Non-invasive brain stimulation as a novel approach to the treatment of chronic non-specific low back pain

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Chronic non-specific low back pain (CNSLBP) is a widespread but poorly understood condition that places a substantial burden on the sufferer, health services and the wider economy. Existing approaches to management do not demonstrate impressive levels of effectiveness. There is growing evidence that CNSLBP is associated with significant alterations in central nervous system (CNS) structure and function, suggesting a possible role for the brain in the aetiology of the condition, and presenting a case for novel therapies which aim to treat CNSLBP by affecting brain function. One such potential therapeutic approach is non-invasive brain stimulation (NIBS). Following a literature review discussing the epidemiology and management of low back pain, the evidence for altered CNS function and the potential role of brain stimulation in CNSLBP and chronic pain generally this thesis includes 3 original scientific studies: A Cochrane systematic review of the effectiveness of NIBS techniques for the treatment of chronic pain. A randomised double-blind exploratory study of transcranial direct current stimulation of the motor cortex in the treatment of CNSLBP Is blinding to the stimulation condition maintained in trials comparing 2mA tDCS with sham stimulation? A randomised cross-over study. RESULTS: There is limited existing evidence that some forms of NIBS may have a beneficial effect on chronic pain, though caution is warranted. Exploratory data from study 2 is not suggestive that tDCS to the motor cortex is effective for treating CNSLBP. Commonly used sham controls in trials of tDCS do not ensure adequate blinding, and so introduce a potential source of bias to the existing evidence base. CONCLUSION: Further research is required to establish the value of NIBS as a treatment for chronic pain and CNSLBP. Future research in tDCS will need to develop and employ fully validated sham controls to ensure adequate blinding. NIBS cannot currently be recommended for the treatment of CNSLBP.This study is partly funded by the BackCare UK and the Rosetrees Trust

Tactile Thresholds are Preserved yet Cortical Sensory Function is Impaired in Chronic Non-Specific Low Back Pain Patients

Introduction: A substantial amount of evidence points to an alteration in brain structure and function patients with chronic non-specific low back pain (CNSLBP) [1-6]. One interpretation of these findings is that the observed brain changes may represent a disruption of the brain’s representations of the body part and the resultant body perception disturbance may underpin this clinical problem. The current study aimed to investigate sensory dysfunction in CNSLBP. Specifically we aimed to distinguish cortically mediated sensory dysfunction from peripheral dysfunction by comparing simple tactile thresholds with more complex cortically mediated sensory tests Methods: We investigated tactile thresholds (TTH), two point discrimination (TPD) and graphaesthesia over the lumbar spine of 19 CLBP patients and 19 age and sex matched healthy controls as a way of investigating whether CLBP patients present with a perceptual disturbance of their lumbar spine. Differences in performance of the sensory tests was explored using the Mann Whitney U Test and one-way between groups multivariate analysis of variance. Results: We found no difference in tactile threshold between the two groups (P=.0.751). There was a statistically significant difference between controls and LBP for TPD: F(1,36)=10.15, p=.003 and letter error rate: F(1, 36)=6.54 p=0.015. The data indicate that LBP patients had a larger lumbar TPD distance and a greater letter recognition error rate. Discussion: Both TPD and graphaesthesia are dependant on the integrity of the primary sensory cortex [7]. These data support existing findings of perceptual abnormality in chronic back pain [8] and the preservation of tactile thresholds is suggestive of cortical rather than peripheral sensory dysfunction. Amelioration of these abnormalities may present a target for therapeutic intervention

Rethinking clinical trials of transcranial direct current stimulation: Participant and assessor blinding is inadequate at intensities of 2mA

Copyright @ 2012 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and 85 reproduction in any medium, provided the original author and source are credited. The article was made available through the Brunel University Open Access Publishing Fund.Background: Many double-blind clinical trials of transcranial direct current stimulation (tDCS) use stimulus intensities of 2 mA despite the fact that blinding has not been formally validated under these conditions. The aim of this study was to test the assumption that sham 2 mA tDCS achieves effective blinding. Methods: A randomised double blind crossover trial. 100 tDCS-naïve healthy volunteers were incorrectly advised that they there were taking part in a trial of tDCS on word memory. Participants attended for two separate sessions. In each session, they completed a word memory task, then received active or sham tDCS (order randomised) at 2 mA stimulation intensity for 20 minutes and then repeated the word memory task. They then judged whether they believed they had received active stimulation and rated their confidence in that judgement. The blinded assessor noted when red marks were observed at the electrode sites post-stimulation. Results: tDCS at 2 mA was not effectively blinded. That is, participants correctly judged the stimulation condition greater than would be expected to by chance at both the first session (kappa level of agreement (κ) 0.28, 95% confidence interval (CI) 0.09 to 0.47 p = 0.005) and the second session (κ = 0.77, 95%CI 0.64 to 0.90), p = <0.001) indicating inadequate participant blinding. Redness at the reference electrode site was noticeable following active stimulation more than sham stimulation (session one, κ = 0.512, 95%CI 0.363 to 0.66, p<0.001; session two, κ = 0.677, 95%CI 0.534 to 0.82) indicating inadequate assessor blinding. Conclusions: Our results suggest that blinding in studies using tDCS at intensities of 2 mA is inadequate. Positive results from such studies should be interpreted with caution.GLM is supported by the National Health & Medical Research Council of Australia ID 571090

