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Background: Peripheral nerve biopsy is a valuable final diagnostic tool; however, histopathological results can be non‐diagnostic. Aims: We aim to identify quality improvement measures by evaluating the pre‐biopsy assessment and diagnostic yield of specific histopathological diagnosis. Methods: This was a retrospective study based on 10 years of experience with peripheral nerve biopsies at a single centre. Clinical data were obtained regarding pre‐biopsy history, examination, serum and cerebrospinal fluid (CSF) investigations, neurophysiology and peripheral nerve imaging. Based upon a histopathological outcome, patients were grouped into vasculitis, granulomatous and infiltrative (diagnostic) group, or a comparison group of non‐specific axonal neuropathy and normal (non‐specific/normal) group. Results: From a cohort of 64 patients, 21 (32.8%) were included in the diagnostic group and 30 (46.9%) in the non‐specific/normal group. Clinical parameters associated with the diagnostic group were shorter history (mean 10.2 months vs 38.1), stepwise progression (81% vs 20%), neuropathic pain (85.7% vs 56.7%), vasculitic rash (23.8% vs 0%), mononeuritis multiplex (57.1% vs 10%), asymmetry (90.5% vs 60%), raised white cell count (47.6% vs 16.7%), myeloperoxidase antibody (19.1% vs 0%) and abnormal peripheral nerve imaging (33.3% vs 10%). Conclusion: Selection of patients undergoing nerve biopsy requires careful consideration of clinical parameters, including peripheral nerve imaging. Several quality improvement measures are proposed to improve yield of clinically actionable information from nerve biopsy. [ABSTRACT FROM AUTHOR]

Small fiber neuropathy usually presents with gradual and progressive chronic length‐dependent pain. Acute small fiber neuropathy is rarely reported. Three patients with acute onset neuropathic pain after Oxford‐AstraZeneca ChAdOx1‐S vaccination are described. Two patients were identified at the Oxford University NHS Foundation Trust, Oxford, UK and one patient in Red de Salud UC Christus, Santiago, Chile. All patients underwent a clinical assessment that included a detailed neurological examination, laboratory investigations, nerve conduction studies, thermal threshold testing, and skin biopsy for intra‐epidermal nerve fiber density. Patients seen in Oxford underwent MRI of the brain and spinal cord. Cerebrospinal analysis was not performed. Neuropathic symptoms (burning pain, dysaesthesias) developed in the hands and feet within 2 weeks of vaccination. On clinical examination, there was pinprick and thermal hyposensitivity in the area of neuropathic pain. Laboratory investigation, nerve conduction tests, sympathetic skin responses, and MRI showed no relevant abnormalities. Thermal thresholds were abnormal and intra‐epidermal nerve fiber density in the lower leg was reduced. In two cases symptoms persist after several months. Three cases of definite acute small fiber neuropathy after Oxford‐AstraZeneca ChAdOx1‐S vaccination are described. At follow up, neuropathic pain was present in two of the patients. [ABSTRACT FROM AUTHOR]

Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs). In the mouse, we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch. [ABSTRACT FROM AUTHOR]

We characterized the time course of inflammatory cytokine release at the site of injury and in plasma after surgery on the rat tail. Anesthetized Sprague-Dawley rats had a 20 mm [...]

Objective: Axonal excitability reflects ion channel function, and it is proposed that this may be a biomarker in painful (vs painless) polyneuropathy. Our objective was to investigate the relationship between axonal excitability parameters and chronic neuropathic pain in deeply phenotyped cohorts with diabetic or chemotherapy‐induced distal symmetrical polyneuropathy. Methods: Two hundred thirty‐nine participants with diabetic polyneuropathy were recruited from sites in the UK and Denmark, and 39 participants who developed chemotherapy‐induced polyneuropathy were recruited from Denmark. Participants were separated into those with probable or definite neuropathic pain and those without neuropathic pain. Axonal excitability of large myelinated fibers was measured with the threshold tracking technique. The stimulus site was the median nerve, and the recording sites were the index finger (sensory studies) and abductor pollicis brevis muscle (motor studies). Results: Participants with painless and painful polyneuropathy were well matched across clinical variables. Sensory and motor axonal excitability measures, including recovery cycle, threshold electrotonus, strength–duration time constant, and current–threshold relationship, did not show differences between participants with painful and painless diabetic polyneuropathy, and there were only minor changes for chemotherapy‐induced polyneuropathy. Interpretation: Axonal excitability did not significantly differ between painful and painless diabetic or chemotherapy‐induced polyneuropathy in a multicenter observational study. Threshold tracking assesses the excitability of myelinated axons; the majority of nociceptors are unmyelinated, and although there is some overlap of the "channelome" between these axonal populations, our results suggest that alternative measures such as microneurography are required to understand the relationship between sensory neuron excitability and neuropathic pain. ANN NEUROL 2022;91:506–520 [ABSTRACT FROM AUTHOR]

