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People with chemotherapy-induced peripheral neuropathy (CIPN) have abnormalities in Quantitative Sensory Test (QST) findings. However, the predictive utility of QST for the early detection of CIPN in individuals has not been demonstrated. This will require longitudinal QST during chemotherapy treatments. However, QST is time-consuming, requires expertise and complex, costly equipment which has largely prevented its adoption in routine clinical practice. We aimed to assess approaches to develop a reliable, straightforward, time efficient and sensitive sensory testing method. Guided by patient partner input and previous literature, we selected thermal and vibration detection thresholds as target QST parameters. A series of iterative experiments was conducted to determine the optimal body test site and to develop a novel vibration testing protocol. The thenar eminence emerged as the best candidate due to higher sensitivity to all stimulus modalities, lower variance and less age-related change compared to the feet. We demonstrated significant differences in thermal thresholds between healthy participants and people with CIPN measured at the thenar but not the feet. The vibration testing protocol, employing a linear resonant actuator, performed better than a calibrated tuning fork being sufficiently sensitive to identify age-related and body site differences in sensory function well as tracking sensory loss induced by local anaesthetic nerve block. These findings establish a testing framework to deliver QST at a single convenient body site with a reduced set of modalities to efficiently track multifibre sensory function for patients at risk of developing neuropathy.

BackgroundPaediatric chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is common (prevalence 1%–2%). Two-thirds of children experience moderate or severe pain, which is associated with increased fatigue and poorer physical function. However, we do not know if treatment for CFS/ME improves pain.ObjectiveIdentify whether specialist treatment of paediatric CFS/ME improves pain.MethodsWe conducted a detailed search in MEDLINE, EMBASE, PsycINFO and the Cochrane Library. Two researchers independently screened texts published between 1994 and 24 January 2019 with no language restrictions. Inclusion criteria were (1) randomised controlled trials and observational studies; (2) participants aged <19 years with CFS/ME; and (3) measure of pain before and after an intervention.ResultsOf 1898 papers screened, 26 studies investigated treatment for paediatric CFS/ME, 19 of which did not measure pain at any time point. Only five treatment studies measured pain at baseline and follow-up and were included in this review. None of the interventions were specifically targeted at treating pain. Of the included studies, two showed no improvement in pain scores, one suggested an improvement in one subgroup and two studies identified improvements in pain measures in ‘recovered’ patients compared with ‘non-recovered’ patients.ConclusionsDespite the prevalence and impact of pain in children with CFS/ME surprisingly few treatment studies measured pain. In those that did measure pain, the treatments used focused on overall management of CFS/ME and we identified no treatments that were targeted specifically at managing pain. There is limited evidence that treatment helps improve pain scores. However, patients who recover appear to have less pain than those who do not recover. More studies are needed to determine if pain in paediatric CFS/ME requires a specific treatment approach, with a particular focus on patients who do not recover following initial treatment.PROSPERO registration numberCRD42019117540.

Our goal was to develop and refine a decerebrate arterially perfused rat (DAPR) preparation that allows the complete bladder filling and voiding cycle to be investigated without some of the restrictions inherent with in vivo experimentation [e.g., ease and speed of set up (30 min), control over the extracellular milieu and free of anesthetic agents]. Both spontaneous (naturalistic bladder filling from ureters) and evoked (in response to intravesical infusion) voids were routinely and reproducibly observed which had similar pressure characteristics. The DAPR allows the simultaneous measurement of bladder intra-luminal pressure, external urinary sphincter-electromyogram (EUS-EMG), pelvic afferent nerve activity, pudendal motor activity, and permits excellent visualization of the entire lower urinary tract, during typical rat filling and voiding responses. The voiding responses were modulated or eliminated by interventions at a number of levels including at the afferent terminal fields (intravesical capsaicin sensitization-desensitization), autonomic (ganglion blockade with hexamethonium), and somatic motor (vecuronium block of the EUS) outflow and required intact brainstem/hindbrain-spinal coordination (as demonstrated by sequential hindbrain transections). Both innocuous (e.g., perineal stimulation) and nociceptive (tail/paw pinch) somatic stimuli elicited an increase in EUS-EMG indicating intact sensory feedback loops. Spontaneous non-micturition contractions were observed between fluid infusions at a frequency and amplitude of 1.4 ± 0.9 per minute and 1.4 ± 0.3 mmHg, respectively and their amplitude increased when autonomic control was compromised. In conclusion, the DAPR is a tractable and useful model for the study of neural bladder control showing intact afferent signaling, spinal and hindbrain co-ordination and efferent control over the lower urinary tract end organs and can be extended to study bladder pathologies and trial novel treatments.

The brainstem region, locus coeruleus (LC), has been remarkably conserved across vertebrates. Evolution has woven the LC into wide-ranging neural circuits that influence functions as broad as autonomic systems, the stress response, nociception, sleep, and high-level cognition among others. Given this conservation, there is a strong possibility that LC activity is inherently similar across species, and furthermore that age, sex, and brain state influence LC activity similarly across species. The degree to which LC activity is homogenous across these factors, however, has never been assessed due to the small sample size of individual studies. Here, we pool data from 20 laboratories (1,855 neurons) and show diversity across both intrinsic and extrinsic factors such as species, age, sex and brain state. We use a negative binomial regression model to compare activity from male monkeys, and rats and mice of both sexes that were recorded across brain states from brain slices or under different anesthetics or during wakefulness . LC activity differed due to complex interactions of species, sex, and brain state. The LC became more active during aging, independent of sex. Finally, in contrast to the foundational principle that all species express two distinct LC firing modes (\"tonic\" or \"phasic\"), we discovered great diversity within spontaneous LC firing patterns. Different factors were associated with higher incidence of some firing modes. We conclude that the activity of the evolutionarily-ancient LC is not conserved. Inherent differences due to age and species-sex-brain state interactions have implications for understanding the role of LC in species-specific naturalistic behavior, as well as in psychiatric disorders, cardiovascular disease, immunology, and metabolic disorders.

The development of analogical reasoning has traditionally been understood in terms of theories of adult competence. This approach emphasizes structured representations and structure mapping. In contrast, we argue that by taking a developmental perspective, analogical reasoning can be viewed as the product of a substantially different cognitive ability – relational priming. To illustrate this, we present a computational (here connectionist) account where analogy arises gradually as a by-product of pattern completion in a recurrent network. Initial exposure to a situation primes a relation that can then be applied to a novel situation to make an analogy. Relations are represented as transformations between states. The network exhibits behaviors consistent with a broad range of key phenomena from the developmental literature, lending support to the appropriateness of this approach (using low-level cognitive mechanisms) for investigating a domain that has normally been the preserve of high-level models. Furthermore, we present an additional simulation that integrates the relational priming mechanism with deliberative controlled use of inhibition to demonstrate how the framework can be extended to complex analogical reasoning, such as the data from explicit mapping studies in the literature on adults. This account highlights how taking a developmental perspective constrains the theory construction and cognitive modeling processes in a way that differs substantially from that based purely on adult studies, and illustrates how a putative complex cognitive skill can emerge out of a simple mechanism.