A multi-layer extension of the stochastic heat equation

Motivated by recent developments on solvable directed polymer models, we define a 'multi-layer' extension of the stochastic heat equation involving non-intersecting Brownian motions.Comment: v4: substantially extended and revised versio

Tactile thresholds are preserved yet complex sensory function is impaired over the lumbar spine of chronic non-specific low back pain patients. A preliminary investigation

Objectives: To investigate impairments in sensory function in chronic non-specific low back pain patients and the relationship between any impairment and the clinical features of the condition. Design: A cross-sectional case-control study. Setting: Laboratory based study. Participants: Nineteen chronic non-specific low back pain patients and nineteen healthy controls. Main Outcome measures: Tactile threshold, two point discrimination distance and accuracy at a task involving recognizing letters drawn over the skin of the lower back (graphaesthesia) were assessed over the lumbar spine in both groups. Pain duration, pain intensity, physical function, anxiety and depression were assessed by questionnaire in the back pain group Results: We found no difference in tactile threshold between the two groups (median difference 0.00 95% CI -0.04 – 0.04). There was a significant difference between controls and back pain patients for two point discrimination (mean difference 17.85 95% CI 5.93 – 29.77) and graphaesthesia accuracy (mean difference 6.13 95% CI 1.27-10.99). Low back pain patients had a larger lumbar two point discrimination distance threshold and a greater letter recognition error rate. In the patient group, we found no relationship between clinical profile and sensory function and no relationship between the sensory tests. Conclusions: These data support existing findings of perceptual abnormalities in chronic non-specific low back pain patients and are suggestive of cortical rather than peripheral sensory dysfunction. Amelioration of these abnormalities may present a target for therapeutic intervention

A School-Based Environmental Intervention to Reduce Smoking among High School Students: The Acadiana Coalition of Teens against Tobacco (ACTT)

A school-based environmental program to reduce adolescent smoking was conducted in 20 schools (10 intervention; 10 control) in south central Louisiana. The 9th grade cohort (n = 4,763; mean age = 15.4 yrs; 51% female; 61% Caucasian; 30-day smoking prevalence at baseline = 25%) was followed over four years for 30-day smoking prevalence with the school as the unit of analysis. Although prevalence decreased in intervention schools and increased in control schools in Year 2 the significant difference between the two groups at baseline was not overcome by the intervention and increases in prevalence were observed in both groups in Years 3 and 4. The higher the percentage of white students in a school the higher the prevalence rates regardless of intervention/control status. Boys’ and girls’ smoking rates were similar. These outcome data, student feedback and process evaluation provide a basis for continuing to create more innovative adolescent tobacco control programs

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Moving in an environment of induced sensorimotor incongruence does not influence pain sensitivity in healthy volunteers: A randomised within-subject experiment

Objectives: It has been proposed that in the same way that conflict between vestibular and visual inputs leads to motion sickness, conflict between motor commands and sensory information associated with these commands may contribute to some chronic pain states. Attempts to test this hypothesis by artificially inducing a state of sensorimotor incongruence and assessing self-reported pain have yielded equivocal results. To help clarify the effect sensorimotor incongruence has on pain we investigated the effect of moving in an environment of induced incongruence on pressure pain thresholds (PPT) and the pain experienced immediately on completion of PPT testing. Methods: Thirty-five healthy subjects performed synchronous and asynchronous upper-limb movements with and without mirror visual feedback in random order. We measured PPT over the elbow and the pain evoked by testing. Generalised linear mixed-models were performed for each outcome. Condition (four levels) and baseline values for each outcome were within-subject factors. Results: There was no effect of condition on PPT (p = 0.887) or pressure-evoked pain (p = 0.771). A sensitivity analysis using only the first PPT measure after each condition confirmed the result (p = 0.867). Discussion: Inducing a state of movement related sensorimotor incongruence in the upper-limb of healthy volunteers does not influence PPT, nor the pain evoked by testing. We found no evidence that sensorimotor incongruence upregulates the nociceptive system in healthy volunteer

Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans

Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10–15 d after the onset of COVID-19 symptoms. However, due to the recent emergence of SARS-CoV-2 in the human population, it is not known how long antibody responses will be maintained or whether they will provide protection from reinfection. Using sequential serum samples collected up to 94 d post onset of symptoms (POS) from 65 individuals with real-time quantitative PCR-confirmed SARS-CoV-2 infection, we show seroconversion (immunoglobulin (Ig)M, IgA, IgG) in >95% of cases and neutralizing antibody responses when sampled beyond 8 d POS. We show that the kinetics of the neutralizing antibody response is typical of an acute viral infection, with declining neutralizing antibody titres observed after an initial peak, and that the magnitude of this peak is dependent on disease severity. Although some individuals with high peak infective dose (ID50 > 10,000) maintained neutralizing antibody titres >1,000 at >60 d POS, some with lower peak ID50 had neutralizing antibody titres approaching baseline within the follow-up period. A similar decline in neutralizing antibody titres was observed in a cohort of 31 seropositive healthcare workers. The present study has important implications when considering widespread serological testing and antibody protection against reinfection with SARS-CoV-2, and may suggest that vaccine boosters are required to provide long-lasting protection