Objective Smartwatch Indices of Affective Switching: A Pilot Study in Premenstrual Dysphoric Disorder.

Wearable devices offer a unique opportunity to provide real-time monitoring of affective switching (the mood transition into and out of dysregulated affective state), a critical window to detect and prevent depression and suicide. To model affective switching, we studied premenstrual dysphoric disorder (PMDD): a depressive disorder with a regularly occurring monthly trigger. Results supported feasibility of smartwatch monitoring protocol and preliminary evidence that objective physiological and behavioral metrics were associated with affective state.

Expanding capabilities to evaluate readiness for return to duty after mTBI: The CAMP study protocol.

Physical Therapists affiliated with Intrepid Spirit Centers evaluate and treat Active Duty Service Members (ADSM) who have duty-limiting post-concussion symptoms to improve the ability to perform challenging tasks associated with military service. The Complex Assessment of Military Performance (CAMP) is a test battery that more closely approximates the occupational demands of ADSM without specific adherence to a particular branch of service or military occupational specialty. Subtasks were developed with military collaborators to include high level skills that all service members must be able to perform such as reacting quickly, maintaining visual stability while moving and changing positions, and scanning for, noting, and/or remembering operationally relevant information under conditions of physical exertion. OBJECTIVE: The purpose of this observational longitudinal study is to: 1- establish typical performance parameters for ADSM on the CAMP test battery 2- determine the element of the CAMP battery that demonstrate the greatest differences from standard performance and serve as predictors for successful return to duty and 3- develop clinician-facing feedback algorithms and displays and 4-develop materials for clinical dissemination. This ongoing multi-site study is currently funded through the CDMRP and has been approved by the Naval Medical Center Portsmouth IRB. METHODS: ADSM undergoing post-concussion rehabilitation at the Intrepid Spirit Centers will be tested within one week of their initial Physical Therapy evaluation and after completing Physical Therapy. Control participants will include males, females, and ADSM from the Special Operations community. Participants will complete an intake form that includes questions about demographics, military service, deployment and concussion history, and profile and duty status. Other measures include those that explore concussion symptoms, sleep quality, post-traumatic stress, and perceptions of resilience. The CAMP includes three separate 10-15 minute tasks. Movement is recorded by wearable inertial sensors and heart rate variability is recorded with a POLAR10 monitor. The "Run-Roll" task requires rapid position changes, combat rolls and quick running forwards and backwards while carrying a simulated weapon. Visual stability before and after the task is also performed. The "Dual-Task Agility" task includes rapid running with and without a weighted vest and a working memory task. The "Patrol Exertion" task requires repeated stepping onto an exercise step while watching a virtual patrol video. Additional tasks include monitoring direction of travel, observing for signs of enemy presence, and reacting to multiple auditory signals embedded in the video. DISCUSSION: Measures that evaluate relevant skills are vital to support safe return to duty for ADSM who may be exposed to imminent danger as part of training or mission demands. The CAMP is designed to be an ecologically valid and clinically feasible assessment that may be more sensitive to capturing subtle impairments that impact duty performance as test skills are integrated into dual and multi-tasks that reflect occupational demands. Assessment results may serve as a more robust indicator of readiness for full return to duty after concussion.

Validity and Responsiveness of the Portable Warrior Test of Tactical Agility After Rehabilitation in Service Members With Mild Traumatic Brain Injury.

OBJECTIVE: The Portable Warrior Test of Tactical Agility (POWAR-TOTAL) is a performance-based test designed to assess active-duty service members diagnosed with mild traumatic brain injuries (mTBIs) and could potentially inform return to duty decisions. To examine the validity and responsiveness of the POWAR-TOTAL measure, this study collected self-reported and performance measures by active-duty service members before and after an episode of physical therapist care. METHODS: Seventy-four individuals, enrolled in care for mTBI symptoms at 1 of 2 concussion specialty Intrepid Spirit Centers, were examined the week that they initiated physical therapy with the intention to return to active duty. Self-reported measures of concussion symptoms, pain, posttraumatic stress, headache, dizziness, and sleep quality were used, as were concurrent measures of mobility and balance. The POWAR-TOTAL task (motor and cognitive skills in single and dual-task conditions) was administered. Forty-nine active-duty service members returned for posttherapy testing using the same test battery. Effect sizes for change in measures were calculated. Construct validity was assessed by correlating change scores on POWAR with concurrent self-report and mobility measures. Responsiveness was evaluated using an anchor-based approach. RESULTS: Significant improvements in self-reported and performance-based measures, including POWAR, were observed after therapy with moderate to large effect sizes. Improvement in POWAR performance correlated with improvement in both performance and self-reported measures. After therapy, individuals who registered improvement on the Patient Global Impression of Change scale demonstrated significantly faster POWAR motor performance than those who rated little or no improvement in their condition. CONCLUSION: The POWAR-TOTAL captured improvement on a military-specific task after completing physical therapy for mTBI and could serve as an indicator of physical recovery and readiness for return to duty. IMPACT: Challenging cognitive and motor measures for service members may aid in the assessment of recovery and the ability to successfully return to duty after concussion as part of a comprehensive examination approach.

