Neuroimaging as a selection tool and endpoint in preclinical and clinical trials

Standard imaging in acute stroke enables the exclusion of non-stroke structural CNS lesions and cerebral haemorrhage from clinical and pre-clinical ischaemic stroke trials. In this review, the potential benefit of imaging (e.g., angiography and penumbral imaging) as a translational tool for trial recruitment and the use of imaging endpoints are discussed for both clinical and pre-clinical stroke research. The addition of advanced imaging to identify a “responder” population leads to reduced sample size for any given effect size in phase 2 trials and is a potentially cost-efficient means of testing interventions. In pre-clinical studies, technical failures (failed or incomplete vessel occlusion, cerebral haemorrhage) can be excluded early and continuous multimodal imaging of the animal from stroke onset is feasible. Pre- and post-intervention repeat scans provide real time assessment of the intervention over the first 4–6 h. Negative aspects of advanced imaging in animal studies include increased time under general anaesthesia, and, as in clinical studies, a delay in starting the intervention. In clinical phase 3 trial designs, the negative aspects of advanced imaging in patient selection include higher exclusion rates, slower recruitment, overestimated effect size and longer acquisition times. Imaging may identify biological effects with smaller sample size and at earlier time points, compared to standard clinical assessments, and can be adjusted for baseline parameters. Mechanistic insights can be obtained. Pre-clinically, multimodal imaging can non-invasively generate data on a range of parameters, allowing the animal to be recovered for subsequent behavioural testing and/or the brain taken for further molecular or histological analysis

Translational perspectives on perfusion-diffusion mismatch in ischemic stroke

Magnetic resonance imaging has tremendous potential to illuminate ischemic stroke pathophysiology and guide rational treatment decisions. Clinical applications to date have been largely limited to trials. However, recent analyses of the major clinical studies have led to refinements in selection criteria and improved understanding of the potential implications for the risk vs. benefit of thrombolytic therapy. In parallel, preclinical studies have provided complementary information on the evolution of stroke that is difficult to obtain in humans due to the requirement for continuous or repeated imaging and pathological verification. We review the clinical and preclinical advances that have led to perfusion–diffusion mismatch being applied in phase 3 randomized trials and, potentially, future routine clinical practice

Versatile Digital GHz Phase Lock for External Cavity Diode Lasers

We present a versatile, inexpensive and simple optical phase lock for applications in atomic physics experiments. Thanks to all-digital phase detection and implementation of beat frequency pre-scaling, the apparatus requires no microwave-range reference input, and permits phase locking at frequency differences ranging from sub-MHz to 7 GHz (and with minor extension, to 12 GHz). The locking range thus covers ground state hyperfine splittings of all alkali metals, which makes this system a universal tool for many experiments on coherent interaction between light and atoms.Comment: 4.5 pages, 5 figures v3: fixed error in schematic: R10 connects to other end of C

A Monolithic Filter Cavity for Experiments in Quantum Optics

By applying a high-reflectivity dielectric coating on both sides of a commercial plano-convex lens, we produce a stable monolithic Fabry-Perot cavity suitable for use as a narrow band filter in quantum optics experiments. The resonant frequency is selected by means of thermal expansion. Owing to the long term mechanical stability, no optical locking techniques are required. We characterize the cavity performance as an optical filter, obtaining a 45 dB suppression of unwanted modes while maintaining a transmission of 60%.Comment: 4 pages, 4 figure

Pain in traumatic upper limb amputees in Sierra Leone.

Data on 40 upper limb amputees (11 bilateral) with regard to stump pain, phantom sensation and phantom pain is presented. All the patients lost their limbs as a result of violent injuries intended to terrorise the population and were assessed 10-48 months after the injury. All amputees reported stump pain in the month prior to interview and ten of the 11 bilateral amputees had bilateral pain. Phantom sensation was common (92.5%), but phantom pain was only present in 32.5% of amputees. Problems in translation and explanation may have influenced the low incidence of phantom pain and high incidence of stump pain. In the bilateral amputees phantom sensation, phantom pain and telescoping all showed bilateral concordance, whereas stump pain and neuromas did not show concordance. About half the subjects (56%) had lost their limb at the time of injury (primary) while the remainder had an injury, then a subsequent amputation in hospital (secondary). There was no association between the incidence of phantom pain and amputation irrespective of being primary or secondary

