Temporal Sensitivity for Achromatic and Chromatic Flicker across the Visual Cortex.

The retinal ganglion cells (RGCs) receive different combinations of L, M, and S cone inputs and give rise to one achromatic and two chromatic postreceptoral channels. The goal of the current study was to determine temporal sensitivity across the three postreceptoral channels in subcortical and cortical regions involved in human vision. We measured functional magnetic resonance imaging (fMRI) responses at 7 T from three participants (two males, one female) viewing a high-contrast, flickering, spatially uniform wide field (∼140°). Stimulus flicker frequency varied logarithmically between 2 and 64 Hz and targeted the L + M + S, L - M, and S - (L + M) cone combinations. These measurements were used to create temporal sensitivity functions of the primary visual cortex (V1) across eccentricity and spatially averaged responses from the lateral geniculate nucleus (LGN), and the V2/V3, hV4, and V3A/B regions. fMRI responses reflected the known properties of the visual system, including higher peak temporal sensitivity to achromatic versus chromatic stimuli and low-pass filtering between the LGN and V1. Peak temporal sensitivity increased across levels of the cortical visual hierarchy. Unexpectedly, peak temporal sensitivity varied little across eccentricity within area V1. Measures of adaptation and distributed pattern activity revealed a subtle influence of 64 Hz achromatic flicker in area V1, despite this stimulus evoking only a minimal overall response. The comparison of measured cortical responses to a model of the integrated retinal output to our stimuli demonstrates that extensive filtering and amplification are applied to postretinal signals.

Persistent Gram-negative Bloodstream Infection Increases the Risk of Recurrent Bloodstream Infection With the Same Species.

The association between persistent gram-negative bloodstream infection (GN-BSI), or ongoing positive cultures, and recurrent GN-BSI has not been investigated. Among 992 adults, persistent GN-BSI was associated with increased recurrent GN-BSI with the same bacterial species and strain (6% vs 2%; P = .04). Persistent GN-BSI may be a marker of complicated infection.

Clinical and Molecular Analyses of Recurrent Gram-Negative Bloodstream Infections.

BACKGROUND: The causes and clinical characteristics of recurrent gram-negative bacterial bloodstream infections (GNB-BSI) are poorly understood. METHODS: We used a cohort of patients with GNB-BSI to identify clinical characteristics, microbiology, and risk factors associated with recurrent GNB-BSI. Bacterial genotyping (pulsed-field gel electrophoresis [PFGE] and whole-genome sequencing [WGS]) was used to determine whether episodes were due to relapse or reinfection. Multivariable logistic regression was used to identify risk factors for recurrence. RESULTS: Of the 1423 patients with GNB-BSI in this study, 60 (4%) had recurrent GNB-BSI. Non-White race (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.38-4.01; P = .002), admission to a surgical service (OR, 2.18; 95% CI, 1.26-3.75; P = .005), and indwelling cardiac device (OR, 2.73; 95% CI, 1.21-5.58; P = .009) were associated with increased risk for recurrent GNB-BSI. Among the 48 patients with recurrent GNB-BSI whose paired bloodstream isolates underwent genotyping, 63% were due to relapse (30 of 48) and 38% were due to reinfection (18 of 48) based on WGS. Compared with WGS, PFGE correctly differentiated relapse and reinfection in 98% (47 of 48) of cases. Median time to relapse and reinfection was similar (113 days; interquartile range [IQR], 35-222 vs 174 days; IQR, 69-599; P = .13). Presence of a cardiac device was associated with relapse (relapse: 7 of 27, 26%; nonrelapse: 65 of 988, 7%; P = .002). CONCLUSIONS: In this study, recurrent GNB-BSI was most commonly due to relapse. PFGE accurately differentiated relapse from reinfection when compared with WGS. Cardiac device was a risk factor for relapse.

Projected warming disrupts the synchrony of riparian seed release and snowmelt streamflow.

Globally, spring phenology and abiotic processes are shifting earlier with warming. Differences in the magnitudes of these shifts may decouple the timing of plant resource requirements from resource availability. In riparian forests across the northern hemisphere, warming could decouple seed release from snowmelt peak streamflow, thus reducing moisture and safe sites for dominant tree recruitment. We combined field observations with climate, hydrology, and phenology models to simulate future change in synchrony of seed release and snowmelt peaks in the South Platte River Basin, Colorado, for three Salicaceae species that dominate western USA riparian forests. Chilling requirements for overcoming winter endodormancy were strongest in Salix exigua, moderately supported for Populus deltoides, and indiscernible in Salix amygdaloides. Ensemble mean projected warming of 3.5°C shifted snowmelt peaks 10-19 d earlier relative to S. exigua and P. deltoides seed release, because decreased winter chilling combined with increased spring forcing limited change in their phenology. By contrast, warming shifted both snowmelt peaks and S. amygdaloides seed release 21 d earlier, maintaining their synchrony. Decoupling of snowmelt from seed release for Salicaceae with strong chilling requirements is likely to reduce resources critical for recruitment of these foundational riparian forests, although the magnitude of future decoupling remains uncertain.

