Mark Rowland Hutchinson

Childhood dementias are a group of paediatric neurodegenerative disorders characterised by neurocognitive decline, and in many cases underpinned by pathophysiological mechanisms similar to adult-onset dementias. In this study, we use patient-derived induced pluripotent stem cells (iPSCs) from children with one of the most prevalent childhood dementias, Mucopolysaccharidosis Type IIIA (MPS IIIA), also known as Sanfilippo syndrome. The derived cortical cultures exhibit lysosomal dysfunction, heparan sulfate accumulation, progressive neurodegeneration and astrocytic reactivity, recapitulating prototypical in-vivo phenotypes. Using a multimodal drug screening platform that integrates machine learning, high-content confocal imaging, single-nuclei transcriptomics and electrophysiology, we identify at least nine repurposed compounds that significantly mitigate these adverse effects within two weeks of treatment in vitro, demonstrating potential for rapid clinical translation. This human preclinical model for MPS IIIA, coupled with a robust multimodal therapeutic interrogation platform, serves as an exemplar for advancing drug discovery for childhood dementias and the broader neurodegenerative disease spectrum.

Objective: To validate a modified algometer method for assessing mechanical nociceptive threshold (MNT) in lambs before and after husbandry procedures (marking) under field conditions by testing the precision, intra-operator reliability and agreement, and minimal detectable change (MDC). Animals: Forty-six randomly allocated Merino lambs: 6 control (sham handled), 13 hot knife tail docked, 13 rubber ring tail docked, 7 hot knife tail docked and rubber ring castrated, and 7 rubber ring tail docked and castrated. Methods: MNT (mean triplicate measurements at each replicate) was assessed at the tail base, using three replicate measurements before, and three hours after marking to assess precision, reliability, agreement, and MDC. A single operator performed all testing, with lambs restrained by one of three handlers (randomly) for each replicate. Within-animal/-occasion (pre- or post-marking) relative and absolute precision were evaluated using the coefficient of variation (CV) and a combination of standard deviation (SD) and dispersion modelling, respectively. Agreement was assessed using Bland-Altman plots, and linear mixed effects regression was used to determine the intra-class correlation coefficient (ICC) for intra-operator reliability, and any systematic effects of replicate order or handler. MDC was calculated from the standard error of measurement. Responsiveness to marking was analyzed by comparing MNT change from pre- to post-marking using linear mixed effects regression. Results: The overall median MNT was 3.07 kgf (IQR = 2.00–3.84, range = 1.23–5.00). Greater body weight was associated with significantly higher absolute imprecision ( p = 7 × 10 ⁻⁵ ). Median CV was 12.5% (IQR = 7.29–18.16, range = 1.5–55.4) and was significantly higher post-marking ( p = 0.0003), likely related to lower post-marking MNT. The agreement between replicates was good with small mean differences (0.02–0.26 kgf), although there were wide Bland-Altman limits of agreement (2.27–3.51 kgf). There was good intra-operator reliability [ICC (95% CI) = 0.83 (0.81–0.94)]. The minimum detectable change was 1.38 kgf. There was a significant reduction in MNT after marking for all marking groups ( p < 0.01). Conclusions: Modified algometer MNT measurement in lambs around the time of marking was feasible with sufficient precision and responsiveness to demonstrate a reduction in nociceptive threshold following husbandry procedures.

Alterations in synaptic homeostasis are linked to cognitive and behavioural impairments in brain disorders. However, synaptic dysfunction in childhood dementia is poorly understood. Here, we generate human cortical circuits from induced pluripotent stem cells (iPSCs) derived from donors with Mucopolysaccharidosis Type IIIA (MPS IIIA), also known as Sanfilippo syndrome, a common form of childhood-onset dementia. Action potential firing capacity and morphology of MPS IIIA patient neurons in culture are similar to those of neurons from neurotypical donors. However, long-term neural maturation reveals excitation/inhibition imbalances caused by hyperactive excitatory synapses, disrupted network dynamics, and dysregulated gene expression linked to synaptic homeostasis. This study validates in vitro human neural models to detect neurophysiological phenotypes in childhood dementias and supports drug discovery strategies that target synaptic dysfunction to improve cognition in MPS IIIA and related brain disorders.

