Testing hemifield independence for divided attention in visual object tasks.

In this study, we asked to what degree hemifields contribute to divided attention effects observed in tasks with object-based judgments. If object recognition processes in the two hemifields were fully independent, then placing stimuli in separate hemifields would eliminate divided attention effects; in the alternative extreme, if object recognition processes in the two hemifields were fully integrated, then placing stimuli in separate hemifields would not modulate divided attention effects. Using a dual-task paradigm, we compared performance in a semantic categorization task for relevant stimuli arranged in the same hemifield to performance for relevant stimuli arranged in separate left and right hemifields. In two experiments, there was a reliable decrease in divided attention effects when stimuli were shown in separate hemifields compared to the same hemifield. However, the effect of divided attention was not eliminated. These results reject both the independent and integrated hypotheses, and instead support a third alternative - that object recognition processes in the two hemifields are partially dependent. More specifically, the magnitude of modulation by hemifields was closer to the prediction of the integrated hypothesis, suggesting that for dual tasks with objects, dependent processing is mostly shared across the visual field.

PySilSub: An open-source Python toolbox for implementing the method of silent substitution in vision and nonvisual photoreception research.

The normal human retina contains several classes of photosensitive cell-rods for low-light vision, three cone classes for daylight vision, and intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing melanopsin for non-image-forming functions, including pupil control, melatonin suppression, and circadian photoentrainment. The spectral sensitivities of the photoreceptors overlap significantly, which means that most lights will stimulate all photoreceptors to varying degrees. The method of silent substitution is a powerful tool for stimulating individual photoreceptor classes selectively and has found much use in research and clinical settings. The main hardware requirement for silent substitution is a spectrally calibrated light stimulation system with at least as many primaries as there are photoreceptors under consideration. Device settings that will produce lights to selectively stimulate the photoreceptor(s) of interest can be found using a variety of analytic and algorithmic approaches. Here we present PySilSub (https://github.com/PySilentSubstitution/pysilsub), a novel Python package for silent substitution featuring flexible support for individual colorimetric observer models (including human and mouse observers), multiprimary stimulation devices, and solving silent substitution problems with linear algebra and constrained numerical optimization. The toolbox is registered with the Python Package Index and includes example data sets from various multiprimary systems. We hope that PySilSub will facilitate the application of silent substitution in research and clinical settings.

CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.

The post-genomic era has seen many advances in our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing's sarcoma cancer cell lines. Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing's sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts. Mechanistically, it prevents the release of newly synthesized pre-mRNAs, resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. This study implicates pre-mRNA processing, and specifically CPSF3, as a druggable target providing an avenue to therapeutic intervention in cancer.

Author Correction: CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Parallel spatial channels converge at a bottleneck in anterior word-selective cortex.

In most environments, the visual system is confronted with many relevant objects simultaneously. That is especially true during reading. However, behavioral data demonstrate that a serial bottleneck prevents recognition of more than one word at a time. We used fMRI to investigate how parallel spatial channels of visual processing converge into a serial bottleneck for word recognition. Participants viewed pairs of words presented simultaneously. We found that retinotopic cortex processed the two words in parallel spatial channels, one in each contralateral hemisphere. Responses were higher for attended than for ignored words but were not reduced when attention was divided. We then analyzed two word-selective regions along the occipitotemporal sulcus (OTS) of both hemispheres (subregions of the visual word form area, VWFA). Unlike retinotopic regions, each word-selective region responded to words on both sides of fixation. Nonetheless, a single region in the left hemisphere (posterior OTS) contained spatial channels for both hemifields that were independently modulated by selective attention. Thus, the left posterior VWFA supports parallel processing of multiple words. In contrast, activity in a more anterior word-selective region in the left hemisphere (mid OTS) was consistent with a single channel, showing (i) limited spatial selectivity, (ii) no effect of spatial attention on mean response amplitudes, and (iii) sensitivity to lexical properties of only one attended word. Therefore, the visual system can process two words in parallel up to a late stage in the ventral stream. The transition to a single channel is consistent with the observed bottleneck in behavior.

A major role for retrieval and/or comparison in the set-size effects of change detection.

