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PubMed2026

Spatial isoform sequencing at single-cell resolution reveals cell-type-specific spatial isoform variability in multiple brain cell types.

Spatial long-read technologies are increasingly common but usually lack single-cell resolution. This leaves unanswered whether spatially variable isoforms reflect variability within one cell type or differences in region-specific cell-type composition. Here, we developed Spl-ISO-Seq2 (500-nm resolution) and accompanying software, Spl-IsoQuant-2 and Spl-IsoFind, enabling long-read sequencing of >450 million barcodes versus 80,000 previously. Applying this to the adult mouse brain, we compared differential isoform abundance between known regions and spatial isoform patterns independent of predefined regions. Both identified overlapping hits, for example, Rps24 in oligodendrocytes. For known Snap25 spatial isoform variation, we show that it occurs in excitatory neurons. The region-agnostic approach also uncovered patterns missed by region-based comparisons, for example, for Ighm. Notably, many spatial isoform signals are not driven by cell-type composition alone. Finally, our software is applicable to many spatial and single-cell protocols, demonstrating reproducibility between platforms (for example, Visium HD/Stereo-seq). Overall, our experimental/analytical methods enable a submicron-resolution-isoform view and open avenues for spatial isoform disease research.

Animals↗
PubMed2025

Spatial mutual nearest neighbors for spatial transcriptomics data.

MOTIVATION: Mutual nearest neighbors (MNN) is a widely used computational tool to perform batch correction for single-cell RNA-sequencing data. However, in applications such as spatial transcriptomics, it fails to take into account the 2D spatial information. RESULTS: Here, we present spatialMNN, an algorithm that integrates multiple spatial transcriptomic samples and identifies spatial domains. Our approach begins by building a k-nearest neighbors (kNN) graph based on the spatial coordinates, prunes noisy edges, and identifies niches to act as anchor points for each sample. Next, we construct a MNN graph across the samples to identify similar niches. Finally, the spatialMNN graph can be partitioned using existing algorithms, such as the Louvain algorithm to predict spatial domains across the tissue samples. We demonstrate the performance of spatialMNN using large datasets, including one with N = 31 10x Genomics Visium samples. We also evaluate the computing performance of spatialMNN to other popular spatial clustering methods. AVAILABILITY AND IMPLEMENTATION: Our software package is available on GitHub (https://github.com/Pixel-Dream/spatialMNN). The code is available on Zenodo (https://doi.org/10.5281/zenodo.15073963).

Algorithms↗
PubMed2026

SIVA: diagonal integration of spatial multi-omics data via spatially informed variational autoencoders and anchor guidance.

MOTIVATION: Understanding cellular states and regulatory programs requires integrative analysis of multiple omics layers. Although recent spatial sequencing technologies allow molecular profiling of cells within their tissue context, paired spatial multi-omics assays are still limited by technical complexity and cost. This creates a pressing need for diagonal integration methods that enable joint analysis of unpaired spatial omics datasets. RESULTS: We propose SIVA, a deep generative framework based on Spatially-Informed Variational Autoencoders with Anchor Guidance, for diagonal integration of spatial multi-modal data. SIVA employs modality-specific variational autoencoders (VAEs) with a hybrid latent embedding that integrates Gaussian process and standard Gaussian priors, enabling joint modeling of spatially structured variation and dominant underlying data distributions across modalities. To facilitate cross-modal alignment in the absence of one-to-one cell correspondence, SIVA adopts a dual integration strategy combining global distribution alignment via Maximum Mean Discrepancy and local correspondence guidance using mutual nearest neighbor anchors. Extensive experiments across multiple cross-slice integration scenarios demonstrate that SIVA achieves robust and accurate integration of unpaired spatial omics datasets, consistently outperforming existing methods. AVAILABILITY AND IMPLEMENTATION: The source codes are available at https://github.com/PelenJiang/SIVA.

Autoencoder↗
PubMed1990

The effects of temporal modulation and spatial location on the perceived spatial frequency of visual patterns.

The perceived spatial frequency of a visual pattern can increase when a pattern drifts or is presented at a peripheral visual field location, as compared with a foveally viewed, stationary pattern. We confirmed previously reported effects of motion on foveally viewed patterns and of location on stationary patterns and extended this analysis to the effect of motion on peripherally viewed patterns and the effect of location on drifting patterns. Most central to our investigation was the combined effect of temporal modulation and spatial location on perceived spatial frequency. The group data, as well as the individual sets of data for most observers, are consistent with the mathematical concept of separability for the effects of temporal modulation and spatial location on perceived spatial frequency. Two qualitative psychophysical models suggest explanations for the effects. Both models assume that the receptive-field sizes of a set of underlying psychophysical mechanisms monotonically change as a function of temporal modulation or visual field location, whereas the perceptual labels attached to a set of channels remain invariant. These models predict that drifting or peripheral viewing of a pattern will cause a shift in the perceived spatial frequency of the pattern to a higher apparent spatial frequency.