Pain is a under‐recognized association of leucine‐rich glioma‐inactivated 1 (LGI1) and contactin‐associated protein‐like 2 (CASPR2) antibodies. Of 147 patients with these autoantibodies, pain was experienced by 17 of 33 (52%) with CASPR2‐ versus 20 of 108 (19%) with LGI1 antibodies (p = 0.0005), and identified as neuropathic in 89% versus 58% of these, respectively. Typically, in both cohorts, normal nerve conduction studies and reduced intraepidermal nerve fiber densities were observed in the sampled patient subsets. In LGI1 antibody patients, pain responded to immunotherapy (p = 0.008), often rapidly, with greater residual patient‐rated impairment observed in CASPR2 antibody patients (p = 0.019). Serum CASPR2 antibodies, but not LGI1 antibodies, bound in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia, suggesting pathophysiological differences that may underlie our clinical observations. ANN NEUROL 2021;90:683–690 [ABSTRACT FROM AUTHOR]

Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. Up to half of patients with diabetes develop neuropathy during the course of their disease, which is accompanied by neuropathic pain in 30-40% of cases. Peripheral nerve injury in diabetes can manifest as progressive distal symmetric polyneuropathy, autonomic neuropathy, radiculo-plexopathies, and mononeuropathies. The most common diabetic neuropathy is distal symmetric polyneuropathy, which we will refer to as DN, with its characteristic glove and stocking like presentation of distal sensory or motor function loss. DN or its painful counterpart, painful DN, are associated with increased mortality and morbidity; thus, early recognition and preventive measures are essential. Nevertheless, it is not easy to diagnose DN or painful DN, particularly in patients with early and mild neuropathy, and there is currently no single established diagnostic gold standard. The most common diagnostic approach in research is a hierarchical system, which combines symptoms, signs, and a series of confirmatory tests. The general lack of long-term prospective studies has limited the evaluation of the sensitivity and specificity of new morphometric and neurophysiological techniques. Thus, the best paradigm for screening DN and painful DN both in research and in clinical practice remains uncertain. Herein, we review the diagnostic challenges from both clinical and research perspectives and their implications for managing patients with DN. There is no established DN treatment, apart from improved glycaemic control, which is more effective in type 1 than in type 2 diabetes, and only symptomatic management is available for painful DN. Currently, less than one-third of patients with painful DN derive sufficient pain relief with existing pharmacotherapies. A more precise and distinct sensory profile from patients with DN and painful DN may help identify responsive patients to one treatment versus another. Detailed sensory profiles will lead to tailored treatment for patient subgroups with painful DN by matching to novel or established DN pathomechanisms and also for improved clinical trials stratification. Large randomized clinical trials are needed to identify the interventions, i.e. pharmacological, physical, cognitive, educational, etc., which lead to the best therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Chronic pain affects one in five of the general population and is the third most important cause of disability-adjusted life-years globally. Unfortunately, treatment remains inadequate due to poor efficacy and tolerability. There has been a failure in translating promising preclinical drug targets into clinic use. This reflects challenges across the whole drug development pathway, from preclinical models to trial design. Nociceptors remain an attractive therapeutic target: their sensitization makes an important contribution to many chronic pain states, they are located outside the blood-brain barrier, and they are relatively specific. The past decade has seen significant advances in the techniques available to study human nociceptors, including: the use of corneal confocal microscopy and biopsy samples to observe nociceptor morphology, the culture of human nociceptors (either from surgical or post-mortem tissue or using human induced pluripotent stem cell derived nociceptors), the application of high throughput technologies such as transcriptomics, the in vitro and in vivo electrophysiological characterization through microneurography, and the correlation with pain percepts provided by quantitative sensory testing. Genome editing in human induced pluripotent stem cell-derived nociceptors enables the interrogation of the causal role of genes in the regulation of nociceptor function. Both human and rodent nociceptors are more