Animal models of ischaemic stroke and characterisation of the ischaemic penumbra

Over the past forty years, animal models of focal cerebral ischaemia have allowed us to identify the critical cerebral blood flow thresholds responsible for irreversible cell death, electrical failure, inhibition of protein synthesis, energy depletion and thereby the lifespan of the potentially salvageable penumbra. They have allowed us to understand the intricate biochemical and molecular mechanisms within the ‘ischaemic cascade’ that initiate cell death in the first minutes, hours and days following stroke. Models of permanent, transient middle cerebral artery occlusion and embolic stroke have been developed each with advantages and limitations when trying to model the complex heterogeneous nature of stroke in humans. Yet despite these advances in understanding the pathophysiological mechanisms of stroke-induced cell death with numerous targets identified and drugs tested, a lack of translation to the clinic has hampered pre-clinical stroke research. With recent positive clinical trials of endovascular thrombectomy in acute ischaemic stroke the stroke community has been reinvigorated, opening up the potential for future translation of adjunctive treatments that can be given alongside thrombectomy/thrombolysis. This review discusses the major animal models of focal cerebral ischaemia highlighting their advantages and limitations. Acute imaging is crucial in longitudinal pre-clinical stroke studies in order to identify the influence of acute therapies on tissue salvage over time. Therefore, the methods of identifying potentially salvageable ischaemic penumbra are discussed

Perfluorocarbon Enhanced Glasgow Oxygen Level Dependent (GOLD) magnetic resonance metabolic imaging identifies the penumbra following acute ischemic stroke

The ability to identify metabolically active and potentially salvageable ischaemic penumbra is crucial for improving treatment decisions in acute stroke patients. Our solution involves two complementary novel MRI techniques (Glasgow Oxygen Level Dependant (GOLD) Metabolic Imaging), which when combined with a perfluorocarbon (PFC) based oxygen carrier and hyperoxia can identify penumbra due to dynamic changes related to continued metabolism within this tissue compartment. Our aims were (i) to investigate whether PFC offers similar enhancement of the second technique (Lactate Change) as previously demonstrated for the T2*OC technique (ii) to demonstrate both GOLD metabolic imaging techniques working concurrently to identify penumbra, following administration of Oxycyte® (O-PFC) with hyperoxia. Methods: An established rat stroke model was utilised. Part-1: Following either saline or PFC, magnetic resonance spectroscopy was applied to investigate the effect of hyperoxia on lactate change in presumed penumbra. Part-2; rats received O-PFC prior to T2*OC (technique 1) and MR spectroscopic imaging, which was used to identify regions of tissue lactate change (technique 2) in response to hyperoxia. In order to validate the techniques, imaging was followed by [14C]2-deoxyglucose autoradiography to correlate tissue metabolic status to areas identified as penumbra. Results: Part-1: PFC+hyperoxia resulted in an enhanced reduction of lactate in the penumbra when compared to saline+hyperoxia. Part-2: Regions of brain tissue identified as potential penumbra by both GOLD metabolic imaging techniques utilising O-PFC, demonstrated maintained glucose metabolism as compared to adjacent core tissue. Conclusion: For the first time in vivo, enhancement of both GOLD metabolic imaging techniques has been demonstrated following intravenous O-PFC+hyperoxia to identify ischaemic penumbra. We have also presented preliminary evidence of the potential therapeutic benefit offered by O-PFC. These unique theranostic applications would enable treatment based on metabolic status of the brain tissue, independent of time from stroke onset, leading to increased uptake and safer use of currently available treatment options

Hyperglycaemia does not increase perfusion deficits after focal cerebral ischaemia in male Wistar rats

Background: Hyperglycaemia is associated with a worse outcome in acute ischaemic stroke patients; yet the pathophysiological mechanisms of hyperglycaemia-induced damage are poorly understood. We hypothesised that hyperglycaemia at the time of stroke onset exacerbates ischaemic brain damage by increasing the severity of the blood flow deficit. Methods: Adult, male Wistar rats were randomly assigned to receive vehicle or glucose solutions prior to permanent middle cerebral artery occlusion. Cerebral blood flow was assessed semi-quantitatively either 1 h after middle cerebral artery occlusion using 99mTc-D, L-hexamethylpropyleneamine oxime (99mTc-HMPAO) autoradiography or, in a separate study, using quantitative pseudo-continuous arterial spin labelling for 4 h after middle cerebral artery occlusion. Diffusion weighted imaging was performed alongside pseudo-continuous arterial spin labelling and acute lesion volumes calculated from apparent diffusion coefficient maps. Infarct volume was measured at 24 h using rapid acquisition with refocused echoes T2-weighted magnetic resonance imaging. Results: Glucose administration had no effect on the severity of ischaemia when assessed by either 99mTc-HMPAO autoradiography or pseudo-continuous arterial spin labelling perfusion imaging. In comparison to the vehicle group, apparent diffusion coefficient–derived lesion volume 2–4 h post-middle cerebral artery occlusion and infarct volume 24 h post-middle cerebral artery occlusion were significantly greater in the glucose group. Conclusions: Hyperglycaemia increased acute lesion and infarct volumes but there was no evidence that the acute blood flow deficit was exacerbated. The data reinforce the conclusion that the detrimental effects of hyperglycaemia are rapid, and that treatment of post-stroke hyperglycaemia in the acute period is essential but the mechanisms of hyperglycaemia-induced harm remain unclear