Adult↗
PubMed1999

Effects of lesions to the glutamatergic afferents to the nucleus accumbens in the modulation of reactivity to spatial and non-spatial novelty in mice.

The purpose of this study was to compare the effects of selective lesions of the three main sources of limbic afferents to the nucleus accumbens-fornix, prelimbic cortex and amygdala-with those induced by N-methyl-D-aspartate receptor blockage in this structure, in a non-associative task designed to estimate the ability of rodents to encode spatial and non-spatial relationships between discrete stimuli. The task consists of placing mice in an open field containing five objects and, after three sessions of habituation, examining their reactivity to object displacement (spatial novelty) and object substitution (object novelty). Focal administrations of the competitive N-methyl-D-aspartate antagonist DL-2-amino-5-phosphonopentanoic acid (0.1 microg/side) induced a selective impairment in the ability of mice to react to the spatial change. Lesions to the different structures affect the response of mice to spatial and non-spatial novelty in different ways. In particular, while fornix lesions induced a decrease in re-exploration of the displaced objects, prelimbic cortex lesions enhanced the exploration of both displaced and non-displaced objects. Finally, the basolateral amygdala lesions did not induce any impairment in the detection of the displaced objects but decreased the latencies to approach novel objects. It is concluded that N-methyl-D-aspartate receptor blockage in the nucleus accumbens subsumes the effects of the three lesions. Some hypotheses on the role of glutamatergic transmission in the accumbens on information processing are briefly discussed.

Afferent Pathways↗
PubMed1990

The effects of spatial phase on reaction time to spatially filtered images.

Many studies of visual perception have used periodic stimuli such as sine-wave gratings and checkerboard patterns. It is well known that reaction time (RT) to such stimuli increases with increasing spatial frequency and decreasing contrast. While this is the case with periodic stimuli it is not clear that these relationships obtain for aperiodic stimuli such as natural scenes. A digitized image of an object (a vase) was submitted to two-dimensional Fourier analysis. Four pairs of spatial frequency band-limited images were created for each image. Each pair consisted of a normal-phase (NP) and a scrambled-phase (SP) version, with the magnitude spectrum and space-averaged luminance the same within each pair. Filter band-widths were 1 octave wide. Manual RT was measured for onset and offset of each spatially filtered image. Mean RT for SP images increased significantly with increasing spatial frequency, while no other significant differences were found with the NP images. This suggests that the temporal processing of complex, aperiodic images is influenced by the spatial frequency and contrast of local regions within the image, rather than by the space-averaged contrast of the entire image, and cannot be predicted by global estimates of contrast and spatial frequency.

Adult↗
PubMed1992

Spatial recognition and spatial order memory in patients with dementia of the Alzheimer's type.

Patients diagnosed as having mild or moderate primary degenerative dementia of the Alzheimer's type (PDDAT), and normal elderly subjects were tested for spatial order and a spatial recognition memory. Results for spatial order memory indicated that compared to normal elderly subjects, patients with mild PDDAT showed an impaired memory only for the last serial positions. In contrast, with respect to spatial recognition memory, patients with mild PDDAT showed an impaired memory only for the early serial positions. Patients with moderate PDDAT were impaired on all serial positions for both spatial order and spatial recognition memory. Based on comparable deficit patterns seen in animals and patients with hippocampal and parietal cortex lesions, it is suggested that memory deficits displayed by PDDAT patients might be a function of underlying pathology in the hippocampus and parietal cortex.

Aged↗
PubMed1988

Spatial frequency and orientation tuning of spatial visual mechanisms in human albinos.

A masking paradigm was used to measure the spatial frequency and orientation tuning of spatial mechanisms in the albino visual system. Threshold elevation curves obtained in this manner at test spatial frequencies of 0.25 cycles/deg (cpd), 0.50 cpd, and 1 cpd have the same shape as curves obtained from normal subjects at test frequencies two octaves higher. Additional masking studies showed that contrast processing in albinos obeys the same compressive power law as in normals. Thus, spatial mechanisms in albino central vision have normal spatial frequency and orientation bandwidths. As central cones in the albino are spaced 3-4 times further apart than in the normal fovea, these results support the hypothesis that monocular spatial vision in albinos is primarily limited by this increased receptor spacing. It is hypothesized that this, in turn, is the result of arrested development of the albino retina.

