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<jats:p>The descending pain modulatory system (DPMS) constitutes a network of widely distributed brain regions whose integrated function is essential for effective modulation of sensory input to the central nervous system and behavioural responses to pain. Animal studies demonstrate that young rodents have an immature DPMS, but comparable studies have not been conducted in human infants. In Goksan et al. (2015) we used functional MRI (fMRI) to show that pain-related brain activity in newborn infants is similar to that observed in adults. Here, we investigated whether the functional network connectivity strength across the infant DPMS influences the magnitude of this brain activity. FMRI scans were collected while mild mechanical noxious stimulation was applied to the infant’s foot. Greater pre-stimulus functional network connectivity across the DPMS was significantly associated with lower noxious-evoked brain activity (p = 0.0004, r = -0.86, n = 13), suggesting that in newborn infants the DPMS may regulate the magnitude of noxious-evoked brain activity.</jats:p>
Long-term Consequences of Further Post-stroke Disability in Patients with Pre-morbid Disability: Potential for Acute Stroke Therapies
Objective: To assess the extent to which increased disability following ischaemic stroke influences 5-year mortality and institutionalization in pre-morbidly disabled patients. Background: Patients with pre-morbid disability – typically defined as a modified Rankin Scale score (mRS) ≥2 or ≥3 – are often excluded from trials of acute ischaemic stroke therapies. Decisions to use such therapies in pre-morbidly disabled patients will partly depend on whether long-term clinical outcomes of patients who accumulate greater disability following their stroke differ markedly from those of patients who retain their pre-morbid disability. Design/Methods: In a population-based, prospective cohort of 3-month survivors of ischaemic stroke (Oxford Vascular Study, OXVASC; 2002–2014), we tracked mortality and institutionalization (admission to nursing or residential care home) through overlapping methods of interview-based assessments of patients/carers and ongoing searches of health records. We used Cox regressions – adjusted for age, sex, and initial NIHSS(National Institutes of Health Stroke Scale) score – to compare outcomes of 1-year and 5-year mortality and/or new post-stroke institutionalization in survivors with pre-morbid mRS of 2–4 (excluding severe pre-stroke disability, mRS 5), based on the degree of change in mRS (ΔmRS) from pre-stroke to 3-months post-stroke. Results: Among 1,425 3-month survivors, 420(29.5%) had pre-morbid mRS 2–4; only 2 received thrombolysis. ΔmRS independently predicted 1-year mortality in pre-morbidly disabled patients (adjusted hazard-ratio[aHR] versus no change for ΔmRS 1: 2.52, 95%CI 1.47–4.30, p=0.001; ΔmRS 2: 3.22,1.66–6.24, p=0.001; ΔmRS 3: 4.27,1.40–13.02, p=0.011). Similar results were seen for 5-year mortality/institutionalization (aHR for ΔmRS 1: 1.72,1.30–2.27, p<0.001; ΔmRS 2: 2.19,1.50–3.19, p<0.001; ΔmRS 3: 3.56,1.69–7.47, p=0.001). Results were similar on examining pre-morbid mRS 2, 3, 4 separately (e.g. 5-year institutionalization aHR for pre-morbid mRS 3 with ΔmRS 1: 2.13,1.25–3.64, p=0.006; ΔmRS 2: 3.55,1.76–7.15, p<0.001). Conclusions: Pre-morbidly disabled patients who accumulate additional post-stroke disability have worse mortality and institutionalization outcomes. This justifies trialling or administering acute stroke therapies in patients with mild-moderate disability to potentially mitigate further post-stroke disability.
