Implications of single-neuron gain scaling for information transmission in networks

Summary: 

Many neural systems are equipped with mechanisms to efficiently encode sensory information. To represent natural stimuli with time-varying statistical properties, neural systems should adjust their gain to the inputs' statistical distribution. Such matching of dynamic range to input statistics has been shown to maximize the information transmitted by the output spike trains (Brenner et al., 2000, Fairhall et al., 2001). Gain scaling has not only been observed as a system response property, but also in single neurons in developing somatosensory cortex stimulated with currents of different amplitude (Mease et al., 2010). While gain scaling holds for cortical neurons at the end of the first post-natal week, at birth these neurons lack this property. The observed improvement in gain scaling coincides with the disappearance of spontaneous waves of activity in cortex (Conheim et al., 2010).

We studied how single-neuron gain scaling affects the dynamics of signal transmission in networks, using the developing cortex as a model. In a one-layer feedforward network, we showed that the absence of gain control made the network relatively insensitive to uncorrelated local input fluctuations. As a result, these neurons selectively and synchronously responded to large slowly-varying correlated input--the slow build up of synaptic noise generated in pacemaker circuits which most likely triggers waves. Neurons in gain scaling networks were more sensitive to the small-scale input fluctuations, and responded asynchronously to the slow envelope. Thus, gain scaling both increases information in individual neurons about private inputs and allows the population average to encode the slow fluctuations in the input. Paradoxically, the synchronous firing that corresponds to wave propagation is associated with low information transfer. We therefore suggest that the emergence of gain scaling may help the system to increase information transmission on multiple timescales as sensory stimuli become important later in development. 

Methods:

Networks with one and two layers consisting of hundreds of model neurons were constructed. The ability of single neurons to gain scale was controlled by changing the ratio of sodium to potassium conductances in Hodgkin-Huxley neurons (Mainen et al., 1995). The response of single layer networks was studied with ramp-like stimuli with slopes that varied over several hundreds of milliseconds. Fast fluctuations were superimposed on this slowly-varying mean. Then the response to these networks was tested with continuous stimuli. Gain scaling networks captured the slow fluctuations in the inputs, while non-scaling networks simply thresholded the input. Quantifying information transmission confirmed that gain scaling neurons transmit more information about the stimulus. With the two-layer networks we simulated a cortical network where waves could spontaneously emerge, propagate and degrade, based on the gain scaling properties of the neurons in the network

Cortical Sensory Responses Are Enhanced by the Higher-Order Thalamus

SummaryIn the mammalian brain, thalamic signals reach the cortex via two major routes: primary and higher-order thalamocortical pathways. While primary thalamocortical nuclei transmit sensory signals from the periphery, the function of higher-order thalamocortical projections remains enigmatic, in particular their role in sensory processing in the cortex. Here, by optogenetically controlling the thalamocortical pathway from the higher-order posteromedial thalamic nucleus (POm) during whisker stimulation, we demonstrate the integration of the two thalamocortical streams by single pyramidal neurons in layer 5 (L5) of the mouse barrel cortex under anesthesia. We report that POm input mainly enhances sub- and suprathreshold activity via net depolarization. Sensory enhancement is accompanied by prolongation of cortical responses over long (800-ms) periods after whisker stimulation. Thus, POm amplifies and temporally sustains cortical sensory signals, possibly serving to accentuate highly relevant sensory information

Intrinsic Neuronal Properties Switch the Mode of Information Transmission in Networks

Diverse ion channels and their dynamics endow single neurons with complex biophysical properties. These properties determine the heterogeneity of cell types that make up the brain, as constituents of neural circuits tuned to perform highly specific computations. How do biophysical properties of single neurons impact network function? We study a set of biophysical properties that emerge in cortical neurons during the first week of development, eventually allowing these neurons to adaptively scale the gain of their response to the amplitude of the fluctuations they encounter. During the same time period, these same neurons participate in large-scale waves of spontaneously generated electrical activity. We investigate the potential role of experimentally observed changes in intrinsic neuronal properties in determining the ability of cortical networks to propagate waves of activity. We show that such changes can strongly affect the ability of multi-layered feedforward networks to represent and transmit information on multiple timescales. With properties modeled on those observed at early stages of development, neurons are relatively insensitive to rapid fluctuations and tend to fire synchronously in response to wave-like events of large amplitude. Following developmental changes in voltage-dependent conductances, these same neurons become efficient encoders of fast input fluctuations over few layers, but lose the ability to transmit slower, population-wide input variations across many layers. Depending on the neurons' intrinsic properties, noise plays different roles in modulating neuronal input-output curves, which can dramatically impact network transmission. The developmental change in intrinsic properties supports a transformation of a networks function from the propagation of network-wide information to one in which computations are scaled to local activity. This work underscores the significance of simple changes in conductance parameters in governing how neurons represent and propagate information, and suggests a role for background synaptic noise in switching the mode of information transmission