Adult↗
PubMed1994

The coding of spatial position by the human visual system: effects of spatial scale and retinal eccentricity.

In this study we investigate the nature of the computations that underlie the encoding of spatial position by the human visual system. Specifically, we explore the relationship between alignment accuracy and retinal eccentricity for stimuli where local luminance, local contrast, and orientation cues do not underlie performance. Spatial scale is especially important for such a comparison because of the well documented spatial inhomogeneity of the human visual field. The results suggest that the relationship between spatial localization and eccentricity is invariant with spatial scale if accuracy and eccentricity are expressed in terms of the stimulus envelope size. We show that the photoreceptor disarray does not determine the limit to performance for this task, the limit is post-receptoral and can be modelled in terms of a positional uncertainty within the early filters located before the response envelope has been extracted. This uncertainty varies with eccentricity in a similar way within each spatial array.

Contrast Sensitivity↗
PubMed1988

Sex differences in the lateralization of spatial abilities: a spatial component analysis of extreme group scores.

Sex differences in the cerebral lateralization of two discrete components of spatial processing were investigated in high and low ability males and females using the dual-task paradigm. In the first phase of the experiment, the results indicated a pattern of right hemispheric control for a spatial visualization component, regardless of sex and ability level. In the processing of the spatial orientation component of spatial ability, high ability males and females showed left hemispheric lateralization, whereas low ability males and females displayed right hemispheric control. In the second phase of this study, it was observed that high ability females and low ability males may use a verbal mediation strategy in processing spatial visualization tasks. No verbal mediation effects were found for the spatial orientation component.

Adult↗
PubMed1996

Rats perform better on spatial than brightness delayed matching-to-sample water-escape due to an unlearned bias to use spatial cues.

Rats readily acquire water-escape spatial delayed matching-to-sample (DMTS) tasks and show excellent performance with retention intervals as long as 120 m (17). They also acquire the task more readily with a 5-min retention interval (RI) than with a 1-min RI (16). To determine if these observations are unique to spatial DMTS, or are also true of nonspatial water-escape DMTS, 75-day-old rats were compared on acquisition and subsequent retention of spatial and brightness DMTS. A larger proportion of the rats tested on the spatial problem were able to acquire the task, made fewer acquisition errors, and demonstrated better retention when tested at RIs of 1, 5, 15, 30, 60, and 120 min than did the rats tested on the brightness problem. Acquisition RI did not affect the rate of acquisition on either task. Examination of perserveration errors, the occurrence of intrusions, and position-congruent performance (escape platform in the same physical location on both runs of a trial) revealed that the choices of brightness-trained rats were often more influenced by spatial than brightness cues, suggesting that rats have an unlearned bias to use spatial cues in water-escape DMTS tasks.

Animals↗
PubMed1997

Dissociation of spatial reference memory, spatial working memory, and hippocampal mossy fiber distribution in two rat strains differing in emotionality.

Rats of the inbred strains DA/Han and BDE/Han were compared on two complex spatial learning tasks, a spatial reference memory task in a 16-unit multiple T-maze and a spatial working memory task in an eight-arm radial-maze. In addition, sizes of hippocampal mossy fiber terminal fields were measured. BDE rats showed marked superiority in multiple T-maze learning whereas DA rats outperformed BDE rats on the radial-maze task. DA rats had significantly larger intra- and infrapyramidal mossy fiber terminal fields (IIP-MF). This is consistent with findings from other studies suggesting that large IIP-MF are related to excellent spatial radial-maze learning, but it also indicates that size of IIP-MF is correlated with processing of a specific type of spatial information rather than with overall spatial abilities. BDE rats had more extended suprapyramidal mossy fiber projections (SP-MF) and a larger hilus. Rats of both strains differed in exploratory behaviour and emotionality: DA rats revealed little freezing and had a high rearing activity, whereas BDE rats showed frequent freezing and reared rarely. Results suggest that IIP-MF are involved with flexible expression of memory, updating environmental information and parallel processing whereas SP-MF might be linked to processing of familiar information. Presumably, emotional factors contribute to performance differences.

Animals↗
PubMed1994

Spatial attention and the apprehension of spatial relations.

Seven experiments examined the role of spatial attention in apprehending spatial relations above, below, left, and right. In Experiment 1, visual search was difficult when targets differed from distractors only in the spatial relation between their elements. Reaction time increased linearly with display size with a slope greater than 60 ms/item. In Experiment 2, search was easy (the slope was flat) when targets differed from distractors in the identity of their elements. In Experiments 3 and 4, target position was cued with a discrepant color, and performance was better when attention was pulled toward spatial-relation targets than away from them. Experiments 5-7 generalized the results over different displays and extended practice. The results suggest that apprehending spatial relations requires spatial attention.