The human visual cortex response to melanopsin-directed stimulation is accompanied by a distinct perceptual experience.

The photopigment melanopsin supports reflexive visual functions in people, such as pupil constriction and circadian photoentrainment. What contribution melanopsin makes to conscious visual perception is less studied. We devised a stimulus that targeted melanopsin separately from the cones using pulsed (3-s) spectral modulations around a photopic background. Pupillometry confirmed that the melanopsin stimulus evokes a response different from that produced by cone stimulation. In each of four subjects, a functional MRI response in area V1 was found. This response scaled with melanopic contrast and was not easily explained by imprecision in the silencing of the cones. Twenty additional subjects then observed melanopsin pulses and provided a structured rating of the perceptual experience. Melanopsin stimulation was described as an unpleasant, blurry, minimal brightening that quickly faded. We conclude that isolated stimulation of melanopsin is likely associated with a response within the cortical visual pathway and with an evoked conscious percept.

Predicting future learning from baseline network architecture.

Human behavior and cognition result from a complex pattern of interactions between brain regions. The flexible reconfiguration of these patterns enables behavioral adaptation, such as the acquisition of a new motor skill. Yet, the degree to which these reconfigurations depend on the brain's baseline sensorimotor integration is far from understood. Here, we asked whether spontaneous fluctuations in sensorimotor networks at baseline were predictive of individual differences in future learning. We analyzed functional MRI data from 19 participants prior to six weeks of training on a new motor skill. We found that visual-motor connectivity was inversely related to learning rate: sensorimotor autonomy at baseline corresponded to faster learning in the future. Using three additional scans, we found that visual-motor connectivity at baseline is a relatively stable individual trait. These results suggest that individual differences in motor skill learning can be predicted from sensorimotor autonomy at baseline prior to task execution.

The visual white matter: The application of diffusion MRI and fiber tractography to vision science.

Visual neuroscience has traditionally focused much of its attention on understanding the response properties of single neurons or neuronal ensembles. The visual white matter and the long-range neuronal connections it supports are fundamental in establishing such neuronal response properties and visual function. This review article provides an introduction to measurements and methods to study the human visual white matter using diffusion MRI. These methods allow us to measure the microstructural and macrostructural properties of the white matter in living human individuals; they allow us to trace long-range connections between neurons in different parts of the visual system and to measure the biophysical properties of these connections. We also review a range of findings from recent studies on connections between different visual field maps, the effects of visual impairment on the white matter, and the properties underlying networks that process visual information supporting visual face recognition. Finally, we discuss a few promising directions for future studies. These include new methods for analysis of MRI data, open datasets that are becoming available to study brain connectivity and white matter properties, and open source software for the analysis of these data.

Resting-State Retinotopic Organization in the Absence of Retinal Input and Visual Experience.

Early visual areas have neuronal receptive fields that form a sampling mosaic of visual space, resulting in a series of retinotopic maps in which the same region of space is represented in multiple visual areas. It is not clear to what extent the development and maintenance of this retinotopic organization in humans depend on retinal waves and/or visual experience. We examined the corticocortical receptive field organization of resting-state BOLD data in normally sighted, early blind, and anophthalmic (in which both eyes fail to develop) individuals and found that resting-state correlations between V1 and V2/V3 were retinotopically organized for all subject groups. These results show that the gross retinotopic pattern of resting-state connectivity across V1-V3 requires neither retinal waves nor visual experience to develop and persist into adulthood. Significance statement: Evidence from resting-state BOLD data suggests that the connections between early visual areas develop and are maintained even in the absence of retinal waves and visual experience.

Temporal sensitivity for achromatic and chromatic flicker across the visual cortex.

The retinal ganglion cells (RGCs) receive different combinations of L, M, and S cone inputs and give rise to one achromatic and two chromatic post-receptoral channels. Beyond the retina, RGC outputs are subject to filtering and normalization along the geniculo-striate pathway, ultimately producing the properties of human vision. The goal of the current study was to determine temporal sensitivity across the three post-receptoral channels in subcortical and cortical regions involved in vision. We measured functional magnetic resonance imaging (MRI) responses at 7 Tesla from three participants (two males, one female) viewing a high-contrast, flickering, spatially-uniform wide field (~140°). Stimulus flicker frequency varied logarithmically between 2 and 64 Hz and targeted the L+M+S, L-M, and S-[L+M] cone combinations. These measurements were used to create temporal sensitivity functions of primary visual cortex (V1) across eccentricity, and spatially averaged responses from lateral geniculate nucleus (LGN), V2/V3, hV4, and V3A/B. Functional MRI responses reflected known properties of the visual system, including higher peak temporal sensitivity to achromatic vs. chromatic stimuli, and low-pass filtering between the LGN and V1. Peak temporal sensitivity increased across levels of the cortical visual hierarchy. Unexpectedly, peak temporal sensitivity varied little across eccentricity within area V1. Measures of adaptation and distributed pattern activity revealed a subtle influence of 64 Hz achromatic flicker in area V1, despite this stimulus evoking only a minimal overall response. Comparison of measured cortical responses to a model of integrated retinal output to our stimuli demonstrates that extensive filtering and amplification is applied to post-retinal signals.

