Multi-modal assessment of neurovascular coupling during cerebral ischaemia and reperfusion using remote middle cerebral artery occlusion

Hyperacute changes in cerebral blood flow (CBF) during cerebral ischemia and reperfusion is an important determinant of injury. CBF is regulated by neurovascular coupling (NVC), and disruption of NVC contributes to brain plasticity and repair problems. However, it is unknown how NVC is affected hyperacutely during cerebral ischemia and reperfusion. We have developed a remote middle cerebral artery occlusion (MCAO) model in the rat, which enables multi-modal assessment of NVC immediately prior to, during and immediately following reperfusion. Male Wistar rats were subjected to remote MCAO, where a long filament was advanced intraluminally through a guide cannula in the common carotid artery. Transcallosal stimulation evoked increases in blood flow, tissue oxygenation and neuronal activity, which were diminished by MCAO and partially restored during reperfusion. These evoked responses were not affected by administration of the thrombolytic alteplase at clinically used doses. Evoked CBF responses were fully restored at 24 hours post-MCAO indicating that neurovascular dysfunction was not sustained. These data show for the first time that the rat remote MCAO model coupled with transcallosal stimulation provides a novel method for continuous assessment of hyperacute NVC changes during ischemia and reperfusion, and offers unique insight into hyperacute ischemic pathophysiology

Research priorities for improving infant and young child feeding in humanitarian emergencies

Background There are many challenges during emergencies to ensure that optimal infant and young child feeding is protected, promoted and supported, but there is a dearth of evidence on strategies and programmes to improve Infant and Young Child Feeding in Emergencies (IYCF-E) and a need to determine research priorities. Methods Based on interviews with key informants who are experts in the subject, we developed a list of 48 research questions on IYCF-E. A framework, following the Child Health and Nutrition Research Initiative method to set priorities in child health research, was developed to rank the research questions. Four criteria were applied to create a ranking based on answerability, operational relevance, disease burden reduction and prevention, and originality. Using an on-line survey, prioritisation of research questions was done by 27 people from 14 NGOs, universities and research institutions, and UN organisations. Results The top-ten research questions identified focused on the following: • Use of cash-transfer to buy breast-milk substitutes; • Effectiveness of complementary feeding strategies; • Long-term effect of IYCF-E interventions; • Design of IYCF-E programmes in a context where breastfeeding rates are low and breast milk substitutes use is high; • Design of effective re-lactation interventions; • Provision of psychological support to young children’s care-takers; • Determination of number of beneficiaries and coverage of IYCF-E programmes; • Pros and cons of distributing ready-to-use infant formula compared with distributing powdered infant formula plus kit for safer use of BMS, when use of infant formula is necessary; • Assessment of the impact of specific IYCF-E programmes on nutritional status, morbidity and mortality; • Linking and mainstreaming IYCF-E interventions with other sectors such as health, WASH, food security and child protection. Conclusion The questions found by this study could form the basis of future research on IYCF-E and could be integrated into the agenda of relevant stakeholders. Results of studies based on these questions will be fundamental to fill the evidence gap in IYCF-E, improve IYCF-E programming and ultimately contribute to the reduction in morbidity and mortality among infants and young children in humanitarian emergencies

A critical role for astrocytes in hypercapnic vasodilation in brain

Cerebral blood flow (CBF) is controlled by arterial blood pressure, arterial CO2, arterial O2, and brain activity and is largely constant in the awake state. Although small changes in arterial CO2 are particularly potent to change CBF (1 mmHg variation in arterial CO2 changes CBF by 3-4%), the coupling mechanism is incompletely understood. We tested the hypothesis that astrocytic prostaglandin E2 (PgE2) plays a key role for cerebrovascular CO2 reactivity and that preserved synthesis of glutathione is essential for the full development of this response. We combined two-photon imaging microscopy in brain slices with in vivo work in rats and C57Bl/6J mice to examine the hemodynamic responses to CO2 and somatosensory stimulation before and after inhibition of astrocytic glutathione and PgE2 synthesis. We demonstrate that hypercapnia (increased CO2) evokes an increase in astrocyte [Ca2+]i and stimulates COX-1 activity. The enzyme downstream of COX-1 that synthesizes PgE2 (microsomal prostaglandin E synthase-1) depends critically for its vasodilator activity on the level of glutathione in the brain. We show that when glutathione levels are reduced, astrocyte calcium-evoked release of PgE2 is decreased and vasodilation triggered by astrocyte [Ca2+]i in vitro and by hypercapnia in vivo is inhibited. Astrocyte synthetic pathways, dependent on glutathione, are involved in cerebrovascular reactivity to CO2. Reductions in glutathione levels in ageing, stroke or schizophrenia could lead to dysfunctional regulation of CBF and subsequent neuronal damage