Analysis of Variance↗
PubMed1996

Redistribution of spatial representation in the hippocampus of aged rats performing a spatial memory task.

Young and old rats performed on a maze according to a forced-choice and then a spatial memory procedure either in the same or a different environment. Aged rats were slower to learn the spatial memory task when tested in the same, but not in a different, room. One interpretation of this pattern of results is that although old rats learn new rules as quickly as young rats, they show less flexibility with old rules and familiar spatial information. Impaired choice accuracy during asymptote performance suggests poor processing of trial-unique information by old rats. Spatial correlates of hippocampal CA1 and hilar cells varied with task demand: CA1 cells of aged rats showed more spatially selective place fields, whereas hilar cells showed more diffuse location coding during spatial memory, and not forced-choice, tests. Such representational reorganization may reflect a compensatory response to age-related neurobiological changes in hippocampus.

Aging↗
PubMed1999

In mice tonic estrogen replacement therapy improves non-spatial and spatial memory in a water maze task.

We investigated the effects of estrogen replacement therapy on water maze non-spatial and spatial navigation in mice. Three groups of mice were ovariectomized and two of these groups being implanted with s.c. pellets that produce blood levels of estrogen close to those found in estrous (estrogen low, 75-100 pg/ml blood) or proestrous (estrogen high, 300-400 pg/ml). The behavioral assessment was initiated 7 days after pellet implantation. Non-spatial navigation to a clearly visible platform was stimulated by low and high levels of estrogen. However, spatial navigation to a hidden platform was improved by low estrogen levels. We found that estrogen improves two different types of memory processes that depend on striatal (non-spatial navigation) and hippocampal (spatial) memory systems.

Animals↗
PubMed1998

Hypoxia and hypothermia enhance spatial heterogeneities of repolarization in guinea pig hearts: analysis of spatial autocorrelation of optically recorded action potential durations.

INTRODUCTION: Regional dispersions of repolarization (DOR) are arrhythmogenic perturbations that are closely associated with reentry. However, the characteristics of DOR have not been well defined or adequately analyzed because previous algorithms did not take into account spatial heterogeneities of action potential durations (APDs). Earlier simulations proposed that pathologic conditions enhance DOR by decreasing electrical coupling between cells, thereby unmasking differences in cellular repolarization between neighboring cells. Optical mapping indicated that gradients of APD and DOR are associated with fiber structure and are largely independent of activation. We developed an approach to quantitatively characterize APD gradients and DOR to determine how they are influenced by tissue anisotropy and cell coupling during diverse arrhythmogenic insults such as hypoxia and hypothermia. METHODS AND RESULTS: Voltage-sensitive dyes were used to map APs from 124 sites on the epicardium of Langendorff-perfused guinea pig hearts during (1) cycles of hypoxia and reoxygenation and (2) after 30 minutes of hypothermia (32 degrees to 25 degrees C). We introduce an approach to quantitate DOR by analyzing two-dimensional spatial autocorrelation of APDs along directions perpendicular and parallel to the longitudinal axis of epicardial fibers. A spatial correlation length L was derived as a statistical measure of DOR. It corresponds to the distance over which APDs had comparable values, where L is inversely related to DOR. Hypoxia (30 min) caused a negligible decrease in longitudinal thetaL (from 0.530 +/- 0.138 to 0.478 +/- 0.052 m/sec) and transverse thetaT (from 0.225 +/- 0.034 to 0.204 +/- 0.021 m/sec) conduction velocities and did not alter thetaL/thetaT or activation patterns. In paced hearts (cycle length [CL] = 300 msec), hypoxia decreased APDs (123 +/- 18.2 to 46 +/- 0.6 msec; P < 0.001) within 10 to 15 minutes and enhanced DOR, as indicated by reductions of L from 1.8 +/- 0.9 to 1.1 +/- 0.5 mm (P < 0.005). Hypothermia caused marked reductions of thetaL (0.53 +/- 0.138 to 0.298 +/- 0.104 m/sec) and thetaT (0.225 +/- 0.034 to 0.138 +/- 0.027 m/sec), increased APDs (128 +/- 4.4 to 148 +/- 14.5 msec), and reduced L from 2.0 +/- 0.3 to 1.3 +/- 0.6 mm (P < 0.05). L decreased with increased time of hypoxia and recovered upon reoxygenation. Hypoxia and hypothermia reduced L measured along the longitudinal (L(L)) and transverse (L(T)) axes of cardiac fibers while the ratio of L(L)/L(T) remained constant. CONCLUSION: Conventional indexes of DOR (i.e., APD "range" or "standard deviation," evaluated with extracellular electrodes) did not convey the spatial inhomogeneities of repolarization revealed by L. Spatial autocorrelation analysis provides a statistically significant measurement of DOR, which can take into account intrinsic heterogeneities of APDs and fiber orientation. The data show that hypoxia and hypothermia produce reductions of L, even though they have different effects on mean APD and conduction velocity. The preservation of a constant L(L)/L(T) ratio during hypoxia and hypothermia, despite large reductions in L, is consistent with a mechanism in which reduced cell-to-cell coupling unmasks intrinsic dispersions of APD and reduces L(L) and L(T) by the same factor. Thus, the spatial autocorrelation of APDs provides a sensitive index of DOR under normal and arrhythmogenic conditions. It incorporates the anisotropic nature of the myocardium and therefore is preferable to conventional indexes of DOR.

