Nerve Wrap for Local Delivery of FK506/Tacrolimus Accelerates Nerve Regeneration.

Peripheral nerve injuries (PNIs) occur frequently and can lead to devastating and permanent sensory and motor function disabilities. Systemic tacrolimus (FK506) administration has been shown to hasten recovery and improve functional outcomes after PNI repair. Unfortunately, high systemic levels of FK506 can result in adverse side effects. The localized administration of FK506 could provide the neuroregenerative benefits of FK506 while avoiding systemic, off-target side effects. This study investigates the utility of a novel FK506-impregnated polyester urethane urea (PEUU) nerve wrap to treat PNI in a previously validated rat infraorbital nerve (ION) transection and repair model. ION function was assessed by microelectrode recordings of trigeminal ganglion cells responding to controlled vibrissae deflections in ION-transected and -repaired animals, with and without the nerve wrap. Peristimulus time histograms (PSTHs) having 1 ms bins were constructed from spike times of individual single units. Responses to stimulus onsets (ON responses) were calculated during a 20 ms period beginning 1 ms after deflection onset; this epoch captures the initial, transient phase of the whisker-evoked response. Compared to no-wrap controls, rats with PEUU-FK506 wraps functionally recovered earlier, displaying larger response magnitudes. With nerve wrap treatment, FK506 blood levels up to six weeks were measured nearly at the limit of quantification (LOQ ≥ 2.0 ng/mL); whereas the drug concentrations within the ION and muscle were much higher, demonstrating the local delivery of FK506 to treat PNI. An immunohistological assessment of ION showed increased myelin expression for animals assigned to neurorrhaphy with PEUU-FK506 treatment compared to untreated or systemic-FK506-treated animals, suggesting that improved PNI outcomes using PEUU-FK506 is mediated by the modulation of Schwann cell activity.

Cortical reintegration after facial allotransplantation.

Neural plasticity of the brain or its ability to reorganize following injury has likely coincided with the successful clinical correction of severe deformity by facial transplantation since 2005. In this study, we present the cortical reintegration outcomes following syngeneic hemifacial vascularized composite allograft (VCA) in a small animal model. Specifically, changes in the topographic organization and unit response properties of the rodent whisker-barrel somatosensory system were assessed following hemifacial VCA. Clear differences emerged in the barrel-cortex system when comparing naïve and hemiface transplanted animals. Neurons in the somatosensory cortex of transplanted rats had decreased sensitivity albeit increased directional sensitivity compared with naïve rats and evoked responses in transplanted animals were more temporally dispersed. In addition, receptive fields were often topographically mismatched with the indication that the mismatched topography reorganized within adjacent barrel (same row-arc bias following hemifacial transplant). These results suggest subcortical changes in the thalamus and/or brainstem play a role in hemifacial transplantation cortical plasticity and demonstrate the discrete and robust data that can be derived from this clinically relevant small animal VCA model for use in optimizing postsurgical outcomes.NEW & NOTEWORTHY Robust rodent hemifacial transplant model was used to record functional changes in somatosensory cortex after transplantation. Neurons in the somatosensory cortex of face transplant recipients had decreased sensitivity to stimulation of whiskers with increased directional sensitivity vs. naive rats. Transplant recipient cortical unit response was more dispersed in temporary vs. naive rats. Despite histological similarities to naive cortices, transplant recipient cortices had a mix of topographically appropriate and inappropriate whiskered at barrel cortex relationships.

As if by Magic: An Abrupt Change in Motion Direction Induces Change Blindness.

Magicians claim that an abrupt change in the direction of movement can attract attention, allowing them to hide their method for a trick in plain sight. In three experiments involving 43 total subjects, we tested this claim by examining whether a sudden directional change can induce change blindness. Subjects were asked to detect an instantaneous orientation change of a single item in an array of Gabor patches; this change occurred as the entire array moved across the display. Subjects consistently spotted the change if it occurred while the array moved along a straight path but missed it when it occurred as the array changed direction. This method of inducing change blindness leaves the object in full view during the change; requires no additional distractions, visual occlusion, or global transients; and worked in every subject tested here. This phenomenon joins a body of magic-inspired work that yields insights into perception and attention.

Constraints on generality statements are needed to define direct replication.

Whether or not a replication attempt counts as "direct" often cannot be determined definitively after the fact as a result of flexibility in how procedural differences are interpreted. Specifying constraints on generality in original articles can eliminate ambiguity in advance, thereby leading to a more cumulative science.

