Pain management in patients with head and neck carcinoma.

Pain is one of the feared effects of advancing cancer and can affect a vast majority of head and neck cancer (HNC) patients. HNC's have a devastating impact on patient's lives as both disease and treatment can affect the ability to speak, swallow and breathe due to involvement of the aerodigestive tract. The etiology of pain in this subgroup of patients could be as a result of direct tumor progression, nerve root compression or as a result of the treatment modalities including surgery radiotherapy and chemotherapy. Pain experienced could be nociceptive or neuropathic. A thorough initial and ongoing assessment of the patient is essential for diagnosis and planning the treatment bearing in mind its modification during treatment. Treatment involves a comprehensive approach which is centred around systematic pharmacotherapy, and supplemented by a range of therapeutic interventions and physical and behavioral approaches. In this article we discuss the incidence, etiology, assessment and treatment of this challenging problem using current modalities

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). Summary 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

Oscillatory dynamics in ischaemic pain

Background: The pain experience relies on integration of brain activity across different areas1, including somatosensory, insular, cingulate, prefrontal cortices, thalamus, subcortical areas and brainstem that belong to different functional systems of the brain but are transiently functionally connected (FC) during pain processing2 Pain is associated with complex spatial, temporal and spectral patterns of brain activity3 measured by Magnetoencephalography. Previous imaging has shown altered connectivity between sensorimotor cortex and resting state networks during tourniquet pain4. We aim to demonstrate oscillatory and FC alterations across our tonically painful experimental stimulus. Methods: This was a pilot study with 5 participants. Approval was obtained from Cardiff University School of Psychology ethics committee (EC.17.12.12.5171). Post-ischaemia isometric forearm exercises result in a severe, deep aching pain; closely simulating pathological pain. Pain was rated on a scale 0-10 (0=no pain10= worst possible pain) whenever this changed during the experiment. Data analysis assessed alpha (7-14Hz), beta (15-30Hz), gamma (6090Hz) frequency bands during rest, early pain, late pain and post pain, epoched into 60 trials of 5 second duration. Pre-processing was performed using fieldtrip and beamformed using DICS. We extracted virtual electrodes from left somatosensory cortex (SI), secondary somatosensory cortex, anterior cingulate cortex (ACC), insula and prefrontal cortex using AAL atlas and extracted alpha, beta and gamma amplitude in each ROI across 4 time periods. Connectivity was assessed between pairs of regions. Results: No substantial connectivity changes were seen. Increases in alpha and beta amplitudes were seen in the ACC, during transition from early to late pain phase with increases in gamma amplitude occurring in four participants. Oscillatory increases coincided with moderate to severe pain ratings. Increases in oscillatory activity in the ACC may reflect pain-anxiety interaction due to the tonically painful nature of the pain stimulus and therefore comparable to clinical chronic pain5. Conclusions Ischaemic tourniquet pain may be an experimental surrogate for chronic pain evoking oscillatory brain changes in previously reported pain regions in the brain. Although we were unable to demonstrate alterations to FC we intend to perform whole brain network connectivity with future dataset

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 -40 mmHg 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

A forward modelling approach for the estimation of oxygen extraction fraction by calibrated fMRI

The measurement of the absolute rate of cerebral metabolic oxygen consumption (CMRO2) is likely to offer a valuable biomarker in many brain diseases and could prove to be important in our understanding of neural function. As such there is significant interest in developing robust MRI techniques that can quantify CMRO2 non-invasively. One potential MRI method for the measurement of CMRO2 is via the combination of fMRI and cerebral blood flow (CBF) data acquired during periods of hypercapnic and hyperoxic challenges. This method is based on the combination of two, previously independent, signal calibration techniques. As such analysis of the data has been approached in a stepwise manner, feeding the results of one calibration experiment into the next. Analysing the data in this manner can result in unstable estimates of the output parameter (CMRO2), due to the propagation of errors along the analysis pipeline. Here we present a forward modeling approach that estimates all the model parameters in a one-step solution. The method is implemented using a regularized non-linear least squares approach to provide a robust and computationally efficient solution. The proposed framework is compared with previous analytical approaches using modeling studies and in-vivo acquisitions in healthy volunteers (n = 10). The stability of parameter estimates is demonstrated to be superior to previous methods (both in-vivo and in simulation). In-vivo estimates made with the proposed framework also show better agreement with expected physiological variation, demonstrating a strong negative correlation between baseline CBF and oxygen extraction fraction. It is anticipated that the proposed analysis framework will increase the reliability of absolute CMRO2 measurements made with calibrated BOLD

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

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, temporoparietal 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 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

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 (250 mg) 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

Using dual-calibrated functional MRI to map brain oxygen supply and consumption in multiple sclerosis

Evidence suggests that cerebrovascular function and oxygen consumption are altered in multiple sclerosis (MS). Here, we quantified the vascular and oxygen metabolic MRI burden in patients with MS (PwMS) and assessed the relationship between these MRI measures of and metrics of damage and disability. In PwMS and in matched healthy volunteers, we applied a newly developed dual-calibrated fMRI method of acquisition and analysis to map grey matter (GM) cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen consumption (CMRO2) and effective oxygen diffusivity of the capillary network (DC). We also quantified physical and cognitive function in PwMS and controls. There was no significant difference in GM volume between 22 PwMS and 20 healthy controls (p=0.302). Significant differences in CBF (PwMS vs. controls: 44.91 ± 6.10 vs. 48.90 ± 5.87 ml/100g/min, p=0.010), CMRO2 (117.69 ± 17.31 vs. 136.49 ± 14.48 μmol/100g/min p<0.001) and DC (2.70 ± 0.51 vs. 3.18 ± 0.41 μmol/100g/mmHg/min, p=0.002) were observed in the PwMS. No significant between-group differences were observed for OEF (PwMS vs. controls: 0.38 ± 0.09 vs. 0.39 ± 0.02, p=0.358). Regional analysis showed widespread reductions in CMRO2 and DC for PwMS compared to healthy volunteers. There was a significant correlation between physiological measures and T2 lesion volume, but no association with current clinical disability. Our findings demonstrate concurrent reductions in oxygen supply and consumption in the absence of an alteration in oxygen extraction that may be indicative of a reduced demand for oxygen (O2), an impaired transfer of O2 from capillaries to mitochondria, and/or a reduced ability to utilise O2 that is available at the mitochondria. With no between-group differences in GM volume, our results suggest that changes in brain physiology may precede MRI-detectable GM loss and thus may be one of the pathological drivers of neurodegeneration and disease progression

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