Action Potentials↗
PubMed1989

Spatial summation of heat-induced pain: influence of stimulus area and spatial separation of stimuli on perceived pain sensation intensity and unpleasantness.

1. Psychophysical experiments were initiated to determine the possible influence of increasing stimulus size on perceived pain intensity. Six trained human subjects (5 male, 1 female) made visual analogue scale (VAS) ratings for pain-sensation intensity and unpleasantness in response to nociceptive thermal stimuli. Test stimuli consisted of 5-s duration heat pulses (45-50 degrees C in 1 degrees increments) delivered by one, two, or three contact thermal probes (1 cm2 each) applied to the medial aspect of the anterior forearm. 2. The area of skin receiving noxious thermal stimuli was changed by randomly varying the number of thermodes activated. The effects of varying the distance between the thermal probes also were evaluated. In the first series of experiments, thermal-probe separation was kept close to 0; in subsequent experimental series, the thermodes were separated by either 5 or 10 cm. 3. In each experimental series, considerable spatial summation occurred in both pain-sensation intensity and unpleasantness dimensions of pain. This summation occurred throughout the nociceptive thermal range of 45-50 degrees C and was larger at suprathreshold temperatures (greater than or equal to 47 degrees C) than those near threshold (less than or equal to 46 degrees C). Unlike spatial summation of perceived warmth, that of pain was not characterized by systematic changes in power-function exponents but as approximately upward parallel displacements in double-logarithmic coordinates. 4. Thermal-probe separation over a range of 0-10 cm had no effects on spatial summation of pain-sensation intensity or pain unpleasantness. In contrast, increasing thermal-probe separation increased the subjects' ability to discriminate differences in stimulus size and their ability to detect correctly the number of thermal probes activated. 5. Because affective VAS ratings of unpleasantness were linearly related to, but distinctly and systematically less than, VAS ratings of pain-sensation intensity, it was clear that subjects responded quite differently to these two pain dimensions. Affective judgements were not additionally influenced by thermal probe separation and hence by the ability to perceive stimulus size or number of thermal probes activated. 6. The results indicate that powerful spatial-summation mechanisms exist for heat-induced pain. Spatial summation of pain is likely to be subserved both by local integration mechanisms at the level of single spinothalamic-tract neurons and by recruitment of central nociceptive neurons, because spatial summation of pain occurred to approximately equal extents under conditions of thermode separations over a distance of at least 20 cm.

Adult↗
PubMed1987

Spatial frequency discrimination for sinewave gratings with random, bandpass frequency modulation: evidence for averaging in spatial acuity.

Spatial frequency difference thresholds for vertical, high contrast sinewave gratings were estimated at 1.25, 2.5, 5.0 and 10.0 cyc deg-1. Within an experiment two independent manipulations of the stimulus were employed: (1) the number of cycles of the sinewave grating was varied over a range of 2.0 to 15.0 cycles; and (2) a stationary, random frequency modulation was imposed on the sinewave. The probability density function of the frequency modulation was a Gaussian whose dispersion coefficient was varied, in different experiments, in the range of 0 to 10% of the frequency of the parent sinewave. Both of these experimental variables were found to affect the precision with which spatial frequency discrimination could be performed. The Weber fraction increased both as the number of cycles present was decreased and as the dispersion coefficient of the modulating function was increased. These two effects were independent. The data support previous psychophysical findings that spatial frequency discrimination involves averaging over the total area of the stimulus and are compatible with spatial primitive models of spatial contrast vision. The data are not compatible with those of Hirsch and Hylton (J. opt. Soc. Am. 72, 1367-1374) which suggest that spatial interval discrimination occurs solely by operation of foveal mechanisms.

Adult↗