heterogeneous at a molecular level than previously appreciated, and while we find that there are broad similarities between human and rodent nociceptors there are also important differences involving ion channel function, expression, and cellular excitability. These technological advances have emphasized the maladaptive plastic changes occurring in human nociceptors following injury that contribute to chronic pain. Studying human nociceptors has revealed new therapeutic targets for the suppression of chronic pain and enhanced repair. Cellular models of human nociceptors have enabled the screening of small molecule and gene therapy approaches on nociceptor function, and in some cases have enabled correlation with clinical outcomes. Undoubtedly, challenges remain. Many of these techniques are difficult to implement at scale, current induced pluripotent stem cell differentiation protocols do not generate the full diversity of nociceptor populations, and we still have a relatively poor understanding of inter-individual variation in nociceptors due to factors such as age, sex, or ethnicity. We hope our ability to directly investigate human nociceptors will not only aid our understanding of the fundamental neurobiology underlying acute and chronic pain but also help bridge the translational gap. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the presence and characterization of chemotherapy‐induced neuropathy (CIPN) and neuropathic pain 5 years after adjuvant chemotherapy with docetaxel or oxaliplatin. Patients from an ongoing prospective study, who had received adjuvant chemotherapy with docetaxel or oxaliplatin in 2011 to 2012 were invited to participate. The patients underwent a thorough examination with interview, neurological examination, questionnaires, assessment tools, nerve conduction studies (NCS), quantitative sensory testing, MScan motor unit number estimation (MUNE), and corneal confocal microscopy (CCM). Patients were divided into no, possible, probable, and confirmed CIPN. Out of the 132 eligible patients, 63 agreed to participate: 28 had received docetaxel and 35 had received oxaliplatin. Forty‐one percent had confirmed CIPN, 34% possible or probable CIPN, and 22% did not have CIPN. The CIPN was characterized mainly by sensory nerve fiber loss, with a more pronounced large fiber than small fiber loss but also some motor fiber loss identified on NCS and MUNE. In general, patients had mild neuropathy with relatively low scores on assessment tools and no association with mood and quality of life. CCM was not useful as a diagnostic tool. Of the patients with probable or confirmed CIPN, 30% experienced pain, which was most often mild, but still interfered moderately with daily life in 20% to 25% and was associated with lower quality of life. In conclusion CIPN was confirmed in 41% 5 years after chemotherapy. The neuropathy was generally mild, but in patients with neuropathic pain it was associated with lower quality of life. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to assess chemotherapy‐induced polyneuropathy (CIPN) 5 years after adjuvant chemotherapy in patients with breast and colorectal cancer. The association of CIPN with quality of life, anxiety, and depression was analyzed. Methods: Of a set of 100 patients with breast cancer and of 74 with colorectal cancer who had undergone surgery and adjuvant chemotherapy in 2011‐2012, 80 and 52 patients alive, respectively, were included together with two reference groups of 249 breast cancer patients and 83 colorectal cancer patients who had undergone surgery only. All patients were sent a questionnaire on alcohol consumption, smoking habits, comorbidity, medicine consumption, and oxaliplatin‐specific questions, as well as the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), the Douleur Neuropathique 4 Questions (DN4q), the EQ‐5D, and the Hospital Anxiety and Depression Scale. Possible polyneuropathy was defined as the presence of numbness and/or tingling in the feet, secondly as a score of ≥4 on the MNSIq. Possible painful polyneuropathy was defined as pain in both feet and a score ≥3 on the DN4q. Results: The prevalence of possible polyneuropathy defined by numbness and/or tingling in the feet was 38.8% (28.1‐50.3) after adjuvant docetaxel and 57.7% (43.2‐71.3) after adjuvant oxaliplatin, with no significant difference from a previous 1‐year follow‐up (P >.35). Fewer had possible polyneuropathy as defined by the MNSIq. Patients with possible polyneuropathy after adjuvant chemotherapy reported significantly lower quality of life than patients treated with surgery only. Conclusion: Symptoms of polyneuropathy following adjuvant docetaxel and oxaliplatin persist 5 years after treatment and affect quality of life negatively. [ABSTRACT FROM AUTHOR]

