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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., Sensory hypersensitivity is common in autism spectrum disorders. Using functional MRI, psychophysics, and computational modeling, Schallmo et al. show that differences in visual motion perception in ASD are accompanied by weaker neural suppression in visual cortex.

When one's central vision is deprived, a spared part of the peripheral retina acts as a pseudofovea for fixation. The neural mechanisms underlying this compensatory adjustment remain unclear. Here we report cortical reorganization induced by simulated central vision loss. Human subjects of both sexes learned to place the target at an eccentric retinal locus outside their blocked visual field for object tracking. Before and after training, we measured visual crowding—a bottleneck of object identification in peripheral vision, using psychophysics and fMRI. We found that training led to an axis-specific reduction of crowding. The change of the crowding effect was reflected in the change of BOLD signal, as a release of cortical suppression in multiple visual areas starting as early as V1. Our findings suggest that the adult visual system is capable of reshaping its oculomotor control and sensory coding to adapt to impoverished visual input. SIGNIFICANCE STATEMENT By simulating central vision loss in normally sighted adults, we found that oculomotor training not only induces PRL, but also facilitates form processing in peripheral vision. As subjects learned to place the target at an eccentric retinal locus, “visual crowding”—the detrimental effect of clutter on peripheral object identification—was reduced. The reduction of the crowding effect was accompanied by a release of response suppression in the visual cortex. These findings indicate that the adult visual system is capable of reshaping the peripheral vision to adapt to central vision loss.

There has been long-standing speculation that autism spectrum disorder (ASD) involves an increase in excitation relative to inhibition. However, there is little direct evidence of increased neural excitation in humans with ASD. Here we provide a potential explanation for this discrepancy: we show that increased neural excitation emerges only after repeated stimulation, manifesting as a deficit in neural adaptation. We measured fMRI responses induced by repeated audio-visual stimulation and button presses in early sensory-motor cortical areas. Across all cortical areas we show reduced adaptation in individuals with ASD compared to neurotypical individuals. The degree of adaptation is correlated between cortical areas and with button-press reaction times across subjects. These findings suggest that increased neural excitation in ASD, manifesting as dysregulated neural adaptation, is domain-general and behaviorally-relevant.

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 separately measured fMRI responses to moving gratings in the motion-selective region MT, and perceptual duration thresholds for motion direction discrimination within the same group of male and female subjects. Further, we acquired MR spectroscopy data that allowed us to quantify an index of neurotransmitter levels in the region surrounding MT. We show that individual differences in the Glx (glutamate + glutamine) signal in the MT region are associated with both higher fMRI responses and improved psychophysical task performance. Our results suggest that individual differences in baseline levels of glutamate within MT contribute to motion perception by increasing neural responses in this region.SignificanceWhat factors govern the relationship between neural activity and behavior? Our results suggest that one such factor is the level of glutamate, an excitatory neurotransmitter, within a particular region of cortex. By measuring an index of glutamate in vivo using magnetic resonance spectroscopy, we show that human subjects with more glutamate in the visual motion area known as MT also have larger fMRI responses (an index of neural activity) in this region. Further, people with more glutamate in MT can accurately perceive moving images presented more briefly within a behavioral task. Our findings point to an important role for glutamate levels in determining the relationship between neural responses and behavior during visual motion perception.

Summary 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 , 7 , 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.

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 5 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 driven by GABA-mediated inhibition. Thus, while commonly used spatial suppression paradigms may provide insight into neural response magnitudes in visual areas, they cannot be used to infer neural inhibition.

Crowding, the inability to recognize an individual object in clutter (Bouma H. Nature 226: 177–178, 1970), is considered a major impediment to object recognition in peripheral vision. Despite its significance, the cortical loci of crowding are not well understood. In particular, the role of the primary visual cortex (V1) remains unclear. Here we utilize a diagnostic feature of crowding to identify the earliest cortical locus of crowding. Controlling for other factors, radially arranged flankers induce more crowding than tangentially arranged ones (Toet A, Levi DM. Vision Res 32: 1349–1357, 1992). We used functional magnetic resonance imaging (fMRI) to measure the change in mean blood oxygenation level-dependent (BOLD) response due to the addition of a middle letter between a pair of radially or tangentially arranged flankers. Consistent with the previous finding that crowding is associated with a reduced BOLD response [Millin R, Arman AC, Chung ST, Tjan BS. Cereb Cortex (July 5, 2013). doi:10.1093/cercor/bht159], we found that the BOLD signal evoked by the middle letter depended on the arrangement of the flankers: less BOLD response was associated with adding the middle letter between radially arranged flankers compared with adding it between tangentially arranged flankers. This anisotropy in BOLD response was present as early as V1 and remained significant in downstream areas. The effect was observed while subjects' attention was diverted away from the testing stimuli. Contrast detection threshold for the middle letter was unaffected by flanker arrangement, ruling out surround suppression of contrast response as a major factor in the observed BOLD anisotropy. Our findings support the view that V1 contributes to crowding.