Background and Purpose- Increased blood pressure (BP), heart rate, and their derivatives (variability, pulse pressure, rate-pressure product) are associated with poor clinical outcome in acute stroke. We assessed the effects of glyceryl trinitrate (GTN) on hemodynamic parameters and these on outcome in participants in the ENOS trial (Efficacy of Nitric Oxide in Stroke). Methods- Four thousand and eleven patients with acute stroke and raised BP were randomized within 48 hours of onset to transdermal GTN or no GTN for 7 days. Peripheral hemodynamics were measured at baseline (3 measures) and daily (2 measures) during treatment. Between-visit BP variability over days 1 to 7 (as SD) was assessed in quintiles. Functional outcome was assessed as modified Rankin scale and cognition as telephone mini-mental state examination at day 90. Analyses were adjusted for baseline prognostic variables. Data are mean difference or odds ratios with 95% CI. Results- Increased baseline BP (diastolic, variability), heart rate, and rate-pressure product were each associated with unfavorable functional outcome at day 90. Increased between-visit systolic BP variability was associated with an unfavourable shift in modified Rankin Scale (highest quintile adjusted odds ratio, 1.65; 95% CI, 1.37-1.99), worse cognitive scores (telephone mini-mental state examination: highest quintile adjusted mean difference, -2.03; 95% CI, -2.84 to -1.22), and increased odds of death at day 90 (highest quintile adjusted odds ratio, 1.57; 95% CI, 1.12-2.19). GTN lowered BP and rate-pressure product and increased heart rate at day 1 and reduced between-visit systolic BP variability. Conclusions- Increased between-visit BP variability was associated with poor functional and cognitive outcomes and increased death 90 days after acute stroke. In addition to lowering BP and rate-pressure product, GTN reduced between-visit systolic BP variability. Agents that lower BP variability in acute stroke require further study.
Objective: To compare rates of functional recovery beyond 3-months in patients with lacunar versus non-lacunar strokes in a prospective, population-based cohort study. Background: Non-acute interventions to enhance late stroke recovery are often tested initially in uncontrolled studies in patients with lacunar stroke owing to their low mortality and relatively isolated motor deficits. It is often assumed that neurological recovery is near complete by 3-months after the stroke, but there have been few studies of the capacity for late recovery beyond 3-months. Design/Methods: In 3-month ischaemic stroke survivors of the Oxford Vascular Study (OXVASC; 2002–2014), we examined changes in functional status (modified Rankin Scale [mRS], Rivermead Mobility Index [RMI], Barthel Index[BI]) in lacunar versus non-lacunar strokes from 3–60 months post-stroke, stratifying by age. We used logistic regression adjusted for age, sex, and baseline disability to compare recovery (≥1 mRS grades, ≥1 RMI points and/or ≥2 BI points), particularly from 3–12 months. Results: Among 1,425 3-month survivors, the 234 lacunar stroke patients did not differ from others for outcome at 3-months (aOR for 3-month mRS>2: 1.14, 95%CI 0.75–1.74, p=0.55), but were much more likely to demonstrate further recovery between 3-months and 1-year (aOR: 1.64, 1.17–2.31, p=0.004). Results were similar on restricting the analysis to patients with 3-month mRS 2–4 (the range commonly recruited into recovery studies) and on excluding recurrent events (aOR[mRS] adjusted for age, sex, 3-month mRS: 2.28, 1.34–3.86, p=0.002). Similar results were seen with the BI and RMI (aOR[RMI] adjusted for age, sex, 3-month RMI: 1.78, 1.20–2.64, p=0.004). Conclusions: Lacunar strokes have greater potential for late functional recovery from 3–12 months post-stroke, supporting the focus of studies of restorative therapies on this group. However, such studies cannot assume that improvements after 3-months are treatment-related, and should therefore be randomized and controlled.
Sex Differences in Severity of Stroke in the INSTRUCT Study: a Meta-Analysis of Individual Participant Data.
Background Women have worse outcomes after stroke than men, and this may be partly explained by stroke severity. We examined factors contributing to sex differences in severity of acute stroke assessed by the National Institutes of Health Stroke Scale. Methods and Results We pooled individual participant data with National Institutes of Health Stroke Scale assessment (N=6343) from 8 population-based stroke incidence studies (1996-2014), forming part of INSTRUCT (International Stroke Outcomes Study). Information on sociodemographics, stroke-related clinical factors, comorbidities, and pre-stroke function were obtained. Within each study, relative risk regression using log-binominal modeling was used to estimate the female:male relative risk ( RR ) of more severe stroke (National Institutes of Health Stroke Scale>7) stratified by stroke type (ischemic stroke and intracerebral hemorrhage). Study-specific unadjusted and adjusted RR s, controlling for confounding variables, were pooled using random-effects meta-analysis. National Institutes of Health Stroke Scale data were recorded in 5326 (96%) of 5570 cases with ischemic stroke and 773 (90%) of 855 participants with intracerebral hemorrhage. The pooled unadjusted female:male RR for severe ischemic stroke was 1.35 (95% CI 1.24-1.46). The sex difference in severity was attenuated after adjustment for age, pre-stroke dependency, and atrial fibrillation but remained statistically significant (pooled RR adjusted 1.20, 95% CI 1.10-1.30). There was no sex difference in severity for intracerebral hemorrhage ( RR crude 1.08, 95% CI 0.97-1.21; RR adjusted 1.08, 95% CI 0.96-1.20). Conclusions Although women presented with more severe ischemic stroke than men, much although not all of the difference was explained by pre-stroke factors. Sex differences could potentially be ameliorated by strategies to improve pre-stroke health in the elderly, the majority of whom are women. Further research on the potential biological origin of sex differences in stroke severity may also be warranted.