Set-size effects in change detection have been attributed to capacity limits in a variety of processes, including perception, memory encoding, memory storage, memory retrieval, comparison, and decision. In this study, we investigated the locus of the effect of increasing set size from 1 to 2. The task was to detect a 90 degree change in the orientation of 1 or 2 briefly presented Gabor patterns in noise. To measure purely attentional effects and not another phenomena, such as crowding, a precue was used to manipulate relevant set size while keeping the display constant. The locus of the capacity limit was determined by varying when observers were cued to a single relevant stimulus. To begin, we measured the baseline set-size effect for change detection. Next, a dual-task procedure and a 100% valid postcue was added to test for an effect of decision: This modification did not reliably change the set-size effects. In the critical experiments, a 100% valid cue was provided during the retention interval between displays, or only one stimulus was presented in the second display (local recognition). For both of these conditions, there was only a relatively small set-size effect. These results are consistent with the bulk of capacity limits being in memory retrieval or comparison and not in perception, memory encoding, or memory storage.

Learning to see again: Perceptual learning of simulated abnormal on- off-cell population responses in sighted individuals.

Many forms of artificial sight recovery, such as electronic implants and optogenetic proteins, generally cause simultaneous, rather than complementary firing of on- and off-center retinal cells. Here, using virtual patients-sighted individuals viewing distorted input-we examine whether plasticity might compensate for abnormal neuronal population responses. Five participants were dichoptically presented with a combination of original and contrast-reversed images. Each image (I) and its contrast-reverse (I') was filtered using a radial checkerboard (F) in Fourier space and its inverse (F'). [I * F'] + [I' * F] was presented to one eye, and [I * F] + [I' * F'] was presented to the other, such that regions of the image that produced on-center responses in one eye produced off-center responses in the other eye, and vice versa. Participants continuously improved in a naturalistic object discrimination task over 20 one-hour sessions. Pre-training and post-training tests suggest that performance improvements were due to two learning processes: learning to recognize objects with reduced visual information and learning to suppress contrast-reversed image information in a non-eye-selective manner. These results suggest that, with training, it may be possible to adapt to the unnatural on- and off-cell population responses produced by electronic and optogenetic sight recovery technologies.

Is there a serial bottleneck in visual object recognition?

Divided attention has little effect for simple tasks, such as luminance detection, but it has large effects for complex tasks, such as semantic categorization of masked words. Here, we asked whether the semantic categorization of visual objects shows divided attention effects as large as those observed for words, or as small as those observed for simple feature judgments. Using a dual-task paradigm with nameable object stimuli, performance was compared with the predictions of serial and parallel models. At the extreme, parallel processes with unlimited capacity predict no effect of divided attention; alternatively, an all-or-none serial process makes two predictions: a large divided attention effect (lower accuracy for dual-task trials, compared to single-task trials) and a negative response correlation in dual-task trials (a given response is more likely to be incorrect when the response about the other stimulus is correct). These predictions were tested in two experiments examining object judgments. In both experiments, there was a large divided attention effect and a small negative correlation in responses. The magnitude of these effects was larger than for simple features, but smaller than for words. These effects were consistent with serial models, and rule out some but not all parallel models. More broadly, the results help establish one of the first examples of likely serial processing in perception.

Evidence of Serial Processing in Visual Word Recognition.

To test the limits of parallel processing in vision, we investigated whether people can recognize two words at once. Participants viewed brief, masked pairs of words and were instructed in advance to judge both of the words (dual-task condition) or just one of the words (single-task condition). For judgments of semantic category, the dual-task deficit was so large that it supported all-or-none serial processing: Participants could recognize only one word and had to guess about the other. Moreover, participants were more likely to be correct about one word if they were incorrect about the other, which also supports a serial-processing model. In contrast, judgments of text color with identical stimuli were consistent with unlimited-capacity parallel processing. Thus, under these conditions, serial processing is necessary to judge the meaning of words but not their physical features. Understanding the implications of this result for natural reading will require further investigation.

Structure based design of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors from a phenotypic screen.

Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design. From this approach, two key motifs were identified, the (S,S) cyclopropyl carboxamide and the (S)-1-N-phenylethylamide that endowed compounds with excellent cell based potency. As exemplified by compound 27e such compounds could be useful tools to explore NAMPT biology in vivo.

Evidence for unlimited capacity processing of simple features in visual cortex.

Performance in many visual tasks is impaired when observers attempt to divide spatial attention across multiple visual field locations. Correspondingly, neuronal response magnitudes in visual cortex are often reduced during divided compared with focused spatial attention. This suggests that early visual cortex is the site of capacity limits, where finite processing resources must be divided among attended stimuli. However, behavioral research demonstrates that not all visual tasks suffer such capacity limits: The costs of divided attention are minimal when the task and stimulus are simple, such as when searching for a target defined by orientation or contrast. To date, however, every neuroimaging study of divided attention has used more complex tasks and found large reductions in response magnitude. We bridged that gap by using functional magnetic resonance imaging to measure responses in the human visual cortex during simple feature detection. The first experiment used a visual search task: Observers detected a low-contrast Gabor patch within one or four potentially relevant locations. The second experiment used a dual-task design, in which observers made independent judgments of Gabor presence in patches of dynamic noise at two locations. In both experiments, blood-oxygen level-dependent (BOLD) signals in the retinotopic cortex were significantly lower for ignored than attended stimuli. However, when observers divided attention between multiple stimuli, BOLD signals were not reliably reduced and behavioral performance was unimpaired. These results suggest that processing of simple features in early visual cortex has unlimited capacity.

