Neurological Markers of Maladaptive Brain Activity in Fibromyalgia and their Relationship with Treatment Effectiveness

Chronic pain (CP) is estimated to affect at least one-third of the population in the United Kingdom. Fibromyalgia (FM) is one of the most disabling CP conditions. Epidemiological research suggests its global prevalence to be between 2-8%. The unknown pathogenesis, lack of biological markers to monitor its development, and lack of successful treatment make FM a crucial target of pre-clinical research.The goal of this project is twofold. The project aims to 1) identify robust neurological markers (i.e., electrochemical brain activity) by applying a combination of advanced electroencephalography (EEG) signal processing (i.e., functional connectivity of oscillatory activity) and neuroinflammatory (NI) responses (i.e., estimation of pro-inflammatory cytokines intake), through which 2) characterizing successfully and unsuccessfully treated FM patients (compared to age-matched healthy controls). These measures, seldom combined, have been successfully applied to the study of psychiatric conditions and sleep. Crucially, the identification of neurological markers at rest and during arousing sensory stimulation will allow us to estimate the relationship between these neurological markers and treatment effectiveness. This proposal is important because it aims to generate a robust pre-clinical neurological tool to identify FM and its relationship with measures of treatment effectiveness. The successful identification of neurological markers will improve the assessment of the development of maladaptive changes in FM and will kick-start further research on treatment effectiveness.This project is of great medical relevance as it will identify pathological signatures of FM that can then inform research on etiology and treatment of this condition.

Cognition stays wild: A commentary on Ross and Vallée-Tourangeau’s Rewilding Cognition

A “failed” experiment (Ross & Vallée-Tourangeau, 2021) tried to reveal the role played by materiality in solving an insight problem that made reference to embodied action, leading to valuable insights about the nature of cognition and the experimental method. In this commentary, we argue that this study reveals various forms of interactivity and brings new evidence against the idea that “pure” cognition can be isolated from either materiality or sociality. The question becomes, then, not whether the use of objects helps or hinders problem solving, but how objects, bodies, and other people participate in it, even in controlled lab settings, and to what effect. Reflections are offered on why and how cognition stays wild (i.e., embodied, dialogical, and surprising) and what this means for experimental work.

The GLORIA adherence subproject: problems and randomization mistakes

Medication adherence, which is the extent to which patients take their medication as prescribed, is essential in treating chronic inflammatory diseases such as rheumatoid arthritis (RA). Therefore, we nested a subproject in the two-year multicenter Glucocorticoid Low-dose Outcome in Rheumatoid Arthritis (GLORIA) trial to add a low-dose prednisolone (5 mg/day) or placebo to the standard care in older people (≥65 years) with RA. Adherence was measured with an electronic monitoring cap that recorded bottle openings in all patients. In the subproject, we performed an adherence intervention with an advanced cap that could communicate with an application on the smart device via Bluetooth. We randomized patients with a smart device to receive or not to receive adherence reminders on the smart device for three months. Multiple problems emerged that precluded an answer to the research question: sample size (overly optimistic estimates of older patients with a smart device), logistic issues (availability of smartcaps, data extraction), randomization and treatment allocation errors (despite training of personnel), and low quality of the data in the intervention group (hardware failure, discovered too late because data was read in batches). For future trials planning to include a subproject, we recommend keeping it simple, starting with a field test before the actual study starts, and monitoring data from the beginning of the study.

Rewilding Cognition: Complex Dynamics in Open Experimental Systems

Insight problems are sometimes designed to encourage an incorrect and misleading interpretation that veils a simple answer. The socks problem is one such problem: Given black socks and brown socks in a drawer mixed in a ratio of four to five, how many socks will you have to take out to make sure that you have a pair of the same color? The ratio information is misleading since, with only two colors, pulling three socks will guarantee a matching pair. Recently, offered a distinction between first- and second-order problem-solving: The former proceeds with and through a physical model of the problem, while the latter proceeds in the absence of such interactions with the world, in other words on the basis of mental processes alone. Vallée-Tourangeau and March also proposed a thought experiment, suggesting that the ratio information in the socks problem might be quickly abandoned in a first-order environment, that is, one where participants observe the results of drawing socks out of a bag rather than imagining themselves doing so. We tested this prediction by randomly allocating participants to a low- (second-order) or high- (first-order) interactivity condition. Marginally more participants announced the correct answer within a 5-minute period in the high than in the low condition, although the difference was not significant. Detailed analysis of the video recording revealed the challenges of operationalizing a second-order condition, as participants engaged in dialogical interactions with the experimenter. In addition, the manner in which the high-interactivity condition was designed appeared to encourage the physical reification of the misleading ratio, thus anchoring that information more firmly rather than defusing it through interactivity. We close the paper with some reflections on wide, or systemic, cognition in experimental research on creative problem-solving.

Ponies, Joints, Complexity and the Method of Indifference

An important discipline in biomedical science is the repair of damaged organs by in vitro cultured differentaited stem cells. This article evaluates an article in this field, entitled "The complexity of joint regeneration", by Diloloksumpan et al. (2021), who described a regeneration experiment of artificial damage of the joint of ponies. The experiment failed an I describe the possible cause of this failure by discussing the design of the experiment in the light of J.S.Mill's Method of Difference, published in 1848. I continue with a discussion of the concept of complexity that was introduced by the authors of the paper, by pointing out that three types of complexity may be distinguished; one of these is complicatedness which characterizes the assumed complexity of the joint experiment. I propose that this complicatedness can be solved by the use of the method of difference.

The Complexity of Joint Regeneration: How an Advanced Implant could Fail by Its In Vivo Proven Bone Component

Articular cartilage damage is a major challenge in healthcare due to the lack of long-term repair options. There are several promising regenerative implant-based approaches for the treatment, but the fixation of the implant remains a significant challenge. This study evaluated the potential for repair of an osteochondral implant produced through a novel combined bioprinting-based chondral-bone integration, with and without cells, in an equine model. Implants consisted of a melt electrowritten polycaprolactone (PCL) framework for the chondral compartment, which was firmly integrated with a bone anchor. The bone anchor was produced by extrusion-based printing of a low-temperature setting bioceramic material that had been proven to be effective for osteo-regeneration in an orthotopic, non-load bearing and non-articular site in the same species in an earlier in vivo study. Articular cartilage-derived progenitor cells were seeded into the PCL framework and cultured for 28 days in vitro in the presence of bone morphogenetic protein-9 (BMP-9), resulting in the formation of abundant extracellular matrix rich in glycosaminoglycans (GAGs) and type II collagen. The constructs were implanted in the stifle joints of Shetland ponies with cell-free scaffolds as controls. Clinical signs were monitored, and progression of healing was observed non-invasively through radiographic examinations and quantitative gait analysis. Biochemical and histological analyses 6 months after implantation revealed minimal deposition of GAGs and type II collagen in the chondral compartment of the defect site for both types of implants. Quantitative micro-computed tomography showed collapse of the bone anchor with low volume of mineralized neo-bone formation in both groups. Histology confirmed that the PCL framework within the chondral compartment was still present. It was concluded that the collapse of the osteal anchor, resulting in loss of the mechanical support of the chondral compartment, strongly affected overall outcome, precluding evaluation of the influence of BMP-9 stimulated cells on in vivo cartilage regeneration.