The newly defined field of cognitive neuroscience attempts to draw together the study of all brain mechanisms that underlie our mental life. Historically, the major sensory pathways have provided the most trustworthy insights into how the brain supports cognitive functions such as perception, attention, and short-term memory. The links between neural activity and perception, in particular, have been studied revealingly in recent decades. Here we review the striking progress in this area, giving particular emphasis to the kinds of neural events that underlie the perceptual judgments of conscious observers.
The identification of brain regions that are associated with the conscious perception of visual stimuli is a major goal in neuroscience. Here we present a test of whether the signals on neurons in cortical area V1 correspond directly to our conscious perception of binocular stereoscopic depth. Depth perception requires that image features on one retina are first matched with appropriate features on the other retina. The mechanisms that perform this matching can be examined by using random-dot stereograms, in which the left and right eyes view randomly positioned but binocularly correlated dots. We exploit the fact that anticorrelated random-dot stereograms (in which dots in one eye are matched geometrically to dots of the opposite contrast in the other eye) do not give rise to the perception of depth because the matching process does not find a consistent solution. Anti-correlated random-dot stereograms contain binocular features that could excite neurons that have not solved the correspondence problem. We demonstrate that disparity-selective neurons in V1 signal the disparity of anticorrelated random-dot stereograms, indicating that they do not unambiguously signal stereoscopic depth. Hence single V1 neurons cannot account for the conscious perception of stereopsis, although combining the outputs of many V1 neurons could solve the matching problem. The accompanying paper suggests an additional function for disparity signals from V1: they may be important for the rapid involuntary control of vergence eye movements (eye movements that bring the images on the two foveae into register).
The role of the primate middle temporal area (MT) in depth perception was examined by considering the trial-to-trial correlations between neuronal activity and reported depth sensations. A set of moving random dots portrayed a cylinder rotating about its principal axis. In this structure-from-motion stimulus, the direction of rotation is ambiguous and the resulting percept undergoes spontaneous fluctuations. The stimulus can be rendered unambiguous by the addition of binocular disparities. We trained monkeys to report the direction of rotation in a set of these stimuli, one of which had zero disparity. Many disparity-selective neurons in area MT are selective for the direction of rotation defined by disparity. Across repeated presentations of the ambiguous (zero-disparity) stimulus, there was a correlation between neuronal firing and the reported direction of rotation, as found by Bradley et al. (1998). Quantification of this effect using choice probabilities (Britten et al., 1996) allowed us to demonstrate that the correlation cannot be explained by eye movements, behavioral biases, or attention to spatial location. MT neurons therefore appear to be involved in the perceptual decision process. The mean choice probability (0.67) was substantially larger than that reported for MT neurons in a direction discrimination task (Britten et al., 1996). This implies that MT neurons make a different contribution to the two tasks. For the depth task, either the pool of neurons used is smaller or the correlation between neurons in the pool is larger.
Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. While responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a novel, selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first two patients with TRK fusion-positive cancers that developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.
The tumour stroma regulates nearly all stages of carcinogenesis. Stromal heterogeneity in human triple-negative breast cancers (TNBCs) remains poorly understood, limiting the development of stromal-targeted therapies. Single-cell RNA sequencing of five TNBCs revealed two cancer-associated fibroblast (CAF) and two perivascular-like (PVL) subpopulations. CAFs clustered into two states: the first with features of myofibroblasts and the second characterised by high expression of growth factors and immunomodulatory molecules. PVL cells clustered into two states consistent with a differentiated and immature phenotype. We showed that these stromal states have distinct morphologies, spatial relationships and functional properties in regulating the extracellular matrix. Using cell signalling predictions, we provide evidence that stromal-immune crosstalk acts via a diverse array of immunoregulatory molecules. Importantly, the investigation of gene signatures from inflammatory-CAFs and differentiated-PVL cells in independent TNBC patient cohorts revealed strong associations with cytotoxic T-cell dysfunction and exclusion, respectively. Such insights present promising candidates to further investigate for new therapeutic strategies in the treatment of TNBCs.
Quantitative analysis of the responses of V1 neurons to horizontal disparity in dynamic random-dot stereograms. J Neurophysiol 87: 191-208, 2002; 10.1152/jn.00465.2000. Horizontal disparity tuning for dynamic random-dot stereograms was investigated for a large population of neurons (n ϭ 787) in V1 of the awake macaque. Disparity sensitivity was quantified using a measure of the discriminability of the maximum and minimum points on the disparity tuning curve. This measure and others revealed a continuum of selectivity rather than separate populations of disparity-and nondisparity-sensitive neurons. Although disparity sensitivity was correlated with the degree of direction tuning, it was not correlated with other significant neuronal properties, including preferred orientation and ocular dominance. In accordance with the Gabor energy model, tuning curves for horizontal disparity were adequately described by Gabor functions when the neuron's orientation preference was near vertical. For neurons with orientation preferences near to horizontal, a Gaussian function was more frequently sufficient. The spatial frequency of the Gabor function that described the disparity tuning was weakly correlated with measurements of the spatial frequency and orientation preference of the neuron for drifting sinusoidal gratings. Energy models make several predictions about the relationship between the response rates to monocular and binocular dot patterns. Few of the predictions were fulfilled exactly, although the observations can be reconciled with the energy model by simple modifications. These same modifications also provide an account of the observed continuum in strength of disparity selectivity. A weak correlation between the disparity sensitivity of simultaneously recorded single-and multiunit data were revealed as well as a weak tendency to show similar disparity preferences. This is compatible with a degree of local clustering for disparity sensitivity in V1, although this is much weaker than that reported in area MT. I N T R O D U C T I O NSelectivity for binocular disparity was initially demonstrated using elongated bar stimuli in cat area 17 (Barlow et al. 1967;Pettigrew et al. 1968) and V1 of the awake monkey (Poggio and Fischer 1977). Subsequently, Poggio and colleagues (Poggio 1995;Poggio et al. 1985Poggio et al. , 1988 examined the sensitivity to horizontal disparity in random-dot stereograms (RDS) in macaque V1. None of the studies using RDS has attempted to describe the disparity tuning quantitatively. Consequently, there has been no quantitative analysis of the relationship between disparity selectivity to RDS and other fundamental properties of V1 neurons, such as orientation tuning and ocular dominance.There are several reasons why it is important to study these issues with RDS. First, a change in the disparity of a bar stimulus also generates changes in the monocular images, which by themselves may influence neuronal firing. By contrast the monocular images of random-dot stimuli are spatially homogeneous. There...
Our ability to coordinate the use of our left and right eyes and to make use of subtle differences between the images received by each eye allows us to perceive stereoscopic depth, which is important for the visual perception of three-dimensional space. Binocular neurons in the visual cortex combine signals from the left and right eyes. Probing the roles of binocular neurons in different perceptual tasks has advanced our understanding of the stages within the visual cortex that lead to binocular depth perception.
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