The Fear Reduction Exercised Early (FREE) approach to low back pain: study protocol for a randomised controlled trial

This is the final version of the article. Available from BioMed Central via the DOI in this record.BACKGROUND: Low back pain (LBP) is a major health issue associated with considerable health loss and societal costs. General practitioners (GPs) play an important role in the management of LBP; however, GP care has not been shown to be the most cost-effective approach unless exercise and behavioural counselling are added to usual care. The Fear Reduction Exercised Early (FREE) approach to LBP has been developed to assist GPs to manage LBP by empowering exploration and management of psychosocial barriers to recovery and provision of evidence-based care and information. The aim of the Low Back Pain in General Practice (LBPinGP) trial is to explore whether patients with LBP who receive care from GPs trained in the FREE approach have better outcomes than those who receive usual care. METHODS/DESIGN: This is a cluster randomised controlled superiority trial comparing the FREE approach with usual care for LBP management with investigator-blinded assessment of outcomes. GPs will be recruited and then cluster randomised (in practice groups) to the intervention or control arm. Intervention arm GPs will receive training in the FREE approach, and control arm GPs will continue to practice as usual. Patients presenting to their GP with a primary complaint of LBP will be allocated on the basis of allocation of the GP they consult. We aim to recruit 60 GPs and 275 patients (assuming patients are recruited from 75% of GPs and an average of 5 patients per GP complete the study, accounting for 20% patient participant dropout). Patient participants and the trial statistician will be blind to group allocation throughout the study. Analyses will be undertaken on an intention-to-treat basis. The primary outcome will be back-related functional impairment 6 months post-initial LBP consultation (interim data at 2 weeks, 6 weeks and 3 months), measured with the Roland-Morris Disability Questionnaire. Secondary patient outcomes include pain, satisfaction, quality of life, days off from work and costs of care. Secondary GP outcomes include beliefs about pain and impairment, GP confidence, and actual and reported clinical behaviour. Health economic and process evaluations will be conducted. DISCUSSION: In the LBPinGP trial, we will investigate providing an intervention during the first interaction a person with back pain has with their GP. Because the FREE approach is used within a normal GP consultation, if effective, it may be a cost-effective means of improving LBP care. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12616000888460 . Registered on 6 July 2016.This study is funded and supported by the Accident Compensation Corporation (ACC), Wellington, New Zealand. The study funder has not been involved with study design. The study funder will not be involved with or have ultimate authority over the collection, management, analysis and interpretation of data; the writing of the report; or the decision to submit the report for publication. The funder will have the opportunity to comment on draft reports before publication. SD’s work was supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West Peninsula at the Royal Devon and Exeter NHS Foundation Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health

The Role of Thalamic Population Synchrony in the Emergence of Cortical Feature Selectivity

In a wide range of studies, the emergence of orientation selectivity in primary visual cortex has been attributed to a complex interaction between feed-forward thalamic input and inhibitory mechanisms at the level of cortex. Although it is well known that layer 4 cortical neurons are highly sensitive to the timing of thalamic inputs, the role of the stimulus-driven timing of thalamic inputs in cortical orientation selectivity is not well understood. Here we show that the synchronization of thalamic firing contributes directly to the orientation tuned responses of primary visual cortex in a way that optimizes the stimulus information per cortical spike. From the recorded responses of geniculate X-cells in the anesthetized cat, we synthesized thalamic sub-populations that would likely serve as the synaptic input to a common layer 4 cortical neuron based on anatomical constraints. We used this synchronized input as the driving input to an integrate-and-fire model of cortical responses and demonstrated that the tuning properties match closely to those measured in primary visual cortex. By modulating the overall level of synchronization at the preferred orientation, we show that efficiency of information transmission in the cortex is maximized for levels of synchronization which match those reported in thalamic recordings in response to naturalistic stimuli, a property which is relatively invariant to the orientation tuning width. These findings indicate evidence for a more prominent role of the feed-forward thalamic input in cortical feature selectivity based on thalamic synchronization