Effect of whisker geometry on contact force produced by vibrissae moving at different velocities.

Rats and mice are able to perform a variety of subtle tactile discriminations with their mystacial vibrissae. Increasingly, the design and interpretation of neurophysiological and behavioral studies are inspired by and linked to a more precise understanding of the detailed physical properties of the whiskers and their associated hair follicles. Here we used a piezoelectric sensor (bimorph) to examine how contact forces are influenced by the geometry of individual whisker hairs. For a given point along a whisker, bimorph signals are linearly related to whisker movement velocity. The slope of this linear function, called velocity sensitivity (VS), diminishes nonlinearly as whisker diameter decreases. Whiskers differ in overall length, thickness, and proximal-distal taper. Thus VS varies along an individual whisker and among different whiskers on the mystacial pad. Thinner, shorter whiskers, such as those located rostrally in rats and those in mice, have lower overall VSs, rendering them potentially less effective for mediating discriminations that rely on subtle velocity cues. The nonlinear effect of diameter combined with the linear effect of arc length produces radial distance tuning curves wherein small differences in the proximal-distal location of impacts yields larger differences in signal magnitude. Such position-dependent cues could contribute to the localization of objects near the face. Proximal-to-distal changes in contact location during whisking sweeps could also provide signals that aid texture discrimination.NEW & NOTEWORTHY This study describes the geometry of facial whiskers distributed across the mystacial pad with emphasis on velocity encoding of object strikes. Findings indicate how the shapes, lengths, and thicknesses of individual hairs can contribute to sophisticated vibrissa-based tactile discrimination.

Target-specific M1 inputs to infragranular S1 pyramidal neurons.

The functional role of input from the primary motor cortex (M1) to primary somatosensory cortex (S1) is unclear; one key to understanding this pathway may lie in elucidating the cell-type specific microcircuits that connect S1 and M1. Recently, we discovered that a subset of pyramidal neurons in the infragranular layers of S1 receive especially strong input from M1 (Kinnischtzke AK, Simons DJ, Fanselow EE. Cereb Cortex 24: 2237-2248, 2014), suggesting that M1 may affect specific classes of pyramidal neurons differently. Here, using combined optogenetic and retrograde labeling approaches in the mouse, we examined the strengths of M1 inputs to five classes of infragranular S1 neurons categorized by their projections to particular cortical and subcortical targets. We found that the magnitude of M1 synaptic input to S1 pyramidal neurons varies greatly depending on the projection target of the postsynaptic neuron. Of the populations examined, M1-projecting corticocortical neurons in L6 received the strongest M1 inputs, whereas ventral posterior medial nucleus-projecting corticothalamic neurons, also located in L6, received the weakest. Each population also possessed distinct intrinsic properties. The results suggest that M1 differentially engages specific classes of S1 projection neurons, thereby regulating the motor-related influence S1 exerts over subcortical structures.

Response properties of whisker-associated primary afferent neurons following infraorbital nerve transection with microsurgical repair in adult rats.

The rodent whisker/trigeminal system, characterized by high spatial and temporal resolution, provides an experimental model for developing new therapies for improving sensory functions of damaged peripheral nerves. Here, we use controlled whisker stimulation and single-unit recordings of trigeminal ganglion cells to examine in detail the nature and time course of functional recovery of mechanoreceptive afferents following nerve transection with microsurgical repair of the infraorbital nerve (ION) branch of the trigeminal nerve in adult rats. Response measures include rapid vs. slow adaptation, firing rate, interspike intervals, latency, and angular (directional) tuning. Whisker-evoked responses, readily observable by 3 wk post-transection, recover progressively for at least the next 5 wk. All cells in transected animals, as in control cases, responded to deflections of single whiskers only, but topography within the ganglion was clearly disrupted. The time course and extent of recovery of quantitative response measures were receptor dependent. Cells displaying slowly adapting (SA) properties recovered more quickly than rapidly adapting (RA) populations, and for some response measures-notably evoked firing rates-closely approached or attained control levels by 8 wk post-transection. Angular tuning of RA cells was slightly better than control units, whereas SA tuning did not differ from control values. Nerve conduction times and refractory periods, examined separately using electrical stimulation of the ION, were slower than normal in all transected animals and poorly reflected recovery of whisker-evoked response latencies and interspike intervals. Results underscore the need for multiple therapeutic strategies that target different aspects of functional restitution following peripheral nerve injury.