Introduction: Cold allodynia is often seen in the acute phase of oxaliplatin treatment, but the underlying pathophysiology remains unclear.Methods: Patients scheduled for adjuvant oxaliplatin for colorectal cancer were examined with quantitative sensory testing and nerve excitability tests at baseline and after the second or third oxaliplatin cycle at different skin temperatures.Results: Seven patients were eligible for examination. All patients felt evoked pain and tingling when touching something cold after oxaliplatin infusion. Oxaliplatin decreased motor nerve superexcitability (P < .001), increased relative refractory period (P = .011), and caused neuromyotonia-like after-activity. Cooling exacerbated these changes and prolonged the accommodation half-time.Discussion: The findings suggest that a combined effect of oxaliplatin and cooling facilitates nerve excitability changes and neuromyotonia-like after-activity in peripheral nerve axons. A possible mechanism is the slowing in gating of voltage-dependent fast sodium and slow potassium channels, which results in symptoms of cold allodynia. [ABSTRACT FROM AUTHOR]

Brain plasticity is a key mechanism for learning and recovery. A striking example of plasticity in the adult brain occurs following input loss, for example, following amputation, whereby the deprived zone is "invaded" by new representations. Although it has long been assumed that such reorganization leads to functional benefits for the invading representation, the behavioral evidence is controversial. Here, we investigate whether a temporary period of somatosensory input loss to one finger, induced by anesthetic block, is sufficient to cause improvements in touch perception ("direct" effects of deafferentation). Further, we determine whether this deprivation can improve touch perception by enhancing sensory learning processes, for example, by training ("interactive" effects). Importantly, we explore whether direct and interactive effects of deprivation are dissociable by directly comparing their effects on touch perception. Using psychophysical thresholds, we found brief deprivation alone caused improvements in tactile perception of a finger adjacent to the blocked finger but not to non-neighboring fingers. Two additional groups underwent minimal tactile training to one finger either during anesthetic block of the neighboring finger or a sham block with saline. Deprivation significantly enhanced the effects of tactile perceptual training, causing greater learning transfer compared with sham block. That is, following deafferentation and training, learning gains were seen in fingers normally outside the boundaries of topographic transfer of tactile perceptual learning. Our results demonstrate that sensory deprivation can improve perceptual abilities, both directly and interactively, when combined with sensory learning. This dissociation provides novel opportunities for future clinical interventions to improve sensation. [ABSTRACT FROM AUTHOR]

Small fibre neuropathy (SFN) is characterised by structural injury selectively affecting small diameter sensory and/or autonomic axons. The clinical presentation is dominated by pain. SFN complicates a number of common diseases such as diabetes mellitus and is likely to be increasingly encountered. The diagnosis of SFN is demanding as clinical features can be vague and nerve conduction studies normal. New diagnostic techniques, in particular measurement of intraepidermal nerve fibre density, have significantly improved the diagnostic efficiency of SFN. Management is focused on the treatment of the underlying cause and analgesia, as there is no neuroprotective therapy. A recent and significant advance is the finding that a proportion of cases labelled as idiopathic SFN are in fact associated with gain of function mutations of the voltage-gated sodium channels Nav1.7 and Nav1.8 (encoded by the genes SCN9A and SCN10A, respectively). There is a further group of heritable painful conditions in which gain of function mutations in ion channels alter excitability of sensory neurones but do not cause frank axon degeneration; these include mutations in Nav1.7 (causing erythromelalgia and paroxysmal extreme pain disorder) and TRPA1 (resulting in familial episodic pain disorder). These conditions are exceptionally rare but have provided great insight into the nociceptive system as well as yielding potential analgesic drug targets. In patients with no pre-existing risk factor, the investigation of an underlying cause of SFN should be systematic and appropriate for the patient population. In this review, we focus on how to incorporate recent developments in the diagnosis and pathophysiology of SFN into clinical practice. [ABSTRACT FROM AUTHOR]

A correction to the article "Transcriptional regulator PRDM12 is essential for human pain perception" that was published in the 25 May,2015 issue is presented.