An open resource combining multi-contrast MRI and microscopy in the macaque brain

Understanding brain structure and function often requires combining data across different modalities and scales to link microscale cellular structures to macroscale features of whole brain organisation. Here we introduce the BigMac dataset, a resource combining in vivo MRI, extensive postmortem MRI and multi-contrast microscopy for multimodal characterisation of a single whole macaque brain. The data spans modalities (MRI and microscopy), tissue states (in vivo and postmortem), and four orders of spatial magnitude, from microscopy images with micrometre or sub-micrometre resolution, to MRI signals on the order of millimetres. Crucially, the MRI and microscopy images are carefully co-registered together to facilitate quantitative multimodal analyses. Here we detail the acquisition, curation, and first release of the data, that together make BigMac a unique, openly-disseminated resource available to researchers worldwide. Further, we demonstrate example analyses and opportunities afforded by the data, including improvement of connectivity estimates from ultra-high angular resolution diffusion MRI, neuroanatomical insight provided by polarised light imaging and myelin-stained histology, and the joint analysis of MRI and microscopy data for reconstruction of the microscopy-inspired connectome. All data and code are made openly available

A variational method based on weighted graph states

In a recent article [Phys. Rev. Lett. 97 (2006), 107206], we have presented a class of states which is suitable as a variational set to find ground states in spin systems of arbitrary spatial dimension and with long-range entanglement. Here, we continue the exposition of our technique, extend from spin 1/2 to higher spins and use the boson Hubbard model as a non-trivial example to demonstrate our scheme.Comment: 36 pages, 13 figure

White matter structure and myelin-related gene expression alterations with experience in adult rats

White matter (WM) plasticity during adulthood is a recently described phenomenon by which experience can shape brain structure. It has been observed in humans using diffusion tensor imaging (DTI) and myelination has been suggested as a possible mechanism. Here, we set out to identify molecular and cellular changes associated with WM plasticity measured by DTI. We combined DTI, immunohistochemistry and mRNA expression analysis and examined the effects of somatosensory experience in adult rats. First, we observed experience-induced DTI differences in WM and in grey matter structure. C-Fos mRNA expression, a marker of cortical activity, in the barrel cortex correlated with the MRI WM metrics, indicating that molecular correlates of cortical activity relate to macroscale measures of WM structure. Analysis of myelin-related genes revealed higher myelin basic protein (MBP) mRNA expression. Higher MBP protein expression was also found via immunohistochemistry in WM. Finally, unbiased RNA sequencing analysis identified 134 differentially expressed genes encoding proteins in- volved in functions related to cell proliferation and differentiation, regulation of myelination and neuronal activity modulation. In conclusion, macroscale measures of WM plasticity are supported by both molecular and cellular evidence and confirm that myelination is one of the underlying mechanisms

Tumor pH and Protein Concentration Contribute to the Signal of Amide Proton Transfer Magnetic Resonance Imaging

Abnormal pH is a common feature of malignant tumors and has been associated clinically with suboptimal outcomes. Amide proton transfer magnetic resonance imaging (APT MRI) holds promise as a means to noninvasively measure tumor pH, yet multiple factors collectively make quantification of tumor pH from APT MRI data challenging. The purpose of this study was to improve our understanding of the biophysical sources of altered APT MRI signals in tumors. Combining in vivo APT MRI measurements with ex vivo histological measurements of protein concentration in a rat model of brain metastasis, we determined that the proportion of APT MRI signal originating from changes in protein concentration was approximately 66%, with the remaining 34% originating from changes in tumor pH. In a mouse model of hypopharyngeal squamous cell carcinoma (FaDu), APT MRI showed that a reduction in tumor hypoxia was associated with a shift in tumor pH. The results of this study extend our understanding of APT MRI data and may enable the use of APT MRI to infer the pH of individual patients' tumors as either a biomarker for therapy stratification or as a measure of therapeutic response in clinical settings.Significance: These findings advance our understanding of amide proton transfer magnetic resonance imaging (APT MRI) of tumors and may improve the interpretation of APT MRI in clinical settings