From Mechanisms to Analgesia: Towards the Use of Non-Invasive Neuromodulation for Pain Relief in the Clinic

The use of electricity for analgesic effects has a long history and yet currently neuromodulation devices based on electrical stimulation are typically restricted to being a last resort intervention for pain patients after the failure of pharmacological treatments. Whilst spinal cord stimulation is an established intervention for intractable neuropathic pain, the use of neuromodulation for other forms of pain and targeting different aspects of pain processing is less well established. Non-invasive neuromodulation as part of a standard intervention for pain relief would be ideal for without long term treatment of a chronic pain condition as it would avoid the inevitable side effects associated with long-term use of pharmacological interventions or interactions between different drug treatments. This is particularly relevant as chronic pain can be associated with diseases that would require pharmacological treatment for the primary condition. However, there is currently both a deficit in understanding the mechanisms of the different non-invasive devices and also in how these devices may facilitate pain relief for specific conditions. This review will focus on the application of electric currents non-invasively to different sites for pain relief and outline the future potential of these technologies

Elucidating the complex organization of neural micro-domains in the locust Schistocerca gregaria using dMRI.

To understand brain function it is necessary to characterize both the underlying structural connectivity between neurons and the physiological integrity of these connections. Previous research exploring insect brain connectivity has typically used electron microscopy techniques, but this methodology cannot be applied to living animals and so cannot be used to understand dynamic physiological processes. The relatively large brain of the desert locust, Schistercera gregaria (Forksȧl) is ideal for exploring a novel methodology; micro diffusion magnetic resonance imaging (micro-dMRI) for the characterization of neuronal connectivity in an insect brain. The diffusion-weighted imaging (DWI) data were acquired on a preclinical system using a customised multi-shell diffusion MRI scheme optimized to image the locust brain. Endogenous imaging contrasts from the averaged DWIs and Diffusion Kurtosis Imaging (DKI) scheme were applied to classify various anatomical features and diffusion patterns in neuropils, respectively. The application of micro-dMRI modelling to the locust brain provides a novel means of identifying anatomical regions and inferring connectivity of large tracts in an insect brain. Furthermore, quantitative imaging indices derived from the kurtosis model that include fractional anisotropy (FA), mean diffusivity (MD) and kurtosis anisotropy (KA) can be extracted. These metrics could, in future, be used to quantify longitudinal structural changes in the nervous system of the locust brain that occur due to environmental stressors or ageing

Elucidating the complex organization of neural micro-domains in the locust Schistocerca gregaria using dMRI.

To understand brain function it is necessary to characterize both the underlying structural connectivity between neurons and the physiological integrity of these connections. Previous research exploring insect brain connectivity has typically used electron microscopy techniques, but this methodology cannot be applied to living animals and so cannot be used to understand dynamic physiological processes. The relatively large brain of the desert locust, Schistercera gregaria (Forksȧl) is ideal for exploring a novel methodology; micro diffusion magnetic resonance imaging (micro-dMRI) for the characterization of neuronal connectivity in an insect brain. The diffusion-weighted imaging (DWI) data were acquired on a preclinical system using a customised multi-shell diffusion MRI scheme optimized to image the locust brain. Endogenous imaging contrasts from the averaged DWIs and Diffusion Kurtosis Imaging (DKI) scheme were applied to classify various anatomical features and diffusion patterns in neuropils, respectively. The application of micro-dMRI modelling to the locust brain provides a novel means of identifying anatomical regions and inferring connectivity of large tracts in an insect brain. Furthermore, quantitative imaging indices derived from the kurtosis model that include fractional anisotropy (FA), mean diffusivity (MD) and kurtosis anisotropy (KA) can be extracted. These metrics could, in future, be used to quantify longitudinal structural changes in the nervous system of the locust brain that occur due to environmental stressors or ageing

Elucidating the complex organization of neural micro-domains in the locust Schistocerca gregaria using dMRI

To understand brain function it is necessary to characterize both the underlying structural connectivity between neurons and the physiological integrity of these connections. Previous research exploring insect brain connectivity has typically used electron microscopy techniques, but this methodology cannot be applied to living animals and so cannot be used to understand dynamic physiological processes. The relatively large brain of the desert locust, Schistercera gregaria (Forksȧl) is ideal for exploring a novel methodology; micro diffusion magnetic resonance imaging (micro-dMRI) for the characterization of neuronal connectivity in an insect brain. The diffusion-weighted imaging (DWI) data were acquired on a preclinical system using a customised multi-shell diffusion MRI scheme optimized to image the locust brain. Endogenous imaging contrasts from the averaged DWIs and Diffusion Kurtosis Imaging (DKI) scheme were applied to classify various anatomical features and diffusion patterns in neuropils, respectively. The application of micro-dMRI modelling to the locust brain provides a novel means of identifying anatomical regions and inferring connectivity of large tracts in an insect brain. Furthermore, quantitative imaging indices derived from the kurtosis model that include fractional anisotropy (FA), mean diffusivity (MD) and kurtosis anisotropy (KA) can be extracted. These metrics could, in future, be used to quantify longitudinal structural changes in the nervous system of the locust brain that occur due to environmental stressors or ageing

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine

Enhanced motor learning following task-concurrent dual transcranial direct current stimulation.