Abstract: We aimed to investigate the genetic associations of neuropathic pain in a deeply phenotyped cohort. Participants with neuropathic pain were cases and compared with those exposed to injury or disease but without neuropathic pain as control subjects. Diabetic polyneuropathy was the most common aetiology of neuropathic pain. A standardised quantitative sensory testing protocol was used to categorize participants based on sensory profile. We performed genome-wide association study, and in a subset of participants, we undertook whole-exome sequencing targeting analyses of 45 known pain-related genes. In the genome-wide association study of diabetic neuropathy (N = 1541), a top significant association was found at the KCNT2 locus linked with pain intensity (rs114159097, P = 3.55 × 10-8). Gene-based analysis revealed significant associations between LHX8 and TCF7L2 and neuropathic pain. Polygenic risk score for depression was associated with neuropathic pain in all participants. Polygenic risk score for C-reactive protein showed a positive association, while that for fasting insulin showed a negative association with neuropathic pain, in individuals with diabetic polyneuropathy. Gene burden analysis of candidate pain genes supported significant associations between rare variants in SCN9A and OPRM1 and neuropathic pain. Comparison of individuals with the "irritable" nociceptor profile to those with a "nonirritable" nociceptor profile identified a significantly associated variant (rs72669682, P = 4.39 × 10-8) within the ANK2 gene. Our study on a deeply phenotyped cohort with neuropathic pain has confirmed genetic associations with the known pain-related genes KCNT2, OPRM1, and SCN9A and identified novel associations with LHX8 and ANK2, genes not previously linked to pain and sensory profiles, respectively., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Abstract: Neuropathic pain remains difficult to treat, with drug development hampered by an incomplete understanding of the pathogenesis of the condition, as well as a lack of biomarkers. The problem is compounded by the scarcity of relevant human peripheral tissues, including skin, nerves, and dorsal root ganglia. Efforts to obtain such samples are accelerating, increasing the need for standardisation across laboratories. In this white paper, we report on a consensus meeting attended by neuropathic pain experts, designed to accelerate protocol alignment and harmonization of studies involving relevant peripheral tissues. The meeting was held in London in March 2024 and attended by 28 networking partners, including industry and patient representatives. We achieved consensus on minimal recommended phenotyping, harmonised wet laboratory protocols, statistical design, reporting, and data sharing. Here, we also share a variety of relevant standard operating procedures as supplementary protocols. We envision that our recommendations will help unify human tissue research in the field and accelerate our understanding of how abnormal interactions between sensory neurons and their local peripheral environment contribute towards neuropathic pain., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Competing Interests: Conflicts of interest There are no conflicts of interest.

