How to Distinguish Non-Inflammatory from Inflammatory Pain in RA?

PURPOSE OF THE REVIEW: Managing non-inflammatory pain in rheumatoid arthritis (RA) can be a huge burden for the rheumatologist. Pain that persists despite optimal RA treatment is extremely challenging for patient and physician alike. Here, we outline the latest research relevant to distinguishing non-inflammatory from inflammatory RA pain and review the current understanding of its neurobiology and management. RECENT FINDINGS: Nociplastic pain is a recently introduced term by the international pain community. Its definition encompasses the non-inflammatory pain of RA and describes pain that is not driven by inflamed joints or compromised nerves, but that is instead driven by a functional reorganisation of the central nervous system (CNS). Insights from all areas of nociplastic pain research, including fibromyalgia, support a personalised pain management approach for non-inflammatory pain of RA, with evidence-based guidelines favouring use of non-pharmacological interventions. Future developments include novel CNS targeting pharmacotherapeutic approaches to treat nociplastic pain.

Chronic musculoskeletal impairment is associated with alterations in brain regions responsible for the production and perception of movement.

KEY POINTS: Massive irreparable rotator cuff tear was used as a model to study the impact of chronic pain and motor impairment on the motor systems of the human brain using magnetic resonance imaging. Patients show markers of lower grey/white matter integrity and lower functional connectivity compared with control participants in regions responsible for movement and the perception of visual movement and body shape. An independent cohort of patients showed relative deficits in the perception of visual motion and hand laterality compared with an age-matched control group. These data support the hypothesis that the structure and function of the motor control system differs in patients who have experienced chronic motor impairment. This work also raises a new hypothesis, supported by neuroimaging and behaviour, that a loss of motor function could also be associated with off-target effects, namely a reduced ability to perceive motion and body form. ABSTRACT: Changes in the way we move can induce changes in the brain, yet we know little of such plasticity in relation to musculoskeletal diseases. Here we use massive irreparable rotator cuff tear as a model to study the impact of chronic motor impairment and pain on the human brain. Cuff tear destabilises the shoulder, impairing upper-limb function in overhead and load-bearing tasks. We used neuroimaging and behavioural testing to investigate how brain structure and function differed in cuff tear patients and controls (imaging: 21 patients, age 76.3 ± 7.68; 18 controls, age 74.9 ± 6.59; behaviour: 13 patients, age 75.5 ± 10.2; 11 controls, age 73.4 ± 5.01). We observed lower grey matter density and cortical thickness in cuff tear patients in the postcentral gyrus, inferior parietal lobule, temporal-parietal junction and the pulvinar - areas implicated in somatosensation, reach/grasp and body form perception. In patients we also observed lower functional connectivity between the motor network and the middle temporal visual cortex (MT), a region involved in visual motion perception. Lower white matter integrity was observed in patients in the inferior fronto-occipital/longitudinal fasciculi. We investigated the cognitive domains associated with the brain regions identified. Patients exhibited relative impairment in visual body judgements and the perception of biological/global motion. These data support our initial hypothesis that cuff tear is associated with differences in the brain's motor control regions in comparison with unaffected individuals. Moreover, our combination of neuroimaging and behavioural data raises a new hypothesis that chronic motor impairment is associated with an altered perception of visual motion and body form.

Changes in arterial cerebral blood volume during lower body negative pressure measured with MRI.

Cerebral Autoregulation (CA), defined as the ability of the cerebral vasculature to maintain stable levels of blood flow despite changes in systemic blood pressure, is a critical factor in neurophysiological health. Magnetic resonance imaging (MRI) is a powerful technique for investigating cerebrovascular function, offering high spatial resolution and wide fields of view (FOV), yet it is relatively underutilized as a tool for assessment of CA. The aim of this study was to demonstrate the potential of using MRI to measure changes in cerebrovascular resistance in response to lower body negative pressure (LBNP). A Pulsed Arterial Spin Labeling (PASL) approach with short inversion times (TI) was used to estimate cerebral arterial blood volume (CBVa) in eight healthy subjects at baseline and -40mmHg LBNP. We estimated group mean CBVa values of 3.13 ± 1.00 and 2.70 ± 0.38 for baseline and lbnp respectively, which were the result of a differential change in CBVa during -40mmHg LBNP that was dependent on baseline CBVa. These data suggest that the PASL CBVa estimates are sensitive to the complex cerebrovascular response that occurs during the moderate orthostatic challenge delivered by LBNP, which we speculatively propose may involve differential changes in vascular tone within different segments of the arterial vasculature. These novel data provide invaluable insight into the mechanisms that regulate perfusion of the brain, and establishes the use of MRI as a tool for studying CA in more detail.

Mapping the pharmacological modulation of brain oxygen metabolism: The effects of caffeine on absolute CMRO2 measured using dual calibrated fMRI.