Wearable Sensors Detect Movement Differences in the Portable Warrior Test of Tactical Agility After mTBI in Service Members.

INTRODUCTION: Assessment of functional recovery of service members following a concussion is central to their return to duty. Practical military-relevant performance-based tests are needed for identifying those who might need specialized rehabilitation, for evaluating the progress of recovery, and for making return-to-duty determinations. One such recently developed test is the 'Portable Warrior Test of Tactical Agility' (POWAR-TOTAL) assessment designed for use following concussion in an active duty population. This agility task involves maneuvers used in military training, such as rapid stand-to-prone and prone-to-stand transitions, combat rolls, and forward and backward running. The effect of concussion on the performance of such maneuvers has not been established. MATERIALS AND METHODS: The Institutional Review Board-approved study was conducted at Ft. Bragg, North Carolina, on 57 healthy control (HC) service members (SMs) and 42 well-matched SMs who were diagnosed with concussion and were referred for physical therapy with the intent to return to duty. Each study participant performed five consecutive trials of the POWAR-TOTAL task at full exertion while wearing inertial sensors, which were used to identify the constituent task maneuvers, or phases, and measure their durations. Statistical analyses were performed on durations of three main phases: (1) rising from prone and running, (2) lowering from vertical to prone, and (3) combat rolls. RESULTS: None of the three phases showed significant correlation with age (range 18-45 years) in either group. Gradual improvement in all three phase durations across five trials was observed in the HC group, but not in the concussed group. On average, control subjects performed significantly faster (P < .004 or less) than concussed subjects in all trials in the lowering and rolling phases, but less so in the rising/running phase. Membership in the concussed group had a strong effect on the lowering phase (Cohen's d = 1.05), medium effect on the rolling phase (d = 0.72), and small effect on the rising/running phase (d = 0.49). Individuals in the HC group who had a history of prior concussions were intermediate between the concussed group and the never-concussed group in the lowering and rolling phases. Duration of transitional movements (lowering from standing to prone and combat rolls) was better at differentiating individuals' performance by group (receiver operating characteristic area under the curve [AUC] = 0.83) than the duration of the entire POWAR-TOTAL task (AUC = 0.71). CONCLUSIONS: Inertial sensor analysis reveals that rapid transitional movements (such as lowering from vertical to prone position and combat rolls) are particularly discriminative between SMs recovering from concussion and their concussion-free peers. This analysis supports the validity of POWAR-TOTAL as a useful tool for therapists who serve military SMs.

SHAPE-enabled fragment-based ligand discovery for RNA.

The transcriptome represents an attractive but underused set of targets for small-molecule ligands. Here, we devise a technology that leverages fragment-based screening and SHAPE-MaP RNA structure probing to discover small-molecule fragments that bind an RNA structure of interest. We identified fragments and cooperatively binding fragment pairs that bind to the thiamine pyrophosphate (TPP) riboswitch with millimolar to micromolar affinities. We then used structure-activity relationship information to efficiently design a linked-fragment ligand, with no resemblance to the native ligand, with high ligand efficiency and druglikeness, that binds to the TPP thiM riboswitch with high nanomolar affinity and that modulates RNA conformation during cotranscriptional folding. Principles from this work are broadly applicable, leveraging cooperativity and multisite binding, for developing high-quality ligands for diverse RNA targets.

An Experimental Animal Model that Parallels Neurosensory Assessments of Concussion.