Measuring fibre dispersion in white matter with diffusion magnetic resonance imaging (MRI) remains difficult due to an inherent degeneracy between fibre dispersion and diffusion anisotropy. This means that estimates of fibre dispersion rely on strong assumptions, such as constant anisotropy throughout the white matter or specific biophysical models. Here we present a simple approach for resolving this degeneracy using measurements that combine linear (conventional) and spherical tensor diffusion encoding. In simulations we show that the bias in fibre dispersion is greatly reduced (~5x) for single-shell linear and spherical tensor encoding data compared with single-shell or multi-shell conventional data even if overly simplistic tissue assumptions are used. In in vivo data we find a consistent estimate of fibre dispersion as we reduce the b-value from 3 to 1.5 ms/$\mu$m, increase the repetition time, increase the echo time, or increase the diffusion time. We conclude that the addition of spherical tensor encoded data to conventional linear tensor encoding data greatly reduces the sensitivity of the estimated fibre dispersion to the model assumptions made of the tissue microstructure.
This invention relates to the neural interface comprising one or more electrode-coupled microchannels. Each electrode-coupled microchannel comprises a microchannel for accommodating regenerating nerve axons and one or more electrodes exposed to the interior of said microchannel. The one or more electrodes may comprise (i) a stimulation array suitable for generating an extracellular stimulus current which induces an action potential in an axon in the microchannel and/or (ii) a recording array which detects an extracellular signal in the microchannel indicative of an action potential in an axon in the microchannel. Interfaces as described may be useful in blocking pain, treating misrouted motor nerves repair or treating nerve injury or controlling or providing sensation and/or proprioception from a prosthesis.
BACKGROUND: Trigeminal Neuropathic Pain (TNP) is a chronic facial pain syndrome caused by a lesion or disease affecting one or more branches of the trigeminal nerve. It may, for example, result from accidental injury to a branch of the trigeminal nerve by trauma or during surgery; it may also be idiopathic. TNP is typically constant, in contrast to most cases of the commoner trigeminal neuralgia. In some cases, pain may be refractory to pharmacological treatment. Peripheral nerve field stimulation is recognized as an effective minimally invasive surgical treatment option for this debilitating condition. To date, stimulation has used conventional tonic waveforms, which generate paraesthesia in the stimulated area. This is the first report of the use of paraesthesia-free burst pattern stimulation for TNP. METHODS: Seven patients were treated at the John Radcliffe Hospital for TNP from 2016 to 2018. Mean duration of preoperative symptoms was five years. All patients had exhausted pharmacological measures to limited effect. The initial three patients had tonic stimulation with the subsequent four having burst stimulation. Outcome was assessed using the numeric pain rating scale preoperatively and postoperatively at three and six months and one year. Side-effects and complications were also assessed as well as reduction in analgesic medication use. RESULTS: All patients achieved pain reduction of at least 50% at 6 months (range 50-100%, mean 81%, p = 0.0082). Those in the burst stimulation group were paraesthesia free. One patient developed a postoperative infection for which the system had to be removed and is awaiting reimplantation. There were no other complications in either group. CONCLUSION: Burst stimulation conferred similar pain control to tonic stimulation in our small cohort, and there were similar reductions in pain medication use. An additional benefit of burst stimulation is freedom from paraesthesia. Larger scale studies are needed to further evaluate burst stimulation and compare its efficacy with that of tonic stimulation.