Dynamic Encoding of Natural Luminance Sequences by LGN Bursts

In the lateral geniculate nucleus (LGN) of the thalamus, visual stimulation produces two distinct types of responses known as tonic and burst. Due to the dynamics of the T-type Ca (2+) channels involved in burst generation, the type of response evoked by a particular stimulus depends on the resting membrane potential, which is controlled by a network of modulatory connections from other brain areas. In this study, we use simulated responses to natural scene movies to describe how modulatory and stimulus-driven changes in LGN membrane potential interact to determine the luminance sequences that trigger burst responses. We find that at low resting potentials, when the T channels are de-inactivated and bursts are relatively frequent, an excitatory stimulus transient alone is sufficient to evoke a burst. However, to evoke a burst at high resting potentials, when the T channels are inactivated and bursts are relatively rare, prolonged inhibitory stimulation followed by an excitatory transient is required. We also observe evidence of these effects in vivo, where analysis of experimental recordings demonstrates that the luminance sequences that trigger bursts can vary dramatically with the overall burst percentage of the response. To characterize the functional consequences of the effects of resting potential on burst generation, we simulate LGN responses to different luminance sequences at a range of resting potentials with and without a mechanism for generating bursts. Using analysis based on signal detection theory, we show that bursts enhance detection of specific luminance sequences, ranging from the onset of excitatory sequences at low resting potentials to the offset of inhibitory sequences at high resting potentials. These results suggest a dynamic role for burst responses during visual processing that may change according to behavioral state

Texture Coding in the Rat Whisker System: Slip-Stick Versus Differential Resonance

Rats discriminate surface textures using their whiskers (vibrissae), but how whiskers extract texture information, and how this information is encoded by the brain, are not known. In the resonance model, whisker motion across different textures excites mechanical resonance in distinct subsets of whiskers, due to variation across whiskers in resonance frequency, which varies with whisker length. Texture information is therefore encoded by the spatial pattern of activated whiskers. In the competing kinetic signature model, different textures excite resonance equally across whiskers, and instead, texture is encoded by characteristic, nonuniform temporal patterns of whisker motion. We tested these models by measuring whisker motion in awake, behaving rats whisking in air and onto sandpaper surfaces. Resonant motion was prominent during whisking in air, with fundamental frequencies ranging from approximately 35 Hz for the long Delta whisker to approximately 110 Hz for the shorter D3 whisker. Resonant vibrations also occurred while whisking against textures, but the amplitude of resonance within single whiskers was independent of texture, contradicting the resonance model. Rather, whiskers resonated transiently during discrete, high-velocity, and high-acceleration slip-stick events, which occurred prominently during whisking on surfaces. The rate and magnitude of slip-stick events varied systematically with texture. These results suggest that texture is encoded not by differential resonant motion across whiskers, but by the magnitude and temporal pattern of slip-stick motion. These findings predict a temporal code for texture in neural spike trains

Timing Precision in Population Coding of Natural Scenes in the Early Visual System

The timing of spiking activity across neurons is a fundamental aspect of the neural population code. Individual neurons in the retina, thalamus, and cortex can have very precise and repeatable responses but exhibit degraded temporal precision in response to suboptimal stimuli. To investigate the functional implications for neural populations in natural conditions, we recorded in vivo the simultaneous responses, to movies of natural scenes, of multiple thalamic neurons likely converging to a common neuronal target in primary visual cortex. We show that the response of individual neurons is less precise at lower contrast, but that spike timing precision across neurons is relatively insensitive to global changes in visual contrast. Overall, spike timing precision within and across cells is on the order of 10 ms. Since closely timed spikes are more efficient in inducing a spike in downstream cortical neurons, and since fine temporal precision is necessary to represent the more slowly varying natural environment, we argue that preserving relative spike timing at a ∼10-ms resolution is a crucial property of the neural code entering cortex

Estimating Receptive Fields from Responses to Natural Stimuli with Asymmetric Intensity Distributions

The reasons for using natural stimuli to study sensory function are quickly mounting, as recent studies have revealed important differences in neural responses to natural and artificial stimuli. However, natural stimuli typically contain strong correlations and are spherically asymmetric (i.e. stimulus intensities are not symmetrically distributed around the mean), and these statistical complexities can bias receptive field (RF) estimates when standard techniques such as spike-triggered averaging or reverse correlation are used. While a number of approaches have been developed to explicitly correct the bias due to stimulus correlations, there is no complementary technique to correct the bias due to stimulus asymmetries. Here, we develop a method for RF estimation that corrects reverse correlation RF estimates for the spherical asymmetries present in natural stimuli. Using simulated neural responses, we demonstrate how stimulus asymmetries can bias reverse-correlation RF estimates (even for uncorrelated stimuli) and illustrate how this bias can be removed by explicit correction. We demonstrate the utility of the asymmetry correction method under experimental conditions by estimating RFs from the responses of retinal ganglion cells to natural stimuli and using these RFs to predict responses to novel stimuli

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

The role of dendritic cells in driving genital tract inflammation and HIV transmission risk: are there opportunities to intervene?

CAPRISA, 2015.Abstract available in pdf