INTRODUCTION: Tactile-based quantitative sensory assessments have proven successful in differentiating concussed vs. non-concussed individuals. One potential advantage of this methodology is that an experimental animal model can be used to obtain neurophysiological recordings of the neural activity in the somatosensory cortex evoked in response to the same tactile stimuli that are used in human sensory assessments and establish parallels between various metrics of stimulus-evoked cortical activity and perception of the stimulus attributes. MATERIALS AND METHODS: Stimulus-evoked neural activity was recorded via extracellular microelectrodes in rat primary somatosensory cortex (S1) in response to vibrotactile stimuli that are used in two particular human sensory assessments (reaction time (RT) and amplitude discrimination). Experiments were conducted on healthy control and brain-injured (BI) rats. RESULTS: Similar to the effects of mild traumatic brain injuries (mTBI) on human neurosensory assessments, comparable experimentally induced brain injuries in rats resulted in the following: (1) elevation of S1 responsivity to vibrotactile stimulation that depended nonlinearly on stimulus amplitude, significantly reducing its capacity to discriminate between stimuli of different amplitudes; (2) 50% reduction in S1 signal-to-noise ratios, which can be expected to contribute to elevation of RT in BI rats; and (3) 60% increase in intertrial variability of S1 responses to vibrotactile stimulation, which can be expected to contribute to elevation of RT variability in BI rats. CONCLUSIONS: The results demonstrate suggestive similarities between neurophysiological observations made in the experimental rat mTBI model and observations made in post-concussion individuals with regard to three sensory assessment metrics (amplitude discrimination, RT, and RT variability). This is the first successful model that demonstrates that perceptual metrics obtained from human individuals are impacted by mTBI in a manner consistent with neurophysiological observations obtained from rat S1.

Methodological Problems With Online Concussion Testing.

Reaction time testing is widely used in online computerized concussion assessments, and most concussion studies utilizing the metric have demonstrated varying degrees of difference between concussed and non-concussed individuals. The problem with most of these online concussion assessments is that they predominantly rely on consumer grade technology. Typical administration of these reaction time tests involves presenting a visual stimulus on a computer monitor and prompting the test subject to respond as quickly as possible via keypad or computer mouse. However, inherent delays and variabilities are introduced to the reaction time measure by both computer and associated operating systems that the concussion assessment tool is installed on. The authors hypothesized systems that are typically used to collect concussion reaction time data would demonstrate significant errors in reaction time measurements. To remove human bias, a series of experiments was conducted robotically to assess timing errors introduced by reaction time tests under four different conditions. In the first condition, a visual reaction time test was conducted by flashing a visual stimulus on a computer monitor. Detection was via photodiode and mechanical response was delivered via computer mouse. The second condition employed a mobile device for the visual stimulus, and the mechanical response was delivered to the mobile device's touchscreen. The third condition simulated a tactile reaction time test, and mechanical response was delivered via computer mouse. The fourth condition also simulated a tactile reaction time test, but response was delivered to a dedicated device designed to store the interval between stimulus delivery and response, thus bypassing any problems hypothesized to be introduced by computer and/or computer software. There were significant differences in the range of responses recorded from the four different conditions with the reaction time collected from visual stimulus on a mobile device being the worst and the device with dedicated hardware designed for the task being the best. The results suggest that some of the commonly used visual tasks on consumer grade computers could be (and have been) introducing significant errors for reaction time testing and that dedicated hardware designed for the reaction time task is needed to minimize testing errors.

A nociresponsive specific area of human somatosensory cortex within BA3a: BA3c?

It is well recognized that in primates, including humans, noxious body stimulation evokes a neural response in the posterior bank of the central sulcus, in Brodmann cytoarchitectonic subdivisions 3b and 1 of the primary somatosensory cortex. This response is associated with the 1st/sharp pain and contributes to sensory discriminative aspects of pain perception and spatial localization of the noxious stimulus. However, neurophysiological studies in New World monkeys predict that in humans noxious stimulation also evokes a separate neural response-mediated by C-afferent drive and associated with the 2nd/burning pain-in the depth of the central sulcus in Brodmann area 3a (BA3a) at the transition between the somatosensory and motor cortices. To evoke such a response, it is necessary to use multi-second duration noxious stimulation, rather than brief laser pulses. Given the limited human pain-imaging literature on cortical responses induced by C-nociceptive input specifically within BA3a, here we used high spatial resolution 7T fMRI to study the response to thermonoxious skin stimulation. We observed the predicted response of BA3a in the depth of the central sulcus in five human volunteers. Review of the available evidence suggests that the nociresponsive region in the depth of the central sulcus is a structurally and functionally distinct cortical area that should not be confused with proprioceptive BA3a. It is most likely engaged in interoception and control of the autonomic nervous system, and contributes to the sympathetic response to noxious stimulation, arguably the most intolerable aspect of pain experience. Ablation of this region has been shown to reduce pain sensibility and might offer an effective means of ameliorating some pathological pain conditions.