Population receptive field estimates of human auditory cortex.

Here we describe a method for measuring tonotopic maps and estimating bandwidth for voxels in human primary auditory cortex (PAC) using a modification of the population Receptive Field (pRF) model, developed for retinotopic mapping in visual cortex by Dumoulin and Wandell (2008). The pRF method reliably estimates tonotopic maps in the presence of acoustic scanner noise, and has two advantages over phase-encoding techniques. First, the stimulus design is flexible and need not be a frequency progression, thereby reducing biases due to habituation, expectation, and estimation artifacts, as well as reducing the effects of spatio-temporal BOLD nonlinearities. Second, the pRF method can provide estimates of bandwidth as a function of frequency. We find that bandwidth estimates are narrower for voxels within the PAC than in surrounding auditory responsive regions (non-PAC).

A lack of experience-dependent plasticity after more than a decade of recovered sight.

In 2000, monocular vision was restored to M. M., who had been blind between the ages of 3 and 46 years. Tests carried out over 2 years following the surgery revealed impairments of 3-D form, object, and face processing and an absence of object- and face-selective blood-oxygen-level-dependent responses in ventral visual cortex. In the present research, we reexamined M. M. to test for experience-dependent recovery of visual function. Behaviorally, M. M. remains impaired in 3-D form, object, and face processing. Accordingly, we found little to no evidence of the category-selective organization within ventral visual cortex typically associated with face, body, scene, or object processing. We did observe remarkably normal object selectivity within lateral occipital cortex, consistent with M. M.'s previously reported shape-discrimination performance. Together, these findings provide little evidence for recovery of high-level visual function after more than a decade of visual experience in adulthood.

Not all summary statistics are made equal: Evidence from extracting summaries across time.

Over the past 15 years, a number of behavioral studies have shown that the human visual system can extract the average value of a set of items along a variety of feature dimensions, often with great facility and accuracy. These efficient representations of sets of items are commonly referred to as summary representations, but very little is known about whether their computation constitutes a single unitary process or if it involves different mechanisms in different domains. Here, we asked participants to report the average value of a set of items presented serially over time in four different feature dimensions. We then measured the contribution of different parts of the information stream to the reported summaries. We found that this temporal weighting profile differs greatly across domains. Specifically, summaries of mean object location (Experiment 1) were influenced approximately 2.5 times more by earlier items than by later items. Summaries of mean object size (Experiment 1), mean facial expression (Experiment 2), and mean motion direction (Experiment 3), however, were more influenced by later items. These primacy and recency effects show that summary representations computed across time do not incorporate all items equally. Furthermore, our results support the hypothesis that summary representations operate differently in different feature domains, and may be subserved by distinct mechanisms.

Improving the Reliability and Accuracy of Population Receptive Field Measures Using a Logarithmically Warped Stimulus.

The population receptive field method, which measures the region in visual space that elicits a BOLD signal in a voxel in retinotopic cortex, is a powerful tool for investigating the functional organization of human visual cortex with fMRI (Dumoulin & Wandell, 2008). However, recent work has shown that population receptive field (pRF) estimates for early retinotopic visual areas can be biased and unreliable, especially for voxels representing the fovea. Here, we show that a 'log-bar' stimulus that is logarithmically warped along the eccentricity dimension produces more reliable estimates of pRF size and location than the traditional moving bar stimulus. The log-bar stimulus was better able to identify pRFs near the foveal representation, and pRFs were smaller in size, consistent with simulation estimates of receptive field sizes in the fovea.

Visual callosal topography in the absence of retinal input.