Does working memory capacity predict cross-modally induced failures of awareness?

People often fail to notice unexpected stimuli when they are focusing attention on another task. Most studies of this phenomenon address visual failures induced by visual attention tasks (inattentional blindness). Yet, such failures also occur within audition (inattentional deafness), and people can even miss unexpected events in one sensory modality when focusing attention on tasks in another modality. Such cross-modal failures are revealing because they suggest the existence of a common, central resource limitation. And, such central limits might be predicted from individual differences in cognitive capacity. We replicated earlier evidence, establishing substantial rates of inattentional deafness during a visual task and inattentional blindness during an auditory task. However, neither individual working memory capacity nor the ability to perform the primary task predicted noticing in either modality. Thus, individual differences in cognitive capacity did not predict failures of awareness even though the failures presumably resulted from central resource limitations.

Motor cortex broadly engages excitatory and inhibitory neurons in somatosensory barrel cortex.

Anatomical studies have shown that primary somatosensory (S1) and primary motor (M1) cortices are reciprocally connected. The M1 to S1 projection is thought to represent a modulatory signal that conveys motor-related information to S1. Here, we investigated M1 synaptic inputs to S1 by injecting an AAV virus containing channelrhodopsin-2 and a fluorescent tag into M1. Consistent with previous results, we found labeling of M1 axons within S1 that was most robust in the deep layers and in L1. Labeling was sparse in L4 and was concentrated in the interbarrel septa, largely avoiding barrel centers. In S1, we recorded in vitro from regular-spiking excitatory neurons and fast-spiking and somatostatin-expressing inhibitory interneurons. All 3 cell types had a high probability of receiving direct excitatory M1 input. Both excitatory and inhibitory cells within L4 were the least likely to receive such input from M1. Disynaptic inhibition was observed frequently, indicating that M1 recruits substantial inhibition within S1. Additionally, a subpopulation of L6 regular-spiking excitatory neurons received exceptionally strong M1 input. Overall, our results suggest that activation of M1 evokes within S1 a bombardment of excitatory and inhibitory synaptic activity that could contribute in a layer-specific manner to state-dependent changes in S1.

Working-memory performance is related to spatial breadth of attention.

Working memory and attention are closely related constructs. Models of working memory often incorporate an attention component, and some even equate working memory and attentional control. Although some attention-related processes, including inhibitory control of response conflict and interference resolution, are strongly associated with working memory, for other aspects of attention the link is less clear. We examined the association between working-memory performance and attentional breadth, the ability to spread attention spatially. If the link between attention and working memory is broader than inhibitory and interference resolution processes, then working-memory performance might also be associated with other attentional abilities, including attentional breadth. We tested 123 participants on a variety of working-memory and attentional-breadth measures, finding a strong correlation between performances on these two types of tasks. This finding demonstrates that the link between working memory and attention extends beyond inhibitory processes.

Individual differences in inattentional blindness.

People often fail to notice unexpected objects and events when they are performing an attention-demanding task, a phenomenon known as inattentional blindness. We might expect individual differences in cognitive ability or personality to predict who will and will not notice unexpected objects given that people vary in their ability to perform attention-demanding tasks. We conducted a comprehensive literature search for empirical inattentional blindness reports and identified 38 records that included individual difference measures and met our inclusion criteria. From those, we extracted individual difference effect sizes for 31 records which included a total of 74 distinct, between-groups samples with at least one codable individual difference measure. We conducted separate meta-analyses of the relationship between noticing/missing an unexpected object and scores on each of the 14 cognitive and 19 personality measures in this dataset. We also aggregated across personality measures reflecting positive/negative affectivity or openness/absorption and cognitive measures of interference, attention breadth, and memory. Collectively, these meta-analyses provided little evidence that individual differences in ability or personality predict noticing of an unexpected object. A robustness analysis that excluded samples with extremely low numbers of people who noticed or missed produced similar results. For most measures, the number of samples and the total sample sizes were small, and larger studies are needed to examine individual differences in inattentional blindness more systematically. However, the results are consistent with the idea that noticing of unexpected objects or events differs from deliberate attentional control tasks in that it is not reliably predicted by individual differences in cognitive ability.

Are Familiar Objects More Likely to Be Noticed in an Inattentional Blindness Task?

