving gratings in the motion-selective region MT, and perceptual duration thresholds for motion direction discrimination. Further, we acquired MR spectroscopy data, which allowed us to quantify an index of neurotransmitter levels in the region of area MT. These three measurements were conducted in separate experimental sessions within the same group of male and female subjects. We show that stronger Glx (glutamate + glutamine) signals in the MT region are associated with both higher fMRI responses and superior psychophysical task performance. Our results suggest that greater baseline levels of glutamate within MT facilitate motion perception by increasing neural responses in this region.

Sex Differences in Visual Motion Processing.

The importance of sex as a biological variable has recently been emphasized by major funding organizations [1] and within the neuroscience community [2]. Critical sex-based neural differences are indicated by, for example, conditions such as autism spectrum disorder (ASD) that have a strong sex bias with a higher prevalence among males [51, 3]. Motivated by this broader context, we report a marked sex difference in a visual motion perception task among neurotypical adults. Motion duration thresholds [4, 5]-the minimum duration needed to accurately perceive motion direction-were considerably shorter for males than females. We replicated this result across three laboratories and 263 total participants. This type of enhanced performance has previously been observed only in special populations including ASD, depression, and senescence [6-8]. The observed sex difference cannot be explained by general differences in speed of visual processing, overall visual discrimination abilities, or potential motor-related differences. We also show that while individual differences in motion duration thresholds are associated with differences in fMRI responsiveness of human MT+, surprisingly, MT+ response magnitudes did not differ between males and females. Thus, we reason that sex differences in motion perception are not captured by an MT+ fMRI measure that predicts within-sex individual differences in perception. Overall, these results show how sex differences can manifest unexpectedly, highlighting the importance of sex as a factor in the design and analysis of perceptual and cognitive studies.

Suppression and facilitation of human neural responses.

Efficient neural processing depends on regulating responses through suppression and facilitation of neural activity. Utilizing a well-known visual motion paradigm that evokes behavioral suppression and facilitation, and combining five different methodologies (behavioral psychophysics, computational modeling, functional MRI, pharmacology, and magnetic resonance spectroscopy), we provide evidence that challenges commonly held assumptions about the neural processes underlying suppression and facilitation. We show that: (1) both suppression and facilitation can emerge from a single, computational principle - divisive normalization; there is no need to invoke separate neural mechanisms, (2) neural suppression and facilitation in the motion-selective area MT mirror perception, but strong suppression also occurs in earlier visual areas, and (3) suppression is not primarily driven by GABA-mediated inhibition. Thus, while commonly used spatial suppression paradigms may provide insight into neural response magnitudes in visual areas, they should not be used to infer neural inhibition.

Big GABA: Edited MR spectroscopy at 24 research sites.

Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter γ-aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA-edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within-site, while site-level differences accounted for comparatively more variance (20%) than vendor-level differences (8%). For MM-suppressed GABA data, the variance was distributed equally between site- (50%) and participant-level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community.

Identifying separate components of surround suppression.

Surround suppression is a well-known phenomenon in which the response to a visual stimulus is diminished by the presence of neighboring stimuli. This effect is observed in neural responses in areas such as primary visual cortex, and also manifests in visual contrast perception. Studies in animal models have identified at least two separate mechanisms that may contribute to surround suppression: one that is monocular and resistant to contrast adaptation, and another that is binocular and strongly diminished by adaptation. The current study was designed to investigate whether these two mechanisms exist in humans and if they can be identified psychophysically using eye-of-origin and contrast adaptation manipulations. In addition, we examined the prediction that the monocular suppression component is broadly tuned for orientation, while suppression between eyes is narrowly tuned. Our results confirmed that when center and surrounding stimuli were presented dichoptically (in opposite eyes), suppression was orientation-tuned. Following adaptation in the surrounding region, no dichoptic suppression was observed, and monoptic suppression no longer showed orientation selectivity. These results are consistent with a model of surround suppression that depends on both low-level and higher level components. This work provides a method to assess the separate contributions of these components during spatial context processing in human vision.

Attention Determines Contextual Enhancement versus Suppression in Human Primary Visual Cortex.

Neural responses in primary visual cortex (V1) depend on stimulus context in seemingly complex ways. For example, responses to an oriented stimulus can be suppressed when it is flanked by iso-oriented versus orthogonally oriented stimuli but can also be enhanced when attention is directed to iso-oriented versus orthogonal flanking stimuli. Thus the exact same contextual stimulus arrangement can have completely opposite effects on neural responses-in some cases leading to orientation-tuned suppression and in other cases leading to orientation-tuned enhancement. Here we show that stimulus-based suppression and enhancement of fMRI responses in humans depends on small changes in the focus of attention and can be explained by a model that combines feature-based attention with response normalization. SIGNIFICANCE STATEMENT: Neurons in the primary visual cortex (V1) respond to stimuli within a restricted portion of the visual field, termed their "receptive field." However, neuronal responses can also be influenced by stimuli that surround a receptive field, although the nature of these contextual interactions and underlying neural mechanisms are debated. Here we show that the response in V1 to a stimulus in the same context can either be suppressed or enhanced depending on the focus of attention. We are able to explain the results using a simple computational model that combines two well established properties of visual cortical responses: response normalization and feature-based enhancement.