A newly identified nociresponsive region in the transitional zone (TZ) in rat sensorimotor cortex.

The primary somatosensory cortex (S1) comprises a number of functionally distinct regions, reflecting the diversity of somatosensory receptor submodalities innervating the body. In particular, two spatially and functionally distinct nociceptive regions have been described in primate S1 (Vierck et al., 2013; Whitsel et al., 2019). One region is located mostly in Brodmann cytoarchitectonic area 1, where a subset of neurons exhibit functional characteristics associated with myelinated Aδ nociceptors and perception of 1st/sharp, discriminative pain. The second region is located at the transition between S1 and primary motor cortex (M1) in area 3a, where neurons exhibit functional characteristics associated with unmyelinated C nociceptors and perception of 2nd/slow, burning pain. To test the hypothesis that in rats the transitional zone (TZ) - which is a dysgranular region at the transition between M1 and S1 - is the functional equivalent of the nociresponsive region of area 3a in primates, extracellular spike discharge activity was recorded from TZ neurons in rats under general isoflurane anesthesia. Thermonoxious stimuli were applied by lowering the contralateral forepaw or hindpaw into a 48-51 °C heated water bath for 5-10 s. Neurons in TZ were found to be minimally affected by non-noxious somatosensory stimuli, but highly responsive to thermonoxious skin stimuli in a slow temporal summation manner closely resembling that of nociresponsive neurons in primate area 3a. Selective inactivation of TZ by topical lidocaine application suppressed or delayed the nociceptive withdrawal reflex, suggesting that TZ exerts a tonic facilitatory influence over spinal cord neurons producing this reflex. In conclusion, TZ appears to be a rat homolog of the nociresponsive part of monkey area 3a. A possibility is considered that this region might be primarily engaged in autonomic aspects of nociception.

Quantification of Mild Traumatic Brain Injury via Cortical Metrics: Analytical Methods.

Mild traumatic brain injuries are difficult to diagnose or assess with commonly used diagnostic methods. However, the functional state of cerebral cortical networks can be rapidly and effectively probed by measuring tactile-based sensory percepts (called cortical metrics), which are designed to exercise various components of cortical machinery. In this study, such cortical metrics were obtained from 52 college students before and after they experienced sports-related concussions by delivering vibrotactile stimuli to the index and middle fingertips. Performance on four of the sensory test protocols is described: reaction time, amplitude discrimination, temporal order judgment, and duration discrimination. The collected test performance data were analyzed using methods of uni- and multivariate statistics, receiver operated characteristic (ROC) curves, and discriminant analysis. While individual cortical metrics vary extensively in their ability to discriminate between control and concussed subjects, their combined discriminative performance greatly exceeds that of any individual metric, achieving cross-validated 93.0% sensitivity, 92.3% specificity, 93.0% positive predictive value, and 92.3% negative predictive value. The cortical metrics vector can be used to track an individual's recovery from concussion. The study thus establishes that cortical metrics can be used effectively as a quantitative indicator of central nervous system health status.

Clinical Utility and Analysis of the Run-Roll-Aim Task: Informing Return-to-Duty Readiness Decisions in Active-Duty Service Members.