People often fail to notice the presence of unexpected objects when their attention is engaged elsewhere. In dichotic listening tasks, for example, people often fail to notice unexpected content in the ignored speech stream even though they occasionally do notice highly familiar stimuli like their own name (the "cocktail party" effect). Some of the first studies of inattentional blindness were designed as a visual analog of such dichotic listening studies, but relatively few inattentional blindness studies have examined how familiarity affects noticing. We conducted four preregistered inattentional blindness experiments (total N = 1700) to examine whether people are more likely to notice a familiar unexpected object than an unfamiliar one. Experiment 1 replicated evidence for greater noticing of upright schematic faces than inverted or scrambled ones. Experiments 2-4 tested whether participants from different pairs of countries would be more likely to notice their own nation's flag or petrol company logo than those of another country. These experiments repeatedly found little or no evidence that familiarity affects noticing rates for unexpected objects. Frequently encountered and highly familiar stimuli do not appear to overcome inattentional blindness.

Inattentional blindness in medicine.

People often fail to notice unexpected stimuli when their attention is directed elsewhere. Most studies of this "inattentional blindness" have been conducted using laboratory tasks with little connection to real-world performance. Medical case reports document examples of missed findings in radiographs and CT images, unintentionally retained guidewires following surgery, and additional conditions being overlooked after making initial diagnoses. These cases suggest that inattentional blindness might contribute to medical errors, but relatively few studies have directly examined inattentional blindness in realistic medical contexts. We review the existing literature, much of which focuses on the use of augmented reality aids or inspection of medical images. Although these studies suggest a role for inattentional blindness in errors, most of the studies do not provide clear evidence that these errors result from inattentional blindness as opposed to other mechanisms. We discuss the design, analysis, and reporting practices that can make the contributions of inattentional blindness unclear, and we describe guidelines for future research in medicine and similar contexts that could provide clearer evidence for the role of inattentional blindness.

Neural correlation is stimulus modulated by feedforward inhibitory circuitry.

Correlated variability of neural spiking activity has important consequences for signal processing. How incoming sensory signals shape correlations of population responses remains unclear. Cross-correlations between spiking of different neurons may be particularly consequential in sparsely firing neural populations such as those found in layer 2/3 of sensory cortex. In rat whisker barrel cortex, we found that pairs of excitatory layer 2/3 neurons exhibit similarly low levels of spike count correlation during both spontaneous and sensory-evoked states. The spontaneous activity of excitatory-inhibitory neuron pairs is positively correlated, while sensory stimuli actively decorrelate joint responses. Computational modeling shows how threshold nonlinearities and local inhibition form the basis of a general decorrelating mechanism. We show that inhibitory population activity maintains low correlations in excitatory populations, especially during periods of sensory-evoked coactivation. The role of feedforward inhibition has been previously described in the context of trial-averaged phenomena. Our findings reveal a novel role for inhibition to shape correlations of neural variability and thereby prevent excessive correlations in the face of feedforward sensory-evoked activation.

Thalamocortical dysfunction and thalamic injury after asphyxial cardiac arrest in developing rats.

Global hypoxia-ischemia interrupts oxygen delivery and blood flow to the entire brain. Previous studies of global brain hypoxia-ischemia have primarily focused on injury to the cerebral cortex and to the hippocampus. Susceptible neuronal populations also include inhibitory neurons in the thalamic reticular nucleus. We therefore investigated the impact of global brain hypoxia-ischemia on the thalamic circuit function in the somatosensory system of young rats. We used single neuron recordings and controlled whisker deflections to examine responses of thalamocortical neurons to sensory stimulation in rat survivors of 9 min of asphyxial cardiac arrest incurred on postnatal day 17. We found that 48-72 h after cardiac arrest, thalamocortical neurons demonstrate significantly elevated firing rates both during spontaneous activity and in response to whisker deflections. The elevated evoked firing rates persist for at least 6-8 weeks after injury. Despite the overall increase in firing, by 6 weeks, thalamocortical neurons display degraded receptive fields, with decreased responses to adjacent whiskers. Nine minutes of asphyxial cardiac arrest was associated with extensive degeneration of neurites in the somatosensory nucleus as well as activation of microglia in the reticular nucleus. Global brain hypoxia-ischemia during cardiac arrest has a long-term impact on processing and transfer of sensory information by thalamic circuitry. Thalamic circuitry and normalization of its function may represent a distinct therapeutic target after cardiac arrest.

Similarity of an unexpected object to the attended and ignored objects affects noticing in a sustained inattentional blindness task.