This study tested the hypothesis that diffusion tensor imaging can detect alteration in microscopic integrity of white matter and basal ganglia regions known to be involved in Parkinson's disease (PD) pathology. It was also hypothesized that there is an association between diffusion abnormality and PD severity and subtype. Diffusion tensor imaging at 4 Tesla was obtained in 12 PD and 20 control subjects, and measures of fractional anisotropy and mean diffusivity were evaluated using both region-of-interest and voxel-based methods. Movement deficits and subtypes in PD subjects were assessed using the Motor Subscale (Part III) of the Unified Parkinson's Disease Rating Scale. Reduced fractional anisotropy (P < .05, corrected) was found in PD subjects in regions related to the precentral gyrus, substantia nigra, putamen, posterior striatum, frontal lobe, and the supplementary motor areas. Reduced fractional anisotropy in the substantia nigra correlated (P < .05, corrected) with the increased rating scale motor scores. Significant spatial correlations between fractional anisotropy alterations in the putamen and other PD-affected regions were also found in the context of PD subtypes index analysis. Our data suggest that microstructural alterations detected with diffusion tensor might serve as a potential biomarker for PD.

The blood-oxygen-level-dependent (BOLD) signal measured in functional magnetic resonance imaging (fMRI) experiments is generally regarded as sluggish and poorly suited for probing neural function at the rapid timescales involved in sentence comprehension. However, recent studies have shown the value of acquiring data with very short repetition times (TRs), not merely in terms of improvements in contrast to noise ratio (CNR) through averaging, but also in terms of additional fine-grained temporal information. Using multiband-accelerated fMRI, we achieved whole-brain scans at 3-mm resolution with a TR of just 500 ms at both 3T and 7T field strengths. By taking advantage of word timing information, we found that word decoding accuracy across two separate sets of scan sessions improved significantly, with better overall performance at 7T than at 3T. The effect of TR was also investigated; we found that substantial word timing information can be extracted using fast TRs, with diminishing benefits beyond TRs of 1000 ms.

Proteins interacting at multiple sites on DNA via looping play an important role in many fundamental biochemical processes. Restriction endonucleases that must bind at two recognition sites for efficient activity are a useful model system for studying such interactions. Here we used single DNA manipulation to study sixteen known or suspected two-site endonucleases. In eleven cases (BpmI, BsgI, BspMI, Cfr10I, Eco57I, EcoRII, FokI, HpaII, NarI, Sau3AI and SgrAI) we found that substitution of Ca 21 for Mg 21 blocked cleavage and enabled us to observe stable DNA looping. Forced disruption of these loops allowed us to measure the frequency of looping and probability distributions for loop size and unbinding force for each enzyme. In four cases we observed bimodal unbinding force distributions, indicating conformational heterogeneity and/or complex binding energy landscapes. Measured unlooping events ranged in size from 7 to 7500 bp and the most probable size ranged from less than 75 bp to nearly 500 bp, depending on the enzyme. In most cases the size distributions were in much closer agreement with theoretical models that postulate sharp DNA kinking than with classical models of DNA elasticity. Our findings indicate that DNA looping is highly variable depending on the specific protein and does not depend solely on the mechanical properties of DNA.

We present an algorithm, Sparse Atomic Feature Learning (SAFL), that transforms noisy labeled datasets into a sparse domain by learning atomic features of the underlying signal space via gradient minimization. The sparse signal representations are highly compressed and cleaner than the original signals. We demonstrate the effectiveness of our techniques on fMRI activity patterns. We produce low-dimensional, sparse representations which achieve over 98% compression of the original signals. The transformed signals can be used to classify left-out testing data at a higher accuracy than the initial data.

In peripheral vision, objects in clutter are difficult to identify. The exact cause of this “crowding” effect is unclear. To perceive coherent shapes in clutter, the visual system must integrate certain local features across receptive fields while preventing others from being combined. It is believed that this selective feature integration–segmentation process is impaired in peripheral vision, leading to crowding. We used functional magnetic resonance imaging (fMRI) to investigate the neural origin of crowding. We found that crowding was associated with suppressed fMRI signal as early as V1, regardless of whether attention was directed toward or away from a target stimulus. This suppression in early visual cortex was greatest for stimuli that produced the strongest crowding. In contrast, the pattern of activity was mixed in higher level visual areas, such as the lateral occipital cortex. These results support the view that the deficiency in feature integration and segmentation in peripheral vision is present at the earliest stages of cortical processing.

