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

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

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

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

Emergence of adaptive computation by single neurons in the developing cortex.

Adaptation is a fundamental computational motif in neural processing. To maintain stable perception in the face of rapidly shifting input, neural systems must extract relevant information from background fluctuations under many different contexts. Many neural systems are able to adjust their input-output properties such that an input's ability to trigger a response depends on the size of that input relative to its local statistical context. This "gain-scaling" strategy has been shown to be an efficient coding strategy. We report here that this property emerges during early development as an intrinsic property of single neurons in mouse sensorimotor cortex, coinciding with the disappearance of spontaneous waves of network activity, and can be modulated by changing the balance of spike-generating currents. Simultaneously, developing neurons move toward a common intrinsic operating point and a stable ratio of spike-generating currents. This developmental trajectory occurs in the absence of sensory input or spontaneous network activity. Through a combination of electrophysiology and modeling, we demonstrate that developing cortical neurons develop the ability to perform nearly perfect gain scaling by virtue of the maturing spike-generating currents alone. We use reduced single neuron models to identify the conditions for this property to hold

Cortical control of adaptation and sensory relay mode in the thalamus.

A major synaptic input to the thalamus originates from neurons in cortical layer 6 (L6); however, the function of this cortico-thalamic pathway during sensory processing is not well understood. In the mouse whisker system, we found that optogenetic stimulation of L6 in vivo results in a mixture of hyperpolarization and depolarization in the thalamic target neurons. The hyperpolarization was transient, and for longer L6 activation (>200 ms), thalamic neurons reached a depolarized resting membrane potential which affected key features of thalamic sensory processing. Most importantly, L6 stimulation reduced the adaptation of thalamic responses to repetitive whisker stimulation, thereby allowing thalamic neurons to relay higher frequencies of sensory input. Furthermore, L6 controlled the thalamic response mode by shifting thalamo-cortical transmission from bursting to single spiking. Analysis of intracellular sensory responses suggests that L6 impacts these thalamic properties by controlling the resting membrane potential and the availability of the transient calcium current IT, a hallmark of thalamic excitability. In summary, L6 input to the thalamus can shape both the overall gain and the temporal dynamics of sensory responses that reach the cortex

Corticothalamic Spike Transfer via the L5B-POm Pathway in vivo.

The cortex connects to the thalamus via extensive corticothalamic (CT) pathways, but their function in vivo is not well understood. We investigated "top-down" signaling from cortex to thalamus via the cortical layer 5B (L5B) to posterior medial nucleus (POm) pathway in the whisker system of the anesthetized mouse. While L5B CT inputs to POm are extremely strong in vitro, ongoing activity of L5 neurons in vivo might tonically depress these inputs and thereby block CT spike transfer. We find robust transfer of spikes from the cortex to the thalamus, mediated by few L5B-POm synapses. However, the gain of this pathway is not constant but instead is controlled by global cortical Up and Down states. We characterized in vivo CT spike transfer by analyzing unitary PSPs and found that a minority of PSPs drove POm spikes when CT gain peaked at the beginning of Up states. CT gain declined sharply during Up states due to frequency-dependent adaptation, resulting in periodic high gain-low gain oscillations. We estimate that POm neurons receive few (2-3) active L5B inputs. Thus, the L5B-POm pathway strongly amplifies the output of a few L5B neurons and locks thalamic POm sub-and suprathreshold activity to cortical L5B spiking

Cortical Sensory Responses Are Enhanced by the Higher-Order Thalamus.

In 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

Multiplexed Spike Coding and Adaptation in the Thalamus

High-frequency "burst" clusters of spikes are a generic output pattern of many neurons. While bursting is a ubiquitous computational feature of different nervous systems across animal species, the encoding of synaptic inputs by bursts is not well understood. We find that bursting neurons in the rodent thalamus employ "multiplexing" to differentially encode low- and high-frequency stimulus features associated with either T-type calcium "low-threshold" or fast sodium spiking events, respectively, and these events adapt differently. Thus, thalamic bursts encode disparate information in three channels: (1) burst size, (2) burst onset time, and (3) precise spike timing within bursts. Strikingly, this latter "intraburst" encoding channel shows millisecond-level feature selectivity and adapts across statistical contexts to maintain stable information encoded per spike. Consequently, calcium events both encode low-frequency stimuli and, in parallel, gate a transient window for high-frequency, adaptive stimulus encoding by sodium spike timing, allowing bursts to efficiently convey fine-scale temporal information