Longitudinal Observation of Treatment Patterns and Outcomes for Patients with Fibromyalgia: 12‐Month Findings from the REFLECTIONS Study

Objective To describe 12‐month treatment patterns and outcomes for patients starting a new medication for fibromyalgia in routine clinical practice. Design and Outcome Measures Data from 1,700 patients were collected at baseline and 1, 3, 6, and 12 months. Repeated measures and P oisson regression models controlling for demographic, clinical, and baseline outcomes were used to assess changes in health outcomes ( B rief P ain I nventory severity and interference, S heehan D isability S cale, F ibromyalgia I mpact Q uestionnaire), satisfaction, and economic factors for patients who initiated on pregabalin (214, 12.6%), duloxetine (264, 15.5%), milnacipran (134, 7.9%), or tricyclic antidepressants (66, 3.9%). Sensitivity analyses were run using propensity‐matched cohorts. Results Patients started on 145 unique drugs for fibromyalgia, and over 75% of patients took two or more medications concurrently for fibromyalgia at each time point assessed. Overall, patients showed improvement on the four health outcomes, with few differences across medication cohorts. At baseline, patients reported annual averages of 20.3 visits for outpatient care, 27.7 missed days of work, and 32.6 days of care by an unpaid caregiver. The duloxetine and milnacipran (vs pregabalin or tricyclic antidepressant) cohorts had fewer outpatient visits during the 12‐month study. Patients reported satisfaction with overall treatment and their fibromyalgia medication (46.0% and 42.8%, respectively). Conclusions In this real‐world setting, patients with fibromyalgia reported modest improvements, high resource, and medication use, and were satisfied with the care they received. Cohort differences were difficult to discern because of the high rates of drug discontinuation and concomitant medication use over the 12‐month study period.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100168/1/pme12168.pd

Spondylarthropathies (including psoriatic arthritis): 244. Validity of Colour Doppler and Spectral Doppler Ultrasound of Sacroilicac Joints Againts Physical Examination as Gold Standard

Background: Sacroiliac joints (SJ) involvement is a distinctive and charasteristic feature of Spondyloarthritis (SpA) and x-ray is the test routinely used to make a diagnosis. However, x-ray reveals late structural damage but cannot detect active inflammation. The objective of this study was to assess the validity of Doppler ultrasound in SJ. Methods: Prospective blinded and controlled study of SJ, in which three populations were compared. We studied 106 consecutive cases, who were divided into three groups: a) 53 patients diagnosed with SpA who had inflammatory lumbar and gluteal pain assessed by a rheumatologist; b) 26 patients diagnosed with SpA who didn't have SJ tenderness and had normal physical examination; c) control group of 27 subjects (healthy subjetcs or with mechanical lumbar pain). All patients included that were diagnosed with SpA met almost the European Spondyloarthropathy Study Group (ESSG) classification criteria. Physical examination of the SJ included: sacral sulcus tenderness, iliac gapping, iliac compression, midline sacral thrust test, Gaenslen's test, and Patrick s test were used as gold standard. Both SJ were examined with Doppler ultrasound (General Electric Logiq 9, Wauwatosa WI, USA) fitted with a 9-14 Mhz lineal probe. The ultrasonographer was blinded to clinical data. Doppler in SJ was assessed as positive when both Doppler colour and resistance index (RI) < 0.75 within the SJ area were present. Statistical analysis was performed estimating sensitivity and specificity against gold standard. The Kappa correlation coefficient was used for reliability study. Results: 106 cases (53 female, 55 male; mean age 36 10 years) were studied. There were no statistical differences between groups related to age or sex. Physical examination of SJ was positive in 38 patients (59 sacroiliac joints). US detected Doppler signal within SJ in 37 patients (58 SJ): 33 of them were symptomatic SpA (52 SJ), one of them were asymptomatic SpA (1 SJ) and one was a healthy control (1 SJ). The accuracy of US when compared to clinical data as gold standard at subject level in the overall group was: sensitivity of 68.6% and specificity of 85.7%, positive predictive value of 70.5% and negative predictive value of 84.5%. A positive likelihood ratio of 4.8, a negative likelihood ratio of 0.36 and a kappa coefficient of 0.55 were achieved. Conclusions: Doppler US of SJ seems to be a valid method to detect active SJ inflammation. Disclosure statement: The authors have declared no conflicts of interes