Objective: To investigate features of Guillain-Barré syndrome (GBS) following SARS-CoV-2 vaccines and evaluate for a causal link between the two., Methods: We captured cases of GBS after SARS-CoV-2 vaccination through a national, open-access, online surveillance system. For each case, the certainty of GBS was graded using the Brighton criteria, and the relationship to the vaccine was examined using modified WHO Causality Assessment criteria. We compared age distribution of cases with that of prepandemic GBS cases and clinical features with the International GBS Outcome Study (IGOS)., Results: Between 1 January and 30 June 2021, we received 67 reports of GBS following the ChAdOx1 vaccine (65 first doses) and three reports following the BNT162b2 vaccine (all first doses). The causal association with the vaccine was classified as probable for 56 (80%, all ChAdOx1), possible for 12 (17%, 10 ChAdOx1) and unlikely for two (3%, 1 ChAdOx1). A greater proportion of cases occurred in the 50-59 age group in comparison with prepandemic GBS. Most common clinical variants were sensorimotor GBS (n=55; 79%) and facial diplegia with paraesthesias (n=10; 14%). 10% (n=7/69) of patients reported an antecedent infection, compared with 77% (n=502/652) of the IGOS cohort (p<0.00001). Facial weakness (63% (n=44/70) vs 36% (n=220/620); p<0.00001) and sensory dysfunction (93% (n=63/68) vs 69% (n=408/588); p=0.00005) were more common but disease severity and outcomes were similar to the IGOS study., Interpretation: Most reports of GBS followed the first dose of ChAdOx1 vaccine. While our study cannot confirm or refute causation, this observation, together with the absence of alternative aetiologies, different than expected age distribution and the presence of unusual clinical features support a causal link. Clinicians and surveillance bodies should remain vigilant to the possibility of this very rare adverse event and its atypical variants., Competing Interests: Competing interests: TS was chair/cochair of the UK Research and Innovation/National Institute for Health Research COVID-19 Rapid Response and Rolling Funding Initiatives, was an Advisor to the UK COVID-19 Therapeutics Advisory Panel and is a member of the UK Medicines and Healthcare Products Regulatory Agency COVID-19 Vaccines Benefit Risk Expert Working Group. BCJ is a chair of Steering Committee of IGOS. HM is an invited expert for the Commission on Human Medicines COVID-19 Vaccines Safety Surveillance Methodologies Expert Working Group. The remaining authors have no relevant conflict of interest to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Electrophysiological studies in monkeys show that finger amputation triggers local remapping within the deprived primary somatosensory cortex (S1). Human neuroimaging research, however, shows persistent S1 representation of the missing hand's fingers, even decades after amputation. Here, we explore whether this apparent contradiction stems from underestimating the distributed peripheral and central representation of fingers in the hand map. Using pharmacological single-finger nerve block and 7-tesla neuroimaging, we first replicated previous accounts (electrophysiological and other) of local S1 remapping. Local blocking also triggered activity changes to nonblocked fingers across the entire hand area. Using methods exploiting interfinger representational overlap, however, we also show that the blocked finger representation remained persistent despite input loss. Computational modeling suggests that both local stability and global reorganization are driven by distributed processing underlying the topographic map, combined with homeostatic mechanisms. Our findings reveal complex interfinger representational features that play a key role in brain (re)organization, beyond (re)mapping.

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered 1 . Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants 2 , we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

Background: Neuropathic pain is an increasingly prevalent condition and has a major impact on health and quality of life. However, the risk factors for the development and maintenance of neuropathic pain are poorly understood. Clinical, genetic and psychosocial factors all contribute to chronic pain, but their interactions have not been studied in large cohorts. The DOLORisk study aims to study these factors. Protocol: Multicentre cross-sectional and longitudinal cohorts covering the main causes leading to neuropathic pain (e.g. diabetes, surgery, chemotherapy, traumatic injury), as well as rare conditions, follow a common protocol for phenotyping of the participants. This core protocol correlates answers given by the participants on a set of questionnaires with the results of their genetic analyses. A smaller number of participants undergo deeper phenotyping procedures, including neurological examination, nerve conduction studies, threshold tracking, quantitative sensory testing, conditioned pain modulation and electroencephalography. Ethics and dissemination: All studies have been approved by their regional ethics committees as required by national law. Results are disseminated through the DOLORisk website, scientific meetings, open-access publications, and in partnership with patient organisations. Strengths and limitations: Large cohorts covering many possible triggers for neuropathic painMulti-disciplinary approach to study the interaction of clinical, psychosocial and genetic risk factorsHigh comparability of the data across centres thanks to harmonised protocolsOne limitation is that the length of the questionnaires might reduce the response rate and quality of responses of participants., Competing Interests: Competing interests: DLB has acted as a consultant on behalf of Oxford Innovation for Abide, Biogen, GSK, Lilly, Mitsubishi Tanabe, Mundipharma and TEVA over the last 3 years. NA received speaker honoraria from Pfizer and reported fees for consultant services from Novartis, Teva, Grünenthal, Mundipharma, Sanofi Pasteur, Aptinyx. ASCR has received funding from Orion Pharma. ASCR undertakes consultancy and advisory board work for Imperial College Consultants—in the past 12 months, this has included remunerated work for: Merck, Galapagos, Toray, Quartet, Lateral, Novartis and Orion. ASCR was the owner of share options in Spinifex Pharmaceuticals from which personal benefit accrued on the acquisition of Spinifex by Novartis in July 2015 and from which future milestone payments may occur. ASCR is named as an inventor on patents: Rice A.S.C., Vandevoorde S. and Lambert D.M Methods using N-(2-propenyl)hexadecanamide and related amides to relieve pain, WO 2005/079771 (Google Patents); Okuse K. et al Methods of treating pain by inhibition of vgf activity, EP13702262.0/WO2013 110945 (Google Patents).