INTRODUCTION: The Assessment of Military Multitasking Performance (AMMP1) consists of six dual-task and multitask military-relevant performance-based assessments which were developed to provide assistance in making return-to-duty decisions after concussion or mild traumatic brain injury (mTBI.) The Run-Roll-Aim (RRA) task, one component of the AMMP, was developed to target vulnerabilities following mTBI including attention, visual function, dynamic stability, rapid transition, and vestibular function. One aim of this study was to assess the known-group and construct validity of the RRA, and additionally to further explore reliability limitations reported previously. MATERIALS AND METHODS: A cross-sectional study consisting of 84 Active Duty service members in two groups (healthy control - HC and individuals experiencing persistent mTBI symptoms) completed neurocognitive tests and the RRA. The RRA task requires a high level of mobility and resembles military training activities in a maneuver that includes combat rolls, fast transitions, obstacle avoidance, and visual search. Observational and inertial sensor data were compared between groups and performance across four trial times was compared within groups. Correlations between RRA results and neurocognitive test scores were analyzed. RESULTS: Simple observational measures (time, errors) did not differ between groups. Spectral power analysis of the inertial sensor data showed significant differences in motor performance between groups. Within group one-way ANOVAs showed that in HC trial 1, time was significantly different than trials 2,3 and 4 (F(3,47) = 4.60, p < 0.01, Tukey HSD p < 0.05) while the mTBI group showed no significant difference in time between trials. During testing individuals with mTBI were less likely to complete the multiple test trials or required additional rest between trials than HCs (χ2 = 10.78, p < 0.01). Small but significant correlations were seen with two neurocognitive tests of attention and RRA performance time. CONCLUSION: While observational scores were not sensitive to group differences, inertial sensor data showed motor performance on the forward run, combat roll, and backward run differed significantly between groups. The RRA task appeared challenging and provoked symptoms in the mTBI group, causing 8 of 33 mTBI participants to stop the task or require additional rest between trials while none of the HC participants had to stop. Individuals with mTBI demonstrated slower learning of the complex motor sequence compared to HCs who had significant improvement after one trial of RRA. Complex novel training maneuvers like RRA may aid clinicians in informing return to duty decisions.

Contributions of Nociresponsive Area 3a to Normal and Abnormal Somatosensory Perception.

Traditionally, cytoarchitectonic area 3a of primary somatosensory cortex (SI) has been regarded as a proprioceptive relay to motor cortex. However, neuronal spike-train recordings and optical intrinsic signal imaging, obtained from nonhuman sensorimotor cortex, show that neuronal activity in some of the cortical columns in area 3a can be readily triggered by a C-nociceptor afferent drive. These findings indicate that area 3a is a critical link in cerebral cortical encoding of secondary/slow pain. Also, area 3a contributes to abnormal pain processing in the presence of activity-dependent reversal of gamma-aminobutyric acid A receptor-mediated inhibition. Accordingly, abnormal processing within area 3a may contribute mechanistically to generation of clinical pain conditions. PERSPECTIVE: Optical imaging and neurophysiological mapping of area 3a of SI has revealed substantial driving from unmyelinated cutaneous nociceptors, complementing input to areas 3b and 1 of SI from myelinated nociceptors and non-nociceptors. These and related findings force a reconsideration of mechanisms for SI processing of pain.

Hand-to-Face Remapping But No Differences in Temporal Discrimination Observed on the Intact Hand Following Unilateral Upper Limb Amputation.

Unilateral major limb amputation causes changes in sensory perception. Changes may occur within not only the residual limb but also the intact limb as well as the brain. We tested the hypothesis that limb amputation may result in the detection of hand sensation during stimulation of a non-limb-related body region. We further investigated the responses of unilateral upper limb amputees and individuals with all limbs intact to temporally based sensory tactile testing of the fingertips to test the hypothesis that changes in sensory perception also have an effect on the intact limb. Upper extremity amputees were assessed for the presence of referred sensations (RSs)-experiencing feelings in the missing limb when a different body region is stimulated, to determine changes within the brain that occur due to an amputation. Eight of 19 amputees (42.1%) experienced RS in the phantom limb with manual tactile mapping on various regions of the face. There was no correlation between whether someone had phantom sensations or phantom limb pain and where RS was found. Six of the amputees had either phantom sensation or pain in addition to RS induced by facial stimulation. Results from the tactile testing showed that there were no significant differences in the accuracy of participants in the temporal order judgment tasks (p = 0.702), whereby participants selected the digit that was tapped first by a tracking paradigm that resulted in correct answers leading to shorter interstimulus intervals (ISIs) and incorrect answers increasing the ISI. There were also no significant differences in timing perception, i.e., the threshold accuracy of the duration discrimination task (p = 0.727), in which participants tracked which of the two digits received a longer stimulus. We conclude that many, but not all, unilateral upper limb amputees experience phantom hand sensation and/or pain with stimulation of the face, suggesting that there could be postamputation changes in neuronal circuitry in somatosensory cortex. However, major unilateral limb amputation does not lead to changes in temporal order judgment or timing perception tasks administered via the tactile modality of the intact hand in upper limb amputees.