OBJECTIVE:Transcranial direct current stimulation (tDCS) of the primary motor cortex (M1) has beneficial effects on motor performance and motor learning in healthy subjects and is emerging as a promising tool for motor neurorehabilitation. Applying tDCS concurrently with a motor task has recently been found to be more effective than applying stimulation before the motor task. This study extends this finding to examine whether such task-concurrent stimulation further enhances motor learning on a dual M1 montage. METHOD:Twenty healthy, right-handed subjects received anodal tDCS to the right M1, dual tDCS (anodal current over right M1 and cathodal over left M1) and sham tDCS in a repeated-measures design. Stimulation was applied for 10 mins at 1.5 mA during an explicit motor learning task. Response times (RT) and accuracy were measured at baseline, during, directly after and 15 mins after stimulation. Motor cortical excitability was recorded from both hemispheres before and after stimulation using single-pulse transcranial magnetic stimulation. RESULTS:Task-concurrent stimulation with a dual M1 montage significantly reduced RTs by 23% as early as with the onset of stimulation (p<0.01) with this effect increasing to 30% at the final measurement. Polarity-specific changes in cortical excitability were observed with MEPs significantly reduced by 12% in the left M1 and increased by 69% in the right M1. CONCLUSION:Performance improvement occurred earliest in the dual M1 condition with a stable and lasting effect. Unilateral anodal stimulation resulted only in trendwise improvement when compared to sham. Therefore, task-concurrent dual M1 stimulation is most suited for obtaining the desired neuromodulatory effects of tDCS in explicit motor learning

Pressure pain thresholds increase after preconditioning 1 Hz repetitive transcranial magnetic stimulation with transcranial direct current stimulation.

BACKGROUND: The primary motor cortex (M1) is an effective target of non-invasive cortical stimulation (NICS) for pain threshold modulation. It has been suggested that the initial level of cortical excitability of M1 plays a key role in the plastic effects of NICS. OBJECTIVE: Here we investigate whether transcranial direct current stimulation (tDCS) primed 1 Hz repetitive transcranial magnetic stimulation (rTMS) modulates experimental pressure pain thresholds and if this is related to observed alterations in cortical excitability. METHOD: 15 healthy, male participants received 10 min 1 mA anodal, cathodal and sham tDCS to the left M1 before 15 min 1 Hz rTMS in separate sessions over a period of 3 weeks. Motor cortical excitability was recorded at baseline, post-tDCS priming and post-rTMS through recording motor evoked potentials (MEPs) from right FDI muscle. Pressure pain thresholds were determined by quantitative sensory testing (QST) through a computerized algometer, on the palmar thenar of the right hand pre- and post-stimulation. RESULTS: Cathodal tDCS-primed 1 Hz-rTMS was found to reverse the expected suppressive effect of 1 Hz rTMS on cortical excitability; leading to an overall increase in activity (p<0.001) with a parallel increase in pressure pain thresholds (p<0.01). In contrast, anodal tDCS-primed 1 Hz-rTMS resulted in a corresponding decrease in cortical excitability (p<0.05), with no significant effect on pressure pain. CONCLUSION: This study demonstrates that priming the M1 before stimulation of 1 Hz-rTMS modulates experimental pressure pain thresholds in a safe and controlled manner, producing a form of analgesia

The effect of externally generated loading on predictive grip force modulation

A characteristic of skilled movement is the ability of the CNS to predict the consequences of motor commands. When we lift an object there is an anticipatory increase in grip force that prevents a grasped object from slipping. When an object is pulled from our grasp by an external force, a reflexive modulation in grip force prevents slippage. Here we examine how external perturbations to a grasped object influence anticipatory grip force during object manipulation using a bimanual task, with each hand holding a computer-controlled object. Subjects were instructed to maintain the position of the object held in the right hand. Loading was applied to this restrained object: either self-generated by the action of their left hand or externally generated by a motor. The magnitude of the grip force response to self-generated loading increased after the object was loaded, and the latency of this response remained predictive of load force. This implies that external and self-generated loading increase the anticipatory grip force response. Unlinked trials, where the subject's moved their left hand but no loading was generated on the right-hand object were used to assess the presence of purely predictive control of grip force. External loading soon after self-generated loading maintained an existing predictive response once the linkage between the subject's action and object loading had been removed. However, external loading had no influence as the existing prediction decays. Therefore, the predictive grip force response during object manipulation can be significantly modified by object loading from an external source

Evolution of reaction times at baseline (PRE), during tDCS (DURING) and at post-intervention (POST1 and POST2) for each active stimulation condition (anodal, dual) compared to sham.

<p>* = p<0.05 and ** = p<0.01 from the ANOVA; # = p<0.05 and ## = p<0.01 from the ANCOVA; Error bars are 95% confidence intervals (CI) calculated on the transformed data and transformed back to the original scale.</p