This study tested the hypothesis that diffusion tensor imaging (DTI) can detect alteration in microscopic integrity of white matter (WM) and basal ganglia (BG) regions known to be involved in Parkinson's disease (PD) pathology. It was also hypothesized that there is an association between the DTI abnormality and PD severity and subtype. DTI at 4 Tesla was obtained in 12 PD and 20 control subjects. The DTI measures of fractional anisotropy (FA) and mean diffusivity (MD) were evaluated using both region of interest (ROI) and voxel-based methods. Movement deficits in PD subjects were assessed using Motor Subscale (Part III) of the Unified Parkinson's Disease Rating Scale (UPDRS). Subtype determination of movement deficits was derived based upon results of subjects’ UPDRS ratings. Reduced FA (p

Recent studies associated excess body weight with brain structural alterations, poorer cognitive function, and lower prefrontal glucose metabolism. We found that higher BMI was related to lower concentrations of N-acetyl-aspartate (NAA, a marker of neuronal integrity) in a healthy middle-aged cohort, especially in frontal lobe. Here, we evaluated whether NAA was also associated with BMI in a healthy elderly cohort. We used 4 Tesla proton magnetic resonance spectroscopy (1H MRS) data from 23 healthy, cognitively normal elderly participants (69.4 ± 6.9 years; 12 females) and measured concentrations of NAA, glutamate (Glu, involved in cellular metabolism), choline-containing compounds (Cho, involved in membrane metabolism), and creatine (Cr, involved in high-energy metabolism) in anterior (ACC) and posterior cingulate cortices (PCC). After adjustment for age, greater BMI was related to lower NAA/Cr and NAA/Cho ratios (β < −0.56, P < 0.008) and lower Glu/Cr and Glu/Cho ratios (β < −0.46, P < 0.02) in ACC. These associations were not significant in PCC (β > −0.36, P > 0.09). The existence of an association between NAA and BMI in ACC but not in PCC is consistent with our previous study in healthy middle-aged individuals and with reports of lower frontal glucose metabolism in young healthy individuals with elevated BMI. Taken together, these results provide evidence that elevated BMI is associated with neuronal abnormalities mostly in frontal brain regions that subserve higher cognitive functions and impulse control. Future studies need to evaluate whether these metabolite abnormalities are involved in the development and maintenance of weight problems.

Looping and cleavage of single DNA molecules by the two-site restriction endonuclease Sau3AI were measured with optical tweezers. A DNA template containing many recognition sites was used, permitting loop sizes from ~10 to 10,000 basepairs. At high enzyme concentration cleavage events were detected within 5 seconds and nearly all molecules were cleaved within 5 minutes. Activity decreased ~10-fold as the DNA tension was increased from 0.03 to 0.7 pN. Substituting Ca 2+ for Mg 2+ blocked cleavage, permitting measurement of stable loops. At low tension, the initial rates of cleavage and looping were similar (~0.025 s -1 at 0.1 pN), suggesting that looping is rate limiting. Short loops formed more rapidly than long loops. The optimum size decreased from ~250 to 45 bp and the average number of loops (in 1 minute) from 4.2 to 0.75 as tension was increased from 0.03 to 0.7 pN. No looping was detected at 5 pN. These findings are in qualitative agreement with recent theoretical predictions considering only DNA mechanics, but we observed weaker suppression with tension and smaller loop sizes. Our results suggest that the span and elasticity of the protein complex and protein-induced DNA bending and wrapping play an important role.

DNA looping occurs in many important protein–DNA interactions, including those regulating replication, transcription, and recombination. Recent theoretical studies predict that tension of only a few piconewtons acting on DNA would almost completely inhibit DNA looping. Here, we study restriction endonucleases that require interaction at two separated sites for efficient cleavage. Using optical tweezers we measured the dependence of cleavage activity on DNA tension with 15 known or suspected two-site enzymes (BfiI, BpmI, BsgI, BspMI, Cfr9I, Cfr10I, Eco57I, EcoRII, FokI, HpaII, MboII, NarI, SacII, Sau3AI, and SgrAI) and six one-site enzymes (BamHI, EcoRI, EcoRV, HaeIII, HindIII, and DNaseI). All of the one-site enzymes were virtually unaffected by 5 pN of tension, whereas all of the two-site enzymes were completely inhibited. These enzymes thus constitute a remarkable example of a tension sensing “molecular switch.” A detailed study of one enzyme, Sau3AI, indicated that the activity decreased exponentially with tension and the decrease was ≈10-fold at 0.7 pN. At higher forces (≈20–40 pN) cleavage by the one-site enzymes EcoRV and HaeIII was partly inhibited and cleavage by HindIII was enhanced, whereas BamHI, EcoRI, and DNaseI were largely unaffected. These findings correlate with structural data showing that EcoRV bends DNA sharply, whereas BamHI, EcoRI, and DNaseI do not. Thus, DNA-directed enzyme activity involving either DNA looping or bending can be modulated by tension, a mechanism that could facilitate mechanosensory transduction in vivo .