Neurosensory Assessments of Concussion.

The purpose of this research was to determine if cortical metrics-a unique set of sensory-based assessment tools-could be used to characterize and differentiate concussed individuals from nonconcussed individuals. Cortical metrics take advantage of the somatotopic relationship between skin and cortex, and the protocols are designed to evoke interactions between adjacent cortical regions to investigate fundamental mechanisms that mediate cortical-cortical interactions. Student athletes, aged 18 to 22 years, were recruited into the study through an athletic training center that made determinations of postconcussion return-to-play status. Sensory-based performance tasks utilizing vibrotactile stimuli applied to tips of the index and middle fingers were administered to test an individual's amplitude discrimination, temporal order judgment, and duration discrimination capacity in the presence and absence of illusion-inducing conditioning stimuli. Comparison of the performances in the presence and absence of conditioning stimuli demonstrated differences between concussed and nonconcussed individuals. Additionally, mathematically combining results from the measures yields a unique central nervous system (CNS) profile that describes an individual's information processing capacity. A comparison was made of CNS profiles of concussed vs. nonconcussed individuals and demonstrated with 99% confidence that the two populations are statistically distinct. The study established solid proof-of-concept that cortical metrics have significant potential as a quantitative biomarker of CNS status.

Fluoride Induces a Volume Reduction in CA1 Hippocampal Slices Via MAP Kinase Pathway Through Volume Regulated Anion Channels.

Regulation of cell volume is an important aspect of cellular homeostasis during neural activity. This volume regulation is thought to be mediated by activation of specific transporters, aquaporin, and volume regulated anion channels (VRAC). In cultured astrocytes, it was reported that swelling-induced mitogen-activated protein (MAP) kinase activation is required to open VRAC, which are thought to be important in regulatory volume decrease and in the response of CNS to trauma and excitotoxicity. It has been also described that sodium fluoride (NaF), a recognized G-protein activator and protein phosphatase inhibitor, leads to a significant MAP kinase activation in endothelial cells. However, NaF's effect in volume regulation in the brain is not known yet. Here, we investigated the mechanism of NaF-induced volume change in rat and mouse hippocampal slices using intrinsic optical signal (IOS) recording, in which we measured relative changes in intracellular and extracellular volume as changes in light transmittance through brain slices. We found that NaF (1~5 mM) application induced a reduction in light transmittance (decreased volume) in CA1 hippocampus, which was completely reversed by MAP kinase inhibitor U0126 (10 µM). We also observed that NaF-induced volume reduction was blocked by anion channel blockers, suggesting that NaF-induced volume reduction could be mediated by VRAC. Overall, our results propose a novel molecular mechanism of NaF-induced volume reduction via MAP kinase signaling pathway by activation of VRAC.

Percept of the duration of a vibrotactile stimulus is altered by changing its amplitude.

There have been numerous studies conducted on time perception. However, very few of these have involved tactile stimuli to assess a subject's capacity for duration discrimination. Previous optical imaging studies in non-human primates demonstrated that increasing the duration of a vibrotactile stimulus resulted in a consistently longer and more well defined evoked SI cortical response. Additionally, and perhaps more interestingly, increasing the amplitude of a vibrotactile stimulus not only evoked a larger magnitude optical intrinsic signal (OIS), but the return to baseline of the evoked response was much longer in duration for larger amplitude stimuli. This led the authors to hypothesize that the magnitude of a vibrotactile stimulus could influence the perception of its duration. In order to test this hypothesis, subjects were asked to compare two sets of vibrotactile stimuli. When vibrotactile stimuli differed only in duration, subjects typically had a difference limen (DL) of approximately 13%, and this followed Weber's Law for standards between 500 and 1500 ms, as increasing the value of the standard yielded a proportional increase in DL. However, the percept of duration was impacted by variations in amplitude of the vibrotactile stimuli. Specifically, increasing the amplitude of the standard stimulus had the effect of increasing the DL, while increasing the amplitude of the test stimulus had the effect of decreasing the DL. A pilot study, conducted on individuals who were concussed, found that increasing the amplitude of the standard did not have an impact on the DL of this group of individuals. Since this effect did not parallel what was predicted from the optical imaging findings in somatosensory cortex of non-human primates, the authors suggest that this particular measure or observation could be sensitive to neuroinflammation and that neuron-glial interactions, impacted by concussion, could have the effect of ignoring, or not integrating, the increased amplitude.