This study aims to map the acute effects of caffeine ingestion on grey matter oxygen metabolism and haemodynamics with a novel MRI method. Sixteen healthy caffeine consumers (8 males, age=24.7±5.1) were recruited to this randomised, double-blind, placebo-controlled study. Each participant was scanned on two days before and after the delivery of an oral caffeine (250mg) or placebo capsule. Our measurements were obtained with a newly proposed estimation approach applied to data from a dual calibration fMRI experiment that uses hypercapnia and hyperoxia to modulate brain blood flow and oxygenation. Estimates were based on a forward model that describes analytically the contributions of cerebral blood flow (CBF) and of the measured end-tidal partial pressures of CO2 and O2 to the acquired dual-echo GRE signal. The method allows the estimation of grey matter maps of: oxygen extraction fraction (OEF), CBF, CBF-related cerebrovascular reactivity (CVR) and cerebral metabolic rate of oxygen consumption (CMRO2). Other estimates from a multi inversion time ASL acquisition (mTI-ASL), salivary samples of the caffeine concentration and behavioural measurements are also reported. We observed significant differences between caffeine and placebo on average across grey matter, with OEF showing an increase of 15.6% (SEM±4.9%, p<0.05) with caffeine, while CBF and CMRO2 showed differences of -30.4% (SEM±1.6%, p<0.01) and -18.6% (SEM±2.9%, p<0.01) respectively with caffeine administration. The reduction in oxygen metabolism found is somehow unexpected, but consistent with a hypothesis of decreased energetic demand, supported by previous electrophysiological studies reporting reductions in spectral power with EEG. Moreover the maps of the physiological parameters estimated illustrate the spatial distribution of changes across grey matter enabling us to localise the effects of caffeine with voxel-wise resolution. CBF changes were widespread as reported by previous findings, while changes in OEF were found to be more restricted, leading to unprecedented mapping of significant CMRO2 reductions mainly in frontal gyrus, parietal and occipital lobes. In conclusion, we propose the estimation framework based on our novel forward model with a dual calibrated fMRI experiment as a viable MRI method to map the effects of drugs on brain oxygen metabolism and haemodynamics with voxel-wise resolution.

Reduced brain oxygen metabolism in patients with multiple sclerosis: Evidence from dual-calibrated functional MRI.

Cerebral energy deficiency is increasingly recognised as an important feature of multiple sclerosis (MS). Until now, we have lacked non-invasive imaging methods to quantify energy utilisation and mitochondrial function in the human brain. Here, we used novel dual-calibrated functional magnetic resonance imaging (dc-fMRI) to map grey-matter (GM) deoxy-haemoglobin sensitive cerebral blood volume (CBVdHb), cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen consumption (CMRO2) in patients with MS (PwMS) and age/sex matched controls. By integrating a flow-diffusion model of oxygen transport, we evaluated the effective oxygen diffusivity of the capillary network (DC) and the partial pressure of oxygen at the mitochondria (PmO2). Significant between-group differences were observed as decreased CBF (p = 0.010), CMRO2 (p < 0.001) and DC (p = 0.002), and increased PmO2 (p = 0.043) in patients compared to controls. No significant differences were observed for CBVdHb (p = 0.389), OEF (p = 0.358), or GM volume (p = 0.302). Regional analysis showed widespread reductions in CMRO2 and DC for PwMS. Our findings may be indicative of reduced oxygen demand or utilisation in the MS brain and mitochondrial dysfunction. Our results suggest changes in brain physiology may precede MRI-detectable GM loss and may contribute to disease progression and neurodegeneration.

A flow-diffusion model of oxygen transport for quantitative mapping of cerebral metabolic rate of oxygen (CMRO2) with single gas calibrated fMRI.

One promising approach for mapping CMRO2 is dual-calibrated functional MRI (dc-fMRI). This method exploits the Fick Principle to combine estimates of CBF from ASL, and OEF derived from BOLD-ASL measurements during arterial O2 and CO2 modulations. Multiple gas modulations are required to decouple OEF and deoxyhemoglobin-sensitive blood volume. We propose an alternative single gas calibrated fMRI framework, integrating a model of oxygen transport, that links blood volume and CBF to OEF and creates a mapping between the maximum BOLD signal, CBF and OEF (and CMRO2). Simulations demonstrated the method's viability within physiological ranges of mitochondrial oxygen pressure, PmO2, and mean capillary transit time. A dc-fMRI experiment, performed on 20 healthy subjects using O2 and CO2 challenges, was used to validate the approach. The validation conveyed expected estimates of model parameters (e.g., low PmO2), with spatially uniform OEF maps (grey matter, GM, OEF spatial standard deviation ≈ 0.13). GM OEF estimates obtained with hypercapnia calibrated fMRI correlated with dc-fMRI (r = 0.65, p = 2·10-3). For 12 subjects, OEF measured with dc-fMRI and the single gas calibration method were correlated with whole-brain OEF derived from phase measures in the superior sagittal sinus (r = 0.58, p = 0.048; r = 0.64, p = 0.025 respectively). Simplified calibrated fMRI using hypercapnia holds promise for clinical application.