Using probabilistic diffusion tractography, we examined the retinotopic organization of splenial callosal connections within early blind, anophthalmic, and control subjects. Early blind subjects experienced prenatal retinal "waves" of spontaneous activity similar to those of sighted subjects, and only lack postnatal visual experience. In anophthalmia, the eye is either absent or arrested at an early prenatal stage, depriving these subjects of both pre- and postnatal visual input. Therefore, comparing these two groups provides a way of separating the influence of pre- and postnatal retinal input on the organization of visual connections across hemispheres. We found that retinotopic mapping within the splenium was not measurably disrupted in early blind or anophthalmic subjects compared to visually normal controls. No significant differences in splenial volume were observed across groups. No significant differences in diffusivity were found between early blind subjects and sighted controls, though some differences in diffusivity were noted between anophthalmic subjects and controls. These results suggest that neither prenatal retinal activity nor postnatal visual experience plays a role in the large-scale topographic organization of visual callosal connections within the splenium.

Effects of task and attentional selection on responses in human visual cortex.

Multiple visual tasks can be performed on the same visual input, with different tasks presumably engaging different neuronal populations. The modular layout of the visual system implies that specific cortical regions carry more information about certain stimulus attributes than others. Thus it is reasonable to assume that decisions during a task will be optimal if they are based on the responses of the most informative neuronal signals, which presumably originate in regions with the sharpest tuning for the relevant stimulus feature. Previous studies have supported this position. Here we present the results of two fMRI experiments that confirm these findings and expand on earlier investigations by addressing the effects of the physical properties of an attended stimulus on task-related modulations in human visual cortex. Specifically, we ask whether performing two-alternative forced choice speed- and color-discrimination tasks (and other attentional processes) can modulate neural activity independent of visual stimulation and whether the effect of spatial attention depends on which task is being performed. The results indicate that 1) when stimulation and spatial attention are constant, responses in V4 and MT+ depend on the task being performed and are independent of the tested physical properties of the selected stimulus, 2) this task-dependent modulation might require a stimulus--task-specific preparatory mechanisms alone are not sufficient to drive responses, and 3) independent of which task is being performed, spatial attention adds a baseline shift to responses in MT+ and V4 when a stimulus is present.

The spread of attention across features of a surface.

Contrasting theories of visual attention have emphasized selection by spatial location, individual features, and whole objects. We used functional magnetic resonance imaging to ask whether and how attention to one feature of an object spreads to other features of the same object. Subjects viewed two spatially superimposed surfaces of random dots that were segregated by distinct color-motion conjunctions. The color and direction of motion of each surface changed smoothly and in a cyclical fashion. Subjects were required to track one feature (e.g., color) of one of the two surfaces and detect brief moments when the attended feature diverged from its smooth trajectory. To tease apart the effect of attention to individual features on the hemodynamic response, we used a frequency-tagging scheme. In this scheme, the stimulus features (color and direction of motion) are modulated periodically at distinct frequencies so that the contribution of each feature to the hemodynamics can be inferred from the harmonic response at the corresponding frequency. We found that attention to one feature (e.g., color) of one surface increased the response modulation not only to the attended feature but also to the other feature (e.g., motion) of the same surface. This attentional modulation was evident in multiple visual areas and was present as early as V1. The spread of attention to the behaviorally irrelevant features of a surface suggests that attention may automatically select all features of a single object. Thus object-based attention may be supported by an enhancement of feature-specific sensory signals in the visual cortex.

Enhanced memory for scenes presented at behaviorally relevant points in time.

The ability to remember a briefly presented scene depends on a number of factors, such as its saliency, novelty, degree of threat, or behavioral relevance to a task. Here, however, we show that the encoding of a scene into memory may depend not only on what the scene contains but also when it occurs. Participants performed an attentionally demanding target detection task at fixation while also viewing a rapid sequence of full-field photographs of urban and natural scenes. Participants were then tested on whether they recognized a specific scene from the previous sequence. We found that scenes were recognized reliably only when presented concurrently with a target at fixation. This is evidence of a mechanism where traces of a visual scene are automatically encoded into memory at behaviorally relevant points in time regardless of the spatial focus of attention.

Minimizing biases in estimating the reorganization of human visual areas with BOLD retinotopic mapping.

There is substantial interest in using functional magnetic resonance imaging (fMRI) retinotopic mapping techniques to examine reorganization of the occipital cortex after vision loss in humans and nonhuman primates. However, previous reports suggest that standard phase encoding and the more recent population Receptive Field (pRF) techniques give biased estimates of retinotopic maps near the boundaries of retinal or cortical scotomas. Here we examine the sources of this bias and show how it can be minimized with a simple modification of the pRF method. In normally sighted subjects, we measured fMRI responses to a stimulus simulating a foveal scotoma; we found that unbiased retinotopic map estimates can be obtained in early visual areas, as long as the pRF fitting algorithm takes the scotoma into account and a randomized "multifocal" stimulus sequence is used.