Childhood adversity is linked to persistent pain in adulthood. Nociceptive upregulation may play a role in this relationship. We investigated whether childhood adversity is associated with measures of nociceptive processing, and whether these associations differ by sex. In this experimental observational study, we enrolled pain-free adults with varying severity of childhood adversity, scored on the Childhood Trauma Questionnaire-Short Form. Measures of nociceptive processing included the surface area and magnitude of induced secondary hyperalgesia, temporal summation, and conditioned pain modulation. We used linear regression to investigate whether childhood adversity was associated with increased surface area or magnitude of secondary hyperalgesia, increased temporal summation, or reduced conditioned pain modulation, and whether these relationships differed by sex. Ninety-five participants (61 female; median age 23 [IQR: 9] years) completed the study. Childhood adversity was positively associated with the surface area of secondary hyperalgesia (β=0.32 [95%CI: 0.01; 0.62], p = 0.04), with no evidence of an interaction effect of sex. Childhood adversity was unrelated to the magnitude of secondary hyperalgesia, temporal summation, or conditioned pain modulation. These data suggest that childhood adversity may influence the distribution rather than the magnitude of evoked ascending nociception. Perspective

Psychological distress predicts the onset and worsening of persistent pain, but the mechanisms that underpin this influence are poorly understood. Proinflammatory signalling is a plausible link, given its known connections to distress, pain, and neural upregulation. Sustained distress may prime the inflammatory system to respond more strongly to a phasic noxious challenge, supporting neuroimmune upregulation of central nociceptive signalling and persistent pain. This cross-sectional study tested the hypotheses that in vitro endotoxin-provoked expression of typically proinflammatory cytokines (IL1β, IL6) is a partial mediator between distress and persistent pain, and that it is associated with experimentally induced secondary hyperalgesia, in people with suppressed HIV. Study participants were 99 adults (mean [range] age: 43 [28-64 y/o; 72 females]) with either no pain (n = 54) or persistent pain (n = 45), mostly of black South African ethnicity, low socio-economic status, and with high social support. The results replicated previous reports that distress is associated with persistent pain status and pain severity, and distress was associated with the anatomical extent of pain. However, distress was not associated with provoked cytokine expression, nor was provoked cytokine expression associated with secondary hyperalgesia. The conflict between our findings and prior evidence could reflect the influence of differentially trained immune systems or a more complex relationship arising from diverse psychoneuroimmunological interactions in this sample. This sample's combination of HIV status, African genetic ancestry, financial impoverishment, and rich social interconnectedness is poorly represented in current research and provides an opportunity to deepen insight into psychoneuroimmunological interactions in persistent pain.

Persistent pain represents a significant global health challenge, necessitating innovative biomarker technologies that facilitate personalised prediction, prevention, and treatment. Recent advances in omics, encompassing genomics, proteomics, transcriptomics, lipidomics, epigenomics, and metabolomics, now permit high-resolution mapping of neuroimmune pathways implicated in pain chronification. Yet, biomarkers must transcend isolated molecular or sensory indicators, integrating emotional, cognitive, functional, and social dimensions of pain. Emerging quantum sensing technologies, such as diamond nitrogen-vacancy sensors and portable magnetoencephalography systems, promise precise and wearable tools capable of real-time, multimodal assessment of pain. Concurrently, transparent machine learning methods combining explainable artificial intelligence with physiologically informed modelling are crucial for managing the vast data complexity inherent to these multidimensional omics approaches. Ultimately, achieving economically viable, environmentally sustainable, and universally accessible pain management solutions requires strategically streamlined methods. Here, we outline a visionary framework of measurement-enabled understanding that enables precision pain medicine with rapid feedback that points toward actionable clinical outcomes, harnessing interdisciplinary innovation to address persistent pain comprehensively, just as genomics and immunotherapy have transformed cancer care.