Activity of somatosensory-responsive neurons in high subdivisions of SI cortex during locomotion.

Responses of neurons in the primary somatosensory cortex during movements are poorly understood, even during such simple tasks as walking on a flat surface. In this study, we analyzed spike discharges of neurons in the rostral bank of the ansate sulcus (areas 1-2) in 2 cats while the cats walked on a flat surface or on a horizontal ladder, a complex task requiring accurate stepping. All neurons (n = 82) that had receptive fields (RFs) on the contralateral forelimb exhibited frequency modulation of their activity that was phase locked to the stride cycle during simple locomotion. Neurons with proximal RFs (upper arm/shoulder) and pyramidal tract-projecting neurons (PTNs) with fast-conducting axons tended to fire at peak rates in the middle of the swing phase, whereas neurons with RFs on the distal limb (wrist/paw) and slow-conducting PTNs typically showed peak firing at the transition between swing and stance phases. Eleven of 12 neurons with tactile RFs on the volar forepaw began firing toward the end of swing, with peak activity occurring at the moment of foot contact with floor, thereby preceding the evoked sensory volley from touch receptors. Requirement to step accurately on the ladder affected 91% of the neurons, suggesting their involvement in control of accuracy of stepping. During both tasks, neurons exhibited a wide variety of spike distributions within the stride cycle, suggesting that, during either simple or ladder locomotion, they represent the cycling somatosensory events in their activity both predictively before and reflectively after these events take place.

Möbius-strip-like columnar functional connections are revealed in somato-sensory receptive field centroids.

Receptive fields of neurons in the forelimb region of areas 3b and 1 of primary somatosensory cortex, in cats and monkeys, were mapped using extracellular recordings obtained sequentially from nearly radial penetrations. Locations of the field centroids indicated the presence of a functional system in which cortical homotypic representations of the limb surfaces are entwined in three-dimensional Möbius-strip-like patterns of synaptic connections. Boundaries of somatosensory receptive field in nested groups irregularly overlie the centroid order, and are interpreted as arising from the superposition of learned connections upon the embryonic order. Since the theory of embryonic synaptic self-organization used to model these results was devised and earlier used to explain findings in primary visual cortex, the present findings suggest the theory may be of general application throughout cortex and may reveal a modular functional synaptic system, which, only in some parts of the cortex, and in some species, is manifest as anatomical ordering into columns.

SHAPE analysis of small RNAs and riboswitches.

We describe structural analysis of small RNAs by SHAPE chemical probing. RNAs are treated with 1-methyl-7-nitroisatoic anhydride, a reagent that detects local nucleotide flexibility; and N-methylisatoic anhydride and 1-methyl-6-nitroisatoic anhydride, reagents which together detect higher-order and noncanonical interactions. Chemical adducts are quantified as stops during reverse transcriptase-mediated primer extension. Probing information can be used to infer conformational changes and ligand binding and to develop highly accurate models of RNA secondary structures.

Single-molecule correlated chemical probing of RNA.

Complex higher-order RNA structures play critical roles in all facets of gene expression; however, the through-space interaction networks that define tertiary structures and govern sampling of multiple conformations are poorly understood. Here we describe single-molecule RNA structure analysis in which multiple sites of chemical modification are identified in single RNA strands by massively parallel sequencing and then analyzed for correlated and clustered interactions. The strategy thus identifies RNA interaction groups by mutational profiling (RING-MaP) and makes possible two expansive applications. First, we identify through-space interactions, create 3D models for RNAs spanning 80-265 nucleotides, and characterize broad classes of intramolecular interactions that stabilize RNA. Second, we distinguish distinct conformations in solution ensembles and reveal previously undetected hidden states and large-scale structural reconfigurations that occur in unfolded RNAs relative to native states. RING-MaP single-molecule nucleic acid structure interrogation enables concise and facile analysis of the global architectures and multiple conformations that govern function in RNA.