When focusing attention on some objects and ignoring others, people often fail to notice the presence of an additional, unexpected object (inattentional blindness). In general, people are more likely to notice when the unexpected object is similar to the attended items and dissimilar from the ignored ones. Perhaps surprisingly, current evidence suggests that this similarity effect results almost entirely from dissimilarity to the ignored items, and it remains unclear whether similarity to the attended items affects noticing. Other aspects of similarity have not been examined at all, including whether the similarity of the attended and ignored items to each other affects noticing of a distinct unexpected object. We used a sustained inattentional blindness task to examine all three aspects of similarity. Experiment 1 (n = 813) found no evidence that increasing the similarity of the attended and ignored items to each other affected noticing of an unexpected object. Experiment 2 (n = 610) provided some of the first compelling evidence that similarity to the attended items - in addition to the ignored items - affects noticing. Experiment 3 (n = 1,044) replicated that pattern and showed that noticing rates varied with the degree of similarity to the ignored shapes but not to the attended shapes, suggesting that suppression of ignored items functions differently from the enhancement of attended items.

Effects of training strategies implemented in a complex videogame on functional connectivity of attentional networks.

We used the Space Fortress videogame, originally developed by cognitive psychologists to study skill acquisition, as a platform to examine learning-induced plasticity of interacting brain networks. Novice videogame players learned Space Fortress using one of two training strategies: (a) focus on all aspects of the game during learning (fixed priority), or (b) focus on improving separate game components in the context of the whole game (variable priority). Participants were scanned during game play using functional magnetic resonance imaging (fMRI), both before and after 20 h of training. As expected, variable priority training enhanced learning, particularly for individuals who initially performed poorly. Functional connectivity analysis revealed changes in brain network interaction reflective of more flexible skill learning and retrieval with variable priority training, compared to procedural learning and skill implementation with fixed priority training. These results provide the first evidence for differences in the interaction of large-scale brain networks when learning with different training strategies. Our approach and findings also provide a foundation for exploring the brain plasticity involved in transfer of trained abilities to novel real-world tasks such as driving, sport, or neurorehabilitation.

A reproducible systematic map of research on the illusory truth effect.

People believe information more if they have encountered it before, a finding known as the illusory truth effect. But what is the evidence for the generality and pervasiveness of the illusory truth effect? Our preregistered systematic map describes the existing knowledge base and objectively assesses the quality, completeness and interpretability of the evidence provided by empirical studies in the literature. A systematic search of 16 bibliographic and grey literature databases identified 93 reports with a total of 181 eligible studies. All studies were conducted at Western universities, and most used convenience samples. Most studies used verbatim repetition of trivia statements in a single testing session with a minimal delay between exposure and test. The exposure tasks, filler tasks and truth measures varied substantially across studies, with no standardisation of materials or procedures. Many reports lacked transparency, both in terms of open science practices and reporting of descriptive statistics and exclusions. Systematic mapping resulted in a searchable database of illusory truth effect studies ( https://osf.io/37xma/ ). Key limitations of the current literature include the need for greater diversity of materials as stimuli (e.g., political or health contents), more participants from non-Western countries, studies examining effects of multiple repetitions and longer intersession intervals, and closer examination of the dependency of effects on the choice of exposure task and truth measure. These gaps could be investigated using carefully designed multi-lab studies. With a lack of external replications, preregistrations, data and code, verifying replicability and robustness is only possible for a small number of studies.

Striatal volume predicts level of video game skill acquisition.

Video game skills transfer to other tasks, but individual differences in performance and in learning and transfer rates make it difficult to identify the source of transfer benefits. We asked whether variability in initial acquisition and of improvement in performance on a demanding video game, the Space Fortress game, could be predicted by variations in the pretraining volume of either of 2 key brain regions implicated in learning and memory: the striatum, implicated in procedural learning and cognitive flexibility, and the hippocampus, implicated in declarative memory. We found that hippocampal volumes did not predict learning improvement but that striatal volumes did. Moreover, for the striatum, the volumes of the dorsal striatum predicted improvement in performance but the volumes of the ventral striatum did not. Both ventral and dorsal striatal volumes predicted early acquisition rates. Furthermore, this early-stage correlation between striatal volumes and learning held regardless of the cognitive flexibility demands of the game versions, whereas the predictive power of the dorsal striatal volumes held selectively for performance improvements in a game version emphasizing cognitive flexibility. These findings suggest a neuroanatomical basis for the superiority of training strategies that promote cognitive flexibility and transfer to untrained tasks.