Spatial attention increases the pupillary response to light changes.

We measured pupil size in adult human subjects while we manipulated both the luminance of the visual scene and the location of attention. We found that, with central fixation maintained, pupillary constrictions and dilations evoked by peripheral luminance increments and decrements are larger when spatial attention is covertly (i.e., with no eye movements) directed to the stimulus region versus when it is directed to the opposite hemifield. Irrespective of the size of the attended region (focused at the center of the stimulus or spread within and outside the stimulus), the attentional enhancement is large: more than 20% of the response to stimuli in the unattended hemifield. This indicates that a sizable portion of this simple ocular behavior­often considered a subcortical "reflex"­in fact depends on cortical processing. Together, these features indicate that pupillometry is not only an index of retinal and brainstem function, but also an objective measure of complex constructs such as attention and its effects on sensory processing.

More power to the unconscious: conscious, but not unconscious, exogenous attention requires location variation.

Substantial evidence suggests that unconscious processing can be characterized as a lesser or weaker version of conscious processing. To test this notion, we designed a novel repeated-cuing procedure based on exogenous attention: The location of the attentional cue was first fixed across blocks (fixed-cue blocks), and then the cue was removed in subsequent blocks (no-cue blocks). The visibility of the cue was also manipulated. We found that when the cue was invisible, the response to a prespecified stimulus in the fixed-cue blocks was faster if the stimulus was at the cued location than if it was at the uncued location. But when the cue was visible, this cuing effect was abolished, potentially because of an awareness-dependent, location-based inhibition mechanism, as revealed by an attentional bias against the previously cued location in the no-cue blocks. We call this bias negative attentional aftereffect. These results provide novel evidence against the weaker-version characterization of unconscious effects, highlighting dissociable components of orienting and inhibition in exogenous cuing through awareness and temporal dynamics.

Automaticity of unconscious response inhibition: comment on Chiu and Aron (2014).

A recent study (Chiu & Aron, 2014) suggested that unconscious response inhibition is maintained when subliminal stimuli are mixed with supraliminal stimuli that are associated with response inhibition (mixed session), but it is abolished when they are presented alone (single session). However, awareness of the subliminal stimuli is likely to differ in the 2 sessions because of priming of awareness--awareness for subliminal stimuli is elevated (e.g., no longer subliminal) when mixed with supraliminal stimuli (Lin & Murray, 2014a). Here, in a novel design, we measured the awareness level in both sessions and found that the session-dependent effect was due to an awareness difference: The effect disappeared when awareness was comparable and emerged only when awareness was different. Arguments based on the lack of correlation between awareness and unconscious effects are refuted because typical correlation analysis underestimates the true correlation because of range restriction and it speaks only about individual differences that cannot explain within-subject effects (e.g., stimulus context here). Our findings also point to an attention-based mechanism underlying priming of awareness: Supraliminal trials are less attention-demanding, allowing for more attentional resources for subliminal trials in the mixed than single sessions. We discuss 2 implications. First, unconscious effects depend on top-down task sets and bottom-up stimulus strength. Second, to properly demonstrate unconscious processing, we stress the importance of having equivalent trial sequences between the main and awareness tests, promote a conjunction method that can strengthen inference, and discuss establishing a limit for equivalence between observed and chance performance.

Feature-based attention modulates surround suppression.

Stimuli appearing in the surround of the classical receptive field (CRF) can reduce neuronal firing and perceived contrast of a preferred stimulus in the CRF, a phenomenon referred to as surround suppression. Suppression is greatest when the surrounding stimulus has the same orientation and spatial frequency (SF) as the central target. Although spatial attention has been shown to influence surround suppression, the effects of feature-based attention have yet to be characterized. Using behavioral contrast adaptation in humans, we examined center-surround interactions between SF and orientation, and asked whether attending to one feature dimension versus the other influenced suppression. A center-surround triplet comprised of a central target Gabor and two flanking Gabors were used for adaptation. The flankers could have the same SF and orientation as the target, or differ in one or both of the feature dimensions. Contrast thresholds were measured for the target before and after adapting to center-surround triplets, and postadaptation thresholds were taken as an indirect measure of surround suppression. Both feature dimensions contributed to surround suppression and did not summate. Moreover, when center and surround had the same feature value in one dimension (e.g., same orientation) but had different values in the other dimension (e.g., different SF), there was more suppression when attention was directed to the feature dimension that matched between center and surround than when attention was directed to the feature dimension that differed. These results demonstrate that feature-based attention can influence center-surround interactions by enhancing the effects of the attended dimension.

Keeping a large-pupilled eye on high-level visual processing.

The pupillary light response has long been considered an elementary reflex. However, evidence now shows that it integrates information from such complex phenomena as attention, contextual processing, and imagery. These discoveries make pupillometry a promising tool for an entirely new application: the study of high-level vision.