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.

Deafferentation-induced plasticity of visual callosal connections: predicting critical periods and analyzing cortical abnormalities using diffusion tensor imaging.

Callosal connections form elaborate patterns that bear close association with striate and extrastriate visual areas. Although it is known that retinal input is required for normal callosal development, there is little information regarding the period during which the retina is critically needed and whether this period correlates with the same developmental stage across species. Here we review the timing of this critical period, identified in rodents and ferrets by the effects that timed enucleations have on mature callosal connections, and compare it to other developmental milestones in these species. Subsequently, we compare these events to diffusion tensor imaging (DTI) measurements of water diffusion anisotropy within developing cerebral cortex. We observed that the relationship between the timing of the critical period and the DTI-characterized developmental trajectory is strikingly similar in rodents and ferrets, which opens the possibility of using cortical DTI trajectories for predicting the critical period in species, such as humans, in which this period likely occurs prenatally. Last, we discuss the potential of utilizing DTI to distinguish normal from abnormal cerebral cortical development, both within the context of aberrant connectivity induced by early retinal deafferentation, and more generally as a potential tool for detecting abnormalities associated with neurodevelopmental disorders.

The TRIM9/TRIM67 neuronal interactome reveals novel activators of morphogenesis.

TRIM9 and TRIM67 are neuronally enriched E3 ubiquitin ligases essential for appropriate morphogenesis of cortical and hippocampal neurons and fidelitous responses to the axon guidance cue netrin-1. Deletion of murine Trim9 or Trim67 results in neuroanatomical defects and striking behavioral deficits, particularly in spatial learning and memory. TRIM9 and TRIM67 interact with cytoskeletal and exocytic proteins, but the full interactome is not known. Here we performed the unbiased proximity-dependent biotin identification (BioID) approach to define TRIM9 and TRIM67 protein-protein proximity network in developing cortical neurons and identified putative neuronal TRIM interaction partners. Candidates included cytoskeletal regulators, cytosolic protein transporters, exocytosis and endocytosis regulators, and proteins necessary for synaptic regulation. A subset of high-priority candidates was validated, including Myo16, Coro1A, MAP1B, ExoC1, GRIP1, PRG-1, and KIF1A. For a subset of validated candidates, we utilized total internal reflection fluorescence microscopy to demonstrate dynamic colocalization with TRIM proteins at the axonal periphery, including at the tips of filopodia. Further analysis demonstrated that the RNA interference-based knockdown of the unconventional myosin Myo16 in cortical neurons altered growth cone filopodia density and axonal branching patterns in a TRIM9- and netrin-1-dependent manner. Future analysis of other validated candidates will likely identify novel proteins and mechanisms by which TRIM9 and TRIM67 regulate neuronal form and function. [Media: see text].

Anatomical and functional plasticity in early blind individuals and the mixture of experts architecture.

As described elsewhere in this special issue, recent advances in neuroimaging over the last decade have led to a rapid expansion in our knowledge of anatomical and functional correlations within the normal and abnormal human brain. Here, we review how early blindness has been used as a model system for examining the role of visual experience in the development of anatomical connections and functional responses. We discuss how lack of power in group comparisons may provide a potential explanation for why extensive anatomical changes in cortico-cortical connectivity are not observed. Finally we suggest a framework-cortical specialization via hierarchical mixtures of experts-which offers some promise in reconciling a wide range of functional and anatomical data.

Diffusion tensor imaging detects early cerebral cortex abnormalities in neuronal architecture induced by bilateral neonatal enucleation: an experimental model in the ferret.

Diffusion tensor imaging (DTI) is a technique that non-invasively provides quantitative measures of water translational diffusion, including fractional anisotropy (FA), that are sensitive to the shape and orientation of cellular elements, such as axons, dendrites and cell somas. For several neurodevelopmental disorders, histopathological investigations have identified abnormalities in the architecture of pyramidal neurons at early stages of cerebral cortex development. To assess the potential capability of DTI to detect neuromorphological abnormalities within the developing cerebral cortex, we compare changes in cortical FA with changes in neuronal architecture and connectivity induced by bilateral enucleation at postnatal day 7 (BEP7) in ferrets. We show here that the visual callosal pattern in BEP7 ferrets is more irregular and occupies a significantly greater cortical area compared to controls at adulthood. To determine whether development of the cerebral cortex is altered in BEP7 ferrets in a manner detectable by DTI, cortical FA was compared in control and BEP7 animals on postnatal day 31. Visual cortex, but not rostrally adjacent non-visual cortex, exhibits higher FA than control animals, consistent with BEP7 animals possessing axonal and dendritic arbors of reduced complexity than age-matched controls. Subsequent to DTI, Golgi-staining and analysis methods were used to identify regions, restricted to visual areas, in which the orientation distribution of neuronal processes is significantly more concentrated than in control ferrets. Together, these findings suggest that DTI can be of utility for detecting abnormalities associated with neurodevelopmental disorders at early stages of cerebral cortical development, and that the neonatally enucleated ferret is a useful animal model system for systematically assessing the potential of this new diagnostic strategy.