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Early Real-World Experience of Tofacitinib for Psoriatic Arthritis: Data from a United States Healthcare Claims Database.

INTRODUCTION: This study characterized real-world demographic and baseline clinical characteristics, as well as treatment persistence and adherence, in patients with psoriatic arthritis (PsA) who had newly initiated tofacitinib treatment. METHODS: This retrospective cohort study included patients aged 18 years or older in the IBM MarketScan™ US database with at least one tofacitinib claim (first = index) between December 14, 2017 and April 30, 2019; PsA diagnoses on/within 12 months pre-index; and no diagnoses of rheumatoid arthritis any time pre-index. Patients were continuously enrolled for 12 months pre-index and 6 months post-index, with no pre-index claims for tofacitinib. Patient demographic and clinical characteristics on the day of index, and history of advanced treatments (including tofacitinib monotherapy or combination therapy), were recorded. Outcomes at 6 months post-index included tofacitinib persistence (less than 60-day gap without tofacitinib treatment) and adherence (proportion of days covered [PDC] and medication possession ratio 80% or higher). RESULTS: Of the 10,354 patients with tofacitinib claims within the study period, 318 patients with PsA met the inclusion criteria. More than 60% of patients received tofacitinib monotherapy post-index, with a mean duration of PsA of 760.5 days at index. For patients who received tofacitinib combination therapy post-index, methotrexate was the most common concomitant conventional synthetic disease-modifying antirheumatic drug. At 6 months post-index, persistence was similar in patients receiving tofacitinib monotherapy (69.8%) versus combination therapy (73.1%); adherence (as measured by PDC ≥ 0.8) was numerically lower in patients receiving tofacitinib monotherapy (56.8%) versus combination therapy (65.5%). CONCLUSIONS: This analysis of US-based claims data described patients who had newly initiated tofacitinib treatment an average of 2 years after PsA diagnosis, with approximately two-thirds of patients receiving tofacitinib monotherapy. Observed rates of tofacitinib persistence were similar across patients who received tofacitinib monotherapy and combination therapy 6 months after initiation; adherence rates were numerically lower in patients receiving monotherapy

Monosynaptic trans-collicular pathways link mouse whisker circuits to integrate somatosensory and motor cortical signals.

The superior colliculus (SC), a conserved midbrain node with extensive long-range connectivity throughout the brain, is a key structure for innate behaviors. Descending cortical pathways are increasingly recognized as central control points for SC-mediated behaviors, but how cortico-collicular pathways coordinate SC activity at the cellular level is poorly understood. Moreover, despite the known role of the SC as a multisensory integrator, the involvement of the SC in the somatosensory system is largely unexplored in comparison to its involvement in the visual and auditory systems. Here, we mapped the connectivity of the whisker-sensitive region of the SC in mice with trans-synaptic and intersectional tracing tools and in vivo electrophysiology. The results reveal a novel trans-collicular connectivity motif in which neurons in motor- and somatosensory cortices impinge onto the brainstem-SC-brainstem sensory-motor arc and onto SC-midbrain output pathways via only one synapse in the SC. Intersectional approaches and optogenetically assisted connectivity quantifications in vivo reveal convergence of motor and somatosensory cortical input on individual SC neurons, providing a new framework for sensory-motor integration in the SC. More than a third of the cortical recipient neurons in the whisker SC are GABAergic neurons, which include a hitherto unknown population of GABAergic projection neurons targeting thalamic nuclei and the zona incerta. These results pinpoint a whisker region in the SC of mice as a node for the integration of somatosensory and motor cortical signals via parallel excitatory and inhibitory trans-collicular pathways, which link cortical and subcortical whisker circuits for somato-motor integration