Mechanical manipulation of single DNA molecules can provide novel information about protein-DNA interactions. Here we review two examples studied by our group. First, we have studied the forced unraveling of nucleosomes assembled on heterogeneous DNA using core histones, the histone chaperone NAP-1, and ATP-dependent chromatin assembly and remodeling factor (ACF). We measure abrupt events releasing ~55 to 95 base pairs of DNA, which are attributable to non-equilibrium unraveling of individual nucleosomes. Wide variations observed in the unraveling force and sudden DNA re-wrapping events may have an important regulatory influence on DNA directed biochemical processes. Second, we have studied the mechanics and dynamics of single DNA looping and cleavage by "two-site" restriction enzymes. Cleavage is measured as a function of DNA tension, incubation time, and enzyme concentration, distinguishing enzymes that require DNA looping from ones that do not. Forced disruption of fixed DNA loops formed in the absence of Mg 2+ is observed, allowing the distribution of number of loops, loop length, and disruption force to be measured as a function of time, DNA tension, and ionic conditions.

International audience; Mechanical manipulation of single DNA molecules can provide novel information about DNA properties and protein-DNA interactions. Here we describe and characterize a useful method for manipulating desired DNA sequences from any organism with optical tweezers. Molecules are produced from either genomic or cloned DNA by PCR using labeled primers and are tethered between two optically trapped microspheres. We demonstrate that human, insect, plant, bacterial and viral sequences ranging from approximately 10 to 40 kilobasepairs can be manipulated. Force-extension measurements show that these constructs exhibit uniform elastic properties in accord with the expected contour lengths for the targeted sequences. Detailed protocols for preparing and manipulating these molecules are presented, and tethering efficiency is characterized as a function of DNA concentration, ionic strength and pH. Attachment strength is characterized by measuring the unbinding time as a function of applied force. An alternative stronger attachment method using an amino-carboxyl linkage, which allows for reliable DNA overstretching, is also described.

Bone marrow cellularity estimated by biopsy was compared to the cellularity of the aspirate particle smear and the volumetric method in two groups of children. In the first group, 101 consecutive bone marrow biopsies and aspirates were evaluated from patients with various diagnoses. In the second group, 20 patients with acute nonlympho-blastic leukemia were studied with 80 biopsies and aspirates at diagnosis and following chemotherapy. A wide discrepancy was noted between bone marrow cellularity confirmed by biopsy vs. the particle smear or the volumetric method in both groups. Neither the volumetric nor the particle method provides a good correlation of bone marrow cellularity. We also compared the volumetric method with that of the biopsy to evaluate the efficacy of the former method in detecting bone marrow infiltration by solid tumors. The volumetric method is an accurate modality of identifying solid tumor infiltration in the bone marrow.

Looping and cleavage of single DNA molecules by the two-site restriction endonuclease Sau3AI were measured with optical tweezers. A DNA template containing many recognition sites was used, permitting loop sizes from approximately 10 to 10,000 basepairs. At high enzyme concentration, cleavage events were detected within 5 s and nearly all molecules were cleaved within 5 min. Activity decreased approximately 10-fold as the DNA tension was increased from 0.03 to 0.7 pN. Substituting Ca(2+) for Mg(2+) blocked cleavage, permitting measurement of stable loops. At low tension, the initial rates of cleavage and looping were similar (approximately 0.025 s(-1) at 0.1 pN), suggesting that looping is rate limiting. Short loops formed more rapidly than long loops. The optimum size decreased from approximately 250 to 45 basepairs and the average number of loops (in 1 min) from 4.2 to 0.75 as tension was increased from 0.03 to 0.7 pN. No looping was detected at 5 pN. These findings are in qualitative agreement with recent theoretical predictions considering only DNA mechanics, but we observed weaker suppression with tension and smaller loop sizes. Our results suggest that the span and elasticity of the protein complex, nesting of loops, and protein-induced DNA bending and wrapping play an important role.